mycophenolic-acid and Kidney-Failure--Chronic

Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN.. We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer.. Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%).. This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.

Topics: Adult; Azathioprine; Bone Marrow Diseases; Cyclophosphamide; Glucocorticoids; Herpes Zoster; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Neoplasms; Network Meta-Analysis; Recurrence; Tacrolimus; Treatment Outcome

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might increase the risk of invasive pulmonary aspergillosis (IPA). Although several case reports and small series have been reported in the general population, scarce information is available regarding coronavirus disease 2019 (COVID-19)-associated IPA in the setting of solid organ transplantation. We describe a case of a kidney transplant recipient with severe COVID-19 that was subsequently diagnosed with probable IPA on the basis of the repeated isolation of Aspergillus fumigatus in sputum cultures, repeatedly increased serum (1 → 3)-β-d-glucan levels, and enlarging cavitary nodules in the CT scan. The evolution was favorable after initiation of isavuconazole and nebulized liposomal amphotericin B combination therapy and the withdrawal of immunosuppression.

Topics: Acute Kidney Injury; Administration, Inhalation; Amphotericin B; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Antifungal Agents; Azithromycin; Ceftriaxone; COVID-19; Deprescriptions; Female; Glucocorticoids; Graft Rejection; Humans; Hydroxychloroquine; Hyperoxaluria, Primary; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Invasive Pulmonary Aspergillosis; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Nitriles; Oxygen Inhalation Therapy; Prednisone; Pyridines; Renal Dialysis; SARS-CoV-2; Sputum; Tacrolimus; Tomography, X-Ray Computed; Triazoles

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Castleman Disease; Cyclophosphamide; Doxorubicin; Humans; Immunoglobulins; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Lymph Nodes; Male; Mycophenolic Acid; Prednisone; Tacrolimus; Transplantation, Homologous; Treatment Outcome; Vincristine

IgA nephropathy is the most common glomerulonephritis world-wide. IgA nephropathy causes end-stage kidney disease (ESKD) in 15% to 20% of affected patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a Cochrane review first published in 2003 and updated in 2015.. To determine the benefits and harms of immunosuppression strategies for the treatment of IgA nephropathy.. We searched the Cochrane Kidney and Transplant Register of Studies up to 9 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included randomised controlled trials (RCTs) and quasi-RCTs of treatment for IgA nephropathy in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non-immunosuppressive agents.. Two authors independently assessed study risk of bias and extracted data. Estimates of treatment effect were summarised using random effects meta-analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Risks of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE methodology.. Fifty-eight studies involving 3933 randomised participants were included. Six studies involving children were eligible. Disease characteristics (kidney function and level of proteinuria) were heterogeneous across studies. Studies evaluating steroid therapy generally included patients with protein excretion of 1 g/day or more. Risk of bias within the included studies was generally high or unclear for many of the assessed methodological domains. In patients with IgA nephropathy and proteinuria > 1 g/day, steroid therapy given for generally two to four months with a tapering course probably prevents the progression to ESKD compared to placebo or standard care (8 studies; 741 participants: RR 0.39, 95% CI 0.23 to 0.65; moderate certainty evidence). Steroid therapy may induce complete remission (4 studies, 305 participants: RR 1.76, 95% CI 1.03 to 3.01; low certainty evidence), prevent doubling of serum creatinine (SCr) (7 studies, 404 participants: RR 0.43, 95% CI 0.29 to 0.65; low certainty evidence), and may lower urinary protein excretion (10 studies, 705 participants: MD -0.58 g/24 h, 95% CI -0.84 to -0.33;low certainty evidence). Steroid therapy had uncertain effects on glomerular filtration rate (GFR), death, infection and malignancy. The risk of adverse events with steroid therapy was uncertain due to heterogeneity in the type of steroid treatment used and the rarity of events. Cytotoxic agents (azathioprine (AZA) or cyclophosphamide (CPA) alone or with concomitant steroid therapy had uncertain effects on ESKD (7 studies, 463 participants: RR 0.63, 95% CI 0.33 to 1.20; low certainty evidence), complete remission (5 studies; 381 participants: RR 1.47, 95% CI 0.94 to 2.30; very low certainty evidence), GFR (any measure), and protein excretion. Doubling of serum creatinine was not reported. Mycophenolate mofetil (MMF) had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, infection, and malignancy. Death was not reported. Calcineurin inhibitors compared with placebo or standard care had uncertain effects on complete remission, SCr, GFR, protein excretion, infection, and malignancy. ESKD and death were not reported. Mizoribine administered with renin-angiotensin system inhibitor treatment had uncertain effects on progression to ESKD, complete remission, GFR, protein excretion, infection, and malignancy. Death and SCr were not reported. Leflunomide followed by a tapering course with oral prednisone com. In moderate certainty evidence, corticosteroid therapy probably prevents decline in GFR or doubling of SCr in adults and children with IgA nephropathy and proteinuria. Evidence for treatment effects of immunosuppressive agents on death, infection, and malignancy is generally sparse or low-quality. Steroid therapy has uncertain adverse effects due to a paucity of studies. Available studies are few, small, have high risk of bias and generally do not systematically identify treatment-related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible due to a lack of studies. There is no evidence that other immunosuppressive agents including CPA, AZA, or MMF improve clinical outcomes in IgA nephropathy.

Topics: Adult; Calcineurin Inhibitors; Cause of Death; Child; Confidence Intervals; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Leflunomide; Mycophenolic Acid; Proteinuria; Randomized Controlled Trials as Topic; Remission Induction; Ribonucleosides; Risk; Steroids

Systemic lupus erythematosus is a multisystem autoimmune disease that commonly affects the kidneys. Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus and a major risk factor for morbidity and mortality. The pathophysiology of LN is heterogeneous. Genetic and environmental factors likely contribute to this heterogeneity. Despite improved understanding of the pathogenesis of LN, treatment advances have been few and risk for kidney failure remains unacceptably high. This installment in the Core Curriculum of Nephrology provides an up-to-date review of the current understanding of LN epidemiology, pathogenesis, diagnosis, and treatment. Challenging issues such as the management of LN in pregnancy, timing of transplantation, and the evolving role of corticosteroid use in the management of LN are discussed. We review the currently accepted approach to care for patients with LN and highlight deficiencies that need to be addressed to better preserve long-term kidney health and improve outcomes in LN.

Topics: Adaptive Immunity; Adrenal Cortex Hormones; Age Distribution; Autoantibodies; Autoimmunity; Biopsy; Cyclophosphamide; Female; Humans; Hydroxychloroquine; Immunity, Innate; Immunologic Factors; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Maintenance Chemotherapy; Male; Mycophenolic Acid; Pregnancy; Pregnancy Complications; Renal Dialysis; Urinalysis

Following successful kidney transplantation, recipients usually regain fertility. Post-engraftment pregnancies should be planned and the teratogenic mycophenolic acid should be replaced with azathioprine before conception. To avoid unintentional pregnancies, pre-conception counseling is mandatory in women of reproductive age who are scheduled for a kidney transplant. Counseling should be repeated after transplantation. Female recipients should receive advice to use long-acting reversible contraception and avoid pregnancy for a minimum of 1 year following transplantation. Conception should be deferred even longer in female recipients with moderate to severe proteinuria, uncontrolled hypertension or reduced graft function and be very carefully discussed in highly HLA-sensitized patients. The recipient wishes, values and acceptance of pregnancy-related risk should receive attention. Assisted fertilization increases the risk of pre-eclampsia, but still result in live births. Pregnancy management in kidney transplant recipients should be provided by a multidisciplinary team consisting of a nephrologist, a midwife and an obstetrician with expertise in high-risk pregnancies. Until measurement of unbound fraction of calcineurin inhibitors becomes clinically available, we recommend to adjust calcineurin inhibitor dose according to whole blood trough level, even though it overestimates the effective drug concentration during pregnancy. If nephrotoxicity is suspected, the calcineurin inhibitor dose should be reduced. Breastfeeding should be accepted after kidney transplantation since infant immunosuppressive drug exposure via breastmilk is extremely low. The prevalence of congenital malformations in children fathered by male recipients, including patients on mycophenolic acid therapy at the time of conception, is at level with the general population.

Topics: Abatacept; Azathioprine; Basiliximab; Breast Feeding; Calcineurin Inhibitors; Contraceptive Agents; Counseling; Decision Making; Female; Graft Rejection; HLA Antigens; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant, Newborn; Kidney Failure, Chronic; Kidney Transplantation; Lactation; Male; Mycophenolic Acid; Patient Care Team; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Reproductive Health

Patients with POAG have lower corneal endothelial cell density than healthy controls of the same age. This may be attributed to mechanical damage from elevated IOP and toxicity of glaucoma medications.. Mycophenolic acid was detected in all cats. The dose 10 mg/kg given q12h for 1 week was tolerated (n = 3). The efficacy of MMF as an immunosuppressant and long-term safety in cats of this dosage regimen is unknown.. T

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Maintenance therapy for lupus nephritis (LN) remains controversial. This meta-analysis of randomized controlled trials (RCTs) describes the comparative benefits and safety of mycophenolate mofetil (MMF) versus azathioprine (AZA) as maintenance therapy in patients with LN.. RCTs that compared the maintenance regimens of MMF and AZA in the treatment of LN were included. Outcomes were mortality, end-stage renal disease (ESRD), renal relapse, doubling of serum creatinine, and adverse effects. We performed the meta-analysis using Review Manager software (version 5.3).. Seven RCTs were included in the meta-analysis. There were no significant differences between the MMF and AZA groups in regards to mortality, relapse, ESRD, doubling of serum creatinine, infection, or gastrointestinal upset. However, the MMF group incurred lower risks of leukopenia (RR = 0.16, 95% CI = 0.06 - 0.40; p = 0.0001) and amenorrhea (RR = 0.23, 95% CI = 0.09 - 0.59, p = 0.002) compared with the AZA group.. MMF seems more effective than AZA as maintenance therapy for LN although the differences did not reach statistical significance. Furthermore, the MMF group incurred lower risk of leukopenia than AZA. However, more RCTs are needed to confirm the conclusion.

Topics: Azathioprine; Creatinine; Disease Progression; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Randomized Controlled Trials as Topic; Recurrence; Survival Rate

To avoid graft rejection during pregnancy, frequent monitoring of serum drug levels is recommended. Pregnancy induces hyperfiltration in transplanted kidneys, as in native kidneys; therefore, detection of rejection can be difficult when monitoring by serum creatinine. If rejection is suspected, ultrasonographguided graft biopsy can be done; once proven, it can be treated with pulse steroids, but data are scarce regarding other agents. Here, we present a 28-year-old pregnant female patient with resistant acute rejection but with successful pregnancy outcome. Our patient had end-stage kidney disease secondary to lupus nephropathy and underwent living-donor renal transplant in May 2013 after hemodialysis support for 1 year. She received thymoglobulin as induction therapy and was maintained on prednisolone, mycophenolate mofetil, and tacrolimus. She had normal renal graft function without proteinuria. After she received counseling, she became pregnant in February 2015. In June 2015, she presented with acute graft dysfunction with serum creatinine level of 365 μmol/L. Her abdominal ultrasonography showed mild hydronephrosis and viable fetus. She received empirical pulse steroids with partial response, and her graft biopsy showed acute T-cell-mediated rejection and negative C4d. Intravenous immunoglobulins and minipulse steroids were administered but without response. After gynecologic counseling and informed consent, she received 5 doses of thymoglobulin. She was dialysis dependent until premature vaginal labor, which resulted in birth of a viable 2-kg boy. We suggest that successful pregnancy outcomes could occur with close monitoring and daily dialysis in female kidney transplant patients with resistant rejection.

Topics: Acute Disease; Adult; Antilymphocyte Serum; Drug Resistance; Drug Substitution; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunity, Cellular; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Live Birth; Living Donors; Lupus Nephritis; Mycophenolic Acid; Prednisolone; Pregnancy; Pregnancy, Unplanned; Renal Dialysis; Risk Factors; T-Lymphocytes; Tacrolimus; Treatment Outcome

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has the propensity to acquire a devastating disease course. Despite the advances in therapeutics, a significant proportion of patients progress to end-stage renal disease (ESRD). Renal transplantation is being increasingly employed in this population, with gradual improvement in outcomes over the years, however, recurrence of disease requires constant surveillance and is associated with graft failure. Areas covered: A structured literature search in PubMed and Medline and abstracts of international conferences was performed to identify cases and cohorts of AAV patients who had undergone renal transplantation for ESRD. The primary objective was to describe the long-term allograft and patient survival and to reflect on current trends in transplantation in AAV and provide recommendations for the phases of pre- and post-transplantation. Expert commentary: Renal transplantation is the treatment of choice for AAV patients with ESRD. The risk of relapse is low with modern immunosuppressive regimes employing mycophenolate mofetil and tacrolimus. It is recommended that the vasculitis be in clinical remission for 12 months prior to transplantation. Although ANCA positivity is not a contraindication for renal transplantation, these patients should be monitored closely for vasculitis relapse post-transplant.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Graft Rejection; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Survival Analysis; Tacrolimus; Treatment Outcome

The prevalence of end-stage renal disease is increasing worldwide. The best treatment is kidney transplantation, although life-long immunosuppressive therapy is then mandatory. Currently, the cornerstone immunosuppressive therapy relies on tacrolimus (Tac), a calcineurin inhibitor that is nephrotoxic but whose exposition can be minimized in a delicate balance. Area covered: We addressed whether, in the setting of kidney transplantation, Tac-based therapy can be tailored to medical needs: to achieve this, we searched for suitable articles in PubMed. Expert commentary: Too over-minimization of Tac, when associated with mycophenolic acid (MPA), may cause the development of de novo donor-specific alloantibodies (DSA). However, Tac minimization, in the context of everolimus-associated therapy instead of MPA, does not increase DSA formation as demonstrated in the TRANSFORM study and, in addition, can prevent cytomegalovirus (CMV) infection/reactivation. Nonetheless, Tac therapy, regardless of its formulation (immediate or extended release) compared to cyclosporine A, increases the risk of posttransplant diabetes mellitus; this increase is not affected by steroid therapy. Tac-based immunosuppression remains the best immunosuppressive therapy in kidney-transplant recipients and can be tailored according to patients' need.

Topics: Calcineurin Inhibitors; Cyclosporine; Everolimus; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Tacrolimus

JC polyomavirus-associated nephropathy (JC-PVAN) is a rare but challenging cause of renal dysfunction. We report JC-PVAN in a renal allograft recipient and highlight the obstacles in definitive diagnosis of this disease entity. A deceased-donor renal transplant recipient was diagnosed with JC polyomavirus nephritis 4 years after transplantation. Immunosuppressive agents were subsequently reduced, resulting in an initial stabilization of renal function. We present this interesting case and discuss the challenges with diagnosing and treating this rare entity.

Topics: Biopsy; BK Virus; Creatinine; Graft Rejection; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Isoxazoles; JC Virus; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polymerase Chain Reaction; Polyomavirus Infections; Sirolimus; Tacrolimus; Transplantation, Homologous; Viremia

Despite recent developments and treatment successes, the outcome, and prognosis of patients with lupus nephritis (LuN) have not greatly changed since the 1980s. This review covers the application of new concepts to the understanding of renal inflammation and the study of new pharmacologic agents to improve patient outcomes.. Studies have shown that the presence of anti-vimentin antibodies and T follicular helper cells in patient biopsies is associated with more severe interstitial inflammation, which has been tied to faster disease progression and onset of end-stage renal disease. Additionally, data regarding the role of serum IgE antidouble-stranded DNA antibodies in LuN by means of mediating IFN1 production by plasmacytoid dendritic cells are highlighted. Finally, a thorough review of completed and currently open clinical trials of therapeutic agents is provided.. Current management of LuN is guided almost exclusively by glomerular involvement. Based on the data provided in this review, we argue that renal tubulointerstitial inflammation is no less important and represents an overlooked feature in the current clinical approach to patients. Tubulointerstitial inflammation is driven by both adaptive and innate immune mechanisms that are still poorly understood. Studying these pathogenic processes promises to reveal new therapeutic opportunities for those LuN patients with the worst prognosis.. Alternate video abstract introduction (see Video, Supplemental Digital Content 1, with introduction by two of the authors - VL and KT). Abstract Video: http://links.lww.com/COR/A35.

Topics: Abatacept; Antibodies, Monoclonal, Humanized; Autoantibodies; Biopsy; Cyclophosphamide; Dendritic Cells; Disease Progression; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammation; Interferon Type I; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Prognosis; Quinolones; Recombinant Fusion Proteins; Remission Induction; Ribonucleosides; Severity of Illness Index; T-Lymphocytes, Helper-Inducer; Treatment Outcome; Vimentin

End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival.. To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation.. Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost).. Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.. Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC.. The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence.. TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study.. This study is registered as PROSPERO CRD42014013544.. The National Institute for Health Research HTA programme.

Topics: Abatacept; Antibodies, Monoclonal; Antilymphocyte Serum; Azathioprine; Basiliximab; Child; Clinical Trials as Topic; Cost-Benefit Analysis; Drug Therapy, Combination; Everolimus; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Economic; Mycophenolic Acid; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Technology Assessment, Biomedical

End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival.. To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation.. Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.. Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY.. For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled.. High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome.. Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY.. This study is registered as PROSPERO CRD42014013189.. The National Institute for Health Research Health Technology Assessment programme.

Topics: Abatacept; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Bayes Theorem; Cost-Benefit Analysis; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Economic; Mycophenolic Acid; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Technology Assessment, Biomedical

Renal involvement is frequent during natural history of systemic lupus erythematosus (SLE) and has a major prognostic value in this systemic disease. Screening for renal symptoms, such as proteinuria, micro-haematuria or renal failure must be performed at initial diagnosis and repeated during subsequent follow-ups. Any significant abnormality of these parameters may reveal active glomerulonephritis (GN) and should lead to a renal biopsy, which will significantly impact the therapeutic choices. Proliferative GN, defined as class III or IV by the actual histo-pathological classification, is the most severe form of SLE-associated nephropathy and can lead to end-stage renal disease (ESRD) in up to 60% of cases, according to ethnicity and follow-up duration. Standard induction treatment of active proliferative GN includes corticosteroids combined with an immunosuppressive drug, which can either be cyclophosphamide or mycophenolate mofetil (MMF). Even though, recent biotherapies have not yet proved their efficacy in the field of lupus nephritis, new protocols are expected, aiming higher remission rates and avoidance of high-dose corticosteroids regimens. When remission is achieved in proliferative GN, a maintenance therapy is required to decrease the risk of relapse, using either azathioprine or MMF. Immunosuppressive drugs are responsible for an increased risk of infectious or neoplastic complications but cardiovascular disease is actually one of the main causes of mortality among lupus patients, especially for patients with SLE-related kidney disease, well before reaching ESRD.

Topics: Cyclophosphamide; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid

Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients' quality of life. Significant improvements in one-year renal allograft and patients' survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%-5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, "omics" techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient's genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.

Topics: Azathioprine; Calcineurin Inhibitors; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Pharmacogenetics; Precision Medicine

Few data are available on pregnancy in renal transplanted women for lupus nephritis (LN).. Among 38 women with LN who received a renal transplant in our Unit, three had nine pregnancies. During the pregnancies, patients were followed by a multidisciplinary team including gynecologists and nephrologists.. Two patients received a living related and one a deceased kidney transplant. The immunosuppressive therapy consisted of steroids calcinurin inhibithors and mycophenolate mofetil. The last drug was substituted with azathioprine in prevision of pregnancy. All patients had normal renal function and urinalysis. In two patients some signs of immunological activity persisted after transplantation. Five pregnancies ended in miscarriage and four in live births. Two pregnancies were uneventful. Pre-eclampsia occurred in a hypertensive patient in two pregnancies that ended in preterm delivery in one case and in a small for gestation age in both cases. And finally, follow-up graft function and urinalysis continued to be normal in all patients.. After renal transplantation our LN women continue to have frequent miscarriages. The other pregnancies ended in live births and, with the exception of pre-eclampsia in a hypertensive patient, no renal or extra-renal complications occurred during or after pregnancy, even in cases with active immunological tests.

Topics: Abortion, Spontaneous; Adult; Anti-Inflammatory Agents; Antibodies, Antinuclear; Antihypertensive Agents; Azathioprine; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lupus Nephritis; Mycophenolic Acid; Pre-Eclampsia; Prednisone; Pregnancy; Pregnancy Complications; Pregnancy Outcome

There continues to be disagreement related to the appropriate therapeutic regimen to be used when the donor and the recipient in kidney transplant operations are identical twins. Here we present two cases of kidney transplantation between identical twins. Both recipients had end-stage renal disease (ESRD) caused by primary nephropathy. We also present information gleaned from a literature review of similar cases. The first recipient was a 26-year-old man who experienced biopsy-proven IgA nephropathy 10 months post-transplantation. Mycophenolate mofetil (MMF), angiotensin receptor blockers (ARBs), and steroids were used to reverse this pathologic condition. Till now, 76 months post-transplantation, the patient is stable, and the new kidney is functioning well. The second recipient was a 20-year-old woman who had hematuria and proteinuria 3 months post-transplantation, and crescent glomerulonephritis with mild to moderate interstitial injury was proven by biopsy 11 months postoperatively. This patient did not respond to various treatments and resumed hemodialysis 15 months post-transplantation. These case studies show that immunosuppressive therapy should be maintained in kidney transplant recipients who are identical twins with ESRD caused by initial nephropathy.

Topics: Adult; Angiotensin Receptor Antagonists; Female; Glomerulonephritis, IGA; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Time Factors; Twins, Monozygotic

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The development and progression of DN might involve multiple factors. Connective tissue growth factor (CCN2, originally known as CTGF) is the one which plays a pivotal role. Therefore, increasing attention is being paid to CCN2 as a potential therapeutic target for DN. Up to date, there are also many drugs or agents which have been shown for their protective effects against DN via different mechanisms. In this review, we only focus on the potential renoprotective therapeutic agents which can specifically abolish CCN2 expression or nonspecifically inhibit CCN2 expression for retarding the development and progression of DN.

Topics: Animals; Anthocyanins; Antibodies, Monoclonal; Connective Tissue Growth Factor; Diabetes Mellitus; Diabetic Nephropathies; Disease Progression; Exenatide; Guanidines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney; Kidney Failure, Chronic; Mice; Mycophenolic Acid; Oligonucleotides, Antisense; ortho-Aminobenzoates; Peptides; Renin-Angiotensin System; rho-Associated Kinases; Spironolactone; Venoms

IgA nephropathy is the most common primary glomerular disease worldwide and also the most frequent cause of kidney failure. Mycophenolate mofetil (MMF) is a selective immunosuppressant widely used in many autoimmune diseases. However, the benefits and risks of MMF for the treatment of IgA nephropathy remain uncertain.. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to assess the efficacy and safety of MMF in IgA nephropathy patients, using the statistical software Review Manager 5.1.. Eight RCTs involving 357 patients were identified and included in this review. Overall, no statistical difference was found in the therapeutic effect of MMF treatment compared with other therapies. MMF had no significant effects on reducing proteinuria or protecting renal function. However, subgroup analysis indicated that relatively short-term therapy (<18 months) might be beneficial in IgA nephropathy patients while longer term MMF use conferred no advantage. There was also no statistical difference between MMF and control groups in the incidence of side effects. When compared with other immunosuppressants, MMF was considered superior to cyclophosphamide in terms of better therapeutic effects and fewer adverse reactions, but no difference was found between MMF and leflunomide.. Our current evidence indicates that a relatively short course of MMF may be beneficial in treating IgA nephropathy. However, high-quality RCTs with large sample size as well as a well-designed study to evaluate the long-term effects of MMF are needed to further evaluate the efficacy and safety of MMF in this disease.

Topics: Creatinine; Drug Administration Schedule; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Proteinuria

Idiopathic focal and segmental glomerular sclerosis is a frequent cause of nephrotic syndrome and end-stage renal disease. The pathogenesis is still unknown, although the body of evidence suggests that focal and segmental glomerular sclerosis is caused by a not clearly identified circulating factor that alters the permselectivity of the glomerular barrier. Proteinuria is followed by podocyte injury. Glucocorticoids, calcineurin inhibitors, cytotoxic agents and mycophenolate mofetil, either given alone or in combination, may obtain complete or partial remission of proteinuria in 50-60% of patients and protect them from end-stage renal disease, but the remaining patients are resistant to the available drugs. A number of new drugs, including rituximab, galactose and antifibrotic agents, are under investigation.

Topics: Adult; Antibodies, Monoclonal, Murine-Derived; Calcineurin Inhibitors; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Kidney Failure, Chronic; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Rituximab

Fertility in women with kidney failure is restored by transplantation. It requires careful planning and is only advisable in women with good kidney function, controlled blood pressure, and general good health. Immunosuppressive drugs carry risks for the fetus, but the risks of prednisone, azathioprine, cyclosporine, and tacrolimus are surprisingly low. Mycophenolate is teratogenic. The success rate for pregnancy in kidney transplant recipients is lower than in the general population with 70% to 80% of pregnancies resulting in surviving infants. Prematurity, intrauterine growth restriction, and preeclampsia are all increased. Complications are higher and outcomes are worse for women with serum creatinine levels over 1.3 mg/dL. Ten to 15% of women have a temporary or permanent decline in kidney function, particularly if prepregnancy creatinine is high. Transplant-related infections can be serious for the mother and fetus. A multidisciplinary team should coordinate care.

Topics: Anemia; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Female; Herpes Simplex; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Preconception Care; Prednisone; Pregnancy; Pregnancy Complications; Tacrolimus; Toxoplasmosis; Urinary Tract Infections

The safety and efficacy of early steroid withdrawal or avoidance in patients receiving a kidney transplant (KT) are controversial.. We performed a systematic review and a meta-analysis of the randomized controlled studies about steroid avoidance or withdrawal after a few days in patients receiving a KT and treated with antibody induction and cyclosporine (CsA) or tacrolimus (Tac) plus mycophenolate mofetil (MMF) (nine available studies and 1934 participants).. Death and graft loss (including or excluding death with function) were similar in steroid avoidance and control patients, with no differences between CsA and Tac studies. After steroid avoidance, acute rejection was more frequent than conventional steroid use in CsA trials [risk ratios (RR) 1.59, 95% confidence intervals (95% CI) 1.01-2.49] but not when Tac was used (RR 1.06, 95% CI 0.79-1.42). Steroid avoidance was associated with less frequent new-onset diabetes mellitus, but this decrease was only evident with CsA (RR 0.54, 95% CI 0.30-0.98), whereas this difference was not significant analysing Tac studies (RR 0.75, 95% CI 0.32-1.77). Despite this trend, the corresponding interaction tests were not statistically significant (P = 0.140 and P = 0.535, for acute rejection and new-onset diabetes mellitus, respectively). Serum creatinine, creatinine clearance, mean blood pressure, serum cholesterol and serum triglycerides were similar in both groups.. Steroid avoidance or early withdrawal within the first 2 weeks is safe in KT recipients receiving induction with anti-interleukin-2 receptor antibodies or thymoglobulin and a drug regimen based on calcineurin inhibitor and MMF. However, the real benefits remain unclear.

Topics: Adrenal Cortex Hormones; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Care; Prognosis; Randomized Controlled Trials as Topic; Survival Analysis; Tacrolimus; Time Factors; Transplantation Immunology; Withholding Treatment

Chronic, progressive, and irreversible loss of a transplanted kidney function, previously named chronic allograft nephropathy, is the leading cause of chronic allograft failure among kidney transplant recipients. Chronic allograft dysfunction (CAD) is a multifactorial process associated with progressive interstitial fibrosis and tubular atrophy. Current Data confirms that an additive series of time-dependent immunological factors such as acute and chronic antibody- and/or cell-mediated rejection and nonimmunological factors are involved in development of interstitial fibrosis and tubular atrophy as the fundamental parts of CAD. The use of calcineurin inhibitors has produced a major impact on achieving successful organ transplantation; however, although this assumption has been doubted recently, calcineurin inhibitors are deemed to be associated with nephrotoxicity and subsequent interstitial fibrosis, tubular atrophy, and kidney dysfunction. The early fibrotic changes are due to implantation stress, T-cell-mediated rejection, and infection; however, usually they do not lead to progressive fibrosis and allograft dysfunction per se. In the setting of CAD, many factors occurring lately after 1 year, such as chronic antibody-mediated rejection, recurrent or de novo glomerulonephritis, and nonadherent adequately address the existence of ongoing injuries and progression to fibrosis. Identification of patients who are at risk, close clinical monitoring, and optimization and individualization of their maintenance immunosuppressive regimen are among the means that could help us to improve the long-term outcome of kidney transplantation.

Topics: Calcineurin Inhibitors; Chronic Disease; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Primary Graft Dysfunction; Tacrolimus; Transplantation, Homologous

Patient survival and renal survival of patients with lupus nephritis improved, but still in a significant proportion of patients the disease progresses to end-stage renal failure, possibly at least partly due to slow and incomplete response to induction treatment and high relapse rate on the maintenance treatment. Mycophenolate mofetil was recently demonstrated to be a comparably effective and safe induction treatment of lupus nephritis as high-dose cyclophosphamide pulses, in Caucasian patients it has become a reasonable alternative to low-dose cyclophosphamide pulses according to the EUROLUPUS protocol. Mycophenolate was shown to be more effective than azathioprine in the maintenance treatment and is currently the treatment of choice for this phase of the disease. Rituximab should be reserved for patients refractory (or intolerant) to cyclophosphamide and/or mycophenolate. Therapy of lupus nephritis should be individually tailored; more aggressive therapy should be reserved for patients at high risk for renal dysfunction and its progression.

Topics: Antibodies, Monoclonal, Murine-Derived; Azathioprine; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclophosphamide; Disease Progression; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Rituximab

Whether mycophenolate mofetil is superior to cyclophosphamide as induction therapy for lupus nephritis (LN) remains controversial.. Our objective was to investigate the efficacy and safety of mycophenolate mofetil compared with cyclophosphamide as induction therapy for LN patients.. Randomized controlled trials (RCTs) on humans were identified in searches of PubMed/MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (all to 1 December 2011). Studies that compared the efficacy and safety between mycophenolate mofetil and cyclophosphamide as induction therapy in LN patients were selected. Methodological quality of the included trials was assessed according to Cochrane criteria and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The fixed effects model was applied for pooling where there was no significant heterogeneity, otherwise the random effects model (Dersimonian and Laird method) was performed.. Seven trials were identified, including 725 patients. The Dersimonian and Laird method was applied for renal remission in the presence of significant heterogeneity, and no statistically significant differences were distinguished between mycophenolate mofetil and cyclophosphamide. To explore the possible source of heterogeneity, meta-regression was performed. It was suggested that no obvious study- or patient-level factors could explain interstudy heterogeneity with statistical significance. Among all these factors, the mode of administration of cyclophosphamide could explain most of the heterogeneity, although the coefficient was insignificant. Therefore, we performed a sensitivity analysis by excluding the trial in which cyclophosphamide was administered orally instead of intravenously, which suggested that mycophenolate mofetil was more effective than intravenous cyclophosphamide for inducing complete remission (relative risk [RR] 1.72; 95% CI 1.17, 2.55; p = 0.006) and complete or partial remission (RR 1.18; 95% CI 1.04, 1.35; p = 0.01). In addition, mycophenolate mofetil was superior to cyclophosphamide for significantly reducing end-stage renal disease (ESRD) or death (RR 0.64; 95% CI 0.41, 0.98; p = 0.04). For the safety comparison, lower risks of leukopenia, amenorrhoea and alopecia, and a higher risk of diarrhoea were found with mycophenolate mofetil. No statistical differences in infection and gastrointestinal symptoms were distinguished between mycophenolate mofetil and cyclophosphamide. The relatively small number and the open-label fashion of eligible RCTs may limit the value of our meta-analysis.. Mycophenolate mofetil is superior to intravenous cyclophosphamide for inducing renal remission, and has a significant advantage over cyclophosphamide for reducing ESRD or death. Furthermore, mycophenolate mofetil has lower risks of leukopenia, amenorrhoea and alopecia, but a higher risk of diarrhoea than cyclophosphamide. However, our conclusions need to be proved further in larger well designed trials.

Topics: Adult; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Male; Mycophenolic Acid; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome; Young Adult

The incidence of cancer compared for age groups is 3-4 times higher in transplant recipients than the general population. The increased risk is related to immunosuppressive therapy as well as the use of increasingly older donors and recipients. Although cardiovascular disease with a functioning transplant is the leading cause of death (47%), cancer mortality is significant especially among older patients. However, the most frequent posttransplantation cancers relate to hemolymphopoietic organs and skin, whereas the occurrence of solid tumors elsewhere is rare. Herein we have described a rare case of synchronous double malignancy of endocrine organs (thyroid-adrenal) in a young woman who underwent renal transplantation.. A 37-year-old woman with end-stage renal disease for 18 years underwent transplantation when she was 30 years old with a 17-year-old standard cadaveric donor receiving immunosuppressive therapy with mycophenolate mofetil, cyclosporine, and steroids. Follow-up demonstrated good indices of renal function with negative tumor pathology at 79 months when, at an annual ultrasound monitoring, we found a lesion in the right lobe of the thyroid and left adrenal neoplasm of dubious interpretation. The cytology for the thyroid was highly suspicious of papillary carcinoma, whereas the histological examination after surgery diagnosed a thyroid multifocal papillary microcarcinoma (mpT1NxMx) and an oxyphil cell adrenocortical carcinoma (pT2, N0).. Six months after total thyroidectomy with central lymphadenectomy and left kidney and adrenal gland removal the patient showed no evidence of recurrent lesions and stable graft function.. The rare occurrence of solid tumors after transplantation has no known etiopathogenetic relation. Despite the young age of the patient and the double neoplasm that could have produced an unfavorable outcome for the patient and the graft, careful follow-up for tumor pathologies and multidisciplinary management achieved an early diagnosis of both tumors with a surgical eradication without adjuvant therapy, preserving the life of the patient and the function of the graft.

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocortical Carcinoma; Adult; Biopsy; Carcinoma; Carcinoma, Papillary; Cyclosporine; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymph Node Excision; Multiple Endocrine Neoplasia; Mycophenolic Acid; Neoplasm Staging; Nephrectomy; Oxyphil Cells; Steroids; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyroidectomy; Tomography, X-Ray Computed; Treatment Outcome

This review summarizes the focus shift from ischemia-reperfusion injury and avoidance of rejection to long-term outcome after pediatric renal transplantation over the past decade. Although there has been excellent 1-year graft and patient survival, low rejection rates can be achieved with modern immunosuppression after pediatric renal transplantation, and patient survival is improved substantially in comparison with dialysis, pediatric renal transplant recipients experience a high prevalence of infections, malignancies, medication side effects, nonadherence, and, most importantly, cardiovascular morbidity and mortality. Additional challenges occur because of a high prevalence of obesity after transplantation and vascular calcifications. There is also in an underappreciation of chronic kidney disease (CKD) in transplant recipients. The etiology of CKD is multifactorial and can affect graft and patient survival. The rigors of treatment for CKD are less compared with CKD in nontransplant recipients. Almost all immunosuppressive drugs are implicated with a risk of hypertension, hyperlipidemia, and diabetogenicity, all of which contribute to cardiovascular morbidity. Corticosteroids exhibit the most substantial risk and also stunt growth. Effective new treatment protocols such as the recent European Tacrolimus and WIthdrawal of STeroids (TWIST) study with rapid steroid withdrawal after 5 days provide promising results without increasing the rejection risk. The shift in focus on long-term complications allows for improved graft outcome. Side effects of immunosuppressive medications require continued attention to further improve long-term outcomes.

Topics: Child; Graft Rejection; Humans; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Reperfusion Injury

Cardiac transplantation has become an established method for end-stage heart disease. A calcineurin-inhibitor (CNI)-based regimen is the cornerstone of immunosuppressive therapy after cardiac transplantation. CNIs have reduced acute rejection and infection and markedly increased survival of cardiac transplantation patients. However, the dose- and time-dependent nephrotoxic effects of CNIs can limit long-term survival, and chronic renal failure is a major cause of morbidity and mortality in long-term cardiac transplant patients. Early experience on withdrawal of CNIs (and maintenance of patients on azathioprine and steroids) in patients, who developed chronic renal dysfunction, resulted in rejection episodes with, sometimes, fatal outcome. The introduction of newer immunosuppressive drugs, like thymoglobulin, anti CD-25 monoclonal antibodies, mycophenolate mofetil, everolimus or sirolimus into clinical practice, has given transplant physicians new tools to adapt immunosuppression to patients' needs. Changes of immunosuppressive protocols by using new drugs early and late after transplantation and simultaneous reduction or weaning of CNIs have become attractive options. The aim of this article is to review strategies to delay, reduce or prevent CNIs after cardiac transplantation as means to improve short- and long-term outcome mainly by protecting renal function.

Topics: Calcineurin Inhibitors; Clinical Trials as Topic; Drug Administration Schedule; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Sirolimus

Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay - with induction therapy for bridging - followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.

Topics: Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Drug Administration Schedule; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Liver Transplantation; Mycophenolic Acid; Tacrolimus

Since mycophenolate mofetil (MMF) has emerged as an immunosuppressant for treating proliferative lupus nephritis, the role of cyclophosphamide (CYC)-containing regimens is being challenged. Efficacy data from randomized controlled trials (RCTs) and previous meta-analyses comparing these two agents for treating lupus nephritis have been inconsistent as they were heterogeneous in design and of small sample size. An updated meta-analysis is therefore required.. Publications in the English literature were searched with the keywords 'mycophenoate', 'mycophenolic', 'lupus nephritis', 'nephritis' and 'glomerulonephritis' for RCTs in electronic databases. Primary outcome was relative risk (RR) of renal remission at 6 months. Secondary outcome included RRs of mortality, development of end-stage renal failure (ESRF) and side effects. Meta-regression was performed to identify factors explaining the heterogeneity of the effect sizes.. Ten eligible RCTs involving 847 patients were included. MMF offers similar efficacy in inducing renal remission as CYC (RR 1.052; 95% CI 0.950, 1.166) and the risks of death (RR 0.709; 95% CI 0.373, 1.347) and ESRF (RR 0.453; 95% CI 0.183, 1.121) were comparable. Significantly fewer patients receiving MMF developed amenorrhoea (RR 0.212; 95% CI 0.094, 0.479) and leucopenia (RR 0.473; 95% CI 0.269, 0.832) while the risks of herpes infection and pneumonia tended to be lower and that of diarrhoea appeared higher in the MMF groups. Meta-regression revealed that the non-white and non-Asian ethnicities contributed significantly to the heterogeneity of the effect sizes of renal remission.. MMF offers similar efficacy in renal remission and survival as CYC. MMF appears safer than CYC in the treatment of proliferative lupus nephritis.

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic; Regression Analysis; Treatment Outcome

Thousands of patients with chronic renal failure die yearly and are unable to have a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to remove ABO antibodies and permit ABO-incompatible (ABO-I) kidney transplants, but there is only limited research within this area and a lack of standardized protocols for TPE. This article reviews the literature to provide a historical perspective of TPE for ABO-I kidney transplantation and also provides the Johns Hopkins Hospital protocol with a focus on both titers and TPE.. The TPE treatment plan is based on ABO titers with the goal of a titer of 16 or less at the anti-human globulin (AHG) phase before surgery. Pretransplant therapy consists of every-other-day TPE followed immediately by cytomegalovirus hyperimmune globulin. ABO antibody titers are closely monitored before and after transplantation. After transplantation, TPE therapy is performed for all patients to prevent rebound of anti-A and anti-B titers until tolerance or accommodation occurs. TPE is discontinued and reinstituted based on the clinical criteria of creatinine levels, biopsy results, and ABO titer.. Fifty-three ABO-I kidney transplants have been completed with no episodes of hyperacute antibody-mediated rejection (AMR) and only three episodes of AMR. One-year death-censored graft survival is 100 percent and patient survival is 97.6 percent.. While randomized clinical trials are needed to evaluate the optimal method and protocol to remove ABO antibodies, the current literature and our results indicate a critical role for TPE in ABO-I renal transplantation.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Cytomegalovirus; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Isoantibodies; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Plasma Exchange; Plasmapheresis; Preoperative Care; Retrospective Studies; Splenectomy; Survival Analysis; Tacrolimus

We reviewed the literature in 2007 on 3 groups of systemic diseases affecting the kidney: lupic nephropathy (LN), small vessel vasculitis (SVV) and renal amyloidosis. A systematic review of 268 patients with LN pooled from 4 studies found that mycophenolic acid (MPA) in the induction phase caused more remissions and achieved greater renal survival than cyclophosphamide (CP), confirming it as a valid alternative to CP. Using a protocol including rituximab and MPA in the induction phase (14 days), MPA alone without corticoids is effective and safe in the maintenance phase. Rituximab has also been successfully used in CP-resistant forms of LN, where it reduces clinical activity and mesangial proliferation. Plasma exchanges achieve better results than bolus corticoids in SVS with severe renal failure. Complications are severe. Anti- TNF-alpha agents provide no benefit in this indication. Prolonged administration of low-dose corticoids reduces the incidence of relapses. MPA is an alternative to CP if this drug cannot be administered. Good results are achieved with rituximab in CP-resistant forms. According to a controlled trial, treatment of AL amyloidosis with dexamethasone and melphalan has equivalent results to highdose melphalan and rescue with hematopoietic stem cell transplant. In AA amyloidosis, eprosidate slows the rate of progression of renal failure.

Topics: Adrenal Cortex Hormones; Amyloidosis; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Combined Modality Therapy; Cyclophosphamide; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Lupus Nephritis; Melphalan; Mycophenolic Acid; Plasma Exchange; Randomized Controlled Trials as Topic; Recurrence; Rituximab; Vasculitis

The aim of this study was to determine the effectiveness of mycophenolate mofetil (MMF) in IgA nephropathy (IgAN).. A search through Cochrane Library, EMBASE and PubMed was carried out. Randomised controlled trials (RCTs), which compared MMF with conventional treatments, were identified. Patients' baseline, treatment strategies and study end-points were compared.. Four RCTs (168 patients) were selected. All patients had histologically-confirmed IgAN and proteinuria greater than 1 g/day. The follow-up duration ranged from 1.5 to 3.0 years. MMF was used at a titrated dose of 1-2 g/day. In the two trials with subjects having moderate to high risk for progressive disease, MMF did not demonstrate any significant difference in retarding the decline in renal function and proteinuria reduction. One trial concluded that there was a trend towards worse outcomes when MMF was used in moderately-advanced disease. Only one trial involving subjects with less advanced disease (reflected by a favourable histological grade) showed a significant decrease in proteinuria in the MMF-treated group. No serious adverse events occurred in all the four trials using MMF.. No benefit was seen in moderately-advanced IgAN treated with MMF. In a selected group of patients with less advanced disease, MMF was effective in proteinuria reduction. Larger randomised studies are needed to confirm or reject these results.

Topics: Creatinine; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Mycophenolic Acid; Placebos; Proteinuria; Quality Control; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome

The nephrotoxic and extra-renal adverse effects associated with calcineurin inhibitor (CNI) therapies appear to have a negative impact on long-term graft survival. Several CNI minimization protocols have been recently studied. These protocols involve either early CNI avoidance or CNI withdrawal. CNI withdrawal strategies are associated with a significant improvement in renal function and graft survival on both a short and long-term basis. Delayed and progressive withdrawal appears to be safer. Maintaining a high mycophenolate mofetil (MMF) or sirolimus (SIR) exposure minimizes the risk of acute rejection. CNI avoidance regimens using maintenance mono-therapy or combination therapies without induction appear to be immunologically risky and unsafe. In contrast, the combination of SIR + MMF with induction therapy reduces markedly the incidence of acute rejection and chronic allograft nephropathy (CAN). Two year patient and graft survival levels were comparable. CAN as well as the incidence and the risk for cancer in addition to blood pressure profiles and uric acid levels were overall lower in the SIR-based treatment. In contrast, hyperlipidemia, delayed wound healing, lymphocele, arthralgias, thrombocytopenia and study protocol deviations were reported more frequently in the SIR-maintenance protocols. Longer-term follow-ups are definitely needed to determine whether these avoidance strategies will result in a significant improvement in long-term patient and graft survival. Outcome differences among various protocols within the same CNI elimination strategy are probably related to study design, patient selection criteria, immunosuppression monitoring methods, indications for graft biopsies, environmental, and both genetic and ethnic factors. All monitoring techniques are unreliable short of a graft biopsy. Preliminary results on drug lymphocyte binding may offer new guidelines for tailoring immunosuppression. Whether these protocols based on SIR or SIR + MMF can also be extended to high risk patients is currently unknown. These encouraging results allow speculation but with caution that the use of the combination of non-nephrotoxic immunosuppression such as SIR and MMF, might change dramatically the natural course of CAN and may influence long-term patient survival.

Topics: Azathioprine; Calcineurin Inhibitors; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Patient Selection; Risk Assessment; Sirolimus; Treatment Outcome

The management of lupus nephritis is typified by popular misconceptions: that there is a 'standard of care', that treatment has well-defined aims and that the optimum length of treatment is established. In reality, however, uncertainties still exist and the evidence base remains weak. Until recently, initial therapy for class IV lupus nephritis typically involved intravenous cyclophosphamide, yet although cyclophosphamide is superior to azathioprine in improving renal function, it is not superior in terms of mortality. In fact, recent studies show mycophenolate mofetil to be superior to cyclophosphamide in terms of response rate and safety profile and at least as effective as other immunosuppressants. The role of steroids is unclear. Clearly, no standard of care exists in lupus nephritis. The Euro-Lupus Nephritis Trial found that treatment response at six months, in terms of reduced serum creatinine and proteinuria, was the best predictor of long-term renal outcome. Proteinuria, however, can take a long time to reach baseline levels, and normalization of urine is not the same as loss of histological disease activity. Response to treatment thus is not the same as disease remission. Although treatment should aim to reduce the risk of end-stage renal disease and death, control of proteinuria and prevention of flares are also important. Patients who have nephritic flares are almost seven times as likely to progress to end-stage renal disease compared with those who do not. Regimens involving maintenance phases have been developed, but uncertainty remains about the risk of flares and how they can be predicted. The optimum duration of treatment has yet to be determined.

Topics: Azathioprine; Cyclophosphamide; Drug Administration Schedule; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid

Large between- and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P<0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.

Topics: Adult; Aged; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Randomized Controlled Trials as Topic; Reference Values; Retrospective Studies; Transplantation Immunology

Mycophenolate mofetil (MMF) was approved for the prevention of acute rejection following renal transplantation based on the results of three groundbreaking, large, clinical trials that demonstrated a significantly reduced risk of acute rejection in patients receiving MMF when compared with those receiving placebo or azathioprine. These three multicenter, prospective, double-blind trials performed at 55 transplant centers on three continents were the largest immunosuppressive drug trials ever attempted and the first prospective, randomized, double-blind trials ever performed in transplantation. These pivotal trials established a foundation for widespread acceptance of MMF in combination with cyclosporine and steroids as a maintenance regimen for renal transplant patients. The findings of these initial trials that led to the approval of MMF for renal transplantation, including long-term follow-up data, will be reviewed in this paper. The expanding scope of major trials of MMF, including trials in pediatric patients, combination regimens with novel induction therapies or other maintenance agents, and trials in special patient populations such as those at high immunological risk or with deteriorating kidney function, will also be discussed.

Topics: Adolescent; Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Azathioprine; Child; Clinical Trials as Topic; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Multicenter Studies as Topic; Mycophenolic Acid; Receptors, Interleukin-2; Sirolimus; Tacrolimus

Chronic allograft nephropathy is a devastating complication of kidney transplantation that is responsible for a significant proportion of graft loss. This complication is characterized by a progressive decline in kidney function, which is not attributable to a specific cause. Many risk factors exist for the development of chronic allograft nephropathy, including donor-, recipient-, and transplant-related factors (eg, use of calcineurin inhibitors and acute rejection episodes), as well as comorbid conditions such as hypertension and hyperlipidemia. There is no definitive treatment for this complication; management has focused on minimization or withdrawal of calcineurin inhibitors in conjunction with addition of sirolimus or mycophenolate mofetil. Alterations in the immunosuppressive regimen must be done cautiously, as precipitating acute rejection will cause further damage to the allograft. Optimal control of blood pressure, particularly with the use of agents such as angiotensin II receptor blockers, in conjunction with management of dyslipidemia may be effective concurrent therapies in patients with chronic allograft nephropathy.

Topics: Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Calcineurin Inhibitors; Drug Monitoring; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Risk Factors; Severity of Illness Index; Sirolimus; Transplantation, Homologous; Treatment Outcome

Chronic allograft nephropathy is one of the leading causes of long-term graft failure in kidney transplant recipients. The etiology of this condition is multifactorial, but administration of calcineurin inhibitors is often implicated. With the introduction of newer immunosuppressive agents, strategies for calcineurin inhibitor minimization, avoidance, and withdrawal have been emerging in the literature. These strategies may improve long-term kidney allograft function, but are not without risks. Results from recent clinical trials evaluating the safety and efficacy of these strategies to prevent chronic allograft nephropathy in kidney transplant recipients are summarized and reviewed. Patients who had never received a calcineurin inhibitor or who had cyclosporine withdrawn from their regimens had better kidney function than patients who received or kept receiving a calcineurin inhibitor. The impact of the improvement in kidney function on long-term graft survival remains to be determined. In addition, the benefit in renal function must be weighed against the bone marrow toxicities and/or metabolic complications associated with these regimens.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Patient Selection; Postoperative Care; Safety; Sirolimus; Tacrolimus; Transplantation, Homologous

A prolonged course with corticosteroids represents the first therapeutic approach for nephrotic patients with focal segmental glomerulosclerosis (FSGS). In patients with contraindications to steroids or in those who do not respond to steroids or cyclosporine, cytotoxic agents, mycophenolate mofetil (MMF), plasmapheresis, and low-density lipoprotein (LDL) apheresis have been tried as alternative treatments. A short-term treatment with cytotoxic agents often is ineffective in steroid-resistant patients However, an aggressive and prolonged treatment with cytotoxic agents combined with corticosteroids proved to be effective in more than half of steroid-resistant children. In adults, the response to cytotoxic agents was good in steroid-responsive patients, but was poor in steroid-resistant patients. Better results were observed when cytotoxic therapy was prolonged for several months. The problem with these drugs is that long-term immunosuppression may be complicated by severe side effects including a major risk for cancer. Uncontrolled studies reported that MMF can induce some reduction of proteinuria, but complete remission of proteinuria was rare and no data on long-term follow-up evaluation with this drug are available. Good results have been reported with plasmapheresis, immunoadsorption, and lipopheresis. However, all the reports were uncontrolled, small sized, and with short-term follow-up evaluation. In conclusion, there are several therapeutic options for patients who respond to steroids and have further relapses of nephrotic syndrome, but how to treat steroid-resistant patients is still a matter of debate. Nevertheless, a 6-month trial with cytotoxic agents or MMF can be offered to steroid-resistant patients to identify the few patients who respond to these agents. The preliminary results with plasmapheresis or lipopheresis are promising but further studies are needed to assess the role of these treatments.

Topics: Disease Progression; Dose-Response Relationship, Drug; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Nephrotic Syndrome; Proteins; Proteinuria

Most pharmacoeconomic studies of mycophenolate mofetil have focused on its use as part of maintenance immunosuppression for renal transplantation, involving short-term (3 to 12 months) time frames. In general, mycophenolate mofetil reduced the treatment costs for rejection episodes and graft failure which offset its higher drug acquisition cost compared with azathioprine. Several cost analyses have been modelled on the large multicentre trials of adult renal transplant recipients. The use of mycophenolate mofetil was associated with either cost savings or no additional costs after 6 or 12 months in French, US and Canadian analyses of triple or quadruple immunosuppressant therapy. A further cost analysis utilising a registry database of renal transplant recipients in the US found mycophenolate mofetil to be cost saving compared with azathioprine after 6.4 years when evaluating costs due to graft loss only. Of the limited cost-effectiveness analyses with the drug, one US study modelled the 1- and 10-year cost effectiveness of mycophenolate mofetil and various other immunosuppressants used in combined regimens. Long-term use of mycophenolate mofetil was less cost effective than other regimens, but the use of long-term mycophenolate mofetil in high-risk patients was shown to be a relatively cost-effective strategy. In another US analysis comparing mycophenolate mofetil with azathioprine as part of quadruple therapy, mycophenolate mofetil was associated with slightly lower costs during the first year after renal transplantation as well as improved clinical outcomes.. Pharmacoeconomic studies support the use of mycophenolate mofetil as part of immunosuppressant therapy in renal transplantation, at least in the short term. Although the cost effectiveness of mycophenolate mofetil in the long term is less clear, limited pharmacoeconomic data available appear promising. Among issues to be examined in future economic analyses in renal transplantation are the calcineurin-sparing potential of mycophenolate mofetil and the feasibility of using more efficient mycophenolate mofetil dosage regimens when using the drug on a long-term basis. Additional pharmacoeconomic analyses of mycophenolate mofetil are also needed in other types of solid organ transplantation.

Topics: Cost-Benefit Analysis; Costs and Cost Analysis; Economics, Pharmaceutical; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Organ Transplantation; Quality of Life; Registries

We present a case of living, related-donor kidney transplantation during the first trimester of pregnancy. The patient received mycophenolate mofetil (MMF), tacrolimus, and prednisone throughout the entire pregnancy. This is the first reported case of use of MMF during pregnancy. The mother did well, except for mild preeclampsia and mild renal insufficiency at term. The baby girl was born prematurely at week 353/7. The only possible teratogenic effects detected included hypoplastic nails and short fifth fingers. No chromosomal abnormalities were found. The child is growing and developing normally. Although we do not recommend the use of mycophenolate mofetil during pregnancy based on this experience, it is reassuring to know that a successful outcome can be expected in mothers treated with MMF during pregnancy.

Topics: Abnormalities, Drug-Induced; Adult; Drug Therapy, Combination; Female; Fingers; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Mycophenolic Acid; Nails, Malformed; Prednisone; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Tacrolimus

New insights have been recently obtained about pharmacokinetic and pharmacodynamic characteristics of mycophénolate mofetil (MMF). One of the already described MPA metabolite, the acylglucuronide of MPA may be both active and responsible for some side-effects. Glucuronidation is mediated by at least two uridine diphosphate glucuronosyltransferase (UGT) forms, namely UGT1A8 and UGT1A10 whose variability could explain the inter- and intra-individual variability of MMF metabolism. MPA pharmacokinetic data in dialyzed patients or in patients with chronic renal failure are now available. After renal transplantation, MPA levels vary between immediate post-transplant period, at three months and at two years. The target enzyme is inosine monophosphate dehydrogenase (IMPDH). The genes of the two IMPDH isoforms have been cloned. The bicyclic ring system of MPA packs underneath the hypoxanthine ring of IMPDH, thereby trapping this covalent intermediate of the enzymatic reaction. After renal transplantation, a randomized trial has shown that clinical efficacy is correlated with MPA AUC but side effects are correlated with MMF dosage. When associated with cyclosporine, there is a significant decrease of MPA level. Better knowledge of MMF metabolism, of variability factors and target levels to reach in clinical practice should allow a better use of MMF.

Topics: Animals; Biological Availability; Biotransformation; Cattle; Drug Evaluation, Preclinical; Drug Interactions; Enzyme Inhibitors; Glucuronosyltransferase; Graft vs Host Disease; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Isoenzymes; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Multicenter Studies as Topic; Mycophenolic Acid; Nucleic Acids; Rabbits; Randomized Controlled Trials as Topic; Renal Dialysis

Mycophenolate mofetil (MMF) is now widely used in solid organ transplantation. MMF is rapidly converted to its active form, mycophenolic acid (MPA), upon reaching the systemic circulation. MPA is metabolized to its glucuronide metabolite, mycophenolic acid glucuronide (MPAG), by glucoronyl transferases in the liver and possibly elsewhere. MPAG is then excreted by the kidney. MPA is extensively and avidly bound to serum albumin. Previous studies have demonstrated that it is only the free (non-protein-bound) fraction of MPA that is available to exert its action. In vivo and in vitro studies demonstrate that renal insufficiency decreases the protein binding of MPA and increases free MPA concentrations. This decrease in protein binding seems to be caused both by the uremic state itself and by competition with the retained metabolite MPAG. The disposition of MPA in patients with severe renal impairment may be significantly affected by this change in protein binding.

Topics: Biotransformation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid

Three major double-blind trials in kidney transplantation patients have shown that mycophenolic acid (mycophenolate mofetil), added to an immunosuppressive regimen consisting of cyclosporine and prednisone, reduces the incidence of acute rejection after kidney transplantation by 50%, during the first six months. This statistically significant reduction is achieved equally with daily doses of 2 or of 3 g. In view of the fact that the side effects (diarrhoea, abdominal cramps, leukopenia) are more frequently found in the patients treated with 3 g, it is advised to prescribe 2 g mycophenolic acid. As acute rejection is a risk factor for the development of chronic rejection and because a beneficial effect of mycophenolic acid on chronic rejection in animal models has been observed, there may also be an effect on late graft loss due to chronic rejection after kidney transplantation in man.

Topics: Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Prednisone

The role of mycophenolate mofetil (MMF) in management of immunoglobulin A nephropathy (IgAN) remains highly controversial.. To evaluate the efficacy and safety of MMF in patients with IgAN at high risk of kidney function loss.. This randomized clinical trial with open-label, blinded end-point design was conducted among adults with IgAN, proteinuria greater than 1.0 g/d, and estimated glomerular filtration rate (eGFR) greater than 30 and less than 60 mL/min/1.73m2 or with persistent hypertension from September 2013 to December 2015. During a 3-month run-in period, 238 patients received optimized supportive care (SC), including losartan. Patients with a urinary protein excretion rate of 0.75 g/d or greater despite of 3 months optimized SC were enrolled into the trial for 3 years. Survivors of the trial who did not receive dialysis or transplant were followed up after the trial for a median (IQR) of 60 (47-76) months. Data were analyzed from March through June 2022.. A total of 170 participants were randomized in a 1:1 ratio to receive MMF (initially, 1.5 g/d for 12 months, maintained at 0.75-1.0 g for at least 6 months) plus SC or SC alone.. The primary outcomes were (1) a composite of doubling of serum creatinine, end-stage kidney disease (dialysis, transplant, or kidney failure without receiving kidney replacement therapy), or death due to kidney or cardiovascular cause and (2) progression of chronic kidney disease.. Among 170 randomized patients (mean [SD] age 36.6 [9.4] years; 94 [55.3%] male patients), 85 patients received MMF with SC and 85 patients received SC alone. The mean (SD) eGFR was 50.1 (17.9) mL/min/1.73m2 and mean (SD) proteinuria level was 1.9 (1.7) g/d; 168 patients (98.8%) completed the trial, and 157 participants (92.4%) survived and did not receive dialysis or transplant. Primary composite outcome events occurred in 6 patients (7.1%) in the MMF group and 18 patients (21.2%) in the SC group (adjusted hazard ratio [aHR], 0.23; 95% CI, 0.09-0.63). Progression of chronic kidney disease occurred in 7 participants (8.2%) in the MMF group and 23 participants (27.1%) in the SC group (aHR, 0.23; 95% CI, 0.10-0.57). The effect of MMF treatment on primary outcomes was consistent across prespecified subgroups, with no significant interaction per subgroup. During posttrial follow-up, annual loss of eGFR accelerated after discontinuation of MMF; mean (SD) annual eGFR loss during the study period was 2.9 (1.0) mL/min/1.73m2 in the MMF group and 6.1 (1.2) mL/min/1.73m2 among 66 patients in the MMF group who discontinued MMF after the trial. Serious adverse events were not more frequent with MMF vs SC alone.. This study found that addition of MMF to SC compared with SC alone significantly reduced risk of disease progression among patients with progressive IgAN.. ClinicalTrials.gov Identifier: NCT01854814.

Topics: Adult; Female; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Renal Dialysis

Remission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival.. Cohort analysis of clinical trial participants.. Patients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone.. Reduction in proteinuria measured during 26 weeks after initiating treatment.. Repeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization.. Multivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome.. 138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90mL/min/1.73m. Limited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years.. These findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.

Topics: Adolescent; Child; Cohort Studies; Creatinine; Cyclosporine; Dexamethasone; Disease Progression; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Mortality; Mycophenolic Acid; Prognosis; Proportional Hazards Models; Proteinuria; Remission Induction; Tissue Survival; Treatment Outcome; Young Adult

In a prospective randomized controlled trial, between May 2001 and January 2003, 132 live-donor kidney transplant recipients were randomized to receive sirolimus primary immunosuppression, either in combination with low dose tacrolimus (Tac group) or in combination with mycophenolate mofetil (MMF group). We have previously reported on 2- and 5-year follow-up results, with favorable patient and graft outcomes obtained in both groups. In view of recent published reports of increased risk of inferior outcomes among sirolimus-treated patients, we herein present results of an observational extension of the previously randomized patients 15 years post-transplantation. Mortality rates were 10.8% and 3% in Tac and MMF groups respectively after mean follow-up period of 11.2-11.8 years. Comparable graft survival rates were obtained in both groups ranging from 60% to 62.7%. The (MMF) group continued to have the advantage of remaining on primary plan of immunosuppression (56.7% of patients) as well as to maintain better graft function in terms of serum creatinine level. Herein, we presented longest term published data for sirolimus-based immunosuppression among live-donor kidney transplants with favorable outcome in terms of survival and graft function.

Topics: Adolescent; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Mycophenolic Acid; Prognosis; Retrospective Studies; Risk Factors; Sirolimus; Survival Rate; Tissue Donors

The optimal immunosuppressive regimen for recipients of expanded criteria donor (ECD) kidneys has not been identified. In this single-center study, 171 recipients of ECD kidney transplants were randomized to receive antithymocyte globulin induction, and delayed introduction of reduced dose tacrolimus, prednisone and everolimus (r-ATG/EVR, n = 88), or mycophenolate (r-ATG/MPS, n = 83). No cytomegalovirus (CMV) pharmacological prophylaxis was used. The primary endpoint was the incidence of CMV infection/disease at 12 months. Secondary endpoints included treatment failure [first biopsy-proven acute rejection (BPAR), graft loss, or death] and safety. Patients treated with EVR showed a 89% risk reduction (13.6 vs. 71.6%; HR 0.11, 95% CI 0.06-0.220, P < 0.001) in the incidence of first CMV infection/disease. Incidences of BPAR (16% vs. 5%, P = 0.021), graft loss (11% vs. 1%, P = 0.008), death (10% vs. 1%, P = 0.013), and treatment discontinuation (40% vs. 28%, P = 0.12) were higher in the r-ATG/EVR, leading to premature study termination. Mean glomerular filtration rate was lower in r-ATG/EVR (31.8 ± 18.8 vs. 42.6 ± 14.9, P < 0.001). In recipients of ECD kidney transplants receiving no CMV pharmacological prophylaxis, the use of everolimus was associated with higher treatment failure compared with mycophenolate despite the significant reduction in the incidence of CMV infection/disease (ClinicalTrials.gov.NCT01895049).

Topics: Aged; Antilymphocyte Serum; Cytomegalovirus Infections; Delayed Graft Function; Donor Selection; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Risk Assessment; Risk Factors; Tacrolimus; Treatment Outcome

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.

Topics: Australia; Cyclosporine; Everolimus; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Sirolimus; Skin Neoplasms; Transplant Recipients

This analysis compared efficacy, renal function, and histology in kidney transplant recipients receiving tacrolimus (TAC) combined with everolimus (EVR) or mycophenolate (MPS).. This was a retrospective analysis from a randomized trial in kidney transplant recipients who received a single 3 mg/kg dose of rabbit antithymocyte globulin (r-ATG), TAC, EVR, and prednisone (PRED; r-ATG/EVR, n = 85), basiliximab (BAS), TAC, EVR, and PRED (BAS/EVR, n = 102) or BAS, TAC, MPS, and PRED (BAS/MPS, n = 101). We evaluated the incidence of de novo donor-specific anti-human leukocyte antigens antibodies (DSA) and histology on protocol biopsies at 12 months, and the incidence of acute rejection, estimated glomerular filtration rate (eGFR) and proteinuria at 36 months.. At 12 months, there were no differences in de novo DSA (6.4 vs. 3.4 vs. 5.5%) or in subclinical inflammation (2.0 vs. 4.8 vs. 10.2%), interstitial fibrosis/tubular atrophy (57.1 vs. 58.5 vs. 53.8%) and C4d deposition (2.0 vs. 7.3 vs. 2.6%). At 36 months, there were no differences in the incidence of treatment failure (19.0 vs. 27.7 vs. 27.7%, p = 0.186), first biopsy-proven acute rejection (9.5 vs. 21.8 vs. 16.8%, p = 0.073), and urine protein/creatinine ratios (0.53 ± 1.05 vs. 0.62 ± 0.75 vs. 0.71 ± 1.24). eGFR was lower in the BAS/EVR compared to that in the BAS/MPS group (53.4 ± 20.9 vs. 50.8 ± 19.5 vs. 60.7 ± 21.2 mL/min/1.73 m2, p = 0.017) but comparable using a sensitive analysis (49.5 ± 23 vs. 47.5 ± 22.6 vs. 53.6 ± 27.8 mL/min/1.73 m2, p = 0.207).. In this cohort, the use of EVR and reduced TAC concentrations were associated with comparable efficacy, renal function, and histological parameters compared to the standard-of-care immunosuppressive regimen.

Topics: Adult; Allografts; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Biopsy; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus; Tissue Donors; Treatment Failure; Treatment Outcome; Withholding Treatment; Young Adult

Randomized trials have shown that early adoption of everolimus-based immunosuppressive regimens without a calcineurin inhibitor (CNI) improves long-term kidney graft function, but the optimal strategy for CNI minimization remains uncertain.. In a prospective, randomized, multicentre, 12-month trial, 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid (clinical trials registry: ClinicalTrials.gov-NCT00514514).. The primary endpoint, change in estimated glomerular filtration rate (eGFR) (Nankivell) from randomization to Month 12, was significantly greater in the CNI-free arm versus standard CNI therapy: mean difference 5.6 mL/min/1.73 m 2 [95% confidence interval (CI) 2.8-8.3 mL/min/1.73 m 2 , P < 0.001]. The improvement in eGFR in the CNI-free arm was also higher than in the low-CNI group (mean difference 5.5 mL/min/1.73 m 2 , 95% CI 2.8-8.2 mL/min/1.73 m 2 , P < 0.001), while results were similar in the low-CNI and standard CNI arms. The post-randomization incidence of biopsy-proven acute rejection was 11.7%, 8.1% and 7.9% in the CNI-free, low-CNI and standard CNI groups, respectively (CNI-free versus standard CNI, P = 0.27; low-CNI versus standard CNI, P = 1.00). Adverse events led to study drug discontinuation in 28.7%, 15.5% and 15.2% of CNI-free, low-CNI and standard CNI patients, respectively.. Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Treatment Outcome

ADHERE was a randomized, open-label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolonged-release tacrolimus-based immunosuppressive regimens. On Days 0-27, patients received prolonged-release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged-release tacrolimus plus MMF (Arm 1) or prolonged-release tacrolimus (≥25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full-analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m

Topics: Adrenal Cortex Hormones; Adult; Aged; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus; Time Factors; Transplant Recipients; Treatment Outcome

In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m

Topics: Adolescent; Adult; Aged; Equivalence Trials as Topic; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Safety; Tacrolimus; Young Adult

To compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN).. This is an open randomised controlled parallel group study.. Adult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06-0.1 mg/kg/day) or MMF (2-3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time.. 150 patients (92% women; aged 35.5±12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (-12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8±26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by ≥30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35).. TAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen.. Hospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319).

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Creatinine; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Proteinuria; Recurrence; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

To report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome.. In 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up.. Death (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events. Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients. Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome. The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%). Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker.. The long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome.. NCT00204022.

Topics: Adult; Azathioprine; Disease Progression; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Longitudinal Studies; Lupus Nephritis; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Treatment Outcome

To evaluate the safety and tolerability of immunosuppressive drugs used in a planned randomized conversion from a calcineurin inhibitor, tacrolimus, to a mammalian target of rapamycin inhibitor, sirolimus, in de novo kidney transplant recipients.. Prospective safety analysis of data from a prospective, randomized, open-label, controlled study.. A total of 119 adult kidney transplant recipients who received tacrolimus (TAC), mycophenolate sodium (MPS), and prednisone between February 2008 and May 2010; after 3 months of this regimen, 60 of these patients were randomized to conversion from TAC to sirolimus (SRL/MPS group), and 59 patients continued with the TAC regimen (TAC/MPS group).. Both groups were followed for 24 months after transplantation for immunosuppressive regimen-associated and time-dependent occurrences of adverse events (AEs) and serious adverse events (SAEs). Before conversion from TAC to SRL, the cumulative incidence of AEs was 98%; 25% were SAEs. Gastrointestinal AEs (66%) and infections (58%) were the most frequent AEs. The incidences of TAC and MPS dose reductions due to AEs were 1.7% and 12%, respectively. After conversion, no significant differences were noted in the SRL/MPS group versus the TAC/MPS group in the cumulative incidences of AEs (100% vs. 98%) and SAEs (27% vs. 30%). The most common AEs were gastrointestinal (70% vs. 54%, p=0.23) and infection (77% vs. 73%, p=0.79) in the SRL/MPS versus TAC/MPS groups. The incidence of aphthous ulcer (28% vs. 0%, p=< 0.01), sinusitis (10% vs. 0%, p=0.01), dermatitis (15% vs. 3%, p=0.03), and dyslipidemia (35% vs. 14%, p=0.02) were higher in the SRL/MPS group compared with the TAC/MPS group. Cox proportion regression analysis showed a higher relative risk for gastrointestinal (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.01, p<0.05) and skin and subcutaneous tissue (HR 2.5, 95% CI 1.1-4.1, p<0.05) AEs in the SRL/MPS group compared with the TAC/MPS group. AE-related dose reductions occurred in 18.3% of patients receiving SRL and 3.3% of patients receiving TAC. MPS dose reductions due to AEs occurred in 11.7% of patients receiving SRL and 13.6% of patients receiving TAC.. SRL/MPS treatment was associated with a time-dependent higher incidence of gastrointestinal and skin and subcutaneous tissue AEs, which occurred mainly during the first 6 months after conversion from TAC/MPS. Although the treatments with SRL or TAC after 3 months of transplantation showed different safety profiles, both regimens demonstrated adequate tolerability, with low rates of early discontinuation related to AEs.

Topics: Adult; Brazil; Calcineurin Inhibitors; Drug Eruptions; Drug Monitoring; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Severity of Illness Index; Sirolimus; Subcutaneous Tissue; Tacrolimus; TOR Serine-Threonine Kinases

Graft failure due to chronic rejection is greater among renal transplant patients with donor-specific antibody (DSA) than among DSA-free patients. For patients dependent on deceased donor transplantation, preoperative desensitization to eliminate DSAs may be impractical. We speculated that perioperative desensitization might eliminate preexisting DSAs and prevent de novo DSAs and improve graft outcomes. We report that brief perioperative desensitization using either intravenous immunoglobulin (IVIG) or plasmapheresis/IVIG (PP/IVIG) treatment improves clinical outcomes among patients with positive crossmatches.. Immediately following deceased donor transplantation, 235 renal recipients were assigned points for PRA and flow crossmatches (FCXM): delayed graft function (DGF) ≤ 1 point received standard therapy; 2 points received high-dose IVIG; and ≥3 points received PP/IVIG. The DSAs were serially monitored by single antigen bead luminex for 1 year. Five-year clinical outcomes were determined from the chart review.. All desensitized patients had preoperatively positive FCXM with DSA. Rejection was more common (P < .05) among desensitized than nonsensitized groups. However, overall graft survivals were similar between the groups (P = not significant) and superior to historic untreated patients (P < .05). Treatment with PP/IVIG more effectively eliminated preexisting DSAs (67% vs 33%, P < 0.05) than IVIG, but neither regimen prevented de novo formation of DSA (20%, P = not significant). Graft survival was >90% in all desensitizated patients with DSA elimination as well as PP/IVIG patients with residual DSA. In contrast, IVIG patients with persistent DSA had poorer graft survival (45%, P < .05).. Preemptive perioperative desensitization improved overall graft survival of sensitized patients compared to historic untreated patients. Plasmapheresis/IVIG had greater impact on DSA eradication and graft survival than IVIG alone.

Topics: Adult; Antibodies; Antilymphocyte Serum; Cadaver; Cohort Studies; Delayed Graft Function; Desensitization, Immunologic; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone Hemisuccinate; Middle Aged; Mycophenolic Acid; Perioperative Care; Plasmapheresis; Tacrolimus

The metabolic syndrome (MS) is an important risk factor for graft dysfunction and patient death after renal transplantation. The aim of this sub-analysis of the Symphony study was to assess the progression of the laboratory parameters associated with MS in the first year after transplantation.. Data collected from the Symphony study were used; 1645 patients were randomized to receive standard-dose cyclosporine (Stand-CsA), low-dose cyclosporine (Low-CsA), tacrolimus (Low-Tac) or sirolimus (Low-SRL), in addition to mycophenolate mofetil (MMF) and corticosteroids. Data were collected for levels and progression over the first year post-transplantation of systolic and diastolic blood pressure, uric acid, triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and fasting glucose levels by treatment arm.. The low-SRL group had significantly higher levels of triglycerides and LDL. The two CsA arms were associated with the highest uric acid levels at each time point. There were no significant differences in overall levels or changes in glucose or HDL. Patients in the standard-CsA arm had significantly higher diastolic blood pressure than those in the Low-SRL and Low-Tac arms. Systolic blood pressure was higher in the Low-CsA arm than in the Low-Tac arm. The use of antihypertensive and antidiabetic agents was similar between the treatment arms. In the Low-SRL arm, more patients were treated with lipid-lowering therapy. Mean daily steroid doses were the highest in the Low-SRL arm.. This sub-analysis demonstrates that there is a difference in metabolic parameters between immunosuppressive groups. CsA therapy was associated with the highest values of uric acid and systolic and diastolic blood pressure. Patients on SRL therapy had the worst lipaemic control. A possible effect of Tac on new-onset diabetes could not be excluded.

Topics: Adrenal Cortex Hormones; Adult; Blood Chemical Analysis; Blood Pressure Determination; Body Mass Index; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Metabolic Syndrome; Middle Aged; Monitoring, Physiologic; Mycophenolic Acid; Prognosis; Reference Values; Risk Assessment; Sirolimus; Tacrolimus; Transplantation Immunology

Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen.. A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993-98, N = 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999-2007, N = 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD).. In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48-1.46], solid tumours (0.89; 95% CI 0.46-1.67) and PTLD (0.82; 95% CI 0.28-2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001).. Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.

Topics: Adult; Antibiotics, Antineoplastic; Antibodies, Anti-Idiotypic; Drug Combinations; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Prognosis; Receptors, Interleukin-2; Retrospective Studies; Survival Rate; Tacrolimus

Early calcineurin inhibitor (CNI) withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about excess acute rejection. Therapeutic drug monitoring may be advantageous when the CNI or MMF is withdrawn.. This prospective, randomized, concentration-controlled withdrawal study enrolled 177 stable renal transplant recipients on maintenance CNI-based immunosuppression, combined with steroids and MMF. After the feasibility phase of the study, patients were randomized to MMF-withdrawal (target area under the time-concentration curve-cyclosporine: 3250 ng·hr/mL or tacrolimus: 120 ng·hr/mL) or CNI-withdrawal (target area under the time-concentration curve-mycophenolic acid: 75 μg·hr/mL).. The estimated glomerular filtration rate (modification of diet in renal disease) remained significantly better after CNI elimination (59.5±2.1 mL/min vs. 51.1±2.1 mL/min, P = 0.006) up to 3 years and resulted in less functional decline, including the subgroup with an estimated glomerular filtration rate less than 50 mL/min at baseline (P = 0.03). At 6 months, one patient in the MMF-withdrawal group (1.3%) and three in the CNI-withdrawal group (3.8%) experienced acute rejection (P = 0.62). The defined higher mycophenolic acid exposure was well tolerated.. These data indicate that with time the large majority of stable renal transplant recipients can be safely reduced to dual therapy with MMF or CNIs, applying concentration-controlled dosing. CNI-free patients, including those with moderate renal allograft dysfunction, have the benefit of improved renal function, whereas the risk of acute rejection after late withdrawal is low.

Topics: Acute Disease; Biopsy; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Feasibility Studies; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Treatment Outcome

We investigated the safety and efficacy of Campath induction and tacrolimus (TAC) maintenance therapy compared to ATG induction with TAC +MMF + steroids in de novo kidney-pancreas transplanted patients.. 14 patients (Group A) received Campath 30 mg + methylprednisolone 500 mg before revascularization followed by TAC monotherapy, and 16 patients (Group B) ATG 8 mg/kg with TAC + MMF+ steroids (withdrawn at month 3). TAC trough levels (ng/mL) of 12-15 were aimed for in both groups until month 6 and thereafter 6-12.. 1-year patient survival was 100% in both groups; kidney and pancreas survival in Group A was 93% each. In Group B 1-year kidney and pancreas survival was 100% and 87%, respectively. A total of three pancreas grafts were lost due to thrombosis of the graft vein within the first month. The only kidney loss was due to initial non-function. All biopsy-proven acute rejections of renal transplants (n=3 in Group A, n=0 in Group B) were reversible. No acute pancreas graft rejection was demonstrated. Infectious complications, lipid metabolism and blood pressure were comparable in both groups, as were other adverse events. No tumor occurred. At 12 months 13 patients in each group were steroid-free; the mean serum creatinine level was 1.44 mg/dL in Group A and 1.33 mg/dL in Group B. All patients were exogenous insulin-free.. At one year efficacy and safety of Campath +TAC monotherapy were comparable to those of ATG + TAC + MMF + steroids in a limited number of combined kidney-pancreas transplant recipients.

Topics: Adolescent; Adult; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Maintenance Chemotherapy; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Mycophenolate mofetil (MMF) is widely used for immunosuppressive therapy in renal transplantation, but comparative data regarding efficacy and safety in paediatric vs. adult kidney allograft recipients in one and the same study are lacking.. We therefore performed this subgroup analysis of the FDCC trial, a 12-month, prospective, randomised study, comparing fixed-dose (FD) with concentration-controlled (CC) MMF dosing in paediatric and adult renal transplant recipients. Sixty-two paediatric and 839 adult de novo patients in 19 countries were randomised 1:1 to receive fixed-dose or concentration-controlled MMF therapy in combination with calcineurin inhibitors and corticosteroids.. Both patient and allograft survival proved to be excellent in paediatric patients (98.4% and 90.3%) and adults (96.8% and 95.0%). The rates of biopsy-proven acute rejections (BPAR) and treated acute rejection episodes (ARE) were comparable between paediatric (12.9% and 17.7%) and adult patients (15.5% and 20.7%). Transplant function at 12 months post-transplant was similar in paediatric (67.8 ± 45.6 mL/min/1.73 m2;) and adult recipients (64.7 ± 23.3 mL/min/1.73 m2;). Children < 6 years (n = 10) exhibited a numerically higher frequency of leucocytopaenia (20%), diarrhoea (40%) and weight loss (10%) than older children (6-18 years; 5.8%, 28.8% and 1.9%) and adults (16.1%, 24.7% and 1.5%). On the whole, the percentage of patients who experienced adverse events causing interruption of MMF therapy were numerically lower in children (4.8%) than in adults (12.5%). Conclusions. The overall efficacy and tolerability of MMF appear to be comparable between paediatric and adult patients. Further studies are needed to validate these results.

Topics: Adult; Child; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Risk Factors; Safety; Survival Rate; Transplantation, Homologous; Young Adult

Non-nephrotoxic immunosuppressive strategies that allow reduction of calcineurin-inhibitor exposure without compromising safety or efficacy remain a goal in kidney transplantation. Immunosuppression based on the mammalian-target-of-rapamycin inhibitor everolimus was assessed as a strategy for elimination of calcineurin-inhibitor exposure and optimisation of renal-graft function while maintaining efficacy.. In the ZEUS multicentre, open-label study, 503 patients (aged 18-65 years) who had received de-novo kidney transplants were enrolled. After initial treatment with ciclosporin, based on trough concentrations, and enteric-coated mycophenolate sodium (1440 mg/day, orally), corticosteroids (≥5 mg/day prednisolone or equivalent, orally), and basiliximab induction (20 mg, intravenously, on day 0 [2 h before transplantation], and on day 4), 300 (60%) patients were randomly assigned at 4·5 months in a 1:1 ratio to undergo calcineurin-inhibitor elimination (everolimus-based regimen that was based on trough concentrations [6-10 ng/mL] and enteric-coated mycophenolate sodium [1440 mg/day] with corticosteroids), or continue standard ciclosporin-based treatment. Randomisation was done by use of a central, validated system that automated the random assignment of treatment groups to randomisation numbers. The primary objective was to show better renal function (glomerular filtration rate [GFR]; Nankivell formula) with the calcineurin-inhibitor-free everolimus regimen at 12 months after transplantation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00154310.. 118 (76%) of 155 everolimus-treated patients and 117 (81%) of 145 ciclosporin-treated patients completed treatment with study drug up to 12 months after transplantation. At this timepoint, the everolimus regimen was associated with a significant improvement in GFR versus the ciclosporin regimen (71·8 mL/min per 1·73 m(2) vs 61·9 mL/min per 1·73 m(2), respectively; mean difference 9·8 mL/min per 1·73 m(2), 95% CI -12·2 to -7·5). Rates of biopsy-proven acute rejection were higher in the everolimus group than in the ciclosporin group after randomisation (15 [10%] of 154 vs five [3%] of 146; p = 0·036), but similar for the full study period (23 [15%] vs 22 [15%]). Compared with the ciclosporin regimen, higher mean lipid concentrations, slightly increased urinary protein excretion, and lower haemoglobin concentrations were noted with the everolimus regimen; thrombocytopenia, aphthous stomatitis, and diarrhoea also occurred more often in the everolimus group. A higher incidence of hyperuricaemia was noted with ciclosporin.. Early elimination of calcineurin inhibitor by use of everolimus-based immunosuppression improved renal function at 12 months while maintaining efficacy and safety, indicating that this strategy may facilitate improved long-term outcomes in selected patients.. Novartis Pharma.

Topics: Administration, Oral; Adolescent; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

The natural course of idiopathic membranous nephropathy (IMN) is variable and the role of immunosuppressive therapy is controversial. In our centre, the strategy has been conservative: the immunomodulating treatment (glucocorticoids and/or cyclosporine A) has been targeted to patients at high risk of developing progressive renal disease and the cytotoxic drugs have been used cautiously. The aim of this retrospective observational study was to evaluate the efficacy of this strategy.. We evaluated the clinical course and outcome of IMN patients diagnosed between 1993 and 2003. Risk assessment was done during an observation period of ≥6 months after the initial renal biopsy. Patients were followed up until death, the development of end-stage renal disease (ESRD) or the last clinical visit (before December 2006). Treatments and their side effects were recorded.. One hundred and forty-two patients with membranous nephropathy were diagnosed of which 81 were idiopathic. The clinical course of 76 IMN patients (38 high risk and 38 low risk) were followed up [mean duration 66 ± 40 (median 59) months]. Thirty-five patients were treated with immunosuppressive drugs, and at last follow-up, 71% of them were in complete or partial remission. The overall response rate of this therapy was 83%. 11% of the high-risk patients had reached ESRD. For the high-risk patients, 10-year survival (alive with glomerular filtration rate >10 mL/min/1.73 m(2)) was 79%. No major side effects were observed.. This study suggests that targeted, stepwise, cytotoxic drug-sparing immunosuppressive treatment in IMN was associated with favourable renal, as well as overall survival among patient at risk of developing ESRD.

Topics: Cyclophosphamide; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Mycophenolic Acid; Remission Induction; Retrospective Studies; Survival Rate; Treatment Outcome

The aim of this study was to determine the relationship between single-nucleotide polymorphisms (SNPs) in MRP2 genes and mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients of the Symphony Pharmacogenomic substudy.. Sixty-six renal transplant recipients of eight Spanish centres were randomized into four branches of immunosuppressive regimen: low dose of cyclosporine, standard dose of cyclosporine, tacrolimus and sirolimus, all in addition to mycophenolate mofetil and steroids. Fifty-five patients were genotyped for SNPs in MRP2, C24T and C3972T. Pharmacokinetic sampling was done before MPA administration and up to 12 h post-dose at Day 7, 1 month and 3 months post-transplant. Relationships of area under the curve (AUC) of MPA and MPAG plasma sampling with the presence of MRP2 SNPs and with the immunosuppressive regimens were studied.. At steady-state conditions, MPA-reduced exposure was observed in C24T variant allele in MRP2 (CC: 68.73 ± 6.78; *T: 48.12 ± 4.90, P = 0.023); no significant differences linked to C3972T SNP were observed. Taking into account groups of treatment, lower MPA AUC in variant allele of C24T was only found under macrolides treatment with statistically significant differences at Month 3 (Tac and SRL, CC: 86.52 ± 10.98 versus *T: 41.99 ± 4.82, P = 0.001; CsA, CC: 52.31 ± 5.30 versus *T: 54.24 ± 8.30, P = 0.772); for C3972T, the same tendency was found but differences at steady state did not reach statistical significance.. Renal transplant recipients T carriers of C24T MRP2 with macrolides treatment were associated with reduced MPA AUC in steady-state conditions. Patients treated with cyclosporine lost the effect of this polymorphism.

Topics: Area Under Curve; Cyclosporine; DNA; Female; Follow-Up Studies; Genotype; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Microfilament Proteins; Middle Aged; Mycophenolic Acid; Pharmacogenetics; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Prognosis; Sirolimus; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tacrolimus

More than 20,000 candidates for kidney transplantation in the United States are sensitized to HLA and may have a prolonged wait for a transplant, with a reduced transplantation rate and an increased rate of death. One solution is to perform live-donor renal transplantation after the depletion of donor-specific anti-HLA antibodies. Whether such antibody depletion results in a survival benefit as compared with waiting for an HLA-compatible kidney is unknown.. We used a protocol that included plasmapheresis and the administration of low-dose intravenous immune globulin to desensitize 211 HLA-sensitized patients who subsequently underwent renal transplantation (treatment group). We compared rates of death between the group undergoing desensitization treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group).. In the treatment group, Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons).. Live-donor transplantation after desensitization provided a significant survival benefit for patients with HLA sensitization, as compared with waiting for a compatible organ. By 8 years, this survival advantage more than doubled. These data provide evidence that desensitization protocols may help overcome incompatibility barriers in live-donor renal transplantation. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Charles T. Bauer Foundation.).

Topics: Adult; Case-Control Studies; Desensitization, Immunologic; Female; Histocompatibility Testing; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Plasmapheresis; Renal Dialysis; Tacrolimus; Transplantation Conditioning; Transplantation Immunology

Both atorvastatin and mycophenolate mofetil (MMF) have been used for panel reactive antibodies (PRA) reduction in transplant candidates. The purpose of this study was to compare the effect of low-dose MMF and atorvastatin on PRA in sensitized hemodialysis patients waiting for kidney transplantation.. A total of 40 adult patients with end-stage renal disease who were highly sensitized to human leukocyte antigens (PRA > 40%) were enrolled and randomly assigned into atorvastatin or low-dose MMF groups. All of the patients received the treatments for 2 months. The PRA status was determined at the end of the 1st and 2nd month.. Forty percent of the patients in the atorvastatin group compared with 5% in the low-dose MMF group showed complete response, defined as a minimum 50% reduction in PRA (P = .02). Reduction of PRA in the atorvastatin group was significantly higher than that in the low-dose MMF group (P = .01). No major infectious or other complications occurred in our patients.. Atorvastatin has a significant effect on lowering of PRA in sensitized hemodialysis patients waiting for kidney transplantation. In addition, a short course of low-dose MMF is safe in ESRD patients; however, it has no effect on reduction of PRA.

Topics: Adult; Atorvastatin; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Mycophenolic Acid; Pyrroles; Renal Dialysis

FTY720 (fingolimod), a novel immunomodulator, has demonstrated potential for prevention of acute rejection in combination with cyclosporine.. This study evaluated FTY720 2.5 mg versus mycophenolate mofetil (MMF) in a combination regimen with standard tacrolimus and corticosteroids in de novo renal transplant recipients for the composite efficacy within 6 months of transplantation.. Incidence of treated biopsy-proven acute rejection was 22.9% with FTY720 and 18.5% with MMF. Increased incidence of macular oedema, transient decrease in heart rate and low rate of infections were seen in the FTY720 arm.. FTY720 combined with tacrolimus and steroids did not show a significant therapeutic advantage over MMF for the prevention of acute rejection in de novo renal transplant recipients.

Topics: Adolescent; Adult; Aged; Cyclosporine; Drug Therapy, Combination; Female; Fingolimod Hydrochloride; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Propylene Glycols; Sphingosine; Survival Rate; Tacrolimus; Young Adult

We conducted the first prospective, randomized, open-label multicenter study in low-immunologic risk adult recipients of primary cadaver kidney transplants receiving rabbit anti-T-lymphocyte globulin, mycophenolate mofetil, cyclosporine microemulsion introduced on day 5, with and without corticosteroids. Patients were randomly assigned according to age and cold ischemia time to receive corticosteroids for at least 6 months or no corticosteroids at all. The main efficacy evaluation criterion was acute rejection (including all treated episodes and those biopsy-confirmed) during the first year following transplantation. For this purpose, this report includes the actual results of the whole 12-month follow-up of all randomized patients. For efficacy analysis, 98 patients were evaluated in the Steroid avoidance group and 99 in the Steroid maintenance group. Taken as a whole, 81% of the patients (n = 159) never received anti-rejection treatment. From the 38 patients who received anti-rejection treatment, 25 (25.5%) were in the Steroid avoidance group and 13 (13.1%) in the Steroid maintenance group (P < 0.031), experiencing respectively 17 (17.3%) and 7 (7.1%) biopsy-proven first episodes of acute rejection (P < 0.031). Borderline changes (6 vs. 3) were not considered as biopsy-proven acute rejections. Onset of first rejection was significantly shorter in the Steroid avoidance group (P < 0.027). First-line anti-rejection treatment response, need for any rescue therapy, as well as histologic severity of rejection episodes did not statistically differ between the groups. One-year post-transplantation analysis showed no differences in delayed graft function, serum creatinine, creatinine clearance, 24-h proteinuria, as well as serious adverse events between the groups. De novo diabetes (P < 0.07) or dyslipidemia (P < 0.01) as well as newly diagnosed malignancies (P < 0.059) were however more frequently observed in the Steroid maintenance group. At the end of the first post-transplant year, 99% of patients in the Steroid avoidance group and 97% of patients in the Steroid maintenance group were respectively alive (P = 0.34), with respectively 95% and 93.2% of functioning kidney grafts (P = 0.62). Our results showed that total avoidance of corticosteroids from the day of transplantation was associated with a significantly increased number of clinically diagnosed and treated, and biopsy-proven acute rejections during the first year of transplantation. Nevertheless, over

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Animals; Antilymphocyte Serum; Cyclosporine; Emulsions; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Rabbits; T-Lymphocytes; Young Adult

Although cyclosporine maintenance therapy reduces the risk of acute rejection and increases short-term graft survival in renal transplant recipients, its associated nephrotoxicity increases the risk of chronic graft dysfunction. The dose that allows an optimal risk-to-benefit ratio has not been established.. This multicentre study enrolled stable renal allograft recipients receiving cyclosporine and mycophenolate mofetil without corticosteroids in their second year post-transplant. Patients were randomized to a cyclosporine dose targeted to a standard area under the concentration-time curve (AUC)(0-12 h) (usual exposure, n = 104) or 50% of the study standard AUC(0-12 h) (low exposure, n = 108) using a three-point pharmacokinetic sampling. The primary endpoint was the percentage of patients with treatment failure at 24 months (graft loss/acute rejection/nephrotoxicity/>15% serum creatinine level increase).. Treatment failure was reported in 37 out of 101 (37%) patients in the usual-exposure and 19 out of 106 (18%) patients in the low-exposure groups (P = 0.003). Mean estimated glomerular filtration rate decreased from baseline to 2 years with usual exposure and increased with low exposure (P < 0.001). Mean systolic and diastolic blood pressures were lower with low exposure (P = 0.03 and P = 0.008, respectively).. In renal transplant recipients receiving maintenance therapy without corticosteroids, a minimization strategy using three-point pharmacokinetic sampling to reduce and maintain cyclosporine exposure to 50% of the usual levels is safe and reduces the risk of graft dysfunction.

Topics: Adolescent; Adult; Aged; Area Under Curve; Cadaver; Creatinine; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Survival Rate; Tissue Distribution; Tissue Donors; Treatment Outcome; Young Adult

De novo sirolimus in calcineurin inhibitor-free regimens, although potentially useful to improve early renal function, are complicated by various drug-related side effects.. We report a prospective open-label, multicenter, randomized trial to evaluate early conversion from a CsA-based to a sirolimus (SRL)-based regimen 10 to 24 days after renal transplantation. Of the 196 patients, 141 patients with a low-to-moderate immunological risk were eligible to be converted to SRL or to continue CsA. All patients received antithymocyte globulin-F single-bolus induction, mycophenolate mofetil, and steroids.. The primary endpoint, renal function determined by S-creatinine and estimated glomerular filtration rate calculated by Nankivell formula at 12 months was significantly better in the SRL group (1.51+/-0.59 vs. 1.87+/-0.98 mg/dL or 64.5+/-25.2 vs. 53.4+/-18.0 mL/min/1.73 m). Patient survival, graft survival, and incidence of biopsy-proven acute rejection after conversion were not statistically different. Drug discontinuations were significantly higher in the SRL group (36.2% vs. 19.7%). Significantly, more patients in the SRL group reported acne, aphtous, and temporary hyperlipidemia, whereas cytomegalovirus viremia was significantly decreased (7.3% vs. 28.2%).. Early conversion to a calcineurin inhibitor-free regimen with SRL in combination with mycophenolate mofetil may be a useful strategy to improve renal function. The identification of appropriate candidates and safe management of SRL-related adverse events will be a key to avoid the high rate of dropouts, which currently limit the broad applicability of this protocol.

Topics: Acne Vulgaris; Adrenal Cortex Hormones; Adult; Antilymphocyte Serum; Calcineurin Inhibitors; Creatinine; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Survival; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Patient Selection; Prospective Studies; Safety; Sirolimus; Time Factors; Tissue Donors

It is reported that a conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) relieves gastrointestinal (GI) symptom burden and improves health-related quality of life (HRQoL). However, it is unclear whether renal transplant recipients using tacrolimus receive the same benefit from the conversion. In this prospective, multi-center, open-label trial, patients were categorized into two groups by their GI symptom screening. Equimolar EC-MPS (n=175) was prescribed for patients with GI burdens; those with no complaints remained on MMF (n=83). Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) were evaluated at baseline and after one month. Patients and physicians completed Overall Treatment Effect (OTE) at one month. EC-MPS-converted patients had worse GSRS and GIQLI scores at baseline than MMF-continued patients (all P<0.001). Significant improvements in GSRS and GIQLI scores were observed for EC-MPS-converted patients at one month, but MMF-continued patients showed worsened GSRS scores (all P<0.05). OTE scale indicated that EC-MPS patients improved in overall GI symptoms and HRQoL more than MMF patients did (P<0.001). In tacrolimus-treated renal transplant recipients with GI burdens, a conversion from MMF to EC-MPS improves GI-related symptoms and HRQoL.

Topics: Adolescent; Adult; Aged; Female; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Quality of Life; Surveys and Questionnaires; Tablets, Enteric-Coated; Tacrolimus

Chronic kidney disease (CKD) has emerged as a significant cause of morbidity and a risk factor for mortality after orthotopic liver transplantation (OLT). The use of calcineurin inhibitor (CNI)-based immunosuppression is an important etiologic factor for developing CKD. CNI discontinuation or minimization protocols with replacement of the CNI with non-nephrotoxic drugs, such as mycophenolate mofetil (MMF) or sirolimus (SRL), may have the potential to preserve or recover renal function.. In this prospective, randomized, single-center study with CNI discontinuation, OLT recipients with CKD (measured glomerular filtration rate [GFRm] 15-45 mL/min/1.73 m(2)) were randomized to either SRL or MMF-based immunosuppression. The main objective was to study the effect of CNI discontinuation on renal function. Secondary aims were to assess the frequency of biopsy-proven acute rejection episodes (BPAR) and adverse events (AE). Renal function was followed with GFRm using 51-Chromium EDTA clearance at baseline, 3 months, and 1 year. Patients were stratified according to baseline GFRm > versus <30 mL/min/1.73 m(2). The 25 patients were enrolled for MMF (n = 13) or SRL (n = 12). The median age at inclusion was 59 years (range, 25-66) and the median number of years after OLT was 4.4 (range, 1-13). Twenty-two patients were followed up for a year; MMF (n = 12) and SRL (n = 10).. Mean GFRm for the whole cohort (n = 25) was 31+/-8 mL/min/1.73 m(2) at baseline. After 3 months the GFRm (n = 23) increased to 40+/-10 mL/min/1.73 m(2) (P = .0001) and at 1 year 42 +/- 11 mL/min/1.73 m(2) (n = 22). There was not significant difference between the MMF and the SRL study arms. The cohort (n = 8) with baseline GFRm <30 mL showed a 63% (P = .003) increased filtration after 1 year. There was no significant difference in the frequency or severity of AE between the study arms with the exception of oral ulcerations and persistent hypertriglyceridemia in the SRL group. Two deaths occurred, 1 in each study arm, both probably unrelated to the change in immunosuppression. There were no BPAR episodes.. CNI discontinuation and replacement with either MMF or SRL resulted in a significant improvement in renal function even in those patients with severe CKD. The protocol was effective with no acute rejection episodes. The SRL arm showed a higher frequency of oral apthous ulcerations and hypertriglyceridemia. Future studies addressing long-term renal function after CNI discontinuation are needed.

Topics: Adult; Antihypertensive Agents; Calcineurin Inhibitors; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Liver Transplantation; Mycophenolic Acid; Prospective Studies; Sirolimus

Calcineurin-inhibitor-(CNI)-induced renal failure is one major cause of morbidity in cardiac transplantation (HTx). In this prospective, randomized, multicenter trial, the impact of immunosuppressive conversion toward CNI-free (mycophenolate mofetil [MMF] and sirolimus) or a CNI-reduced immunosuppressive regimen on renal function, efficacy, and safety was evaluated.. Since 2004, 63 HTx-patients (0.5-18.4 years after HTx) with CNI-based immunosuppression and reduced creatinine clearance less than 60 mL/min (39+/-15 mL/min) were included in this trial. Patients in the CNI-free-Group (group 1) were converted to sirolimus that was started with 2 mg/day until target trough levels (8-14 ng/mL) were achieved. Subsequently, CNIs were withdrawn. In CNI-reduction-Group (group 2), CNI target trough levels were reduced by 40%. In both groups MMF was continued and trough level adjusted (1.5-4 microg/mL).. Patients demographics and survival (mean follow-up time: 16.7+/-9 months) was equal (100%). Renal function improved significantly after complete CNI withdrawal while remaining unchanged with CNI-reduction (Creatinine clearance after 12 months: 53+/-24 mg/dL [group 1] vs. 38+/-20 mg/dL [group 2], P=0.01). End-stage renal failure (hemodialysis) was avoided by CNI-withdrawal and occurred only after CNI reduction (n=6; P=0.01). Acute rejection episodes were more common in group 2 (4 vs. 2). Graft function remained stable (echocardiography) within both groups. Adverse events were more common in group 1 (65%) than in group 2 (n=40%) and were responsible for discontinuation in 4 and 0 cases, respectively.. Conversion toward a CNI-free immunosuppression (Mycophenolate, sirolimus) is superior to CNI-reduced immunosuppression in improving renal failure in late HTx-recipients. However, this benefit is relativized by the increased incidence and severity of sirolimus/MMF-associated side effects.

Topics: Adult; Aged; Calcineurin Inhibitors; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Mycophenolic Acid; Patient Selection; Sirolimus

Chronic kidney disease is frequent in patients after orthotopic liver transplantation (OLT) and has impact on survival. Patients receiving calcineurin inhibitors (CNI) are at increased risk to develop impaired renal function. Early CNI reduction and concomitant use of mycophenolat mofetil (MMF) has been shown to improve renal function.. The aim of this trial was to compare dose-reduced CNI/MMF versus CNI-free MMF/prednisone-based treatment in stable patients after OLT with respect to glomerular filtration rate (GFR). 21 patients (GFR 44.9 ' 9.9 mL/min/1.73m2 measured by 99m-Tc-DTPA-clearance, serum creatinine (SCr) 1.5 ' 0.42 mg/dL) were randomized either to exchange CNI for 10 mg prednisone (group 1; n = 8) or to receive CNI at 25% of the initial dose (group 2; n = 13) each in combination with 1000 mg MMF b.i.d.. At month 12 mean SCr (-0.3 ' 0.4 mg/dL, p = 0.031) and GFR improved (8.6 ' 13.1 mL/min/ 1.73m superset2, p = 0.015) in group 2 but remained unchanged in group 1. Main side effects were gastroinstestinal symptoms (14.3%) and infections (4.8%). Two biopsy proven, steroid-responsive rejections occurred. In group 1 mean diastolic blood pressure (BP) increased by 11 ' 22 mmHg (p = 0.03).. Reduced dose CNI in combination with MMF but not CNI-free-immunosuppression leads to improvement of GFR in patients with moderately elevated SCr levels after OLT. Addition of steroids resulted in increased diastolic blood pressure presumably counterbalancing the benefits of CNI withdrawal on renal function.

Topics: Alanine Transaminase; Calcineurin Inhibitors; Creatinine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Glucocorticoids; Humans; Immunosuppression Therapy; Kidney; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisone

Increasing long-term allograft survival is the main challenge in organ transplantation, and allograft loss due to chronic rejection has been found to correlate with episodes of early acute rejection. It is important to understand the mechanisms that maintain the donor-specific hyporesponsive state. This study prospectively evaluates immune events related to donor-specific hyporesponsiveness in the stable transplant patients on calcineurin inhibitors (CNIs).. Peripheral blood mononuclear cells of transplant recipients on CNI (n=19) were tested in mixed lymphocyte reaction (MLR) against donor and third-party peripheral blood mononuclear cells pretransplant and at 6 to 8 weeks, 14 to 18 weeks, and 6 to 8 months posttransplant. Interleukin (IL)-10 and transforming growth factor-beta were quantitated in cultures supernatants by enzyme-linked immunosorbent assay. CD4CD25 T-regulatory cells (Tregs) were enumerated using flow cytometry.. All patients showed sharp decline in anti-donor and third-party MLR response at 6 to 8 weeks posttransplant with progressive decline up to 6 to 8 months. This was accompanied by increased IL-10 levels in the supernatant at all the follow-ups. Transforming growth factor-beta level in the supernatant was significantly lower at 14 to 18 weeks. Frequency of CD4CD25 Tregs showed a significant decrease at 6 to 8 weeks posttransplant, which was sustained up to 6 to 8 months.. The study shows that the maintenance of good graft function in early posttransplant period in recipients on CNI is associated with a decrease in donor-specific and third-party MLRs. There is a decline in Treg numbers along with increased IL-10 levels. High IL-10, probably from a non-Tregs source, may have an important role in maintaining hyporesponsiveness and good graft function.

Topics: Adult; Calcineurin Inhibitors; Cell Proliferation; Cells, Cultured; Cyclosporine; Drug Therapy, Combination; Enzyme Inhibitors; Everolimus; Female; Graft Survival; Humans; Immunosuppressive Agents; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Count; Lymphocyte Culture Test, Mixed; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Prospective Studies; Sirolimus; T-Lymphocytes, Regulatory; Tacrolimus; Time Factors; Transforming Growth Factor beta; Transplantation Tolerance; Up-Regulation; Young Adult

Cytomegalovirus (CMV) infection is a major complication after renal transplantation and is involved in graft rejection. The anti-interleukin-2-receptor antibody daclizumab reduces the incidence of acute rejection without increasing the incidence of CMV infection.. This multicentre, randomized trial compared safety and efficacy, at 1 year, of two doses of daclizumab (54 patients, group D) with thymoglobulin (55 patients, group T) plus delayed cyclosporine (CsA), MMF (mycophenolate mofetil) and steroids in first cadaver kidney transplant patients. Primary criterion was CMV infection/syndrome/disease. D+/R- patients received oral ganciclovir prophylaxis for 90 days.. Status for CMV was identical in the both groups. The incidence of CMV infection/syndrome/disease was 39% in group D versus 51% in group T (NS). Time to onset of CMV replication was delayed in group D (P = 0.015) and mean number of pp65-positive cells was lower at 4 and 6 months (P < 0.001). Incidence of symptomatic CMV episodes was not reduced in whole group D (5.6% versus 16.4%, NS), but lower in D+/R+ and D-/R+ patients without chemoprophylaxis, compared to group T (2.8% versus 21.6%, P = 0.028). Patient and graft survivals and incidence of biopsy-proven acute rejection were identical.. Limited dosing regimen of daclizumab with MMF, steroids and delayed CsA introduction was safe and effective. The incidence of CMV infection was not significantly different, but without chemoprophylaxis, clinical manifestations and viral replication were reduced with this regimen.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Cyclosporine; Cytomegalovirus Infections; Daclizumab; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Reference Values; Treatment Outcome

Calcineurin inhibitor (CNI)-related nephrotoxicity significantly contributes to chronic renal failure after liver transplantation.. In this prospective study, liver transplantation patients with renal dysfunction were randomized either to receive mycophenolate mofetil (MMF) followed by stepwise reduction of CNI with defined minimal CNI-trough levels (MMF group), or to continue their maintenance CNI dose (control group). Immune monitoring was performed in a subgroup of the patients.. In the MMF group (n = 50), renal function assessed by serum creatinine improved >10% in 62% of patients, was stable in 36% and deteriorated >10% in 2% after 12 months compared with baseline values. Mean serum creatinine levels (+/- s.d.) significantly decreased from 1.90 +/- 0.44 mg/dL to 1.61 +/- 0.39 mg/dL and the corresponding calculated glomerular filtration rate significantly increased from 38.8 +/- 9.6 mL/min/1.73 m(2) to 47.0 +/- 11.8 mL/min/1.73 m(2) over a 12-month follow-up period. Blood pressure and levels of liver enzymes significantly decreased. In the control group (n = 25), there were no significant changes with respect to the investigated parameters. The MMF group had significantly lower numbers of circulating cytotoxic T cells compared with the controls; whereas regulatory T cells significantly increased.. Combined MMF and minimal dose CNI therapy after liver transplantation is nephroprotective and may promote allograft tolerance.

Topics: Adult; Aged; Calcineurin Inhibitors; Cardiovascular Diseases; Creatinine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Risk Factors

Mycophenolate sodium (MPS) was designed to reduce the gastrointestinal side effects of mycophenolic acid. The aim of our study was to determine the safety and efficacy of MPS in de novo renal transplant recipients.. This 6-month, multicenter, open-label, single-arm, prospective study was carried out in three centers in Poland. Thirty patients were recruited. Immunosuppressive regimen contained of MPS and cyclosporine (CsA) with or without steroids.. The 6-month graft and patient survival was 100%. The incidence of suspected acute rejection episodes (ARE) was 5/30 (16.7%), including biopsy-proven ARE in 2 (6.7%) cases. ARE reversed after therapy. At month 6, the mean serum creatinine level was 1.4 mg/dL, and the mean creatinine clearance (according to the Cockroft-Gault formula) was >70 mL/min. The most frequent adverse effects included diarrhea, delayed graft function, anemia, and lymphocele. Among infections, most common were infections of urinary tract, cytomegalovirus infections, and infections of respiratory tract. Only three patients (10.0%) terminated the study prematurely, including two who discontinuated because of an adverse event, and one because of noncompliance.. An immunosuppressive regimen, including MPS and CsA, with or without steroids, provided effective antirejecton prophylaxis and was well tolerated.

Topics: Adult; Creatinine; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Isoantibodies; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Reoperation; Safety

Enteric-coated mycophenolate sodium is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying MPA release until the small intestine.. Two studies were undertaken to identify the absolute bioavailability and dose-proportionality of enteric-coated mycophenolate sodium in stable renal transplant patients receiving cyclosporine.. Study 1: The mean MPA AUC(0-t) was shown to be greater after MPA infusion than after oral enteric-coated mycophenolate sodium (42.1 vs. 28.9 microg x h/ml). Mean absolute bioavailability was 0.71 +/- 0.21 (SD). Study 2: The AUC(0-t) and C(max) for MPA were proportional to the dose of enteric-coated mycophenolate sodium, similarly mean AUC(0-infinity) and C(max) for MPA glucuronide were proportional to dose administered.. In patients receiving cyclosporine the absolute bioavailability of MPA provided by enteric-coated mycophenolate sodium is equivalent to that provided by mycophenolate mofetil when administered in combination with cyclosporine, and exhibits dose-proportionality. Enteric-coated mycophenolate sodium was well tolerated from 180 - 2,160 mg with no serious adverse events reported.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Biological Availability; Cross-Over Studies; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glucuronides; Half-Life; Humans; Immunosuppressive Agents; Injections, Intravenous; Intestinal Absorption; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tablets, Enteric-Coated

The purpose of this study was to evaluate the effects of the conversion from azathioprine (AZA) to mycophenolate mofetil (MMF) followed by calcineurin inhibitor (CNI) elimination or minimization in patients with progressive chronic allograft dysfunction (CAD).. Between November 6, 1999 and February 12, 2003, 169 patients receiving CNI/AZA/prednisone (153 CsA; 14 tacrolimus) were included in this study. Demographics, immunosuppression, graft function, hematology, and biochemistry were obtained before (-6, -3, and -1 month) and 1, 3, 6, 9 and 12 months after and at last follow-up visit after conversion.. Mean age was 34 +/- 12 years, 66% males, 51% Caucasian, and 72% living allograft recipients. Mean follow-up times before and after conversion were 32.4 and 19.4 months; 10 patients completed 3 years of follow-up. CNI elimination was performed in 39% and minimization in 61% of patients. Overall there was significantly improved graft function at 1 year after conversion (2.6 +/- 1.0 vs 2.1 +/- 0.6 mg/dL, P = .038). The slopes of the regression lines of 1/Cr vs time were significantly improved from preconversion to after conversion (-0.026 vs +0.007 mg(-1)/dL per day(-1), P = .001). There was a significant decrease in mean systolic (141 +/- 21 vs 135 +/- 22 mm Hg, P = .015) and diastolic (89 +/- 15 vs 84 +/- 14 mm Hg, P = .005) blood pressure values at 1 year. There were four episodes of acute rejection (Banff IA) treated with steroids. Three years after conversion, patient and graft survivals were 95% and 79%, respectively. One patient developed posttransplant lymphoproliferative disease.. Among patients with CAD, conversion from AZA to MMF followed by CNI minimization or elimination was a safe and effective strategy to preserve or improve graft function.

Topics: Adult; Azathioprine; Chronic Disease; Ethnicity; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Time Factors; Transplantation, Homologous

The purpose of the study was to introduce mycophenolate mofetil (MMF) in liver transplant recipients with renal dysfunction to decrease calcineurin inhibitor (CNI) dosages without increasing rejection risk. In this prospective, multicenter, randomized study, chronic CNI-related renal dysfunction was defined by an increase in serum creatinine with values >140 micromol/L and <300 micromol/L. Patients were randomized in 2 groups.. combination of MMF (2 to 3 g/day) and reduced dose of CNI >or=50% of initial dose; control group: no MMF, but with the ability to reduce CNI doses, but not below 75% of initial dose. Fifty-six patients were included, 27 in the study group and 29 in the control group. In the study group, there was a significant decrease in serum creatinine values, from 171.7 +/- 24.2 micromol/L at day 0 to 143.4 +/- 19 micromol/L at month 12 and a significant increase in creatinine clearance, from 42.6 +/- 10.9 mL/min to 51.7 +/- 13.8 mL/min. No rejection episode was observed in the study group. In the control group, there was no improvement of renal function, assessed by the changes in serum creatinine values, from 175.4 +/- 23.4 micromol/L at day 0 to 181.6 +/- 63 micromol/L at month 12, and in creatinine clearance, from 42.8 +/- 12.8 mL/min to 44.8 +/- 19.7 mL/min. The differences between the 2 groups were significant: P = 0.001 for serum creatinine, and P = 0.04 for creatinine clearance. In conclusion, the introduction of MMF combined with the reduction of at least 50% of CNI dose allowed the renal function of liver transplant recipients to significantly improve at 1 year, without any rejection episode and without significant secondary effects.

Topics: Aged; Calcineurin Inhibitors; Creatinine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications

We characterized the pharmacokinetics of tacrolimus and everolimus in a combined immunosuppressive regimen.. This was an open-label exploratory trial in eight maintenance renal transplant patients with calcineurin inhibitor intolerance initially receiving mycophenolate mofetil (MMF) and tacrolimus. At enrollment, MMF was discontinued and replaced with everolimus 1.5 mg twice a day in study period 1 (days 1 to 10). In period 2 (day 11 to month 3), tacrolimus dose was reduced by half.. At study entry tacrolimus trough level (C0) was 7.9 +/- 3.9 ng/mL and area under the curve over a dosing interval (AUC) was 132 +/- 56 ng x h/mL. The addition of everolimus in period 1 did not change tacrolimus exposure: C0 8.4 +/- 4.0 ng/mL, AUC 134 +/- 70 ng x h/mL. Everolimus pharmacokinetics in the presence of tacrolimus in period 1 were: C0 3.3 +/- 1.2 ng/mL, Cmax 10.4 +/- 5.1 ng/mL, AUC 58 +/- 20 ng x h/mL. When compared to pharmacokinetic data from a previous study in 47 renal transplant patients receiving everolimus at the same fixed dose (1.5 mg twice a day) with cyclosporine, everolimus exposure was 2.5-fold higher with cyclosporine relative to the data in this study with tacrolimus. After tacrolimus dose reduction in period 2, there was no clinically relevant change in everolimus exposure: C0 3.0 +/- 1.1 ng/mL, Cmax 8.2 +/- 1.3 ng/mL, AUC 49 +/- 10 ng x h/mL.. Tacrolimus appears to have a minimal effect on everolimus blood levels compared with the influence of cyclosporine. The dose of everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine in order to reach a given everolimus blood level.

Topics: Adrenal Cortex Hormones; Adult; Aged; Area Under Curve; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Everolimus; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus

Mycophenolate mofetil (MMF) and the sequential use of cyclophosphamide followed by azathioprine (CTX-AZA) demonstrate similar short-term efficacy in the treatment of diffuse proliferative lupus nephritis (DPLN), but MMF is associated with less drug toxicity. Results from an extended long-term study, with median follow-up of 63 mo, that investigated the role of MMF as continuous induction-maintenance treatment for DPLN are presented. Thirty-three patients were randomized to receive MMF, and 31 were randomized to the CTX-AZA treatment arm, both in combination with prednisolone. More than 90% in each group responded favorably (complete or partial remission) to induction treatment. Serum creatinine in both groups remained stable and comparable over time. Creatinine clearance increased significantly in the MMF group, but the between-group difference was insignificant. Improvements in serology and proteinuria were comparable between the two groups. A total of 6.3% in the MMF group and 10.0% of CTX-AZA-treated patients showed doubling of baseline creatinine during follow-up (P = 0.667). Both the relapse-free survival and the hazard ratio for relapse were similar between MMF- and CTX-AZA-treated patients (11 and nine patients relapsed, respectively) and between those with MMF treatment for 12 or >/=24 mo. MMF treatment was associated with fewer infections and infections that required hospitalization (P = 0.013 and 0.014, respectively). Four patients in the CTX-AZA group but none in the MMF group reached the composite end point of end-stage renal failure or death (P = 0.062 by survival analysis). It is concluded that MMF and prednisolone constitute an effective continuous induction-maintenance treatment for DPLN in Chinese patients.

Topics: Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Cyclophosphamide; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Incidence; Kidney; Kidney Failure, Chronic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Recurrence; Remission Induction; Survival Analysis; Time Factors

This report examines the early and late secondary effects of tacrolimus, cyclosporin microemulsion (ME), mycophenolate mofetil (MMF) and rabbit anti-thymocyte globulin (rATG) in simultaneous pancreas-kidney (SPK) recipients.. Of the 205 patients participating in the Euro-SPK 001 study, 103 were randomized to tacrolimus (0.2 mg/kg) and 102 to cyclosporin-ME (7 mg/kg). All patients received rATG for 4 days [ATG-Fresenius (ATG-F) 4 mg/kg/day or Thymoglobulin (Thymo-S) 1.25 mg/kg/day] plus MMF and short-term corticosteroids.. Thymo-S induction therapy was associated with a lower white cell count in the first 3 months than was seen with ATG-F, while ATG-F caused a lower initial nadir in platelet count. Both polyclonal preparations were well tolerated and no clinically relevant differences were observed with respect to side effects such as infections and malignancies. High cyclosporin-ME trough levels were associated with pancreas graft thrombosis, and concentrations >150 ng/ml were associated with poor renal allograft function. Treatment discontinuation was higher with cyclosporin-ME (57.8%) than with tacrolimus-based therapy (36.9%) due to more frequent toxicity, graft loss and lack of efficacy requiring a switch to tacrolimus. The main reason for withdrawal in the tacrolimus group was MMF discontinuation; MMF-related side effects resulted in more frequent dose reductions to <2 g/day and discontinuations in the tacrolimus group, and indirectly indicate a higher dose-corrected exposure to mycophenolic acid, as previously observed in kidney transplant patients.. Short-term induction therapy is effective and well tolerated in patients undergoing SPK transplantation. Tacrolimus was the preferred immunosuppressive agent, resulting in fewer cases of pancreas graft loss and drug discontinuation compared with cyclosporin-ME.

Topics: Antilymphocyte Serum; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug Tolerance; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukocyte Count; Mycophenolic Acid; Pancreas Transplantation; Tacrolimus; Time Factors; Treatment Outcome

Simultaneous pancreas-kidney (SPK) transplantation is the treatment of choice for selected diabetic patients. Corticosteroids are an important element of immunosuppressive protocols, but their long-term use has detrimental effects on patients' health, necessitating eventual discontinuation.. This prospective study evaluated the safety and feasibility of corticosteroid withdrawal in 205 SPK transplant recipients randomized to immunosuppressive treatment with either tacrolimus and mycophenolate mofetil (MMF) (n = 103) or cyclosporin microemulsion (ME) and MMF (n = 102).. Corticosteroid withdrawal was successful in the majority of in-study patients (66% tacrolimus, 73% cyclosporin-ME). Compared with out-of-study patients or those continuing corticosteroid therapy, in-study patients withdrawn from corticosteroids experienced fewer pancreas or kidney graft losses, fewer episodes of acute rejection and were less likely to be withdrawn from the study. Acute rejection occurred after corticosteroid withdrawal in two patients who had a previous rejection and in five patients who were rejection-free before corticosteroid withdrawal. No rejection episodes were associated with graft loss or immediate serious consequences. Overall, corticosteroid withdrawal was achieved with an increase in the dose of both MMF and tacrolimus.. A long-term survey of corticosteroid withdrawal in SPK transplantation with multifactorial analyses is necessary to confirm these early results and to evaluate the positive effects on glucose metabolism and hypertension.

Topics: Biopsy; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Europe; Feasibility Studies; Follow-Up Studies; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Israel; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Pancreas Transplantation; Prospective Studies; Safety; Tacrolimus; Time Factors; Treatment Outcome; Withholding Treatment

Effect of early steroid withdrawal protocol using basiliximab in kidney transplantation (KTx) on the clinical outcomes was investigated as compared with triple regimen.. Kidney transplant patients in group 1 (n = 62) were treated with 8 mg/kg of cyclosporine (CsA), 2000 mg of MMF, two bolus IV injections of 20 mg of basiliximab and 500 mg of methylprednisolone (MP) rapidly tapered and withdrawn at 14 postoperative days (POD). Group 2 (n = 56) was treated with same dose of CsA and MMF, and 250 mg of MP tapered and continued. Acute rejection (AR) episodes were treated with MP pulse therapy followed by muromonab CD3 (OKT3) in case of steroid-resistant rejection.. In 46 of 62 cases (74.2%) in group 1, steroid was successfully withdrawn at 13.7 +/- 1.7 POD. Graft survival at 3, 6, and 12 months in group 1 was 100%, 100%, and 98.4% (one death with functioning graft), and 100%, 98.2%, and 96.4% in group 2, respectively. The incidence of AR was 12.9% for group 1 and 42.9% for group 2, among which 21 cases in group 2 were treated with ALG or OKT3; no patient needed ALG or OKT3 in group 1. Fifteen cases in group 1 and 13 cases in group 2 developed CMV antigenemia, among which febrile episode was exhibited in 3 cases (4.8%) in group 1 and 5 cases (8.9%) in group 2.. Early steroid withdrawal protocol using basiliximab is promising for reducing the incidence of AR (especially steroid-resistant rejection), CMV diseases, and steroid-related complications.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Cadaver; Calcineurin; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Muromonab-CD3; Mycophenolic Acid; Recombinant Fusion Proteins; Tissue Donors; Treatment Outcome

Maintenance immunosuppression with cyclosporine (CsA) is associated with nephrotoxicity, hyperlipidemia, and hypertension. This long-term study (core study + 4 yr of follow-up) investigated the long-term efficacy and safety of CsA withdrawal from a mycophenolate mofetil (MMF)-based regimen. Seventy-seven patients were maintained on CsA, MMF, and steroids (CsA-MMF group), and 74 were given a CsA-free regimen of MMF and steroids (MMF group). Serum creatinine and creatinine clearance were measured at 6-month intervals. Patient and graft survival, acute rejection episodes, malignancies, BP, and lipid profile were also recorded. At 5 yr, patient and graft survival was 93 and 88%, respectively, for the MMF group and 95 and 92%, respectively, for the CsA-MMF group. During follow-up, seven MMF patients experienced acute rejection episodes compared with one CsA-MMF patient (P = 0.0283). Nine grafts were lost to chronic rejection in the MMF group versus three in the CsA-MMF group. No demographic or immunologic characteristics were associated with acute or chronic rejection in the MMF group, but the doses of both MMF and steroids decreased significantly between 1 and 5 yr. The MMF group showed a trend toward improved creatinine clearance (67.4 versus 61.7 ml/min; P = 0.0500). Withdrawal of CsA from an MMF-containing immunosuppressive regimen resulted in an increased risk for acute rejection episodes and graft loss as a result of rejection throughout the 5-yr study period. The creatinine clearance-confirmed improvement in renal function observed at year 1 was maintained at 5 yr BP and cholesterol levels were well controlled in both groups.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Cyclosporine; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prospective Studies; Treatment Outcome; Withholding Treatment

We conducted a study to assess the safety of staged, late steroid withdrawal in kidney or kidney/pancreas transplant recipients on steroids, tacrolimus, and mycophenolate mofetil (MMF).. We studied 50 patients including 33 recipients of cadaveric kidneys, eight living donor kidneys, and nine kidney-pancreas transplants. The mean time posttransplantation was 5.1 years (range 2.1 to 7.9 years). All patients were induced on prednisolone, tacrolimus, and MMF; steroids were withdrawn over 5 to 6 months. The rate of steroid reduction was altered in the face of typical steroid withdrawal symptoms (limb-girdle arthralgia/myalgia).. No rejection episodes occurred during steroid withdrawal. No patient required transplant biopsy for graft dysfunction. Six patients failed steroid withdrawal: five due to arthralgia/myalgia and one due to recurrent pulmonary sarcoidosis. The unexplained rise in serum creatinine following steroid withdrawal described in several other steroid withdrawal studies was not observed in this patient cohort. The mean serum creatinine was 137 micromol/L with deltacreatinine -6.8 micromol/y per year prior to steroid cessation versus 132 micromol/L with deltacreatinine -5.9 micromol/y in the year post-steroid cessation. There were 14 patients with posttransplant diabetes mellitus in this cohort: eight on gliclazide and six on insulin. We observed a reduction in their daily insulin/gliclazide requirements from 52 units to 41 units, and 73 mg to 65 mg, respectively. Two patients became gliclazide-independent at the time of steroid cessation.. Careful steroid withdrawal from a platform of tacrolimus and MMF is safe and not associated with a significant risk of rejection or graft dysfunction.

Topics: Adult; Creatinine; Drug Administration Schedule; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucocorticoids; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Safety; Tacrolimus; Time Factors

IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Up to 40% progress to end-stage renal disease (ESRD) over 10-20 years. Currently, treatment is limited. We studied the use of mycophenolate mofetil (MMF) vs placebo in a group of North American IgAN patients at high risk for progressive disease.. Included were 32 patients aged 18-75 years from multiple centres who had their biopsies read at Columbia and who had at least 1 g of proteinuria per day plus at least two of the following risk factors: (i) male sex; (ii) hypertension >150/90 mmHg or requiring antihypertensive medications; (iii) creatinine clearance, measured by 24 h urine collection, <80 and >20 ml/min at time of enrolment; and (iv) presence of glomerulosclerosis or tubulointerstitial atrophy and fibrosis on renal biopsy. Patients were randomized to either 1 year of MMF, titrated up to a dose of 1000 mg bid, or placebo. Total follow-up was 2 years. All patients received angiotensin inhibition medication. The primary outcome was a 50% increase in baseline serum creatinine (SCr). Secondary outcomes were an increase of 0.5 mg/dl SCr, ESRD and a 50% reduction in proteinuria.. The mean baseline SCr was 2.4 mg/dl. No statistically significant differences were observed for any outcome. Five of 17 who received MMF vs two of 15 patients in the placebo group reached a 50% increase in SCr (P = 0.4). In both groups, all patients who reached the primary outcome also reached ESRD. Ten who received MMF vs seven who received placebo had a 0.5 mg/dl increase in SCr (P = 0.7) Only three MMF and two placebo patients had a 50% reduction in 24 h proteinuria. No serious adverse events occurred in either group.. No benefit was seen in patients who received MMF in this high risk group, probably reflecting the relatively advanced stage of disease of our population. We conclude that MMF is probably not effective in patients with IgAN who already have moderate renal insufficiency.

Topics: Adult; Aged; Creatinine; Double-Blind Method; Female; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Risk Factors

The side effects associated with corticosteroids have led to efforts to minimize their use in renal transplant patients. In this study we compared two corticosteroid-free tacrolimus-based regimens with a standard triple therapy.. This was a 6-month, phase III, open-label, parallel-group, multicenter study. The total analysis set comprised 451 patients, randomized (1:1:1) to receive tacrolimus (Tac) monotherapy following basiliximab (Bas) administration (n=153), Tac/mycophenolate mofetil (MMF) (n=151), or, Tac/MMF/corticosteroids triple therapy as a control (n=147).. The study was completed by 91.2% (triple therapy), 94.7% (Tac/MMF), and 82.4% (Bas/Tac) of patients. Patient baseline characteristics were similar in all groups. The incidences of biopsy-proven acute rejection were 8.2% (triple therapy), 30.5% (Tac/MMF), and 26.1% (Bas/Tac), p<0.001 (multiple test for comparison with triple therapy); Bas/Tac vs. Tac/MMF, p=ns. The incidences of corticosteroid-resistant acute rejection were 2.0%, 4.0%, and 5.2%, p=ns. Graft survival (95.9%, 96.7%, and 94.7%, p=ns) and patient survival (100%, 99.3%, and 99.3%, p=ns) were similar in all groups. Median serum creatinine at month 6 was 123.0 micromol/L (triple therapy), 134.7 micromol/L (Tac/MMF) and 135.8 micromol/L (Bas/Tac). The overall safety profiles were similar; differences (p<0.05) were reported for anaemia (24.5% vs. 12.6% vs. 14.5%), diarrhoea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple therapy, Tac/MMF, and Bas/Tac group, respectively. The incidences of new-onset diabetes mellitus were 4.6%, 7.1%, and 1.4%, respectively.. Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal; Basiliximab; Drug Administration Schedule; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Survival Analysis; Tacrolimus; Treatment Failure; Treatment Outcome

Long-term therapy with cyclophosphamide enhances renal survival in patients with proliferative lupus nephritis; however, the beneficial effect of cyclophosphamide must be weighed against its considerable toxic effects.. Fifty-nine patients with lupus nephritis (12 in World Health Organization class III, 46 in class IV, and 1 in class Vb) received induction therapy consisting of a maximum of seven monthly boluses of intravenous cyclophosphamide (0.5 to 1.0 g per square meter of body-surface area) plus corticosteroids. Subsequently, the patients were randomly assigned to one of three maintenance therapies: quarterly intravenous injections of cyclophosphamide, oral azathioprine (1 to 3 mg per kilogram of body weight per day), or oral mycophenolate mofetil (500 to 3000 mg per day) for one to three years. The base-line characteristics of the three groups were similar, with the exception that the chronicity index was 1.9 points lower in the cyclophosphamide group than in the mycophenolate mofetil group (P=0.009).. During maintenance therapy, five patients died (four in the cyclophosphamide group and one in the mycophenolate mofetil group), and chronic renal failure developed in five (three in the cyclophosphamide group and one each in the azathioprine and mycophenolate mofetil groups). The 72-month event-free survival rate for the composite end point of death or chronic renal failure was higher in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group (P=0.05 and P=0.009, respectively). The rate of relapse-free survival was higher in the mycophenolate mofetil group than in the cyclophosphamide group (P=0.02). The incidence of hospitalization, amenorrhea, infections, nausea, and vomiting was significantly lower in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group.. For patients with proliferative lupus nephritis, short-term therapy with intravenous cyclophosphamide followed by maintenance therapy with mycophenolate mofetil or azathioprine appears to be more efficacious and safer than long-term therapy with intravenous cyclophosphamide.

Topics: Adult; Amenorrhea; Azathioprine; Cyclophosphamide; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infections; Infusions, Intravenous; Kidney Failure, Chronic; Lupus Nephritis; Male; Mycophenolic Acid; Prednisone; Recurrence; Remission Induction; Survival Analysis

Calcineurin inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this prospective study was to evaluate the safety and efficacy of a completely CNI-free immunosuppressive regimen [mycophenolate mofetil (MMF) and sirolimus (Sir)] in HTx-recipients with late post-transplant renal impairment.. Since 2001, 30 HTx-patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine >1.9 mg/dl were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Conversion was started with 6 mg Sir or 500 mg MMF according to the pre-existing regimen and was continued with the dose adjusted to achieve target trough levels between 8 and 14 ng/ml (Sir) or 1.5 and 4 microg/ml (mycophenolate). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up included endomyocardial biopsies, echocardiography and laboratory studies. Additionally, every HTx-patient treated at our centre between 1996 and 2001 due to chronic renal failure without immunosuppressive conversion and fulfilling the inclusion criteria were retrospectively analysed and acted as control group.. Patient demographics and 1-year survival [93 (conversion) vs 90% (control)] were compared. No acute rejection episode was detected in either group. Renal function improved significantly in the conversion group (creatinine: 3.18+/-0.71 vs 2.22+/-0.79 mg/dl, P=0.001; cystatin pre- vs post-conversion: 2.95+/-1.06 vs 2.02+/-1.1 mg/l, P=0.01). In three patients haemodialysis therapy was stopped completely after conversion. In the control group renal impairment was deteriorating, creatinine increased from 2.44+/-0.8 to 3.28+/-1 mg/dl (P=0.01). In 10 out of 33 patients chronic haemodialysis had to be initiated within 1 year. Although side effects of CNI-free immunosuppression were common (76%), no patient had to be excluded due to adverse effects.. Conversion from CNI-based immunosuppression to MMF and Sir in HTx-patients with chronic renal failure was safe, preserved graft function and improved renal function.

Topics: Blood Pressure; Calcineurin Inhibitors; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Sirolimus

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Basiliximab; Cadaver; Cytomegalovirus Infections; Cytotoxicity, Immunologic; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Recombinant Fusion Proteins; Tissue Donors

Calcineurin-inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this study was to introduce a CNI-free immunosuppressive regimen to HTx recipients with late posttransplant renal impairment and to evaluate the impact of conversion to this new immunosuppression (mycophenolate mofetil [MMF] and sirolimus [Sir]) treatment on renal function.. Thirty-one HTx patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine greater than 1.9 mg/dL were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Mean patient age was 50+/-14 (range 19-74) years. Conversion was started with 6 mg Sir, continued with 2 mg, and the dose was adjusted to achieve target trough levels between 8 and 14 ng/mL. MMF was continued with trough level adjusted (1.5-4 microg/mL). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up (first and every 3 months after conversion) included endomyocardial biopsies, echocardiography, and laboratory studies. Survival was 90% after a mean follow-up of 13+/-95 months. No acute rejection episode was detected during the study period. Renal function improved significantly after conversion: creatinine preconversion vs. postconversion: 3.14+/-0.76 mg/dL vs. 2.14+/-0.83 mg/dL, P =0.001. Cystatin preconversion vs. postconversion: 2.95+/-1.06 mg/L vs. 2.02+/-1.1 mg/L, P =0.01. In three patients, hemodialysis therapy was stopped completely after conversion. Graft function remained stable. Fractional shortening preconversion vs. postconversion: 36.9+/-6% vs. 36.4+/-6%. There were no serious adverse events. One patient had to be excluded because of noncompliance.. Conversion from CNI-based immunosuppression to MMF and Sir in HTx patients with chronic renal failure was safe, preserved graft function, and improved renal function.

Topics: Adult; Calcineurin Inhibitors; Cardiovascular System; Dose-Response Relationship, Drug; Female; Heart; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Time Factors

This comparative prospective multi-centre study evaluated efficacy and safety of cyclosporine A downtitration in heart transplant recipients with chronic renal dysfunction potentially attributable to cyclosporine (n=161).. In the intervention arm (n=109, recruited from 9 centres), mycophenolate mofetil was introduced de novo or substituting azathioprine, followed by cyclosporine reduction (target trough levels 2-4 microg/ml and 50 ng/ml, respectively). In controls (n=52, recruited from 1 centre), immunosuppression remained unchanged. Renal function was recorded twelve, six, and three months before, and throughout the eight-month study period.. At study entry, cyclosporine trough levels and renal function parameters were comparable. At study end, mean+/-SD cyclosporine in the intervention arm was 57+/-24 vs. 116+/-36 ng/ml in controls. During the study, creatinine decreased by 23.3+/-50.7 micromol/l (P<0.0001) in the intervention arm but increased by 7.3+/-46.9 micromol/l (P=0.992) in controls (P=0.0001 for comparison between groups). A creatinine reduction of at least 20% was found in 35% of subjects of the intervention arm but only in 4% in the control arm (P<0.0001 for comparison between groups). Improvement in renal function was not weakened after adjustment for baseline characteristics in multiple regression analysis. Renal function improved in strata of creatinine entry values from 150 to 310 micromol/l, regardless of the presence of diabetes. Myocardial biopsies at target levels for cyclosporine and mycophenolate mofetil showed three reversible subclinical rejection episodes.. Cyclosporine downtitration improved renal dysfunction in diabetic and non-diabetic heart transplant recipients across a wide range of creatinine levels. The long-term benefit of this strategy deserves further study.

Topics: Cyclosporine; Female; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Treatment Outcome

Evidence suggests that steroid sparing in renal transplantation is associated with good outcomes, although there are limited data regarding steroid sparing in Tacrolimus and Mycophenolate Mofetil (MMF)-based regimes. In this study we describe the use of these agents in 101 consecutive patients undergoing renal transplantation using only a 7-day course of prednisolone. Median follow-up was 33 months (range 18-44). Patient and graft survival at 1 year were 100% and 98%, respectively. The acute rejection rate at both 6 and 12 months was 19%, with two episodes beyond 12 months. Anti-CD25 monoclonal antibody (anti-CD25 mAb) was administered to 25 patients at high immunological risk: a trend toward a lower rejection rate was seen in these patients compared with those at lower risk but not receiving induction therapy (8% vs. 22%; p = 0.11). Two patients experienced recurrent rejection. Of the twenty-three rejection episodes in total, 26% showed vascular involvement. Allograft function was preserved at 12 months with a mean creatinine of 144 micromol/L and mean estimated glomerular filtration rate (GFR) of 55 mL/min. At 12 months, the incidence of post-transplant diabetes mellitus was 3.5%. This steroid-sparing regime is associated with excellent patient and graft outcomes, and a low incidence of side effects.

Topics: Creatinine; Dose-Response Relationship, Drug; Drug Administration Schedule; Ethnicity; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Racial Groups; Recurrence; Survival Analysis; Tacrolimus; Time Factors

Corticosteroids withdrawal from immunosuppressive regimens has thus far been associated with increased risk of acute rejection episodes. In this study, basiliximab, a chimeric monoclonal interleukin-2 receptor antagonist, added to a maintenance regimen consisting of cyclosporine microemulsion and mycophenolate mofetil was studied for its effectiveness in allowing early corticosteroid withdrawal in de novo renal allograft recipients. Primary renal transplant recipients receiving basiliximab, cyclosporine-microemulsion, and mycophenolate mofetil, were randomized to either corticosteroid withdrawal at day four post-transplantation (n = 40) or standard steroid therapy (n = 43). The primary endpoint was the incidence of biopsy-proven acute rejection episodes. Randomized subjects who underwent transplantation and received at least one dose of basiliximab were analyzed in an intent-to-treat fashion. The incidence of biopsy-proven acute rejection at 12 months was not significantly different between the steroid withdrawal group (20%) and the standard treatment group (16%). Patient and graft survival was 100% in the steroid withdrawal group while one death in a patient with a functioning graft occurred in the standard steroid group. Seventy-two percent of the steroid withdrawal group remained off steroids at 6 months post-transplant. Allograft function and incidence of adverse events and infections were similar between the two groups. Rapid and early corticosteroid withdrawal among renal transplant recipients receiving basiliximab induction and daily therapy with cyclosporine-microemulsion and mycophenolate mofetil was not associated with an increased risk of acute rejection.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Basiliximab; Cyclosporine; Emulsions; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Steroids; Time Factors; Treatment Outcome

Chronic HBsAg carriers are known to have a higher risk of hepatitis-related mortality and morbidity when undergoing kidney transplantation. Immunosuppressants might flare up the infection that could be fulminating. Lamivudine and mycophenolate mofetil (MMF) have been shown to be effective in inhibiting replication of hepatitis B virus (HBV). With these two drugs, hepatitis related adverse outcome might be preventable when these patients are being transplanted. Four Chinese adolescents with chronic HBV infection were transplanted in our Department from 1999 to 2001. Immunosuppresants included prednisolone, cyclosporin A and MMF; azathioprine was not used for its potentially liver toxic effect. Prophylactic lamivudine 3 mg/kg and maximum 100 mg daily was given just before transplantation and was continued afterwards. HBV status and liver enzymes were monitored serially. Patients were followed up for 26.0 +/- 10.3 (11-34) months post-transplant and no mortality was reported. All grafts were functioning and no rejection was noted. MMF and lamivudine were well tolerated. Alanine transaminase was only transiently elevated in the first 2 months post-transplant in all patients and became normal afterwards. The patients were clinically well and liver function was normal at the last follow-up. However, HBV DNA became positive in three patients after the transplantation. YMDD mutant HBV was negative in one patient and undeterminable in the other three due to low virus load. In summary, with prophylactic lamivudine and MMF, short-term follow-up showed that renal transplant might be feasible and safe in chronic HBV carriers.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibiotic Prophylaxis; Antiviral Agents; Female; Follow-Up Studies; Hepatitis B, Chronic; Humans; Kidney Failure, Chronic; Kidney Transplantation; Lamivudine; Male; Mycophenolic Acid; Treatment Outcome

Acute graft rejection remains a major problem in renal transplant recipients, and there is no consensus on the optimal immunosuppressive strategy. Immunoprophylaxis with Thymoglobulin or basiliximab has significantly reduced the incidence of acute rejection episodes and graft loss following kidney transplantation. This open, randomized, multicenter study investigated the efficacy and tolerability of basiliximab (20mg day 0-day 4) plus early cyclosporine from day 0 (n = 50) compared with Thymoglobulin plus delayed cyclosporine (n = 50) in adult kidney transplant patients. In addition, all patients received steroids and mycophenolate mofetil (MMF) at standard doses from day 0. Patient and graft survival rates at 12 months were 98 and 94% in the basiliximab group, respectively, compared with 100 and 96% in the Thymoglobulin' group. The incidences of biopsy-confirmed acute rejection (8.0% in each group) and treatment failure (14% in the basiliximab group vs. 8% in the Thymoglobulin group) were comparable in the two groups. There was a non-significant tendency to more dialysis (14 vs. 6%), and fewer cytomegalovirus (CMV) infections (p = 0.005) in the basiliximab group, but the percentage of clinical CMV was not different between the two groups (6 vs. 12%). Both strategies give excellent results, despite the differences in patterns, in nonhyperimmunized patients receiving their first cadaveric renal allograft.

Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; France; Graft Rejection; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Racial Groups; Recombinant Fusion Proteins; Safety; Time Factors; Tissue Donors

Inducing and maintaining remission in patients with lupus nephritis may be difficult. Current treatments have significant toxicity. Mycophenolate mofetil (MMF) limits damage in murine models of lupus nephritis. We have assessed the efficacy and tolerability of MMF in the treatment of patients with long-standing or resistant lupus nephritis. We have treated 13 patients with biopsy proven lupus nephritis (two membranous nephropathy, four membranous nephropathy with superimposed proliferative changes, seven with proliferative glomerulonephritis). All patients had relapsed on conventional treatment or there were pressing indications to minimise steroid dosage or avoid alkylating agents. Nine out of 13 were treated with MMF and prednisolone, 3/10 with MMF alone and 1/10 with MMF, prednisolone and cyclosporine. Thirteen patients were treated with MMF for up to 37 months (median 25 months). Three patients were withdrawn from MMF during the first 8 months of treatment. The remainder tolerated MMF (median dose 1 g/day). Serological improvements were observed in 9/13 and steroid dosage was reduced in 8/10 patients. Infections occurred in 3/13. One patient relapsed. MMF significantly reduced the rate of decline of renal function. MMF should be considered in the treatment of long-standing or resistant lupus nephritis. Controlled clinical trials are required to confirm these findings.

Topics: Adrenal Cortex Hormones; Adult; Blood Pressure; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Lupus Nephritis; Middle Aged; Mycophenolic Acid; Patient Dropouts; Pilot Projects; Proteinuria; Severity of Illness Index; Treatment Outcome

Topics: Adult; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prednisolone; Premedication; Tacrolimus

Topics: Female; Glucocorticoids; Health Care Costs; Humans; Kidney Failure, Chronic; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pharmaceutical Preparations; Retrospective Studies; United States

To examine whether differences in tacrolimus and mycophenolic acid (MPA) pharmacokinetics contribute to the poorer kidney transplant outcomes experienced by Aboriginal Australians.. Concentration-time profiles for tacrolimus and MPA were prospectively collected from 43 kidney transplant recipients: 27 Aboriginal and 16 Caucasian. Apparent clearance (CL/F) and distribution volume (V/F) for each individual were derived from concentration-time profiles combined with population pharmacokinetic priors, with subsequent assessment for between-group difference in pharmacokinetics. In addition, population pharmacokinetic models were developed using the prospective dataset supplemented by previously developed structural models for tacrolimus and MPA. The change in NONMEM objective function was used to assess improvement in goodness of model fit.. No differences were found between Aboriginal and Caucasian groups or empirical Bayes estimates, for CL/F or V/F of MPA or tacrolimus. However, a higher prevalence of CYP3A5 expressers (26% compared with 0%) and wider between-subject variability in tacrolimus CL/F (SD = 5.00 compared with 3.25 L/h/70 kg) were observed in the Aboriginal group, though these differences failed to reach statistical significance (p = .07 and p = .08).. There were no differences in typical tacrolimus or MPA pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients. This means that Bayesian dosing tools developed to optimise tacrolimus and MPA dosing in Caucasian recipients may be applied to Aboriginal recipients. In turn, this may improve drug exposure and thereby transplant outcomes in this group. Aboriginal recipients appeared to have greater between-subject variability in tacrolimus CL/F and a higher prevalence of CYP3A5 expressers, attributes that have been linked with inferior outcomes.

Topics: Australia; Bayes Theorem; Cytochrome P-450 CYP3A; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Biological; Mycophenolic Acid; Native Hawaiian or Other Pacific Islander; Prospective Studies; Tacrolimus; Transplant Recipients; White People

BACKGROUND Pure red cell aplasia (PRCA) is an uncommon cause of anemia in end-stage kidney disease (ESKD). It is attributed to recombinant human erythropoietin (rHuEPO) administration. Although immunosuppression is the mainstay therapy, its effectiveness varies from 30% to 70%. PRCA in ESKD has been reported to improve following kidney transplantation. CASE REPORT A 46-year-old woman with ESKD secondary to lupus nephritis was treated for uremia at our center. She developed severe anemia. Bone marrow aspiration and biopsy revealed a reduction of erythroid precursors, consistent with PRCA. Because she had no sibling's blood group matched with her, ABO-incompatible kidney transplantation was an option for treatment. She underwent a desensitization protocol consisting of rituximab 375 mg/m2, tacrolimus, mycophenolate mofetil, and prednisolone 4 weeks before surgery, in addition to 3 sessions of double-filtration plasmapheresis (DFPP) every other day followed by intravenous immunoglobulin (IVIG) and 1 session of specific immunoadsorption (Glycosorb® B column) at pre-transplant day -1. She also received low-dose rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) (total 2.0 mg/kg). Maintenance therapy included tacrolimus, mycophenolate mofetil, and prednisolone. Allograft function normalized a few days after transplantation and her Hb gradually increased. CONCLUSIONS We report a rare case of PRCA in a patient with ESKD undergoing ABO-incompatible kidney transplantation. The outcome was satisfactory, with complete correction of anemia and kidney function.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Erythropoietin; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prednisolone; Red-Cell Aplasia, Pure; Renal Dialysis; Tacrolimus; Thailand

Although systemic lupus erythematosus (SLE) disease activity diminishes after starting dialysis, flares have been documented during dialysis. Hence, we studied the various clinical and therapeutic variables of patients with SLE who had a disease flare while on dialysis.. The medical records of patients with SLE who received dialysis at 2 tertiary referral hospitals in South Korea were reviewed. The disease activity was analyzed in terms of the nonrenal SLE Disease Activity Index (SLEDAI), and the factors associated with SLE flares were evaluated.. Of the total of 121 patients with SLE on dialysis, 96 (79.3%) were on hemodialysis (HD) and 25 (20.7%) were on peritoneal dialysis (PD). During a median follow-up of 45 months (IQR 23-120) after the initiation of dialysis, 32 (26.4%) patients experienced an SLE flare (HD, n = 25; PD, n = 7). The most common features of SLE flare were hematologic (40.6%; thrombocytopenia [31.2%] and leukopenia [21.8%]) and constitutional manifestations (40.6%). Fever was the most common (34.3%) feature among the constitutional symptoms. Treatments for disease flares were based on corticosteroids, and 11 (34.3%) patients required additional immunosuppressants, including cyclophosphamide and mycophenolate mofetil. Nonrenal SLEDAI score before dialysis initiation (HR 1.24, 95% CI 1.12-1.36;. More than a quarter of the patients with SLE experienced a disease flare during dialysis, which most commonly had hematologic manifestations, particularly thrombocytopenia. Continued follow-up and appropriate treatments, including immunosuppressants, should be considered for patients with SLE receiving dialysis.

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Erythematosus, Systemic; Mycophenolic Acid; Renal Dialysis; Symptom Flare Up; Thrombocytopenia

To evaluate Pneumocystis jirovecii pneumonia (PJP) infection risk in patients with systemic lupus erythematosus (SLE) in Taiwan.. We identified 24,367 patients with SLE from the National Health Insurance research database between 1997 and 2012 and compared the PJP incidence rates (IRs) with those in 243,670 age- and sex-matched non-SLE controls. PJP risk in the patients was evaluated using a Cox multivariate proportional hazards model.. The SLE patients exhibited a significantly higher PJP risk than the controls, with an IR of 2.63 per 10,000 person-years and IR ratio of 27.65 (95% confidence interval 17.2-45.3; P < 0.001). Male sex (hazard ratio [HR] 2.42, P < 0.01), end-stage renal disease (ESRD; HR 1.74, P = 0.01), recent use of mycofenolate mofetil (MMF; HR 4.43, P < 0.001), intravenous steroid pulse therapy (HR 108.73, P < 0.001), and average oral dosage of >7.5 mg/day prednisolone or equivalent treatment (HR 4.83, P < 0.001) were associated with PJP in SLE, whereas hydroxychloroquine use reduced its risk (HR 0.51, P = 0.01). Of note, cyclophosphamide was not associated with PJP infection in the multivariate Cox proportional hazard model.. Patients with SLE have a considerably high PJP risk. Cyclophosphamide does not increase PJP risk. Male sex, ESRD, MMF use, intravenous steroid pulse therapy, and oral prednisolone or equivalent treatment (>7.5 mg/day) are risk factors for PJP, whereas hydroxychloroquine use reduces PJP risk.

Topics: Cohort Studies; Cyclophosphamide; Humans; Hydroxychloroquine; Kidney Failure, Chronic; Lupus Erythematosus, Systemic; Male; Mycophenolic Acid; Pneumocystis carinii; Pneumonia, Pneumocystis; Prednisolone; Retrospective Studies; Risk Factors; Taiwan

Transplantation of African American (AA) compared to non-AA donor kidneys is generally associated with inferior outcomes. It is unclear whether enhanced genetic risk associated with AA donor kidneys would be counterbalanced by favorable immunologic matching when AA donor kidneys are transplanted into AA recipients. We aimed to compare the outcomes of AA vs non-AA deceased-donor kidneys (DDKs) stratified by kidney donor profile index (KDPI) that were transplanted into AA recipients.. Using the Organ Procurement and Transplant Network/United Network for Organ Sharing database, we identified AA DDK recipients from 2000 to 2015 who received peri-operative induction followed by calcineurin inhibitor/mycophenolate mofetil maintenance. These patients were divided into 4 KDPI groups (0%-20%, 21%-50%, 51%-85%, and 86%-100%). Adjusted long-term graft and patient outcomes were compared between AA recipients of kidneys from AA vs non-AA donors in each KDPI category using a multivariable Cox model.. Among a total of 17,516 AA DDK transplant recipients, 3303 were in KDPI 0%-20% (AA donor = 239; non-AA donor = 3064), 5821 in KDPI 21%-50% (AA donor = 1414; non-AA donor = 4407), 6364 in KDPI 51%-85% (AA donor = 1619; non-AA donor = 4745), and 2028 in KDPI 86%-100% (AA donor = 932; non-AA donor = 1096) groups. Adjusted overall graft, death-censored graft, and patient survival were similar between AA recipients of AA vs non-AA donor kidneys across all KDPI groups.. Our study showed similar outcomes for transplanting AA vs non-AA deceased-donor kidneys into AA recipients despite the generally observed inferior outcomes associated with AA donor kidney transplantation.

Topics: Adult; Black or African American; Calcineurin Inhibitors; Databases, Factual; Female; Graft Survival; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Risk Factors; Tissue and Organ Procurement; Tissue Donors; Treatment Outcome

A 35-year-old male patient with end-stage renal disease due to vesicoureteral reflux preemptively received a renal graft from his father. The patient had a history of allergy to contrast-enhancing media. He received oral tacrolimus (TAC) and mycophenolate mofetil without any problems for 2 days before kidney transplantation. During the induction period of the surgery, his systolic blood pressure (sBP) decreased to 60 mmHg approximately 1 hour after initiating intravenous tacrolimus (TAC-IV) and intravenous piperacillin (PIPC), and the anesthesiologist suspected drug-induced anaphylaxis and stopped administration of the medications. Because TAC had been administered preoperatively without any adverse events, PIPC was suspected as the causative agent of the anaphylaxis. After the patient's hemodynamics returned to baseline, TAC-IV was restarted. However, his sBP rapidly decreased to 40 mmHg and the patient developed wheezing. He was diagnosed with drug-induced anaphylaxis due to castor oil derivatives in the TAC-IV formulation. The patient's sBP was restored with the administration of some vasopressors, and kidney transplantation was then performed without difficulty. Two days after kidney transplantation, oral TAC was administered without anaphylaxis. Clinicians should consider that not only the drug itself but also its additives or metabolites could induce anaphylaxis.

Topics: Administration, Intravenous; Adult; Anaphylaxis; Blood Pressure; Castor Oil; Graft Rejection; Hemodynamics; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Piperacillin; Tacrolimus

Topics: Caliciviridae Infections; Diabetes Mellitus, Type 1; Diagnosis, Differential; Diarrhea; Disease Progression; Drug Tapering; Feces; Fluid Therapy; Gastroenteritis; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Mycophenolic Acid; Pancreas Transplantation; Prednisone; Sapovirus; Tacrolimus

Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS).. We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate).. Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041).. C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.

Topics: Adult; Aged; Allografts; Cytochrome P-450 CYP3A; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Isoantibodies; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Assessment; Tacrolimus

Laparoscopic sleeve gastrectomy induces weight loss via the creation of a restrictive gastric tube for early satiety and is associated with an accelerated gastric transit time. A prospective, single-dose pharmacokinetic study was performed, prior to and after laparoscopic sleeve gastrectomy, for tacrolimus, extended-release tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium. The study included 12 morbidly obese patients in chronic renal failure. The median decrease in body mass index was 8.8 kg/m

Topics: Female; Gastrectomy; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Laparoscopy; Male; Middle Aged; Mycophenolic Acid; Obesity, Morbid; Prospective Studies; Tacrolimus

Dendritic cells (DCs) have a major role in the initiation of an immune response and Immunoglobulin-like transcript 3&4 (ILT3&ILT4) are inhibitory receptors that induce tolerance in DCs. Recent studies show that immunosuppressive agents affect frequency of DCs. Herein, we compared the effect of mycophenolate mofetil (MMF) and sirolimus (SRL) in tacrolimus (TAC)-based immunosuppression on DC subsets frequency and ILT3/ILT4 gene expression in kidney transplant recipients. We enrolled 24 adult transplant recipients who received MMF/TAC (n = 14) or SRL/TAC (n = 10). Peripheral blood samples were obtained from recipients, 24-48 h before transplantation and 4 months after transplantation. The frequency of DC subsets was analyzed by flow cytometry and gene expression of ILT3/ILT4 were estimated by real-time PCR. Our results showed that MMF vs. SRL treated recipient showed an increase in pDC % with increased in the expression of ILT3/ILT4 which is in favor of better allograft survival; However, for confirming the results of this preliminary study, a cohort study with larger sample size is necessary.

Topics: Adult; Blood Cell Count; Cohort Studies; Dendritic Cells; Female; Gene Expression; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Membrane Glycoproteins; Middle Aged; Mycophenolic Acid; Receptors, Immunologic; Sirolimus; Tacrolimus; Transplant Recipients; Transplantation Conditioning; Young Adult

To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN).. Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements.. The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease.. We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

Topics: Antirheumatic Agents; Azathioprine; Calcineurin Inhibitors; Drug Therapy, Combination; Europe; Glomerular Filtration Rate; Glucocorticoids; Humans; Hydroxychloroquine; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Proteinuria; Societies, Medical

Topics: Aged; Betacoronavirus; Cobicistat; Colchicine; Coronavirus Infections; COVID-19; Cytokines; Darunavir; Drug Combinations; Female; Humans; Hydroxychloroquine; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lopinavir; Male; Middle Aged; Mycophenolic Acid; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2; Tacrolimus; Transplant Recipients; Treatment Outcome

The clinical manifestation of COVID-19 can vary from an asymptomatic course to ARDS requiring invasive mechanical ventilation and extracorporeal membrane oxygenation. A kidney transplanted patient infected with SARS CoV-2 infection showed a mild disease despite immune suppression. It is possible that Immunosuppression can "be protective" as the cytokine storm is an important factor in the disease story. Despite the good outcome reported in the present case report, is remains of vital importance the solid organ transplant patients use precautions in order to avoid the infection.

Topics: Betacoronavirus; Ceftriaxone; Coronavirus Infections; COVID-19; Cytokines; Glomerulonephritis, IGA; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pandemics; Pneumonia, Viral; SARS-CoV-2; Tacrolimus; Treatment Outcome

Topics: Abatacept; Coronavirus Infections; COVID-19; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung; Male; Middle Aged; Mycophenolic Acid; Pandemics; Pneumonia, Viral; Prednisone; Radiography, Thoracic; Tomography, X-Ray Computed; Treatment Outcome

In Scotland, standard maintenance immunosuppression following kidney transplantation consists of mycophenolate (MPA), tacrolimus and prednisolone irrespective of recipient age. We analyzed the tolerability of this immunosuppression regimen and the association with transplant outcomes.. A national, multicentre retrospective analysis of patients transplanted in 2015 and 2016, comparing graft function, acute rejection, significant infection rates and immunosuppression dosing between patients aged 18 and 59 years (Group 1) and ≥60 years (Group 2).. Of the 490 patients, 26% were aged ≥60 years. Acute rejection (AR) rates at 1 year were 15% and 11% in Groups 1 and 2, respectively. Full-dose MPA was poorly tolerated with 53% in Group 1 and 77% in Group 2 requiring dose reduction or cessation. Female gender and age ≥60 years were independent predictors for MPA dose changes. One year following MPA dose reduction, AR risk was low (5%) in Group 2, however, those remaining on full dose MPA had a 79% increased rate of serious infections.. The majority of renal transplant recipients aged ≥60 fail to tolerate full-dose MPA. In this group, MPA dose reduction is associated with low rejection rates, but full-dose MPA is associated with high infection rates. We suggest that a tailored approach to immunosuppression in elderly recipients incorporating lower doses of MPA may be appropriate.

Topics: Adult; Age Factors; Aged; Cohort Studies; Dose-Response Relationship, Drug; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; No-Observed-Adverse-Effect Level; Retrospective Studies; Risk Adjustment; Scotland

Lupus nephritis (LN) has a considerable impact on the morbidity and mortality of systemic lupus erythematosus (SLE) patients. Long-term comparative outcome data from the Indian subcontinent on treatment regimens with cyclophosphamide (CYP) and mycophenolate mofetil (MMF) are sparse. We assessed renal and patient survival for these patients in terms of the types of induction - CYP or MMF - and the two maintenance therapies - MMF or azathioprine (AZA).. We retrospectively analysed outcomes of 100 LN patients, 67 treated with CYP (26 class III, 25 class IV, 6 class III + V and 10 class IV + V; 40 Euro lupus regimen and 27 National Institutes of Health regimen) and 33 treated with a MMF-based regimen with steroids between July 2008 and June 2018. Data regarding demographic, clinical and histopathological features and the treatment given to all patients were extracted. Outcomes between the two regimens CYP and MMF were compared in terms of remission, dialysis and patient survival.. Long-term outcomes in terms of patient and renal survival of LN patients treated with CYP and MMF induction are similar. Doubling of serum creatinine occurred more with AZA-based maintenance therapy than with MMF-based maintenance therapy. Most deaths occurred during induction, and sepsis was the most common cause of death.

Topics: Adult; Azathioprine; Cyclophosphamide; Disease-Free Survival; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; India; Infusions, Intravenous; Kidney; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Male; Mycophenolic Acid; Prednisone; Remission Induction; Retrospective Studies; Young Adult

The clinical course and outcomes of immunocompromised patients, such as transplant recipients, with COVID-19 remain unclear. It has been postulated that a substantial portion of the disease burden seems to be mediated by the host immune activation to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present a simultaneous heart-kidney transplant (SHKT) recipient who was hospitalized for the management of respiratory failure from volume overload complicated by failure to thrive, multiple opportunistic infections, and open non-healing wounds in the setting of worsening renal dysfunction weeks prior to the first case of SARS-CoV-2 being detected in the state of Connecticut. After his third endotracheal intubation, routine nucleic acid testing (NAT) for SARS-CoV-2, in anticipation of a planned tracheostomy, was positive. His hemodynamics, respiratory status, and ventilator requirements remained stable without any worsening for 4 weeks until he had a negative NAT test. It is possible that the immunocompromised status of our patient may have prevented significant immune activation leading up to clinically significant cytokine storm that could have resulted in acute respiratory distress syndrome and multisystem organ failure.

Topics: Antibiotics, Antineoplastic; Bacteremia; BK Virus; Cardiomyopathy, Dilated; Cardiotoxicity; COVID-19; COVID-19 Nucleic Acid Testing; Doxorubicin; Graft Rejection; Gram-Positive Bacterial Infections; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidental Findings; Kidney Failure, Chronic; Kidney Transplantation; Male; Malnutrition; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Polyomavirus Infections; Postoperative Complications; Prednisone; Renal Dialysis; SARS-CoV-2; Staphylococcal Infections; Surgical Wound Infection; Tacrolimus; Tracheostomy; Tumor Virus Infections; Vancomycin-Resistant Enterococci; Viremia; Water-Electrolyte Imbalance

Topics: Anti-Infective Agents; Azithromycin; Betacoronavirus; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Testing; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Monitoring, Immunologic; Mycophenolic Acid; Oxygen Inhalation Therapy; Pandemics; Pneumonia, Viral; Prednisolone; SARS-CoV-2; Tacrolimus; Treatment Outcome

Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for the increased risk of gastrointestinal complications in kidney transplant recipients. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. This study evaluated the incidence of post-transplant gastrointestinal complications during screening colonoscopy. Kidney transplant recipients undergoing a colonoscopy for any reasons in the period 2014-2018 were included. Among the 134 patients completing the colonoscopy, 74 patients (56%) had an abnormal finding: an adenoma was found in 25 patients (18.6%), while 19 patients (14.1%) had colitis. Mycophenolic acid/related colitis was the most common colitis (6%), while 7 patients (5.2%) developed a

Topics: Adenoma; Age Distribution; Aged; Anemia; Colitis; Colonoscopy; Colorectal Neoplasms; Diarrhea; Diverticulosis, Colonic; Early Detection of Cancer; Female; Gastrointestinal Hemorrhage; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

C3 glomerulopathy (C3GP) defines a rare group of glomerulonephritis (GN), which could lead to end stage renal disease (ESRD). Histopathologic features of the disease have yet to be defined and the prognostic factors and optimal treatment are not fully known. The purpose of this study was to determine the demographic, histological change, treatment modalities and outcomes among patients with C3GP.. This retrospective observational study was conducted in the Department of Nephrology, Gazi University, Ankara, from 2013 to 2017. All patients with kidney biopsies fulfilling the criteria for C3GP were included in the study.. Twenty-four patients with C3GP (50% male and of middle age - 43 years old) were enrolled in this study. 21% (5/24) patients developed ESRD. Renal biopsy findings such as crescent formation, glomerulo-sclerosis and tubular atrophy were similar in patients with ESRD, when compared to patients who did not develop ESRD. The treatment modalities of the patients were examined in two groups as MMF based and non-MMF based. The difference in the preservation of eGFR did not reach statistical significance between these two groups. The success rate of complete remission was similar between both groups. Serum creatinine levels >2.3 mg/dl at admission and need for renal replacement treatment (RRT) were associated with decreased renal survival.. MMF based or non-MMF based treatments have similar efficacy in C3GP. Serum creatinine level higher than 2.3 mg/dl at the time of diagnosis and need for RRT during admission are a strong predictor of ESRD with high sensitivity and specificity.

Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Complement C3; Complement Inactivating Agents; Creatinine; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Remission Induction; Renal Replacement Therapy; Retrospective Studies; Treatment Outcome; Young Adult

The number of simultaneous liver-kidney transplantations (SLKTs) and use of induction therapy for SLKT have increased recently, without much published evidence, especially in the context of maintenance immunosuppression containing tacrolimus (TAC) and mycophenolic acid (MPA). We queried the Organ Procurement and Transplant Network registry for SLKT recipients maintained on TAC/MPA at discharge in the United States for 2002-2016. The cohort was divided into 3 groups on the basis of induction type: rabbit antithymocyte globulin (r-ATG; n = 831), interleukin 2 receptor antagonist (IL2RA; n = 1558), and no induction (n = 2333). Primary outcomes were posttransplant all-cause mortality and acute rejection rates in kidney and liver allografts at 12 months. Survival rates were analyzed by the Kaplan-Meier method. A propensity score analysis was used to control potential selection bias. Multivariate inverse probability weighted Cox proportional hazard and logistic regression models were used to estimate the hazard ratios (HRs) and odds ratios. Among SLKT recipients, survival estimates at 3 years were lower for recipients receiving r-ATG (P = 0.05). Compared with no induction, the multivariate analyses showed an increased mortality risk with r-ATG (HR, 1.29; 95% confidence interval [CI], 1.10-1.52; P = 0.002) and no difference in acute liver or kidney rejection rates at 12 months across all induction categories. No difference in outcomes was noted with IL2RA induction over the no induction category. In conclusion, there appears to be no survival benefit nor reduction in rejection rates for SLKT recipients who receive induction therapy, and r-ATG appears to increase mortality risk compared with no induction.

Topics: Adult; Aged; Antilymphocyte Serum; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Severity of Illness Index; Survival Rate; Tacrolimus; United States

Tuberculosis (TB) mortality is high among kidney transplant (KT) recipients. Although local epidemiology is an important factor, diagnostic/therapeutic challenges and immunosuppressive therapy (ISS) may influence outcomes. We analyzed the cumulative incidence (CumI) of TB in KT recipients receiving a variety of ISS with long-term follow-up. Our retrospective single-center cohort study included all KT procedures performed between January 1, 1998, and August 31, 2014, with follow-up until August 31, 2014. Induction therapy was based on perceived immunological risk; maintenance ISS included prednisone and calcineurin inhibitor (CNI) plus azathioprine (AZA), and mycophenolic acid (MPA) or mechanistic target of rapamycin inhibitor (mTORi). Thirty-four patients received belatacept/MPA. KT was performed on 11 453 patients and followed for 1989 (IQR 932 to 3632) days. Among these, 152 patients were diagnosed with TB (CumI 1.32%). Median time from KT to TB was 18.8 (IQR 7.2 to 60) months, with 59% of patients diagnosed after the first year. Unadjusted analysis revealed an increasing confidence interval (CI) of TB (0.94% CNI/AZA vs 1.6% CNI/MPA [HR = 1.62, 95% CI = 1.13 to 2.34, P = .009] vs 2.85% CNI/mTORi [HR = 2.45, 95% CI = 1.49 to 4.32, P < .001] vs 14.7% belatacept/MPA [HR = 13.14, 95% CI = 5.27 to 32.79, P < .001]). Thirty-seven (24%) patients died, and 39 (25.6%) patients experienced graft loss. Cytomegalovirus infection (P = .02) and definitive ISS discontinuation (P < .001) were associated with death. Rejection (P = .018) and ISS discontinuation (P = .005) occurred with graft loss. TB occurred at any time after KT and was influenced by ISS.

Topics: Abatacept; Adult; Azathioprine; Calcineurin Inhibitors; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk; TOR Serine-Threonine Kinases; Treatment Outcome; Tuberculosis

Topics: Adolescent; Anti-Bacterial Agents; Biopsy; Bone Marrow; Female; Fever of Unknown Origin; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukocyte Count; Medication Adherence; Mycophenolic Acid; Renal Dialysis; Treatment Outcome

Topics: Adolescent; Amphotericin B; Antigens, Fungal; Antiviral Agents; Biopsy; Bone Marrow; Cytomegalovirus; Cytomegalovirus Infections; Female; Fever of Unknown Origin; Graft Rejection; Histoplasma; Histoplasmosis; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphohistiocytosis, Hemophagocytic; Mycophenolic Acid; Renal Dialysis; Treatment Outcome; Viral Load

Lupus nephritis (LN) is the leading cause of mortality in lupus patients. This study aimed to investigate the treatment outcome and renal histological risk factors of LN in a tertiary referral center. Between 2006 and 2017, a retrospective observational study enrolled 148 biopsy-proven LN patients. After propensity score matching, 75 cases were included for further analysis. The classification and scoring of LN were assessed according to the International Society of Nephrology/Renal Pathology Society. Treatment response was evaluated by daily urine protein and urinalysis at two years after commencing induction treatment and the development of end-stage renal disease (ESRD). In total, 50.7% patients achieved complete remission (CR) or partial remission (PR), while 49.3% patients were categorized as nonresponders. Therapeutic responses in terms of CR/PR rates were associated with Systemic Lupus Erythematosus Disease Activity Index scores (odds ratio (OR): 1.34, 95% confidence interval (CI): 1.12-1.60, p = 0.001). Moreover, higher baseline creatinine levels (hazard ratio (HR): 2.10, 95% CI: 1.29-3.40, p = 0.003), higher renal activity index (HR: 1.30, 95% CI: 1.07-1.58, p = 0.008) and chronicity index (HR: 1.40, 95% CI: 1.06-1.85, p = 0.017) predicted ESRD. Among pathological scores, cellular crescents (HR: 4.42, 95% CI: 1.01-19.38, p = 0.049) and fibrous crescents (HR: 5.93, 95% CI: 1.41-24.92, p = 0.015) were independent risk factors for ESRD. In conclusion, higher lupus activity was a good prognostic marker for renal remission. Renal histology was predictive of ESRD. Large-scale prospective studies are required to verify the efficacy of mycophenolate in combination with azathioprine or cyclosporine in LN patients.

Topics: Adolescent; Adult; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney; Kidney Failure, Chronic; Lupus Nephritis; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Propensity Score; Remission Induction; Retrospective Studies; Risk Factors; Taiwan; Treatment Outcome; Young Adult

BACKGROUND The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age. MATERIAL AND METHODS Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 -post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years). RESULTS Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus. CONCLUSIONS Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.

Topics: Adult; Age Factors; Aged; Delayed-Action Preparations; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Tissue Donors; Transplant Recipients

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune disease characterized by multiple organ system involvement, including renal disease, with low complement levels. We report the case of a 31-year-old woman who presented with nonspecific symptoms including fatigue, diarrhea, macular rash and abdominal pain with acute renal failure leading to end-stage kidney disease. Laboratory results showed hematuria, nephrotic range proteinuria, worsening creatinine and low C1q levels. Left kidney biopsy showed proliferative glomerulonephritis with crescent formation. She was treated with 6 months of intravenous cyclophosphamide, followed by 2 doses of intravenous rituximab (1g each), thereafter maintained on mycophenolate mofetil and glucocorticoid-based therapy. She experienced a full recovery of renal function after 12 months of dialysis dependence. Hypocomplementemic urticarial vasculitis syndrome with crescentic glomerulonephritis is a rare disease with only 5 other reported cases in literature. In our case, we document a delayed but excellent renal recovery during a 2-year follow-up.

Topics: Adult; Complement C1q; Cyclophosphamide; Female; Glomerulonephritis, Membranoproliferative; Hematuria; Humans; Kidney Failure, Chronic; Mycophenolic Acid; Proteinuria; Rituximab; Syndrome; Urticaria; Vasculitis

BACKGROUND Correction of hypovitaminosis D is simple, but it is unclear whether it is associated with an accelerated decline of renal allograft function in pediatric renal transplantation patients. This retrospective single center cohort study aimed at analyzing the effect of vitamin D and covariates on the slope of 1/creatinine after the first year. MATERIAL AND METHODS After ethics committee approval, 37 (14 male) pediatric renal transplant recipients on mycophenolate mofetil, who were followed between 2006 and 2014, were included in this study. We analyzed the slope of 1/creatinine, length of follow-up, average vitamin D levels, calcium, phosphate, alkaline phosphatase levels, intact parathyroid hormone (PTH) levels, and therapeutic drug monitoring parameters. RESULTS Median slope of 1/creatinine was -2.587e-006 L/µmol. We divided the 37 patients into two groups based on slope: 18 patients with a poorer slope and 19 patients with a good slope, with the median slope of 1/creatinine being significantly different between the two groups. Creatinine and cystatin C at one-year post-transplantation did not differ between the two groups. Average vitamin D levels were 71.4±31.01 pmol/L and identical in each group (averages 71.67 and 69.23 pmol/L, respectively). Only the mycophenolic acid coefficient of variation (MPA CV), which may promote formation of donor-specific antibodies, and PTH levels were significantly associated with 1/creatinine slope. CONCLUSIONS Our data suggest that the impact of mild and moderate decreased levels of vitamin D can have a mild impact on the progression of allograft dysfunction in transplant recipients. However, given the medication burden and adherence challenges in adolescents, correction of mildly decreased vitamin D levels may not be necessary.

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Creatinine; Disease Progression; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Vitamin D; Vitamin D Deficiency

Topics: Adult; Amyloidosis; Basiliximab; Biopsy; Familial Mediterranean Fever; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Interleukin-1; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome; Young Adult

This study aims to identify modifiable risk factors for de novo renal cell carcinoma (RCC) after kidney transplantation in a matched-pair approach matching for unmodifiable factors.. One thousand six hundred fifty-five adults who underwent kidney transplantation in the period 1 January 2000 to 31 December 2012 were analyzed. Patients with RCC after kidney transplantation were matched in a 1:2 ratio with those without RCC using the indication for transplantation, age at transplantation (± 10 years), recipient sex (male/female), number of received transplants, living organ donor transplantation (yes/no), and time of follow-up in days as matching criteria. The paired t test was used to compare continuous variables and the Cochran-Mantel-Haenszel test for categorical variables. Multivariable conditional logistic regression modeling was used to identify independent risk factors for RCC.. In matched-pair analysis, a total number of 26 incident cases with RCC after kidney transplantation could be matched. Post-transplant RCC was significantly associated with longer durations of pre-transplant hemodialysis (p = 0.007) and post-transplant immunosuppression with cyclosporine (p = 0.029) and/or mycophenolate mofetil (p = 0.020) and with larger proportions of post-transplant time on mycophenolate mofetil (p = 0.046) and/or prednisolone medication (p = 0.042). Multivariable conditional logistic regression modeling revealed a significant risk increasing multiplicative factor interaction between the duration of pre-transplant dialysis (years) and the time of prednisolone usage (percent/100). Cyclosporine A usage and mycophenolate mofetil usage were also revealed as independent, significant risk factors for RCC development.. Longer pre-transplant dialysis, cyclosporine-based protocols and/or intensified immunosuppression with additional mycophenolate mofetil, and larger proportions of time of prednisolone treatment during follow-up increase de novo RCC risk.

Topics: Adult; Aged; Carcinoma, Renal Cell; Cyclosporine; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Male; Matched-Pair Analysis; Middle Aged; Mycophenolic Acid; Prednisolone; Renal Dialysis; Retrospective Studies; Risk Factors; Time Factors; Young Adult

There are differences in pharmacokinetic of mycophenolic acid among individuals. The UGT1A9 enzyme is of special interest since it is the main enzyme involved in the glucuronidation of MPA. Single nucleotide polymorphisms in the UGT1A9 gene may be responsible for individual differences in the pharmacokinetics of MPA. The aim of this study was to explain MPA pharmacokinetics in UGT1A9 1399 C > T polymorphisms in Turkish renal transplant patients.. One hundred and twenty-five living-donor transplant recipients and 100 healthy control subjects underwent UGT1A9 1399 C > T genotyping using polymerase chain reaction-restriction fragment length polymorphism. Concentrations of MPA were determined with Cloned Enzyme Donor Immunoassay (CEDIA). Besides that, all the patients were monitored for acute rejection and graft function during the study period.. The UGT1A9 1399 C > T CC, CT, and TT genotype frequencies among patients were, respectively, 68.0%, 23.2%, and 8.8%. The CC, CT, and TT genotype frequencies among controls were, respectively, 63.0%, 23.0%, and 14.0%. There was no significant difference between patients and controls (p = .480, p = .999, p = .286, respectively). At first month, respectively, through blood concentrations of MPA were significantly higher in UGT1A9 1399 C > T TT carriers than in CT and CC carriers (p = .046). The doses for these patients were lower at first month (p = .021). Acute rejection episodes were not associated with the CC vs CT or TT genotypes (p = .064).. Our results demonstrated a correlation between the UGT1A9 1399 C > T polymorphism and MPA pharmacokinetics among renal transplant patients. Determination of UGT1A9 polymorphism may help to achieve target of MPA blood concentrations.

Topics: Adult; Female; Follow-Up Studies; Genotype; Glucuronosyltransferase; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Treatment Outcome; Turkey; UDP-Glucuronosyltransferase 1A9

Membranoproliferative glomerulonephritis (MPGN) is a rare cause of glomerulopathy in children. Recently, a new classification based on immunohistological features has been established. Infections and anomalies in complement-regulating genes, leading to alternative complement pathway activation, are suspected to trigger the disease. Nevertheless, little is known about optimal treatment and outcome in children with immune-complex-MPGN (IC-MPGN) and C3-glomerulopathy (C3G).. The method used is retrospective analysis of clinical, histological, and genetic characteristics of 14 pediatric patients with MPGN in two medical centers.. Mean age of the patients was 10.6 ± 4.5 years. Patients were grouped into C3G (n = 6) and IC-MPGN (n = 8). One patient showed a likely pathogenic variant in the CFHR5 gene. All 10 patients had risk polymorphisms in complement-regulating genes. Most patients were treated with ACE inhibition, steroids, and mycophenolate mofetil. Three patients with C3G received eculizumab. Median follow-up was 2.3 years. After 1 year of disease, three patients (two C3G, one IC-MPGN) reached complete, five patients partial (three IC-MPGN, two C3G), and five patients no remission (four IC-MPGN, one C3G). One patient progressed to end-stage renal disease (ESRD) 6 years after disease onset.. IC-MPGN and C3G are rare disorders in children. Most patients have signs of complement activation associated with risk polymorphisms or likely pathogenic variants in complement-regulating genes. Steroids and mycophenolate mofetil seem to be effective and for some patients, eculizumab might be a treatment option. Outcome is heterogeneous and precise differentiation between IC-MPGN and C3G is still pending.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal, Humanized; Child; Complement C3; Complement Inactivator Proteins; Complement Pathway, Alternative; Disease Progression; Female; Follow-Up Studies; Glomerulonephritis, Membranoproliferative; Glucocorticoids; Humans; Kidney Failure, Chronic; Kidney Glomerulus; Male; Mycophenolic Acid; Patient Outcome Assessment; Remission Induction; Retrospective Studies; Thrombomodulin; Treatment Outcome

ABO-incompatible living related kidney transplantation (ABO-iLKT) has increased the possibilities for kidney transplantation in patients with end stage renal disease. Due to advancements in immunosuppressive agents and the identification of immunological conditions following ABO-iLKT, this transplantation technique has achieved the same success rate as ABO-compatible LKT. However, some patients continue to generate anti-blood type antibodies, despite conventional immunosuppressant treatment.. A 60-year-old man was referred to our hospital for kidney transplantation. The proposed transplant was ABO incompatible, from a donor with blood-type A to a recipient with blood-type O. The recipient's anti-A blood-type IgG antibody titer was measured at 4096-fold dilution. Following desensitization therapy, including mycophenolate mofetil (MMF) 750 mg/day for 3 months, intravenous Rituximab 200 mg, and two sessions of double filtration plasmapheresis, the anti-A blood-type IgG antibody titer decreased to only 516-fold dilution and did not meet our target of less than 128-fold dilution. MMF was thus continued for an additional 4 months and four additional sessions of plasmapheresis were undertaken. Following these interventions, antibody titers decreased to 128-fold dilution and ABO-iLKT was performed. Following transplant, antibody-mediated rejection was not observed and renal function was preserved. However, a post-operative renal biopsy 1.5 months later showed evidence of T-cell-mediated rejection IB. The patient was treated with steroids, with no increase in serum creatinine.. Our findings suggest that the long-term single MMF desensitization therapy could be a suitable option for ABO-iLKT with high refractory and rebound anti-blood type antibody. Further studies are required to establish the optimal immunosuppression regimen to control B cell- mediated immunity in ABO-iLKT.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Desensitization, Immunologic; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Plasmapheresis; Rituximab

Successful simultaneous pancreas and kidney transplantation (SPK) or pancreas transplantation alone (PTA) restores glycemic control. Diabetes and impaired kidney function are common side effects of immunosuppressive therapy. This study addresses glucometabolic parameters and kidney function during the first year.. We examined 67 patients with functioning grafts (SPK n = 30, PTA n = 37) transplanted between September 2011 and November 2016 who underwent repeated oral glucose tolerance tests (OGTTs) 8 and 52 weeks after transplantation. Another 19 patients lost their graft the first year post-transplant and 28 patients did not undergo repeated OGTTs and could not be studied. All patients received ATG induction therapy plus tacrolimus, mycophenolate and prednisolone. Glomerular filtration rate was measured before and 8 and 52 weeks after transplantation by serum clearance methods.. From week 8 to 52 after transplantation, mean fasting glucose decreased (SPK: 5.4 ± 0.7 to 5.1 ± 0.8 mmol/L, PTA: 5.4 ± 0.6 to 5.2 ± 0.7 mmol/L; both P < 0.05), and also 120-min post-OGTT glucose (SPK: 6.9 ± 2.9 to 5.7 ± 2.2 mmol/L; P = 0.07, PTA: 6.5 ± 1.7 to 5.7 ± 1.2 mmol/L; P < 0.05). Fasting C-peptide levels also decreased (SPK: 1500 ± 573 to 1078 ± 357 pmol/L, PTA: 1210 ± 487 to 1021 ± 434 pmol/L, both P < 0.005). Measured GFR decreased from enlistment to 8 weeks post transplant in PTA patients (94 ± 22 to 78 ± 19 mL/min/1.73 m2; P < 0.005), but did not deteriorate from week 8 to week 52 (SPK: 55.0 ± 15.1 vs 59.7 ± 11.3 ml/min/1.73 m²; P = 0.19, PTA: 76 ± 19 vs 77 ± 19 mL/min/1.73 m²; P = 0.74).. Glycemic control and kidney function remain preserved in recipients with functioning SPK and PTA grafts 1 year after transplantation.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glomerular Filtration Rate; Glucose Tolerance Test; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin Secretion; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prednisolone; Prospective Studies; Tacrolimus

Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis.

Topics: Adult; Antibiotics, Antitubercular; Brain Stem; DNA; Early Diagnosis; Female; Humans; Immunosuppressive Agents; JC Virus; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Mycophenolic Acid; Tacrolimus

Belatacept use has been constrained by higher rates of acute rejection. We hypothesized that belatacept with low-dose rATG and initial mycophenolate maintenance with conversion to everolimus at 1 month post-transplant ± corticosteroids would improve efficacy and maintain safety. Retrospective single-center analysis of the first 44 low immunologic risk kidney transplant recipients treated with this regimen. The cohort was 59% male, mean age at transplant of 57 years. Diabetes was the most common cause of ESRD (39%). The mean 1-year eGFR was 61.4 (SD 18.4) mL/min/1.73 m

Topics: Abatacept; Adrenal Cortex Hormones; Adult; Aged; Antilymphocyte Serum; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Kidney Transplantation; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Treatment Outcome

Mycophenolic acid (MPA), either given as an ester pro-drug or as an enteric-coated sodium salt, is the most commonly prescribed anti-proliferative immunosuppressive agent used following organ transplantation and widely applied in immune-mediated diseases. Clinicians are well aware of common adverse reactions related to MPA treatment, in particular diarrhea, leukopenia and infections. Here we report a case of severe, persistent ascites associated with MPA treatment. The otherwise unexplained and intractable ascites, requiring repeated paracenteses for more than 8 months, rapidly ceased with stopping the MPA treatment. To our knowledge this is the first case of severe ascites associated with MPA treatment reported in the scientific literature.. A 45-year old female with type 1 diabetes mellitus received a simultaneous kidney-pancreas transplant. The surgery was uneventful. However, post-operatively she developed severe transudative ascites requiring in total more than 40 paracenteses treatments draining in the average 2.8 l of ascites fluid. The ascites formation persisted despite exclusion of a surgical complication, fully functioning kidney and pancreas allografts, lack of any significant proteinuria, normalization of circulating albumin levels, intensive use of diuretics and deliberate attempts to increase the intervals between the paracentesis treatments. Various differential diagnoses, including infectious, hepatic, vascular and cardiac causes were ruled out. Nine months after surgery enteric-coated mycophenolate sodium was switched to azathioprine after which ascites completely resolved. When mycophenolate was recommenced abdominal fullness and weight gain reoccurred. The patient had to be switched to long-term azathioprine treatment. More than 1 year post-conversion the patient remains free of ascites.. MPA is the most widely used antimetabolite immunosuppressive agent. We suggest to consider MPA treatment in the differential diagnosis of severe and unexplained ascites in transplant and non-transplant patients.

Topics: Ascites; Diabetes Mellitus, Type 1; Diagnosis, Differential; Exocrine Pancreatic Insufficiency; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Paracentesis; Postoperative Complications; Treatment Outcome; Withholding Treatment

Topics: Adult; Biological Availability; Graft Rejection; HLA-B27 Antigen; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Spondylarthropathies; T-Lymphocytes; Tacrolimus; Treatment Outcome

In 2012, the U.S. Food and Drug Administration issued guidelines advising kidney transplant recipients (KTRs) to discontinue mycophenolate (MPA) in preparation for pregnancy. Little is known about how this guidance has affected pregnancy and graft outcomes. The purpose of this retrospective cohort study was to investigate any association between the discontinuation of MPA and KTR pregnancy and graft outcomes. Data from the National Transplantation Pregnancy Registry included 382 cases in which KTRs managed on MPA became pregnant. Overall, 22 variables, including the time in which a KTR discontinued MPA, were assessed across four end points: miscarriages, birth defects, and 2- and 5-year postpartum graft loss. Birth defects and miscarriages were similar among KTRs who discontinued MPA >6 and <6 weeks prior to pregnancy and during the first trimester. In contrast, discontinuing MPA during the second trimester or later significantly increased the risk of miscarriages (odds ratio [OR] 9.35, 95% confidence interval [CI] 4.31-20.00, p < 0.001) and birth defects (OR 6.06, 95% CI 1.96-18.87, p = 0.002). Discontinuing MPA <6 weeks prior to pregnancy was associated with an increased risk of 5-year graft loss. For the fetus, there is value to discontinuing MPA anytime prior to the second trimester. Adhering to current guidelines does not negatively affect graft survival.

Topics: Adult; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Mycophenolic Acid; Pregnancy; Pregnancy Outcome; Retrospective Studies; Risk Factors; Transplant Recipients; Young Adult

Condyloma acuminata (CA) are warty lesions caused by human papilloma virus (HPV) that generally affect the external genitalia and mucocutaneous junctions. Involvement of the urinary tract is rare, and involvement of the urinary bladder is thought to be due to immunosuppression. A 30-year-old woman was diagnosed with urethral CA 12 months after renal transplantation. She underwent transurethral resection (TUR) of the urethral lesions. During the operation, multiple sessile warty lesions were found incidentally inside the bladder and were also removed by TUR. The patient's postoperative course was uneventful. Pathological examination confirmed that the lesions were CA. Multiplex real-time polymerase chain reaction was performed to confirm the HPV genotype and revealed type 45 HPV DNA. CA of the urethra are uncommon, and bladder involvement is extremely rare. This case is the first reported, to our knowledge, to involve HPV type 45 in bladder condyloma. TUR may be the preferred option for the management of CA in the urinary bladder.

Topics: Adult; Condylomata Acuminata; Cystoscopy; Diabetes Mellitus, Type 1; Female; Genotype; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidental Findings; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Papillomaviridae; Prednisolone; Real-Time Polymerase Chain Reaction; Tacrolimus; Transplant Recipients; Urethra; Urinary Bladder

Limited access to tertiary-level health care, limited trained pediatric nephrologists and transplant physicians, lack of facilities for dialysis, lack of an effective deceased donor program, non-affordability, and non-adherence to immunosuppressant drugs poses a major challenge to universal availability of pediatric transplantation in developing countries. We present the results of a survey which, to the best of our knowledge, is the first such published attempt at understanding the current state of pediatric renal transplantation in India. A designed questionnaire formulated by a group of pediatric nephrologists with the aim of understanding the current practice of pediatric renal transplantation was circulated to all adult and pediatric nephrologists of the country. Of 26 adult nephrologists who responded, 16 (61.5%) were involved in pediatric transplantation, and 10 of 15 (66.6%) pediatric nephrologists were involved in pediatric transplantation. Most of the centers doing transplants were private/trust institution with only three government institutions undertaking it. Induction therapy was varied among pediatric and adult nephrologists. There were only a few centers (n=5) in the country routinely doing >5 transplants per year. Preemptive transplants and protocol biopsies were a rarity. The results demonstrate lower incidence of undertaking pediatric transplants in children below 6 years, paucity of active cadaveric programs and lack of availability of trained pediatric nephrologists and staff. In contrast to these dissimilarities, the immunosuppressant use seems to be quite similar to Western registry data with majority favoring induction agent and triple immunosuppressant (steroid, mycophenolate mofetil and tacrolimus) for maintenance. The survey also identifies major concerns in availability of this service to all regions of India as well as to all economic segments.

Topics: Adolescent; Adult; Child; Child, Preschool; Developing Countries; Female; Geography; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; India; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Nephrology; Registries; Surveys and Questionnaires; Tissue Donors; Young Adult

We performed a retrospective cohort analysis focusing on lupus nephritis renal flare incidence and outcome predictors. One hundred and eighteen patients with biopsy-proven lupus nephritis were segregated by induction/maintenance regimes. The primary outcome was the proportion of patients experiencing renal flare. Secondary assessment included doubling of serum creatinine and development of end-stage renal disease. After a median follow-up of 31 months (interquartile range 21-46) from the date of response to induction therapy, 47 patients (39.8%) developed a renal flare. Azathioprine-maintained patients had a higher risk of renal flare compared with mycophenolate mofetil-maintained patients (hazard ratio 2.53, 95% confidence interval 1.39-4.59, p < 0.01). Age (hazard ratio 0.96, 0.92-0.99, p = 0.03), serum creatinine at presentation (hazard ratio 1.76, 1.13-2.76, p = 0.01), complete remission after induction therapy (hazard ratio 0.28, 0.14-0.56, p < 0.001) and azathioprine maintenance therapy (hazard ratio 4.78, 2.16-10.6, p < 0.001) were associated with renal flare on multivariate analysis. Ten patients progressed to end-stage renal disease (8.5%) by a median 32.5 months. Age (hazard ratio 0.88, 0.77-0.99, p = 0.05), complete remission after induction therapy (hazard ratio 0.08, 0.01-0.94, p = 0.04) and severe nephritic flare (hazard ratio 13.6, 1.72-107.7, p = 0.01) were associated with end-stage renal disease development. Azathioprine maintenance therapy is associated with a higher incidence of relapse in the Mexican-mestizo population. Younger age and nephritic flares predict development of end-stage renal disease.

Topics: Adolescent; Adult; Azathioprine; Biomarkers; Chi-Square Distribution; Creatinine; Disease Progression; Disease-Free Survival; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Failure, Chronic; Lupus Nephritis; Male; Mexico; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Predictive Value of Tests; Proportional Hazards Models; Recurrence; Remission Induction; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Young Adult

Optimal tacrolimus exposure in transplant recipients is not well established. The results from the Symphony study indicated that low-target tacrolimus (trough concentrations 3-7 µg/L) in de novo standard risk renal transplant recipients should be appropriate. The aim of this study was to evaluate real-life outcomes when applying a similar strategy in a clinical setting.. A single-centre analysis was conducted in standard risk renal transplant recipients receiving low-target tacrolimus, mycophenolate mofetil, glucocorticoids and basiliximab induction. One-year estimated glomerular filtration rate (eGFR, Cockcroft-Gault), one-year biopsy-proven acute rejection rate and graft- and patient survival up to 3 years post-transplant were compared with the outcomes in the Symphony study.. From 1 January 2009 to 31 March 2013, we included 406 patients. One year after transplantation, the mean ± SD eGFR was 76.8 ± 28.3 mL/min (Symphony: 65.4 ± 27.0 mL/min, P < 0.001). Biopsy-proven acute rejections were seen in 14.5% of the patients (Symphony: 12.3%, P = 0.35). Kaplan-Meier estimates [95% confidence interval] of three-year death-censored graft- and patient survival were 96.6% [94.2-99.0%] (Symphony: 93%) and 95.0% [92.6-97.3%] (Symphony: 95%), respectively.. Low-target tacrolimus-based immunosuppression is safe and effective also in a standard clinical setting in de novo standard risk renal transplant recipients.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Biopsy; Dose-Response Relationship, Drug; Drug Monitoring; Female; Glomerular Filtration Rate; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Norway; Outcome and Process Assessment, Health Care; Recombinant Fusion Proteins; Retrospective Studies; Risk Adjustment; Survival Analysis; Tacrolimus

We compared retrospectively the level of hemoglobin and the percentage of patients with anemia among 59 kidney transplant recipients receiving everolimus, cyclosporine, and corticosteroids and 128 treated with cyclosporine, mycophenolic acid, and corticosteroids. We also compared age at the time of transplantation, sex and ferritine, serum creatinine, creatinine clearance, folic acid, cyanocobalamine levels, use od recombinant erythropoietin, mean corpuscolar volume at the last ambulatory control. Statistical analysis included Student t test, χ(2) test, and logistic regression. The analysis was performed using SPSS software. We observed no difference in terms of hemoglobin levels in patients treated with everolimus (12.9 ± 1.6 vs 12.7 ± 1.5 g/dL). Anemia (defined as hemoglobin <13 g/dL in men and <12 g/dL in women, or need to use erythropoietin) was found in 49% and 45% of patients in the 2 groups respectively (P = .6). The other parameters evaluated were similar except for the mean corpuscular volume, which was significantly lower in the everolimus group. In the multivariate analysis only serum creatinine and estimated glomerular filtration rate influenced the level of hemoglobin. We observed no differences in terms of development of anemia in renal transplanted patients treated with everolimus-based regimen.

Topics: Adult; Aged; Anemia; Cyclosporine; Everolimus; Female; Hemoglobins; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies

Renal transplantation is the best therapeutic option for end-stage chronic renal disease. Assuming that it is more advisable if performed early, we aimed to show the clinical, social, and economic advantages in 70% of our patients who were dialyzed only for a short period. For this purpose, we retrospectively collected data over 28 years in 142 kidney transplants performed in patients with <6 weeks on dialysis. 66% of our patients were 30-60 years old; 98% of the patients had living donors. At transplantation, 64% of our patients had no public support; however, 64% of them returned to work and got health insurance 2 months later. Full rehabilitation was achieved in all cases, including integration to the family, return to full-time work, school and university, sports, and reproduction. Immunosuppression consisted of 3 drugs, including steroids, cyclosporine, and azathioprine or mycophenolate. The cost in the 1st year, including patient and donor evaluation, surgery, immunosuppression, and follow-up, was $13,300 USD versus $22,320 for hemodialysis. We conclude that preemptive renal transplantation with <6 weeks on dialysis is the best therapeutic option for end-stage renal failure, especially in developing countries such as Bolivia, where until last year, full public support for renal replacement therapy was unavailable.

Topics: Adult; Aged; Azathioprine; Bolivia; Costs and Cost Analysis; Cyclosporine; Developing Countries; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Renal Dialysis; Renal Replacement Therapy; Retrospective Studies; Transplantation, Homologous

Cardiovascular disease (CVD) is the second major cause of death in kidney-transplanted children. Cardiovascular risk factors (CVRF) prevalence after transplant may increase. The effect of immunosuppressive therapy has not been fully studied in children. The objective of the study was to measure and compare CVRF prevalence in kidney-transplanted children, depending of immunosuppressive therapy.. The study was an observational, transversal, retrospective, comparative study of pediatric patients transplanted at UMAE Hospital General Centro Medico La Raza. All patients were treated with prednisone and mycophenolic acid and any of cyclosporine, tacrolimus, or sirolimus. Demographic, clinical, and biochemical variables and immunosuppressive therapy were evaluated. We used analysis of variance, χ(2), and Fisher tests with the SPSS 18.0 statistical program.. One hundred fifteen patients were studied. Sixty-five (56.5%) were male, and median age was 18.5 ± 2.3 years. Seventy-eight (67.2%) were transplanted from a living related donor. Prevalence of anemia and nephrotic proteinuria was significantly less in patients treated with tacrolimus. Those treated with cyclosporine had a significantly greater prevalence of increased LDL-cholesterol, increased serum phosphorus, and increased calcium-phosphorus. Those treated with tacrolimus had lower, not significant, prevalence of hypertension, hyperuricemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and low serum HDL-cholesterol than those treated with sirolimus and cyclosporine. In multivariate analysis, patients treated with cyclosporine had significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75-41.16, P = .001) and calcium-phosphorus (OR, 37.94; 95% CI, 3.45-416.17, P = .003) than those treated with tacrolimus.. Patients treated with tacrolimus had less prevalence of CVRF than those treated with cyclosporine or sirolimus. Tacrolimus is the best immunosuppressive option to diminish CVRF in children after kidney transplantation.

Topics: Adolescent; Adult; Cardiovascular Diseases; Child; Cyclosporine; Female; Humans; Hypertension; Hypertriglyceridemia; Hyperuricemia; Immunosuppressive Agents; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Young Adult

To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA).. The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons.. In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil.. Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

Topics: Adolescent; Adrenal Cortex Hormones; Age Distribution; Antibodies, Antineutrophil Cytoplasmic; Asia; Azathioprine; Canada; Child; Child, Preschool; Cohort Studies; Cyclophosphamide; Drug Therapy, Combination; Europe; Female; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Lung Diseases; Male; Methotrexate; Microscopic Polyangiitis; Mycophenolic Acid; Nephrotic Syndrome; Oxygen Inhalation Therapy; Plasmapheresis; Proteinuria; Renal Dialysis; Respiratory Insufficiency; Rituximab; United States

Hypomagnesemia is a frequent finding in kidney transplant patients and plays a causal role in insulin resistance and diabetes. The aim of this study was to investigate whether the pretransplant magnesium (Mg) level is a risk factor for the development of new-onset diabetes after kidney transplantation (NODAT) and the presence of relationship between pretransplant hypomagnesemia and the development period of NODAT.. Four hundred and nineteen nondiabetic renal transplant recipients were evaluated retrospectively. The patients were divided into NODAT and non-NODAT groups. The time of diagnosis of patients with NODAT was divided into 0 to 3, 3 to 6, 6 to 12 months, and after 12 months. Patients' characteristics and pretransplant Mg levels in NODAT were compared with non-NODAT, and it was investigated whether pretransplant hypomagnesemia was a risk factor for the development of NODAT.. Totally 70 (16.6%) patients (36 female [F], mean age 51.7 ± 8.2 years) were diagnosed with NODAT. Three hundred and forty-nine patients (115 F, mean age 43.2 ± 12.5 years) did not have NODAT. Pretransplant mean Mg level was 1.97 ± 0.40 mg/dL in patients with NODAT, while it was 2.5 ± 0.45 mg/dL in non-NODAT patients (P < .001). Serum Mg level was found to be similar in subgroups according to the development period of NODAT (P = .07). When patients were stratified according to quartiles of Mg level, the frequency of NODAT was significantly higher in patients in the lower quartile (Mg < 2.1 mg/dL; P < .001). Older age, high body mass index, and low pretransplant serum Mg levels were established as risk factors for developing NODAT. According to the quartile of Mg level, the risk of developing NODAT was highest in the lowest quartile.. Pretransplant hypomagnesemia is an independent risk factor of NODAT. Therefore, it is necessary to closely monitor the Mg levels in the posttransplant period.

Topics: Adult; Age Factors; Body Mass Index; Cyclosporine; Diabetes Mellitus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Insulin Resistance; Kidney Failure, Chronic; Kidney Transplantation; Magnesium; Male; Middle Aged; Mycophenolic Acid; Overweight; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Water-Electrolyte Imbalance

Obesity has been reported as risk factor for reduced posttransplant graft and patient survival and increased delayed graft function (DGF).. The purpose of this work is to analyze the effect of body mass index (BMI) on defined transplant outcomes in patients transplanted under defined guidelines in a kidney transplant program.. Review of a prospectively collected database in renal transplant recipients receiving rabbit antithymocyte globulin induction, mycophenolate mofetil, tacrolimus, and early corticosteroid withdrawal between 2001 and 2011.. This review was conducted in a single abdominal transplant program in the United States.. Primary outcome was death-censored graft survival categorized by posttransplant body mass groups. Secondary outcomes included DGF as well as patient survival.. Four hundred sixty seven patients were identified. No difference was observed in graft survival or DGF between BMI groups. One-year, death-censored graft survival and patient survival rates ranged from 97.5% to 100% and 96.6% to 100%, respectively. Delayed graft function was uncommon across all BMI groups, ranging from 5.3% to 9.1%, with the lowest incidence in patients with a BMI ≥ 35 kg/m(2). Biopsy-proven acute rejection rates at 1 year were similar across all groups (10.1%-14%) as were estimated glomerular filtration rates were at 1, 3, and 5 years.. Our results do not show an effect of BMI on posttransplant outcomes, suggesting that relaxation of BMI criteria may be warranted for recipient selection.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antilymphocyte Serum; Body Mass Index; Comorbidity; Databases, Factual; Delayed Graft Function; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Obesity; Overweight; Retrospective Studies; Survival Rate; Tacrolimus; Thinness; Treatment Outcome

We assessed the effect of hepatitis C seropositivity on the percentage of various T-cells in living donor renal transplant recipients (LDRTRs) and their association with intercurrent infections post renal transplantation (post-Tx).. One hundred and thirty-three matching LDRTRs [A (seronegative) (68 patients) and B (seropositive) (65 patients) by ELISA] were studied prospectively 10 days, 6 months and 12 months post-Tx for intercurrent infections, acute rejection and T-cell% by flow cytometry.. CD4(+), CD8(+), CD4/CD8 were significantly higher 10 days post-Tx in Group B compared to Group A, p < 0.001. A significant increase in CD8% was seen 6-month post-Tx among Group B compared to Group A. No difference was detected between groups in (CD4(+), CD8(+), CD4/CD8, CD3-CD16/65(+)%), rate and severity of intercurrent infection, rate of acute rejection, 12 months post-Tx. A significantly higher rate of severe infections particularly urinary tract infections (UTI) was noted in Group B compared to Group A the first 3 months post-Tx particularly in those who received the combination of antithymocyte globulin (ATG) or basiliximab, tacrolimus, steroids, mycophenolate mofetil (MMF). CD4(+)% correlated negatively with intercurrent infections in Group B 6 months post-Tx.. HCV(+) patients are more prone to intercurrent infections the first 3 months post-Tx. Infection rate correlates positively with pre-transplant HCV seropositivity and immunosuppressive regimen.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Basiliximab; CD4-CD8 Ratio; Child; Egypt; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Regression Analysis; T-Lymphocytes; Tacrolimus; Urinary Tract Infections; Young Adult

The clinic-pathological features and outcomes of Chinese patients with antineutrophil cytoplasmic autoantibody (ANCA)-positive eosinophilic granulomatosis with polyangiitis (EGPA) and renal involvement have not been studied.. Fourteen EGPA patients with renal involvement were included. All patients underwent renal biopsy. Clinic-pathological features and outcomes were retrospectively analyzed.. The most common initial symptom of EGPA was asthma (57.1 %), followed by hemoptysis (21.4 %), gross hematuria (14.3 %), and arthritis (7.1 %). All patients had positive serum ANCA (anti-MPO in 12, anti-PR3 in 2). Elevated eosinophils (median 15 %, range 10-45 %) were found in all patients. The median serum IgE level was 463 g/L (range 200-1000 g/L). All patients presented with renal dysfunction, with a median SCr of 5.4 mg/dL (range 1.47-11 mg/dL), seven patients (50 %) required initial renal replacement therapy. Thirteen patients showed hematuria and proteinuria (median 1.1 g/24 h, range 0.5-7.8 g/24 h). Renal biopsy showed pauci-immune segmental necrotizing glomerulonephritis with crescents in 13 patients and acute interstitial nephritis in one patient. Twelve patients (85.7 %) showed renal interstitial eosinophil infiltration, among whom three had eosinophilic granuloma. Among seven patients (71.4 %) who required initial dialysis, 5 discontinued dialysis, one died, one received maintenance dialysis after glucocorticoids plus immunosuppressive for induction treatment. Twelve patients were followed up for a median of 43.5 months (range 6-83 months), during follow-up, two patients progressed to end-stage renal disease, nine had chronic kidney disease with eGFR < 60 mL/min, and two patients had normal eGFR.. Renal involvement in ANCA-positive EGPA could be severe and showed varied renal histology. Although intensive immunosuppressive therapy effectively improved the renal function, the long-term renal survival was poor. Early diagnosis and treatment are essential to improve long-term renal survival.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Antibodies, Antineutrophil Cytoplasmic; Blood Cell Count; China; Churg-Strauss Syndrome; Creatinine; Cyclophosphamide; Disease Progression; Drug Therapy, Combination; Eosinophils; Female; Glomerular Filtration Rate; Hematuria; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Prednisone; Proteinuria; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Time Factors; Young Adult

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

Topics: ABO Blood-Group System; Acute Disease; Adult; Cystic Fibrosis; Disease-Free Survival; Female; Graft Rejection; HLA Antigens; Humans; Isoantigens; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Lung Transplantation; Middle Aged; Mothers; Mycophenolic Acid; Plasmapheresis; Prednisolone; Sepsis; Tacrolimus; Withholding Treatment

Topics: Adolescent; Anuria; Cyclosporine; Female; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Immunosorbent Techniques; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Plasmapheresis; Postoperative Complications; Prednisolone; Recurrence; Renal Dialysis

Pretransplant removal of antiblood group ABO antibodies is the cornerstone of all current ABO-incompatible (ABOi) transplantation programmes. In our protocol, plasmapheresis (PP) is performed with a plasmafilter followed by immunoadsorption (IA) of anti-ABO antibodies. The bleeding complications of this technique are not known. We analysed the data of all 65 consecutive ABOi kidney transplantations between March 2006 and October 2013 and compared these with matched 130 ABO-compatible (ABOc) kidney transplantations. Cases differed from controls in the pre-operative regimen, which included IA-PP and rituximab, tacrolimus, mycophenolate mofetil, prednisone and immunoglobulines. Data on platelet count, blood loss and red blood cell (EC) transfusions during 48 h postoperatively were collected. ABOi patients received EC transfusions more frequently than controls (29% vs. 12%, P = 0.005). Intra-operative blood loss was higher (544 vs. 355 ml, P < 0.005) and they experienced more major bleeding (≥3 EC within 24 h, 15% vs. 2%, P < 0.0005). Platelet count decreased by 28% after the pre-operative IA. In a multivariate model, only the number of pre-operative IAs was associated with the number of ECs given (OR per IA 1.9, P < 0.05). ABOi kidney transplant recipients have a high postoperative bleeding risk, correlating with the number of pre-operative IA sessions performed.

Topics: ABO Blood-Group System; Antibodies; Antibodies, Monoclonal, Murine-Derived; Antigens; Blood Group Incompatibility; Case-Control Studies; Cohort Studies; Erythrocyte Transfusion; Female; Hemorrhage; Humans; Immunoglobulins; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Platelet Count; Prednisone; Rituximab; Tacrolimus

Little is known about the correlation between the inosine-monophosphate dehydrogenase (IMPDH) activity and mycophenolic acid (MPA) concentrations in peripheral-blood-mononuclear cells (PBMCs), where the drug is acting. The aim of this study was to analyze the relationship between plasma or PBMC MPA levels, as pharmacokinetic (PK) markers, and the intracellular IMPDH enzyme activity, as a pharmacodynamic (PD) biomarker, in kidney transplantation.. Forty de novo renal transplant patients were enrolled in this prospective study. The sampling was performed on the day before transplantation and at T0, T1.5 and T3.5 following the morning dose, on days 2, 4 and 10 post-transplantation. All subjects were treated with a fixed MMF dose (500 mg twice-a-day). IMPDH activities were determined by HPLC, and MPA plasma or PBMC concentrations were obtained by LC-MSMS.. Important inter-patient variability was observed both for the PK and PD biomakers. Pre-dose IMPDH activity, surprisingly, increased during the 10 days post-transplantation. As expected, a significant inverse relationship was found between IMPDH activities and MPA concentrations in both plasma and PBMCs. A significant correlation was found between plasma and PBMC MPA values. Maximum IMPDH inhibition was found mostly at T1.5, before returning to its pre-dose levels at T3.5. IMPDH inhibition at T1.5 better correlated with plasma MPA AUC(0-3.5) (p=0.027) than with PBMC AUC(0-3.5) (p=0.323). Mean MPA plasma concentrations paralleled the enzyme inhibition profiles and decreased strongly at T3.5, whereas the decreasing slope of MPA concentrations in PBMCs appeared slower.. These findings suggest that PBMC MPA concentrations do not provide any better correlation with the IMPDH activity than plasma MPA values, most likely due to the correlation between plasma and PBMC MPA levels and to the important interpatient variability both in MPA levels and enzyme activities.

Topics: Adult; Aged; Area Under Curve; Enzyme Inhibitors; Female; Humans; IMP Dehydrogenase; Kidney Failure, Chronic; Kidney Transplantation; Leukocytes, Mononuclear; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tissue Distribution; Young Adult

The calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs, which are typically employed in the field of organ transplantation. Both drugs have narrow therapeutic indices, highly variable pharmacokinetics, and are associated with severe adverse effects. In current clinical routine, the dose finding of CNIs is based on the measurement of their blood concentrations. However, this method is limited in its ability to determine the biological impact of the drug. Alternative monitoring strategies, focusing on the pharmacodynamics of CNIs, could help to personalize drug dosing and optimize the treatment with CNIs. Therefore, we analyzed the relationship between pharmacokinetic and pharmacodynamic of the CNIs CsA (n = 9) and Tac (n = 8) in stable renal transplant patients during a 12-h dosing period. We observed a significant decrease in the drug-blood concentration during the course of the day and in parallel a significant recovery of T cell function. In addition, our data document that analysis of intracellular interleukin (IL)-2 production and determination of the IL-2 release are accurate parameters for monitoring the pharmacodynamics of CNIs.

Topics: Calcineurin Inhibitors; Cyclosporine; Drug Monitoring; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus; Tissue Distribution

The objective of this study was to assess clinicopathological characteristics and outcomes of lupus nephritis adult patients in China.. Clinicopathological features, treatment strategies, responses and outcome of 681 adult patients with biopsy-proved lupus nephritis were retrospectively analyzed.. Six hundred and eighty-one LN patients were included and followed up for 52.5 ± 14.1 months. Differences in age, disease duration, BP, proteinuria, serum albumin, creatinine, ANCA-positive ratio and SLEDAI scores were noticed between male and female patients, indicating severer disease in male patients. LN IV patients were much severer in systemic damage as well as immunological changes. During follow-up, 354 patients achieved CR, 107 patients achieved PR, 95 patients progressed to ESRD and 36 patients died. Prognosis and treatment response of patients with different histological types differ apparently. Renal outcome of patients with LN II and III was benign, while LN IV, V and VI was poor. Cyclophosphamide was effective in most patients. MMF and CNI could be used as salvage treatment. In multivariate analysis, BP, sCr, hypocomplementemia, severe proliferative lesion (LN IV or VI) and SLEDAI score were recognized as independent indicators of poor renal outcome. Infections, especially pulmonary fungus infection, thrombotic microangiopathy are the most common causes of death in LN patients.. Clinicopathological characteristics, treatment responses and long-term outcomes differ remarkably in LN patients with different gender and pathological subtypes. New indicators of poor renal outcome were identified. Infections and TTP were the most common causes of death in LN patients.

Topics: Adolescent; Adult; Calcineurin Inhibitors; Cause of Death; Child; China; Cyclophosphamide; Disease Progression; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prognosis; Retrospective Studies; Severity of Illness Index; Sex Factors; Treatment Outcome; Young Adult

Background Renal replacement therapy was first introduced in Yemen in 1978 in the form of hemodialysis. Twenty years later, the first renal transplantation was performed. Kidney transplantations were started in socially and financially challenging circumstances in Yemen in 1998. A structured program was established and has been functioning regularly since 2005. A pediatric transplantation program was started in 2011. Material and Methods This was a prospective study of 181 transplants performed at the Urology and Nephrology Center between May 1998 and 2012. All transplants were from living related donors. The immunosuppressive protocol consisted initially of double therapy with steroid and mycophenolate mofetil (MMF). Subsequently, triple therapy with addition of a calcineurin inhibitor was introduced. Primary graft function was achieved in 176 (97.2%) recipients. Results Cold ischemia time was 48-68 min. Episodes of acute rejection in 12 patients were treated with high-dose steroids. Anti-thymocyte globulin (ATG) was used in cases of vascular or steroid-resistant rejection in 2 patients. The post-transplant complications, either surgical or medical, were comparable to those recorded in the literature. Conclusions Renal transplantation is a good achievement in our country. The patients and graft survival rates are comparable to other reports.

Topics: Calcineurin Inhibitors; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Prospective Studies; Survival Rate; Treatment Outcome; Yemen

Data on transplantation survival is widely available for developed countries where cadaveric transplantation is the dominant transplantation type. We aimed to assess patient and graft survival and to determine the possible factors affecting graft survival in a developing country where kidney transplantations were mainly performed from living donors.. We retrospectively analyzed data from 427 adult kidney transplantations performed at our center from January 1990 to November 2010. We collected data from patient files, including characteristics of the recipients and donors, transplantation-related factors, post-transplantation features, causes of graft loss, and patient death. The Kaplan-Meier method was used to analyze survival, and Cox regression analysis was used to evaluate the effects of multiple factors on graft survival.. Most of the recipients (82.6%) received their organs from living donors. One-year and 5-year graft survival rates were 87.5% and 78.3%, respectively, where the 5-year graft survival rates were 87.1% for living donors and 74.8% for cadaveric donors. The 1-year and 5-year patient survival rates were 90.9% and 88.9%, respectively. Univariate analysis showed that predictors for better graft survival were serum creatinine levels <1.5 mg/dL at 1 month after transplantation, proteinuria <500 mg/d at 1 year after transplantation, use of tacrolimus and mycophenolic acid derivative-based immunosuppression at baseline, living-donor transplantation, and transplantations performed in the years 2000-2010.. We report data on kidney transplantation in an emerging country where living-donor transplantation constitutes a large proportion of kidney transplant activities. Modern immunosuppressive medications help to achieve a better survival. Our 5-year results are similar to those of developed countries.

Topics: Adult; Aged; Creatinine; Developing Countries; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Survival Analysis; Survival Rate; Tacrolimus; Tertiary Care Centers; Turkey

The Collaborative Brazilian Pediatric Renal Transplant Registry started in 2004 as a multicenter initiative aiming to analyze, report, and share the results of pediatric kidney transplantation in Brazil. Data from all pediatric kidney transplants performed between January 2004 and December 2013 were recorded electronically and periodically updated. All patients under 18 years old from the participating centers were enrolled. Demographic data, etiology of chronic kidney disease, and patient and graft survival were analyzed. From a total of 2443 pediatric kidney transplants performed in Brazil during the study period, we report data from 1751 pediatric renal transplants performed in 13 centers enrolled in the collaborative study. Median age at transplantation was 12.4 years, and most of recipients were male (56%). The most common underlying renal etiologies were obstructive uropathy (31%) and glomerulopathy (26%).. According to donor source, 1155 (66%) of transplants were performed with deceased donors (DD). Initial immunosuppression consisted mainly of tacrolimus, mycophenolate, steroids, and induction therapy with anti-IL-2R antibodies.. One-year graft survival (death-censored) was 93% and 90% (log rank test, P < .01), respectively, for living donor (LD) and DD. Graft losses (15%) were most frequently caused by vascular thrombosis, chronic allograft nephropathy, death with functioning kidney, acute rejection, and recurrent renal disease. Recipients of DD had 2.02 (95% confidence interval: 1.14-3.59) times the hazard of graft loss compared with those of LD (P = .015). Patient survival rates at 1 and 5 years were 98% and 97% for LD and 97% and 93% for DD, respectively. The mortality rate was 3.8%, mainly as the result of infection and cardiovascular disease.. The results of this collaborative pediatric transplant study are comparable to international registries. Our effort has been able to maintain an exchange of information, both among the participating centers and with other international registries.

Topics: Adolescent; Adrenal Cortex Hormones; Brazil; Child; Child, Preschool; Cooperative Behavior; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Proportional Hazards Models; Recurrence; Registries; Renal Insufficiency, Chronic; Survival Rate; Tacrolimus; Tissue Donors

ANCA-associated vasculitis (AAV) with renal involvement is not uncommon in older individuals. Unfortunately, this can be catastrophic requiring hemodialysis (HD) and may lead to end stage renal disease (ESRD). However, more than 50 % of patients with AAV who require HD initially have renal recovery and discontinue HD. The aim of this study was to describe a retrospective cohort of older patients with AAV and severe renal involvement which required hemodialysis.. Between 1995 and 2013 a total of 30 patients with histologic evidence of pauci-immune glomerulonephritis who required HD were evaluated at a single university center. The association of demographic and clinical parameters with age was assessed. Older age of disease onset was defined as age ≥ 60 years. The risk of developing ESRD at 3 months was examined using univariate logistic regression analysis.. Among 30 patients with AAV who required HD, the mean age of disease onset was 59 ± 17 years (range 22-88 years). Twelve patients were in the older age group, and 18 were in the younger group. Three months after diagnosis, 43 % of the cohort had ESRD with a statistically similar proportion of older (n = 9, 50 %) versus younger (n = 4, 33 %) patients (p = 0.367). Most patients (93 %) received immunosuppressive therapy. There was not a statistically significant association between age and ESRD.. These data suggest that age alone does not predict renal recovery among individuals on HD due to AAV. Renal recovery is a realistic expectation and outcome, if patients are treated, even among older patients with AAV who require HD initially.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Cyclophosphamide; Disease Progression; Female; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Microscopic Polyangiitis; Middle Aged; Mycophenolic Acid; Renal Dialysis; Retrospective Studies; Rituximab; Young Adult

C3 glomerulonephritis is a clinicopathologic entity defined by the presence of isolated or dominant deposits of C3 on immunofluorescence. To explore the effect of immunosuppression on C3 glomerulonephritis, we studied a series of 60 patients in whom a complete registry of treatments was available over a median follow-up of 47 months. Twenty patients had not received immunosuppressive treatments. In the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate mofetil while 18 were treated with other immunosuppressive regimens (corticosteroids alone or corticosteroids plus cyclophosphamide). The number of patients developing end-stage renal disease was significantly lower among treated compared with untreated patients (3 vs. 7 patients, respectively). No patient in the corticosteroids plus mycophenolate mofetil group doubled serum creatinine nor developed end-stage renal disease, as compared with 7 (significant) and 3 (not significant), respectively, in patients treated with other immunosuppressive regimens. Renal survival (100, 80, and 72% at 5 years) and the number of patients achieving clinical remission (86, 50, and 25%) were significantly higher in patients treated with corticosteroids plus mycophenolate mofetil as compared with patients treated with other immunosuppressive regimens and untreated patients, respectively. Thus, immunosuppressive treatments, particularly corticosteroids plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents; Complement C3; Creatinine; Cyclophosphamide; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Survival Rate; Young Adult

Renal transplantation in highly sensitized patients represents a major clinical challenge leading to long periods on the waiting list. When a living donor is available, the use of different strategies to desensitize recipients with preformed human leukocyte antigen antibodies can allow a successful transplantation.. We performed a retrospective observational study including all living donor kidney transplantation (LDKT) with desensitization (DS) from 2008 to 2014 in our transplant unit. The rates of rejection and graft survival were evaluated. DS consisted of plasma exchange (PE), rituximab (RTX), and intravenous immunoglobulin (IVIG) induction with thymoglobulin and maintenance immunosuppression with tacrolimus, corticosteroids, and mycophenolate mofetil.. From 2008 to 2014, we performed 368 LDKT, with 31 receiving desensitization. Seven cases from a clinical trial were excluded. Demographic data and outcomes were recorded. All of the patients received RTX + PE + IVIG. DS was performed for positive complement-dependent cytotoxicity cross-match (4.2%), T-cell- and/or B-cell-positive flow cytometry cross-match (87.5%) and presence of donor-specific antibodies alone (8.3%). We identified 23 episodes of rejection in 12 patients (50%); 79% were antibody-mediated rejections (AMR). Graft failure was 12.5%, with a mean time to graft loss of 229 ± 203 days. Mean follow-up was 37 ± 27 months, and graft survival was 91% and 86% at 1 and 5 years, respectively.. Desensitization in LDKT appears to offer an acceptable option for highly sensitized patients. In our series, 41% presented an AMR and 12.5% showed transplant glomerulopathy in protocol and/or indication biopsies. However, short-term outcomes and graft survival were satisfactory.

Topics: Adult; Aged; Antilymphocyte Serum; Desensitization, Immunologic; Female; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Plasmapheresis; Retrospective Studies; Rituximab; Treatment Outcome; Young Adult

Selective interleukin-2 receptor (IL2R) blockade is one option to decrease acute rejection rates in kidney transplant recipients. However, there are little data on the impact of basiliximab in a triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and low-dose steroids). Thus, this analysis aims at investigating the impact of basiliximab induction on rejection rates and immediate graft function following kidney transplantation.. Basiliximab was introduced in our center according to our center's policy in the beginning of 2011. Patients who received basiliximab (n = 83) were compared with patients without induction therapy (n = 65) transplanted before the introduction of IL2R antibody induction.. The use of basiliximab as induction therapy decreased the incidence of biopsy-proven acute rejection (BPAR) within the 1st year after transplantation (21.5% vs 14.5%; P = .283). Overall rejection episodes (including BPAR and borderline rejection) were significantly reduced in patients with basiliximab compared with patients without (41.5% vs 24.1%; P = .033). However, graft function (incidence of delayed graft function, primary nonfunction, slow graft function, and serum creatinine decline) and overall outcome (patient and graft survivals) were similar in both groups.. We found a favorable impact of basiliximab induction therapy on early acute rejection rate. The impact on long-term outcome must be addressed in further randomized controlled trials.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Retrospective Studies; Steroids; Tacrolimus

Bronchiectasis is characterized by abnormal, permanent and irreversible dilatation of the bronchi, usually responsible for daily symptoms and frequent respiratory complications. Many causes have been identified, but only limited data are available concerning the association between bronchiectasis and renal transplantation.. We conducted a retrospective multicenter study of cases of bronchiectasis diagnosed after renal transplantation in 14 renal transplantation departments (French SPIESSER group). Demographic, clinical, laboratory and CT scan data were collected.. Forty-six patients were included (mean age 58.2 years, 52.2 % men). Autosomal dominant polycystic kidney disease (32.6 %) was the main underlying renal disease. Chronic cough and sputum (50.0 %) were the major symptoms leading to chest CT scan. Mean duration of symptoms before diagnosis was 1.5 years [0-12.1 years]. Microorganisms were identified in 22 patients, predominantly Haemophilus influenzae. Hypogammaglobulinemia was observed in 46.9 % patients. Bronchiectasis was usually extensive (84.8 %). The total bronchiectasis score was 7.4 ± 5.5 with a significant gradient from apex to bases. Many patients remained symptomatic (43.5 %) and/or presented recurrent respiratory tract infections (37.0 %) during follow-up. Six deaths (13 %) occurred during follow-up, but none were attributable to bronchiectasis.. These results highlight that the diagnosis of bronchiectasis should be considered in patients with de novo respiratory symptoms after renal transplantation. Further studies are needed to more clearly understand the mechanisms underlying bronchiectasis in this setting.

Topics: Adult; Agammaglobulinemia; Aged; Aged, 80 and over; Azathioprine; Bronchiectasis; Chronic Disease; Cough; Cyclosporine; Everolimus; Female; Forced Expiratory Volume; Graft Rejection; Haemophilus Infections; Haemophilus influenzae; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polycystic Kidney, Autosomal Dominant; Respiratory Tract Infections; Retrospective Studies; Risk Factors; Rituximab; Sirolimus; Tacrolimus; Tomography, X-Ray Computed; Vital Capacity; Young Adult

Renal transplantation in HIV-positive patients with end-stage renal disease has in recent years become a successful treatment option. We report two patients who underwent renal transplantation using a combination of basiliximab, calcineurin inhibitors, mycophenolate mofetil (MMF), and steroids with a "non-interacting" antiretroviral combination therapy consisting of stavudine or abacavir, lamivudine, and nevirapine. We observed no acute rejection but a BK polyomavirus infection in both patients. In conclusion, a quadruple immunosuppression with an interleukin 2 receptor antagonist, a calcineurin inhibitor, MMF, and steroids appears to be advisable to prevent high rates of acute rejection, but if possible thereafter immunosuppression should be tapered rapidly (eg, MMF stop, prednisolone dose 5 mg/d). The selection of antiretroviral agents should avoid compounds that interact severely with the immunosuppression used.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Calcineurin Inhibitors; Drug Therapy, Combination; Female; Graft Rejection; HIV Infections; Hospitals, University; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Prednisolone; Recombinant Fusion Proteins; Steroids

A recent report has demonstrated that as with mycophenolate mofetil (MMF), everolimus is capable of inhibiting human B-lymphocyte function and activation including B-lymphocyte proliferation, apoptosis, and immunoglobulin production in vitro. Everolimus may therefore be used as an immunosuppressant in ABO-incompatible kidney transplantation.. A three-month pilot study was performed to examine the efficacy and safety of conversion of stable ABO-incompatible kidney transplant recipients from MMF with standard exposure calcineurin inhibitors (CNIs) to everolimus with very low exposure CNIs. Sixteen recipients were enrolled in the study. The patients without acute rejection by graft biopsy were switched from MMF to everolimus with CNI minimization. At three months after conversion, graft biopsies were performed to check for acute rejection and C4d deposition.. Conversion to everolimus with CNI minimization for three months did not induce acute rejection and C4d deposition in all of the ABO-incompatible kidney transplant recipients. A slight elevation of anti-A/B antibody titer occurred in our present study. Everolimus was associated with hyperlipidemia and edema.. These results demonstrated that short-term conversion from MMF to everolimus after one yr post-transplant may be a safe and effective alternate for ABO-incompatible kidney transplant recipients requiring temporary discontinuation of MMF.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prognosis; Sirolimus; Time Factors

Mycophenolic acid Observational REnal transplant (MORE) was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA). Four-yr data on 904 patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) were analyzed to evaluate immunosuppression and graft outcomes in African American (AA, n = 218) vs. non-AA (n = 686) patients. Mean tacrolimus dose was higher in AA vs. non-AA patients but mean tacrolimus trough concentration was similar. Use of the recommended MPA dose in AA patients decreased from 78.9% at baseline to 33.1% at year 3. More AA patients received the recommended MPA dose with EC-MPS than MMF at month 6 (56.2% vs. 35.7%, p = 0.016) and month 36 (46.6% vs. 16.7%, p = 0.029), with no safety penalty. Significantly, more AA patients received corticosteroids than non-AA patients. Biopsy-proven acute rejection was higher in AA vs. non-AA patients (18.9% vs. 10.7%, p = 0.003), as was graft loss (10.9% vs. 4.4%, p = 0.003); differences were confirmed by Cox regression analysis. Patient survival was similar. Estimated GFR was comparable in AA vs. non-AA patients. Kidney allograft survival remains lower for AA vs. non-AA recipients even under the current standard of care.

Topics: Adult; Black or African American; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Prospective Studies; Time Factors

To retrospectively investigate clinico-pathological features and outcomes of patients with renal involvement in propylthiouracil (PTU)-associated antineutrophil cytoplasmic autoantibody (ANCA) vasculitis (PTU-AAV).. Clinico-pathological features and outcomes of 12 patients (female 11, average age 32.4 ± 13.8 years) who developed AAV after treatment with PTU were collected and analyzed. ANCA was detected by both immunofluorescence (IF) and enzyme linked immunosorbent assay (ELISA). All patients had renal biopsy.. Twelve patients received PTU for 2-264 months (median 42 months) when PTUAAV was diagnosed. All patients had positive serum P-ANCA, 11 of them were MPO-ANCA, 1 was MPO and PR3-ANCA double positive. All patients presented with hematuria and proteinuria, 5 of them had gross hematuria, urine protein was 1.9 ± 1.6 g/24 h, 7 of 12 (58.3%) patients had renal dysfunction, among them 3 needed initial renal replacement therapy. Renal biopsy showed pauci-immune segmental necrotizing crescentic glomerulonephritis in ten patients, segmental necrotizing glomerulonephritis superimposed on membranous nephropathy in two patients. All patients withdrew PTU and received steroid and immunosuppressive therapy. After a median follow-up of 42 months (range 21-86), 3 patients developed to ESRD, 7 patients entered complete renal remission. Serum ANCA turned negative only in 2 patients, 10 patients had persistent positive serum ANCA. Three patients relapsed with the elevation of serum ANCA level.. Renal damage of PTU-AAV could be pauci-immune necrotizing crescentic glomerulonephritis, and necrotizing glomerulonephritis coexisted with membranous nephropathy. Most patients had persistent positive serum ANCA and had a risk of relapse and progression to ESRD even after PTU withdrawal and immunosuppressive therapy.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Child; Cyclophosphamide; Disease Progression; Hematuria; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Mycophenolic Acid; Prednisone; Propylthiouracil; Proteinuria; Recurrence; Remission Induction; Renal Replacement Therapy; Retrospective Studies; Thyroid Diseases; Young Adult

mTOR inhibitors avoid calcineurin nephrotoxicity, but sirolimus de novo is associated with unacceptable side effects and higher rejection rates. We have investigated a modified strategy: alemtuzumab induction with tacrolimus and mycophenolate maintenance, switching from tacrolimus to sirolimus at 6 months and stopping mycophenolate at 12 months. Here, we report the 6-year follow-up of 30 patients prospectively recruited to this single-arm pilot study and compare outcomes to a matched contemporaneous control group of 30 patients who received standard induction and calcineurin-inhibitor-based immunosuppression.Six-year patient and graft survival were 83% and 80%(alemtuzumab) versus 77% and 70% (control). Rejection rates in the first 6 months were similar in alemtuzumab (6.6%) and control groups (10%). A higher than expected incidence of rejection in the alemtuzumab group following cessation of mycophenolate at 1 year (17%) was mitigated in later patients by retaining low dose mycophenolate. Mean eGFR was higher in the alemtuzumab group at all time points but not significantly (p¼0.16). Tacrolimus levels in the first 6 months were significantly higher in the contemporaneous control group (p<0.001). Alemtuzumab induction with initial treatment with tacrolimus enables conversion to sirolimus without the side effects and incidence of acute rejection seen in earlier protocols.

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Sirolimus; Survival Rate

Topics: Black or African American; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid

Alemtuzumab is a monoclonal antibody targeting CD52 receptors on B and T lymphocytes and is an effective induction agent in pediatric renal transplantation. We report a seven-yr experience using alemtuzumab induction and steroid-free protocol in the pediatric population as safe and effective. Twenty-one pediatric deceased donor renal transplants were performed at a single academic institution. All received induction with single-dose alemtuzumab and were maintained on a steroid-free protocol using TAC and MMF immunosuppression. There were 15 males and six females in the study whose ages ranged from one to 19 yr. The average follow-up was 32 months (range from 12 to 78.2 months and median 33.7 ± 23.7 months). All patients had immediate graft function. Graft survival was 95%, and patient survival was 100%. Mean 12 and 36 months eGFR were 63.33 ± 21.01 and 59.90 ± 15.27 mL/min/1.73m(2), respectively. Three patients developed acute T-cell-mediated rejection due to non-adherence while no recipients developed cytomegalovirus infection, PTLD, or polyoma BK viral nephropathy. Steroid avoidance with single-dose alemtuzumab induction provides adequate and safe immunosuppression in pediatric deceased donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy.

Topics: Adolescent; Adrenal Cortex Hormones; Alemtuzumab; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Maintenance Chemotherapy; Male; Mycophenolic Acid; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

Racial differences among kidney transplant recipients may impact the total daily tacrolimus dose required to achieve therapeutic tacrolimus concentrations. Previous studies suggest that African Americans require higher doses to achieve similar therapeutic drug concentrations compared with Caucasians. Data were collected on a total of 147 de novo kidney transplant recipients. Tacrolimus total daily dose (TDD) requirements (mg/kg/d) and tacrolimus concentrations were retrospectively reviewed at discharge and at days 30, 60, and 90 after transplant. TDD requirements in African-American and Caucasian patients were 0.14 mg/kg/d and 0.11 mg/kg/d, respectively (p = 0.005), at day 30. TDD requirements at day of hospital discharge and days 60 and 90 following transplant were significantly higher in African-American patients vs. Caucasian patients, with similar tacrolimus concentrations at all time points. This study suggests that when compared to Caucasians, African Americans require significantly higher TDD of tacrolimus to achieve similar tacrolimus concentrations. These findings provide transplant clinicians with a sense of certainty to more rapidly titrate daily tacrolimus doses in African-American patients to achieve therapeutic concentrations.

Topics: Anti-Inflammatory Agents; Black or African American; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Transplant Recipients; White People

Tacrolimus exposure and renal function data to 36 months post-transplant were analyzed from the prospective, observational Mycophenolic acid Observational REnal transplant (MORE) registry in which de novo kidney transplant patients were managed according to local practice. Tacrolimus trough (C0 ) concentration at month 12 was stratified as low (<6 ng/mL), moderate (6-8 ng/mL), or high (>8 ng/mL) in 724 patients. Estimated glomerular filtration rate (eGFR) was stratified as low (<60 mL/min/1.73 m(2) ) or high (≥60 mL/min/1.73 m(2) ). High tacrolimus C0 (>8 ng/mL) was observed in 47.7%, 34.1%, 26.8%, and 26.7% of patients at baseline and months 12, 24, and 36, respectively. Biopsy-proven acute rejection was similar to month 36 regardless of tacrolimus C0 category at month 12. Tacrolimus C0 >8 ng/mL vs. <6 ng/mL at month 12 was predictive of low eGFR at month 24 (p = 0.023) with a nonsignificant trend at month 36 (p = 0.085). Infections (p < 0.013) and BK virus infection (p < 0.001) were most frequent in the low tacrolimus C0 cohort. Neutropenia was most frequent in the high tacrolimus C0 category (p = 0.010). In conclusion, over a quarter of patients were exposed to high tacrolimus C0 to 36 months post-transplant. Tacrolimus exposure did not affect rejection risk, but tacrolimus C0 >8 ng/mL at month 12 was predictive of subsequent low eGFR compared to C0 <6 ng/mL.

Topics: Adult; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Tacrolimus

MORE was a four-yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC-MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC-MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy-proven acute rejection, graft loss or death to be similar for EC-MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC-MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC-MPS and MMF cohorts during follow-up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC-MPS vs. MMF, without an increase in adverse events.

Topics: Adult; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Prospective Studies; Risk Factors; Tablets, Enteric-Coated; Tacrolimus

Using rituximab, we have performed successful ABO-incompatible kidney transplantations in recipients without splenectomy as well as in those with high pretransplant anti-A/B antibody titers. A common and increasingly recognized toxicity of rituximab is late-onset neutropenia (LON), defined as unexplained grades III to IV neutropenia occurring at least 4weeks after the last dose of rituximab in the absence of an alternative explanation.. Between May 2006 and December 2011, 25 patients who received rituximab underwent successful ABO-incompatible kidney transplantation and were enrolled as the subjects in this study. The incidence rate and clinical features of LON as well as the relationship between LON and acute rejection in these patients were studied.. Twelve recipients (48%) experienced LON 2 to 12months after transplantation. Five of the 12 patients (41.6%) who developed LON had an episode of biopsy-confirmed acute cellular rejection, as compared with one of the 13 patients (7.7%) who did not develop LON. Moreover, 3 patients who experienced LON developed steroid and deoxyspergualin-resistant acute cellular rejection requiring OKT-3 administration.. The frequency of acute cellular rejection was higher in ABO-incompatible kidney transplant recipients with LON than in those without LON. Our findings suggested that these recipients who developed LON after rituximab administration may be at an increased risk for acute cellular rejection.

Topics: ABO Blood-Group System; Adolescent; Adult; Aged; Allografts; Antibodies; Antibodies, Monoclonal, Murine-Derived; Antigens, CD19; Antigens, CD20; Blood Group Incompatibility; Female; Graft Rejection; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Subsets; Male; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Neutropenia; Rituximab; Transplant Recipients; Young Adult

One of the main concerns associated with renal transplantation in HIV-infected patients is the high risk of acute rejection, which makes physicians reluctant to use steroid-free immunosuppressive therapy in this subset of patients. However, steroid therapy increases cardiovascular morbidity and mortality. The aim of this study was to define the efficacy of a steroid-sparing regimen in HIV-infected renal transplant recipients. Thirteen HIV-infected patients were consecutively transplanted. The induction therapy consisted of basiliximab and methylprednisolone for 5 days followed by a calcineurin inhibitor plus mycophenolate acid. The mean follow-up was 50 ± 22 months. Eight patients (61.5%) experienced acute rejection, and 75% of the first episodes occurred within 2 months after transplantation. The probability of first acute rejection was 58% after 1 year and 69% after 4 years. Seven of eight patients recovered or maintained their kidney function after antirejection therapy and steroid resumption. At the last follow-up, seven of 13 patients (54%) had resumed steroid therapy. The 4-year patient and graft survivals were 100% and 88.9%, respectively. The benefits of this steroid-free regimen in HIV-infected renal recipients must be reconsidered because of the high rate of acute rejection. New immunosuppressive steroid-free strategies should be identi-fied in this set of patients.

Topics: Adult; Calcineurin Inhibitors; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; HIV Infections; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Assessment; Steroids; Survival Analysis; Transplantation Immunology; Treatment Outcome; Young Adult

There is continued and significant debate regarding the salient etiologies associated with graft loss and racial disparities in kidney transplant recipients.. This was a longitudinal cohort study of all adult kidney transplant recipients, comparing patients with early graft loss (<5 years) to those with graft longevity (surviving graft with at least 5 years of follow-up) across racial cohorts [African-American (AA) and non-AA] to discern risk factors.. 524 patients were included, 55% AA, 151 with early graft loss (29%) and 373 with graft longevity (71%). Consistent within both races, early graft loss was significantly associated with disability income [adjusted odds ratio (AOR) 2.2, 95% CI 1.1-4.5], Kidney Donor Risk Index (AOR 3.2, 1.4-7.5), rehospitalization (AOR 2.1, 1.0-4.4) and acute rejection (AOR 4.4, 1.7-11.6). Unique risk factors in AAs included Medicare-only insurance (AOR 8.0, 2.3-28) and BK infection (AOR 5.6, 1.3-25). Unique protective factors in AAs included cardiovascular risk factor control: AAs with a mean systolic blood pressure <150 mm Hg had 80% lower risk of early graft loss (AOR 0.2, 0.1-0.7), while low-density lipoprotein <100 mg/dl (AOR 0.4, 0.2-0.8), triglycerides <150 mg/dl (AOR 0.4, 0.2-1.0) and hemoglobin A1C <7% (AOR 0.2, 0.1-0.6) were also protective against early graft loss in AA, but not in non-AA recipients.. AA recipients have a number of unique risk factors for early graft loss, suggesting that controlling cardiovascular comorbidities may be an important mechanism to reduce racial disparities in kidney transplantation.

Topics: Adult; Aged; BK Virus; Black or African American; Cardiovascular Diseases; Cohort Studies; Dyslipidemias; Female; Graft Rejection; Graft Survival; Health Status Disparities; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Medicare; Middle Aged; Mycophenolic Acid; Odds Ratio; Polyomavirus Infections; Prednisone; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; United States

Calcineurin inhibitor (CNI) combined with mycophenolate mofetil (MMF) and steroid is mainly used as immunosuppressive therapy after the living-donor liver transplantation (LDLT). However, the nephrotoxicity caused by CNI remains a critical problem for patients with chronic renal failure, especially on early postoperative period. A 62-year-old woman with decompensated liver cirrhosis secondary to hepatitis B (Child-Pugh C, MELD score 11 points) and chronic renal failure due to diabetic nephropathy (Cr 1.56 mg/dl, GFR 27 ml/min/1.73 m2) experienced LDLT. During the reconstruction of hepatic vein, the supra-and infra-hepatic vena cava was totally clamped. The estimated right lobe liver graft volume was 540 g, representing 51.3% of the standard liver volume of the recipient. Because of the perioperative renal dysfunction due to diabetic nephropathy and the total clamping the vena cava which induced the congestion kidney, MMF (1500 mg/day) and steroid (250 mg/day converted into predonisolone) were mainly introduced as an immunosuppressive therapy after LDLT. The low-dose CNI, tacrolimus also induced the nephrotoxicity and was given for only a short time. Finally, according to the postoperative renal function, the low-dose CNI, cyclosporin (50 mg/day) was able to be added to the introduced immunosuppressive therapy. After having left the hospital, MMF (1500 mg/day), steroid (20 mg/day converted into predonisolone) and cyclosporin (75 mg/day) continued to be given as the immunosuppressive therapy and neither acute graft rejection nor drug-induced renal dysfunction was occurred. This is a case report of introducing with mainly MMF and steroid as an immunosuppressive therapy after LDLT for a patient with perioperative renal dysfunction.

Topics: Cyclosporine; Diabetic Nephropathies; Female; Hepatitis B; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Cirrhosis; Liver Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome

Reports on the clinical course of mycophenolic acid (MPA)-related colitis in kidney transplant recipients are scarce. This study aimed at assessing MPA-related colitis incidence, risk factors, and progression after kidney transplantation. All kidney transplant patients taking MPA who had colonic biopsies for persistent chronic diarrhea, between 2000 and 2012, at the Kidney Transplantation Unit of Botucatu Medical School Hospital, Brazil, were included. Cytomegalovirus (CMV) immunohistochemistry was performed in all biopsy specimens. Data on presenting symptoms, medications, immunosuppressive drugs, colonoscopic findings, and follow-up were obtained. Of 580 kidney transplant patients on MPA, 34 underwent colonoscopy. Colonoscopic findings were associated with MPA usage in 16 patients. The most frequent histologic patterns were non-specific colitis (31.3%), inflammatory bowel disease (IBD)-like colitis (25%), normal/near normal (18.8%), graft-versus-host disease-like (18.8%), and ischemia-like colitis (12.5%). All patients had persistent acute diarrhea and weight loss. Six of the 16 MPA-related diarrhea patients (37.5%) showed acute dehydration requiring hospitalization. Diarrhea resolved when MPA was switched to sirolimus (50%), discontinued (18.75%), switched to azathioprine (12.5%), or reduced by 50% (18.75%). No graft loss occurred. Four patients died during the study period. Late-onset MPA was more frequent, and no correlation with MPA dose or formulation was found.

Topics: Adolescent; Adult; Child; Cohort Studies; Colitis; Colonoscopy; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Treatment Outcome; Young Adult

For decades, high-dose intravenous cyclophosphamide (ivCY) given for 24-30 months was regarded as the standard therapy for proliferative lupus nephritis, despite serious side effects. Our aim was to evaluate the effect of induction therapy with short-term high-dose ivCY followed by mycophenolate mofetil (MMF) on disease parameters, mortality and health-related quality of life (HRQoL) in patients with proliferative lupus nephritis.. Between January 2003 and November 2006, 71 patients with biopsy-proven proliferative lupus nephritis were included in the second Dutch Lupus Nephritis Study. All patients were treated with ivCY (750 mg÷m2, six monthly pulses) plus oral prednisone, followed by MMF (2000 mg÷day) plus oral prednisone for 18 months, and then azathioprine (2 mg÷kg÷day) plus oral prednisone. Study endpoints included the occurrence of renal relapse, end-stage renal disease (ESRD) and mortality.. After a median follow-up of 3.8 years (range 0.1-4.5), four (5.6%) of the 71 patients had a renal relapse, one (1.4%) failed treatment, one (1.4%) reached ESRD, and two (2.8%) died. Systemic lupus erythematosus (SLE) Disease Activity Index, serum creatinine, proteinuria and antibodies against anti-dsDNA decreased significantly during treatment and serum levels of complement factor 3 and 4 increased significantly. Furthermore, six of eight domains of the Short Form-36 as well as the number of symptoms and total distress level according to the SLE Symptom Checklist improved significantly over time.. This open-label study shows that induction therapy with short-term (six monthly pulses) high-dose ivCY followed by MMF is effective in preventing renal relapses, ESRD and mortality and improving HRQoL in patients with proliferative lupus nephritis.

Topics: Administration, Intravenous; Adult; Anti-Inflammatory Agents; Azathioprine; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Prednisone; Quality of Life; Recurrence; Survival Rate; Young Adult

Topics: Adolescent; Antibodies, Monoclonal; Basiliximab; Body Weight; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus; Treatment Outcome

Advanced kidney disease is usually considered an absolute contraindication for lung transplantation due to the difficult management of these patients in the post-operative period. Combined lung-kidney transplantation, however, could offer an opportunity for selected patients with renal and pulmonary dysfunction. This study summarizes the long-term success of a double transplantation in a 38-year-old male patient with cystic fibrosis who presented respiratory and kidney failure. After a complicated post-operative period, the patient currently lives completely independently 46 months after the operation and he enjoys excellent pulmonary and renal function.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Basiliximab; Coinfection; Cystic Fibrosis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung Transplantation; Male; Mycophenolic Acid; Pneumonia; Prednisone; Recombinant Fusion Proteins; Recovery of Function; Renal Dialysis; Respiratory Insufficiency; Tacrolimus

Kidney transplantation is the best option for patients with end-stage renal disease (ESRD) failure. Prolonged use of immunosuppressive drugs often causes opportunistic infections and malignancies of skin and mucosae, but due to lack of a careful dermatological screening in several transplantation centers the diagnosis and the treatment of dermatological lesions in kidney transplant patients are underestimated. In addition after the introduction of interleukin (IL)-2 -receptor antagonists (basiliximab/daclizumab), mTOR inhibitors and mycophenolate mofetil (MMF)/mycophenolic acid (MPA) in new immunosuppressive protocols only a few studies have analyzed the skin and mucosal lesions in kidney transplant patients. This study was undertaken to evaluate the cutaneous and mucosal diseases after kidney transplantation, and to investigate the association between these and different immunosuppressive protocols and/or demographic features.. A retrospective analysis was done using medical records of kidney transplantation between 2000 and 2009 at the Transplant Unit of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. The study included 183 patients (M 57.3%, F 42.7%) aged 51.5 ± 11.8 yr) with transplant age 52.3 ± 34.9 months. Induction therapy was basiliximab and steroids based; maintenance therapy included combination-regimes from cyclosporine, tacrolimus, steroids, mycophenolate mofetil (MM), mycophenolic acid (MPA), rapamycin, everolimus. Anti-rejection therapy was steroid and/or thymoglobulines based. Diagnosis of cutaneous disease was made through examination of skin, mucous membranes, nails and hair evaluation. Skin biopsies, specific cultures and serological tests were done when required.. Skin and mucosal diseases were reported in 173 (95.7%) of patients; 88 (50.81%) showed viral lesions; 92 (53.01%) immunosuppression-related lesions; 28 (16.39%) benign tumours; 26 (15.3%) precancers /neoplastic lesions; 24 (14.21%) mycosis; 16 (9.29%) cutaneous xerosis, 15 (8.74%) dermatitis, while absence of cutaneous disease was evident only in 8 (4.37%) cases. An association between drug side effects and anti-rejection treatment ( P ≤ 0.01) and/or calcineurin-inhibitors (CNI) exposure ( P ≤ 0.01) was found. Longer exposure to immunosuppressive drugs (>60 months) was associated with pre-malignancy and malignancy lesions.. Cutaneous diseases are frequent in kidney transplanted patients. Continuous skin monitoring is necessary to make an early diagnosis and to start appropriate treatment.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Daclizumab; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Mycoses; Recombinant Fusion Proteins; Retrospective Studies; Skin Diseases; TOR Serine-Threonine Kinases; Treatment Outcome; Virus Diseases

Dysregulation of complement activation is the most common cause of the atypical haemolytic uraemic syndrome (aHUS). Many patients with aHUS develop end-stage renal disease and consider kidney transplantation. However, the recurrence rate after transplantation ranges from 45-90% in patients with known abnormalities in circulating complement proteins. It was recently proposed that patients with aHUS should be treated prophylactically with plasma exchange or eculizumab to prevent recurrence after transplantation.. A case series describing the successful outcome of kidney transplantation without prophylactic therapy in four adult patients with aHUS and a high risk of disease recurrence. Patients received a living donor kidney and immunosuppression consisting of basiliximab induction, low-dose tacrolimus, prednisone and mycophenolate mofetil. Patients received a statin, and were targeted to a low blood pressure preferably using blockers of the renin-angiotensin system.. After a follow-up of 16-21 months, none of the patients developed recurrent aHUS. Also, no rejection was observed.. Kidney transplantation in adult patients with aHUS can be successful without prophylactic eculizumab, using a protocol that minimises cold ischaemia time, reduces the risk of rejection and provides endothelial protection. Our data suggest that in patients with aHUS, controlled trials are needed to demonstrate the optimal strategy.

Topics: Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Basiliximab; Cold Ischemia; Drug Therapy, Combination; Female; Hemolytic-Uremic Syndrome; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Recombinant Fusion Proteins; Secondary Prevention; Tacrolimus; Young Adult

The porphyrias are a group of disorders of the heme biosynthesis pathway that may present with acute life-threatening attacks, commonly exacerbated by a wide variety of medications. Many newer immunosuppressive medications, which are in use following kidney transplantation, have not been fully explored in acute porphyrias.. A 53-year-old woman received a kidney from a deceased donor, after being on hemodialysis for 4 years. Hereditary coproporphyria was diagnosed at age 19 years. We administered tacrolimus, mycophenolate mofetil and steroid immunosuppression. In the immediate post-transplant periods she displayed abdominal pain and transient uroporphyrin elevation in parallel with slightly elevated (15 ng/mL) tacrolimus concentrations. As the target tacrolimus level was achieved, these findings disappeared.. Tacrolimus, mycophenolate- mofetil, and steroid therapy for hereditery coproporphyri was safe, in the long term.

Topics: Abdominal Pain; Coproporphyria, Hereditary; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Risk Factors; Tacrolimus; Treatment Outcome

ABO-incompatible renal transplantation (ABOi-RTx) following preconditioning with immunoadsorption (IA) and rituximab is a promising approach to facilitate living-related RTx. However, clinical experience is limited in pediatric patients.. Three patients underwent living-related ABOi-RTx in our center. Preoperative IA was performed six, ten and 11 times in patient one, two and three, respectively, to achieve isoagglutinin titers of ≤1:8 on the day of transplantation; rituximab was administered once. The immunosuppressive regimen further comprised tacrolimus, mycophenolate, methylprednisolone and basiliximab; immunoglobulin G (IgG) was infused on the day of ABOi-RTx.. All three patients achieved normal renal function within 2-6 days post-RTx. Major postoperative bleeding occurred in two patients, with one requiring repeated blood transfusions and the other a surgical revision 4 h after RTx, despite local citrate anticoagulation use during the preoperative IA procedures in the latter patient. A pyelonephritis-associated increase of the isoagglutinin IgG/IgM titers to 1:64/1:128 led to a biopsy-proven acute humoral rejection in the third patient, which was treated successfully with plasma exchange and methylprednisolone pulses. The estimated glomerular filtration rate at 18, 8 and 23 months post-RTx was 96, 52 and 74 ml/min/1.73 m(2), respectively.. ABOi-RTx can successfully be performed in pediatric patients after preconditioning with quadruple immunosuppression, rituximab and IA. Caution is required regarding bleeding complications, which are most likely due to the unspecific binding of coagulation factors during repeated IA.

Topics: ABO Blood-Group System; Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Anticoagulants; Basiliximab; Blood Group Incompatibility; Child, Preschool; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Heparin; Humans; Immunoglobulin G; Immunoglobulin M; Immunosorbent Techniques; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Methylprednisolone; Mycophenolic Acid; Postoperative Hemorrhage; Pyelonephritis; Recombinant Fusion Proteins; Rituximab; Tacrolimus; Young Adult

We assess our long-term experience with regards the safety and efficacy of Mycophenolate Mofetil (MMF) in our low risk renal transplant population and compared it retrospectively to Azathioprine (AZA) immunosuppressive regimen. Patients and methods. Between January 1999 and December 2005, 240 renal transplants received MMF as part of their immunosuppressive protocol (MMF group). AZA group of 135 renal transplants was included for comparative analysis (AZA group). Patients received Cyclosporine was excluded from this study.. The incidence of biopsy proven 3-month acute rejections was 30 (12.5%) in MMF group and 22 (16%) in AZA group respectively (P = 0.307). Patient survival rates at 1 and 5 years for the MMF group were 97 and 94%, respectively, compared to 100% and 91% at 1 and 5 years respectively for the AZA group (P = 0.61). Graft survival rates at 1 and 5 years for the MMF group were 95 and 83%, respectively, compared to 97 and 84% at 1 and 5 years, respectively for the AZA group (P = 0.62).. There was no difference in acute rejection episodes between MMF and AZA based immunotherapy. Additionally, we observed no significant difference concerning graft survival in the MMF group when compared to AZA group.

Topics: Adult; Azathioprine; Cohort Studies; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Ireland; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Retrospective Studies; Risk Assessment; Severity of Illness Index; Survival Rate; Transplantation Immunology; Treatment Outcome

Type 2 diabetes mellitus (DM) is the commonest cause of end-stage renal disease (ESRD) worldwide. Renal transplantation (RTx) is the best therapeutic modality for such patients. First-degree relatives of patients with type 2 DM have high risk of diabetes/pre-diabetes. Parents are often too old to be suitable donors, and siblings/children/spouse are either not suitable/acceptable or do not come forward for organ donation. This leaves deceased donation (DD) as only suitable donors. Data scarcity on DDRTx outcome in diabetic nephropathy (DN) prompted us to review our experience. This retrospective single-center 10-year study was undertaken to evaluate patient/graft survival, graft function, rejection episodes, and mortality in these patients.. Between January 2001 and March 2011, thirty-five DN-ESRD patients underwent DDRTx in our center following cardiac fitness assessment of recipients. All patients received single-dose rabbit-anti-thymocyte globulin for induction and steroids, calcineurin inhibitor, and mycophenolate mofetil/azathioprine for maintenance immunosuppression. Mean recipient age was 49.66 ± 6.76 years, and 25 were men. Mean donor age was 50 ± 16.45 years, 23 were men.. Over a mean follow-up of 2.28 ± 2.59 years, patient and graft survival rates were 68.5% and 88.5%, respectively, with mean SCr of 1.9 ± 0.62 mg/dl. Delayed graft function was observed in 34.3% patients, and 25.7% had biopsy-proven acute rejection; 31.5% patients died, mainly because of infections (22.8%), coronary artery disease (2.86%), and cerebrovascular events (5.7%).. DDRTx in patients with DN has acceptable graft function and patient/graft survival over 10-year follow-up in our center and, therefore, we believe it should be encouraged.

Topics: Adult; Aged; Antilymphocyte Serum; Azathioprine; Cadaver; Calcineurin Inhibitors; Creatinine; Delayed Graft Function; Developing Countries; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; India; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Steroids; Treatment Outcome

Some evidence suggest an increase in the prevalence of focal segmental glomerular sclerosis (FSGS) in children. To date, there has been no study of the outcome in children with FSGS and its frequency over several decades in Iran. We aimed to report the changing trend of FSGS incidence and its outcome in a sample of Iranian children.. Between 1982 and 2008, all 716 kidney biopsies performed in children referred to Ali Asghar Children Hospital were recorded and confirmed cases with FSGS lesions were further evaluated. Baseline and clinical characteristics of all FSGS patients were assessed and the therapies and outcomes were reviewed.. The incidence rate of FSGS was 10.1% between 1982 and 1990, which was significantly increased to as high as 20.5% after the year 2000 (P = .001). Among 64 children with FSGS, 20 progressed to end-stage renal disease with a mean survival time of 11.45 years (standard error of mean, 1.34 years). Kidney survival rates were 90.4%, 69%, and 47% at 1, 5 and 10 years of follow-up.. Our study demonstrates an increasing trend in FSGS incidence in Iranian children. However, kidney survival rates of our patients were similar to those reported by others in different countries.

Topics: Child; Child, Preschool; Cyclophosphamide; Cyclosporine; Disease Progression; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Incidence; Iran; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Mycophenolic Acid; Nephrotic Syndrome; Prevalence; Proportional Hazards Models; Steroids; Treatment Outcome

Several landmark studies have recently been published in nephrology. In summary, mycophenolate mofetil is superior to azathioprine in maintaining remission and preventing relapse in lupus nephritis. For patients with type I diabetes, long-term renal function is better preserved when optimal glycaemic control is obtained with intensive diabetes therapy from the onset of disease, and in patients with type 2 diabetes treatment with bardexolone may increase renal function. With respect to chronic kidney disease, the association of simvastatine and ezetimibe is effective in improving cardiovascular outcomes. There is no need to initiate dialysis in asymptomatic patients, and daily haemodialysis seems better than three times weekly hemodialysis. Finally, N-acetylcysteine does not prevent contrast nephropathy.

Topics: Anticholesteremic Agents; Azathioprine; Azetidines; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Nephrology; Renal Dialysis; Secondary Prevention; Simvastatin; Treatment Outcome

Recipients after liver transplantation. (OLT) often experience renal dysfunction. Acute kidney injury (AKI) and chronic kidney disease (CKD) after OLT occur among 20% to 50% and 30% to 90% of recipients, respectively; 2% to 5% of them deteriorate into end-stage renal disease each year. Since the predictable factors for CKD have not been well identified. We sought to investigate the incidence and predictors of CKD at 5 years after OLT.. Between August 2002 and December 2005, we enrolled 77 patients who underwent adult living donor OLT with over 2 years of follow-up. The strategies to prevent renal dysfunction included induction with basiliximab to delay the use of tacrolimus: addition of mycophenolate mofetil to reduce the tacrolimus dosage; avoidance of the calcineurin inhibitor using sirolimus or administration of an angiotensin II receptor antagonist. The clinical variables were reviewed for analysis.. The mean follow-up was 76 ± 14 months. The incidence of AKI (over 50% increase level of creatinine) was 29%. Ten (13.0%) patients developed CKD (creatinine > 2 mg/dL). One (1.3%) subject developed end-stage renal disease requiring hemodialysis. Upon multivariate analysis the development of CKD was significantly associated with the posttransplant 4-week creatinine level: 0.92 ± 0.23 versus 1.37 ± 0.93 mg/dL (P = .008).. The 4-week creatinine value was predictive of the occurence of CKD over 5 years after OLT.

Topics: Acute Kidney Injury; Adult; Angiotensin Receptor Antagonists; Antibodies, Monoclonal; Basiliximab; Creatinine; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

The use of mycophenolate mofetil (MMF) is known to be associated with progressive multifocal leukoencephalopathy (PML). We report a case of PML in a patient receiving MMF, who showed improvement upon discontinuation of the drug. He was restarted on MMF, following which he went into coma. He showed prompt recovery upon stopping the drug again and made full recovery without any residual neurological deficit. This case is being reported to further highlight this neurological side-effect of MMF.

Topics: Adult; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Male; Mycophenolic Acid; Treatment Outcome

Antibody (Ab)-mediated pure red cell aplasia (PRCA) is a rare hematologic disorder. For the first time here, the authors report the use of combination therapy which consists of mycophenolate mofetil 500-1000 mg/day, intravenous cyclophosphamide 600 mg monthly and monthly intravenous methylprednisolone 1 gm/day for 2 days followed by oral prednisolone 10 mg/day. A 62-year-old woman developed Ab-mediated PRCA after using subcutaneous erythropoietin-beta 3000 U weekly for 14 months at the predialysis stage. Ab-mediated PRCA was diagnosed based on (1) the transfusion need of more than 1 unit/wk to keep hemoglobin level stable, (2) corrected reticulocyte count 0.36% and (3) < 5% erythroblasts with normal myeloid cells and megakaryocytes in bone marrow biopsy. Serum assay confirmed the anti-erythropoietin antibody of 230 ng/mL. The patient recovered from PRCA after the triple immunosuppressive therapy for 3 months. The rapid recovery occurred despite the fact that the patient was receiving intravenous erythropoietin-alpha while having the antibody in the serum. The present case describes the acceleration of the recovery and successful resumption of erythropoietin concurrently despite the positive serum anti-erythropoietin antibody.

Topics: Cyclophosphamide; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Middle Aged; Mycophenolic Acid; Prednisolone; Red-Cell Aplasia, Pure

Desensitization protocols reduce donor-specific anti-HLA antibodies (DSA) and enable renal transplantation in patients with a positive complement-dependent cytotoxic cross-match (CDC-CXM). The effect of this treatment on protective antibody and immunoglobulin levels is unknown. Thirteen patients with end-stage renal disease, DSA and positive CDC-CXM underwent desensitization. Sera collected pre- and post-transplantation were analysed for anti-tetanus and anti-pneumococcal antibodies, total immunoglobulin (Ig) levels and IgG subclasses and were compared to healthy controls and contemporaneous renal transplant recipients treated with standard immunosuppression alone. Ten patients developed negative CDC-CXM and enzyme-linked immunosorbent assay (ELISA) and underwent successful transplantation. Eight recipients achieved good graft function without antibody-mediated or late rejection, BK virus or cytomegalovirus infection. One patient had primary non-function due to recurrent oxalosis, and one patient with immediate graft function died from septicaemia. Seven recipients required post-operative transfusion and three developed septicaemia. DSA remained negative by ELISA at 12 months, but were detectable by Luminex(®) . Anti-tetanus and anti-pneumococcal antibodies, total Ig and IgG subclasses were below the normal range but comparable to levels in renal transplant recipients who had not undergone desensitization. Desensitization protocols effectively reduce DSA and allow successful transplantation. Post-operative bleeding and short-term infectious risk is increased. Protective antibody and serum immunoglobulin levels are relatively preserved.

Topics: Adult; Aged; Antibodies; Antibodies, Bacterial; Antibodies, Monoclonal; Basiliximab; Desensitization, Immunologic; Female; HLA Antigens; Humans; Immunoglobulin G; Immunologic Memory; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Recombinant Fusion Proteins; Streptococcus pneumoniae; Tacrolimus; Tetanus; Tissue Donors

The 2008-released FDA safety report described a potential association between use of MMF and progressive multifocal leukoencephalopathy. We here report the case of an 11-yr-old kidney transplanted boy suffering from PML who showed rapid improvement parallel to withdrawal of MMF. This case contributes to the increasing knowledge on side effects of MMF treatment in children.

Topics: Child; Follow-Up Studies; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Male; Mycophenolic Acid; Polyomavirus; Polyomavirus Infections; Risk Assessment; Transplantation Immunology; Tumor Virus Infections; Withholding Treatment

BK virus (BKV) is increasingly found as an important cause of allograft nephropathy. Nephrotic syndrome is not a usual manifestation of BKV nephropathy. Here, we report a 12-year-old boy, a case of end-stage renal disease due to nephronophthisis, who got the kidney transplanted from a 16-year-old cadaver, and after 18 months of uneventful transplantation on triple immunosuppressive therapy (mycophenolate mofetil (MMF), cyclosporin and prednisolone), presented with nephrotic feature (edema, heavy proteinuria, hypoalbuminemia and hyperlipidemia). Kidney biopsy was in favor of BKV infection and eventually ended in graft failure.

Topics: Adolescent; Biopsy; BK Virus; Child; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Nephrotic Syndrome; Polyomavirus Infections; Prednisolone; Time Factors; Transplantation, Homologous; Treatment Outcome; Tumor Virus Infections

Renal transplantation is the treatment of choice of end stage renal failure. It both improves the quality and the quantity of life compared to other techniques, such as hemodialysis. These results are partly related to the use of immunosuppressive therapy more effective and whose handling has improved over time. Advances in understanding the mechanisms of lymphocyte activation and the phenomena of rejection have in fact better defined the use of these treatments and their associations. Treatments can be broadly classified according to their characteristics (biological or chemical). Among chemical treatments, steroids are widely used, although the question of their avoidance or spearing is still a matter of debate. The cornerstone of immunosuppressive regimens remains the calcineurin inhibitors, characterized by a narrow therapeutic index and the need for therapeutic drug monitoring. Inhibitors of mammalian target of rapamycin (mTOR) have interesting antiproliferative effects that could be important against chronic allograft dysfunction and/or carcinogenesis. However, their safety profile makes them difficult to handle. Inhibitors of purine synthesis are largely based on inhibitors of inosine monophosphate dehydrogenase (IMPDH). Their effectiveness makes them privileged partners of other therapeutic classes. Among biological treatments, it is possible to separate the depleting and non depleting antibodies. Among the former, antithymocyte globulins are mainly active in T cells, whereas rituximab, a monoclonal anti-CD20, is active in B cells involved in the phenomena of humoral rejection. The non depleting antibodies are represented by anti-CD25, directed against the receptor for interleukin-2. In the near future it is likely that the belatacept, a costimulation blockade fusion protein will be used to allow calcineurin inhibitors sparing. Other immunosuppressive agents, acting at different levels of the immune response are being evaluated. In addition, advances in pharmacology offered hope of a better individualization of immunosuppressive therapies and better definition of therapeutic strategies used.

Topics: Abatacept; Antibodies, Monoclonal, Murine-Derived; Calcineurin; Calcineurin Inhibitors; Graft Rejection; Humans; Immunoconjugates; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Quality of Life; Rituximab; Sirolimus; Treatment Outcome

Enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF) are prodrugs of mycophenolic acid (MPA). Although many patients still receive MMF as an inosine monophosphate dehydrogenase inhibitor, EC-MPS could be considered a reliable alternative to MMF in the immunosuppressive protocols of kidney transplant recipients. MPA shows high pharmacokinetic variability and consequently a 12-h area under the curve (AUC(0-12)) should be used to guide the therapeutic dosage. However, patient compliance and economic costs make MPA AUC(0-12) an unpractical approach. Limited sampling strategies or predictive systemic drug exposure equation models based on limited sampling times are available only for MMF but lack for EC-MPS.. The present study enrolled 26 kidney transplant recipients receiving EC-MPS as part of their immunosuppressive therapy. Twenty-six full MPA AUC(0-12) were performed. By using multiple stepwise regression analysis, we obtained several predictive equations of MPA systemic exposure in this group of patients. The value of the selected equations was tested in a subsequently enrolled group of 26 kidney transplant recipients.. The best equations obtained in the first group of patients were the following: 22.906 + 3.880·C(0) + 1.117·C(1) + 7.527·C(8) (r = 0.901) and 35.064 +3.784·C(0) + 1.002·C(1) + 1.192·C(2) (r = 0.846). These equation models showed an optimal agreement between the full AUCs and estimated AUCs by using the validation group of patients.. Limited sampling strategies are useful for MPA AUC(0-12) estimation in patients receiving EC-MPS and cyclosporine. The choice of one or the other equation model depends on the pharmacokinetic characteristics of the patients, in particular the potential presence of enterohepatic recirculation.

Topics: Antibiotics, Antineoplastic; Area Under Curve; Cyclosporine; Drug Monitoring; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Prognosis; Survival Rate; Tablets, Enteric-Coated; Tissue Distribution

Immunosuppressive therapy post-kidney transplantation is usually used continuously and should be regularly monitored. Inadequate dosages of immunosuppressive drugs and lack of regular monitoring can lead to either severe side effects or allograft rejection.. To study the hematologic adverse effects and differences between azathioprine and mycophenolate used as maintenance immunosuppressive therapy.. Fifty-nine (32 male and 27 female) renal transplant patients were enrolled in the study. Patients were transplanted and followed at the University Clinic Cologne, Germany. The mean patient age was 48±2.03 years (standard error of the mean) during the study period, and the mean age at transplantation was 46.8±2.04 years. All patients received mycophenolate for 270 days, and then shifted to an azathioprine-based regimen for 720 days. Both regimens contained prednisolone and cyclosporine. The mean dose of mycophenolate and azathioprine was 20.03 mg/kg/d and 1.3 mg/kg/d, respectively. Data were collected and arranged in Excel Microsoft program, and the statistical analysis was carried out by SPSS V16 package. Analysis of variance and paired t test were used to compare the means of changes that occurred before and after the day 0. P value of ≤.5 were considered statistically significant.. White blood cells increased significantly after the transplantation during mycophenolate period (9.2×10(3), P=.001, .017), while after the shift it tended to decrease, although the change was not statistically significant. On the contrary, absolute leukocyte count decreased after starting azathioprine, and the decrease was statistically significant 12 months after (P=.006). MCV was stable during mycophenolate (89.1±0.31 fl), but increased significantly following the switch to azathioprine (91.8±0.02 fl, P<.000). Hemoglobin increased after transplantation and continued to increase steadily, although at -270 day, hemoglobin level was significantly lower than day 0 level (P=.001), and the hematocrit showed the same trend. Serum iron increased significantly (P=.000-.005), and serum transferrin saturation increased also significantly during azathioprine (P=.000-.001), respectively. Thrombocyte count did not change significantly under the two regimes. There was no evidence of hemolysis, and reticulocyte percentage ranged between 1.3% and 2%. Bilirubin and the liver enzymes were almost normal in all the patients.. Mycophenolate and azathioprine hematologic adverse effect are not significantly different as long as close observation and follow-up are performed. Therefore, mycophenolate- and azathioprine-based maintenance regimens can be used interchangeably without significant hematologic adverse effects.

Topics: Adult; Azathioprine; Bone Marrow; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukocytes; Male; Middle Aged; Models, Statistical; Mycophenolic Acid; Platelet Count; Time Factors

It is known that end-stage renal disease patients can display abnormal thyroid gland function, which may cause autoimmune hypothyroidism or subclinical alterations. The impact of thyroid function on graft outcomes is not completely clear among renal transplant patients. The aim of this study was to evaluate thyroid function among a cohort of 136 consecutive renal recipients in correlation with clinical parameters of graft function.. We performed a cross-sectional study on 136 subjects including 84 males and 52 females of overall mean age of 49.71 ± 10.98 years who underwent renal transplantations between 2005 and 2009 and had a mean follow-up of 28.3 ± 15.7 months. All patients were treated with a calcineurin inhibitor, steroids, and mycophenolate mofetil. The exclusion criteria were age below 18 years, multiorgan transplantation, graft failure in the first 6 months, or presence of a thyroid neoplasm. We evaluated levels of serum FT3, FT4, and thyroid-stimulating hormone (TSH) in relation to the following parameters: body mass index (BMI), serum creatinine, estimated glomerular filtration rate estimated glomerular filtration rate (eGFR) by Modification of Diet in Renal Disease (MDRD) formula, proteinuria/24 hours, serum sodium, potassium, calcium, phosphorus, cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and hemoglobin (Hb).. Only 6.4% of our transplant recipients were treated with levothyroxine sodium. The patients showed an average FT3 of 3.24 ± 0.5 mg/dL; average FT4 of 0.84 ± 0.1 mg/dL, and mean TSH of 1.29 ± 0.8 mg/dL. The study showed no relationship between thyroid hormones and age of the transplant, while there was a significant difference in FT3 levels between men and women. We also observed a significant correlation between FT3 and serum creatinine, eGFR, serum sodium, BMI, and Hb; whereas there was no correlation with other variables. The correlations between FT4 and TSH and all examined variables were not significant.. The interactions between the thyroid and the kidney have been incompletely studied among patients with renal transplants. Our data showed that the presence of low serum FT3 levels correlated with worse graft function, anemia, BMI, and serum sodium. Thus low FT3 levels could be predictive of graft function, especially in the 5 years posttransplantation.

Topics: Adult; Biomarkers; Calcineurin Inhibitors; Creatinine; Cross-Sectional Studies; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Italy; Kidney Failure, Chronic; Kidney Transplantation; Linear Models; Male; Middle Aged; Mycophenolic Acid; Steroids; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Time Factors; Treatment Outcome

Lupus nephritis (LN) is an ominous complication of systemic lupus erythematosus, and the risk factors for the disease progression are not well characterized.. In a retrospective study, the authors evaluated the mode of presentation and outcomes of 163 consecutive patients with biopsy-proven LN, who presented to the center between January 1999 and September 2008. Using stepwise logistic regression analysis, the authors assessed risk factors independently associated with response to treatment and to progression to end-stage renal disease (ESRD) in proliferative LN (PLN).. Ninety percent of the patients belonged to minority population. Among 122 patients with class III and IV LN (PLN), 76 patients received intravenous cyclophosphamide and 38 patients received mycophenolate for induction, whereas 34 patients received intravenous cyclophosphamide and 63 patients received mycophenolate for maintenance. Thirty-six (30%) patients with PLN progressed to ESRD, and 3 patients died over a mean follow-up of 37.5 months. In multivariate analysis, chronicity index (CI) (P = 0.0007) and hypertension (P = 0.042) positively correlated with progression to ESRD and death, and CI was associated with increased probability of nonresponse to treatment (P = 0.001). In addition, mycophenolate as maintenance agent was associated with increased likelihood of sustained complete remission and partial remission (P = 0.045).. In patients with LN, hypertension and a high CI are independent risk factors for progression to ESRD or death. Furthermore, a high CI is associated with poor response, and mycophenolate as a maintenance agent may improve the response to treatment.

Topics: Adult; Cyclophosphamide; Disease Progression; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Logistic Models; Lupus Nephritis; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Remission Induction; Retrospective Studies; Risk Factors; Texas; Young Adult

Chronic renal failure (CRF) due to calcineurin inhibitor (CNI) nephrotoxicity is a frequent complication among heart transplant (HT) recipients. Small studies have suggested that the introduction of mycophenolate mofetil (MMF) can help to reduce CNI doses thereby to maintaining or improving renal function. We conducted a 4-year, prospective, multicenter study in 89 maintenance HT recipients at 5.6 ± 2.7 years postgrafting who displayed CRF (serum creatinine > 1.4 mg/dL) and were undergoing treatment with cyclosporine and prednisone ± azathioprine. We introduced MMF and reduced cyclosporine to level below 100 ng/mL. Creatinine clearance (CrCl), acute rejection episodes, and survival were through retrospectively compared with a contemporary cohort of HT recipients who were not treated with MMF (control group; n = 38). After conversion to MMF, a rapid increase was observed in the CrCl, which was maintained over the follow-up: namely, CrCl at month 6 and at 4 years were 51.0 ± 15.6 and 54.1 ± 15.6 mL/min versus 41.9 ± 11.1 mL/min at baseline (P < .0001). No renal function changes were observed among the control group. Acute rejection rates were 5.6% and 2.6% in the MMF versus control groups (P = NS) with 4-year survivals >85%. In conclusion, the introduction of MMF allowed a safe reduction of cyclosporine and significantly improved renal function after 4 years.

Topics: Cyclosporine; Dose-Response Relationship, Drug; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Spain; Survival Rate

Debate continues about the optimal treatment modality of lupus nephritis (LN). We compared the efficacy and safety of intravenous cyclophosphamide (CYC) and mycophenolate mofetil (MMF) for LN treatment in Korea. After searching for systemic lupus erythematosus (SLE) patients diagnosed between 1998 and 2007 with the diagnostic code of ICD10, we selected the 71 patients who were treated with CYC or MMF without any other immunosuppressant except systemic steroid. Composite outcome was defined as progression to end-stage renal disease (ESRD) and/or all-cause mortality. The initial manifestations of the CYC group were more severe than those of the MMF group. The mean daily MMF dose was 980  ±  100  mg for 21.67  ±  18.25 months. The mean monthly dose per CYC pulse therapy was 850  ±  30  mg for 17.04  ±  13.15 months. The incidence of composite outcome was 5/20 (25%) in the MMF group and 4/51 (7.8%) in the CYC group. The relative risk (RR) for composite outcome in the CYC group was 0.249 (95% CI for RR: 0.067-0.934, p = 0.039) compared with the MMF group with Cox's hazard proportional analysis. In Kaplan-Meier analysis, the probability of composite outcome was lower in the CYC group than in the MMF group (Log rank test p-value = 0.026). The results of this retrospective study suggest that intravenous CYC therapy may be more efficacious in averting ESRD and death than MMF. These results need to be confirmed in a larger randomized controlled trial.

Topics: Adolescent; Adult; Child; Cyclophosphamide; Disease Progression; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Failure, Chronic; Korea; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Young Adult

Immunosuppressive treatment following renal transplantation includes induction therapy during the initial period when the risk of rejection is higher. Depleting anti-lymphocyte antibodies are indicated mostly in patients who developped anti-HLA antibodies and following a second graft. Anti-IL2 receptor antibodies may be used in non-responders. After the first month, maintenance therapy mostly consists in the association of several immunosuppressants, mainly corticosteroids, an antimetabolic agent (azathioprine or mycophenolate mofetil) and a calcineurin inhibitor (cyclosporine or tacrolimus). Side effects associated with these treatments led to the development of new immunosuppressive protocols, with the reduction or withdrawal of corticosteroids treatment due to its deleterious effects on statural growth, and decreased doses of anti-calcineurin agents to reduce their nephrotoxic effect. These therapeutic options are possible in patients at low immunological risk.

Topics: Antimetabolites; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Evidence-Based Medicine; Glucocorticoids; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Mycophenolic Acid; Postoperative Care; Tacrolimus; Treatment Outcome

IIH is a syndrome of increased intracranial pressure characterized by headache, visual disturbance, papilledema with normal cranial neuroimaging. It is associated with many factors in childhood. From the renal perspective renal insufficiency, chronic dialysis, steroid treatment, and recombinant human growth hormone have been associated with IIH. It has also been described in pediatric recipients several months to years following kidney transplantation. In this study, we present a pediatric kidney transplant recipient receiving CyA, prednisone, and mycophenolate mofetil who was discovered to have pseudopapilledema during routine ophthalmological examination. He had no additional signs of increased intracranial pressure. Awareness of possible side effects in the follow-up of these patients may improve management of these children.

Topics: Adolescent; Angiography; Antibodies, Monoclonal; Basiliximab; Cyclosporine; Humans; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Papilledema; Prednisone; Pseudotumor Cerebri; Recombinant Fusion Proteins; Syndrome

Since the efficacy of mycophenolate mofetil (MMF) to treat immunoglobulin A (IgA) nephropathy is controversial, we extended our original study by following 40 Chinese patients with established IgA nephropathy for 6 years. All patients were maintained on their angiotensin blockade medication and half were randomized to receive MMF for 6 months. After 6 years, 11 patients required dialysis (2 from the MMF and 9 from the control group). Significantly, only 3 treated (as compared to 10 control) patients reached the composite end point of serum creatinine doubling or end-stage renal disease. Linear regression showed the annualized decline in the estimated glomerular filtration rate was significantly less in the MMF-treated group. Urinary protein excretion and the albumin-to-creatinine ratio were lower with MMF treatment during the first 24 months, beyond which there was no difference between groups. Multivariable Cox regression analysis showed that the baseline estimated glomerular filtration rate and proteinuria, and change in the urine albumin-to-creatinine ratio at 1 year to be important predictors of progression to end-stage renal disease. We found that among Chinese patients with IgA nephropathy who had mild histologic lesions and persistent proteinuria despite maximal angiotensin blockade, MMF treatment may result in transient and partial remission of proteinuria in the short-term and renoprotection in the long-term.

Topics: Adult; Creatinine; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Hong Kong; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Longitudinal Studies; Male; Mycophenolic Acid; Proteinuria; Remission Induction

The immunosuppressive medications that have contributed greatly to the success of liver transplantation are also associated with posttransplant renal dysfunction. We reviewed measured glomerular filtration rate (GFR) data from patients who underwent transplantation more than 10 years ago to assess whether results from specific time points can predict renal failure.. The GFR data were obtained at initial evaluation (IE), at month 3, and at years 1, 2, 5, 10, and 15. Two groupings were compared, one based on GFR at IE and the other at month 3. Patients were further stratified into three GFR (mL/min/1.73 m2) groups: G1, GFR more than 80; G2, GFR 60 to 80; and G3, GFR less than 60.. A total of 592 liver transplant recipients met the inclusion criteria; 114 had paired GFR data from IE to year 15. Analysis of paired and censored data based on IE GFR showed that 62.2% of G3 patients developed renal failure by year 5; another 6.7% did so by year 10 (P=0.027). The month 3 GFR data showed that 56.3% of G3 patients developed renal failure by year 5; another 15.6% did so by year 10. Surprisingly, 37.0% of G2 patients experienced renal failure by year 5; another 11.1% did so by year 10 (P=0.0024).. The month 3 data indicate a slow but steady decline in GFR over years. The lower the initial GFR is after transplant, the sooner renal failure develops. Patients with GFR less than 60 mL/min per 1.73 m2 at month 3 have a higher risk of renal failure; however, those who avoid renal failure seem to maintain renal function long term.

Topics: Azathioprine; Cyclosporine; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Mycophenolic Acid; Patient Selection; Predictive Value of Tests; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Failure

In our Universitary Hospital of Canarias we iniciated in May 2008 a induction therapy protocol for sensitized patients receiving cadaveric renal graft using intravenous immunoglobulins, plasmapheresis and rituximab plus immunosuppression with prednisone, tacrolimus and mycophenolate mofetil. We present the results of four patients. Everyone had anti-HLA antibodies rate (PRA by CDC) more than 75%, were on a waiting list during 4 to 17 years and follow-up time was 10-14 months after transplantation. Patient and graft survival in this period was 100%. Only one patient suffered a humoral acute rejection and another one cellular rejection, in both cases reversible with treatment. During the first year, no evidence of de novo donor-specific antibodies was detected. All patients had significantly reduced the CD19+ cells percentage after infusion of rituximab. Neurological symptoms suggestive of progressive multifocal leukoencephalopathy or serious viral infections after transplantation have not been observed. Additionally, no immediate side effects were observed after administration of medication. In summary, induction therapy by combining immunoglobulin, plasmapheresis and rituximab in hypersensitive patients allows the realization of deceased kidney transplantation with good results in the short and medium-term without serious side effects. It remains to know whether this success will continue in the long term.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cadaver; Combined Modality Therapy; Female; Graft Rejection; Histocompatibility; HLA Antigens; Humans; Immunization; Immunoglobulins, Intravenous; Immunosuppressive Agents; Isoantibodies; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Plasmapheresis; Prednisone; Premedication; Reoperation; Rituximab; Tacrolimus; Tissue Donors

Anti-glomerular basement membrane (GBM) antibody disease may progress to end-stage renal failure, requiring either dialysis or renal transplantation. In patients with end-stage renal disease (ESRD) due to anti-GBM-ab disease, the recurrence rate after transplantation is as high as 50% (2) and delaying renal transplantation until circulating anti-GBM antibody levels have been undetectable for at least 12 months reduces the recurrence rate to 5-15%. We report a case of ESRD due to renal limited anti-GBM disease with circulating anti-GBM-ab resistant to standard treatment approach who achieved undetectable anti-GBM-ab with mycophenolic acid.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Biopsy; Female; Glomerulonephritis; Humans; Kidney; Kidney Failure, Chronic; Mycophenolic Acid; Treatment Outcome

Simultaneous heart and kidney transplantation (SHKT) has become an accepted therapeutic option for patients with end-stage heart failure associated with end-stage renal disease. The immunosuppressive therapy is usually based upon a heart transplantation protocol using a calcineurin inhibitor (CNI). Sirolimus (SRL) is a potent nonnephrotoxic immunosuppressant with antiproliferative activity in nonimmune cells. Its use has recently been reported to show less nephrotoxicity among both heart and kidney transplants. However, the data for the SHKT are limited. We retrospectively examined the causes of 5 patients who received combined SRL-CNI immunosuppressive therapy with reduced CNI doses from 2003 to 2009. There was no mortality during follow-up. Two of the 3 patients who received a conversion regimen recovered renal function. One who suffered severe proteinuria after transplantation proceeded to hemodialysis at 3 years after conversion. Both of the patients who received the combined regimen de novo remained stable regarding their renal function. Cardiac function was stable in these patients; there was neither allograft rejection nor allograft coronary vasculopathy. We observed that patients without dyslipidemia or hyperuricemia before SHKT were less likely to develop these disorders under the combined regimen. Early medical intervention after close follow-up of lipid and uric acid values by dose adjustments resulted in a stable status of our patients.

Topics: Adolescent; Antilymphocyte Serum; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Heart Failure; Heart Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Sirolimus; Tacrolimus; Young Adult

Major histocompatibility complex class 1 chain-related antigen A (MICA) antibodies (Abs) have been associated with renal graft loss in one large cohort. The triggering factors for MICA Abs and their autologous or allogeneic specificity have not been well defined. More data on the impact of MICA on renal grafts outcome are needed.. We tested sera from 494 controls and 597 patients with chronic kidney disease (CKD) for MICA using Luminex. Forty CKD MICA+ patients were genotyped for MICA alleles to determine their auto- or allospecificity. We compared MICA+ with MICA- renal transplant recipients with regard to acute rejection episodes and long-term survival.. Blood transfusions, previous transplantation, and more than two pregnancies were independent risk factors for the presence of MICA Abs, as were CKD stage V status and male gender. Among the 40 genotyped patients, allo-Abs alone were present in 32 patients, both auto- and allo-Abs in 4 patients, and auto-Abs alone in 4 patients. When we compared MICA+ with MICA- patients, the incidence of acute rejection episodes during the first year (10.2% vs. 12.8%), as well as 1-year creatinine and proteinuria, were similar in both groups. At 10 years, actuarial patient (97.8% vs. 87.6%) and overall graft survival (76% vs. 72%) were similar between MICA+ and MICA- patients.. In summary, (1) sensitizing events for MICA Abs are the same as for human leukocyte antigen Abs; (2) MICA Abs did not adversely affect renal graft outcomes in our cohort.

Topics: Adult; Azathioprine; DNA; Female; Genotype; Graft Rejection; Graft Survival; Histocompatibility Antigens Class I; HLA-DR Antigens; Humans; Isoantibodies; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Reference Values; Treatment Outcome

The aim of this study was to develop and characterize a rat glomerulonephritis model, which progresses to renal fibrosis and renal failure. A single immunization of female WKY rats with more than 10 microg of recombinant alpha3(IV)NC1 protein caused severe proteinuria followed by progressive increases in plasma creatinine and blood urea nitrogen (BUN) level within 42 days. Sequential histopathological evaluation revealed crescent formation in glomeruli followed by tubular dilation and interstitial fibrosis. Hydroxyproline content and expression of type I collagen and smooth muscle actin genes in the renal cortex increased as renal dysfunction progressed. Furthermore, the TGF-beta1 level in the renal cortex also increased. In the evaluation of antinephritic agents in this model, prednisolone and mycophenolate mofetil (MMF) treatment significantly decreased plasma creatinine and BUN, and suppressed renal fibrosis and histological changes involving crescent formation, compared with the vehicle-treated nephritic rats, whereas lisinopril treatment failed to improve renal function and histology. We demonstrated that immunization of female WKY rats with a sufficient dose of recombinant alpha3(IV)NC1 induces end-stage kidney disease accompanied by renal fibrosis. The relatively short period needed to induce the disease and the high incidence of functional and structural changes were considered a great advantage of this model for clarifying the mechanisms of progressive glomerulonephritis and for evaluating agents used to treat renal failure.

Topics: Actins; Animals; Autoantigens; Collagen Type I; Collagen Type IV; Creatinine; Disease Models, Animal; Female; Gene Expression; Glomerulonephritis; Hydroxyproline; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Lisinopril; Mycophenolic Acid; Prednisolone; Rats; Rats, Inbred WKY; Recombinant Proteins; Transforming Growth Factor beta1

Ramsay Hunt syndrome develops upon reactivation of a latent virus within the geniculate ganglion. The patient presents with acute facial paralysis, severe ear pain, and a vesicular eruption of the external auditory canal and concha. Varicella zoster virus seropositivity occurs among approximately 90% of members of society. In these persons, virus reactivation may occur especially with advancing age and immunosuppression. We present a case of Ramsay Hunt syndrome that developed in a 35-year-old male patient, who had undergone a renal transplantation 8 months prior and had received maintenance immunosuppression.

Topics: Acyclovir; Adult; Antiviral Agents; Dose-Response Relationship, Drug; Herpes Zoster Oticus; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Treatment Outcome

We report the successful allotransplantation of cryopreserved parathyroid tissue to reverse hypocalcemia in a kidney transplant recipient. A 36-year-old male received a second deceased donor kidney transplant, and 6 weeks later developed severe bilateral leg numbness and weakness, inability to walk, acute pain in the left knee and wrist tetany. His total calcium was 2.6 mg/dL and parathormone level 5 pg/mL (normal 10-60 pg/mL). He underwent allotransplantation of parathyroid tissue cryopreserved for 8 months into his left brachioradialis muscle. Immunosuppression included tacrolimus (target C(0) 10-12 ng/mL), mycophenolate mofetil and steroids. Within 2 weeks, the left knee pain, leg weakness and numbness resolved, and by 1 month he could walk normally. After a peak at month 2, his parathyroid hormone (PTH) level fell to <10 pg/mL; therefore at month 3 he received a second parathyroid transplant from the same donor. Eight months later (11 months after initial graft) he has a total calcium of 9.3 mg/dL, PTH level 15 pg/mL and is clinically asymptomatic. The amount of parathyroid tissue needed to render a patient normocalcemic is not known. In our case, the need for second transplant suggests that the amount of tissue transferred for an allograft may need to be substantially greater than for an autograft.

Topics: Adult; Cryopreservation; Drug Therapy, Combination; Glomerulonephritis; Glucocorticoids; Humans; Hypocalcemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Muscle, Skeletal; Mycophenolic Acid; Parathyroid Glands; Prednisone; Reoperation; Severity of Illness Index; Tacrolimus; Transplantation, Heterotopic; Transplantation, Homologous

Kidney transplantation is the optimal treatment for many patients with end-stage renal disease (ESRD). Due to shortage of donor kidneys in Denmark, there is a need to expand the possibilities for donation. At the Odense University Hospital (OUH), we have introduced ABO-incompatible kidney transplantation. We used antigenspecific immunoadsorptions to remove blood group antibodies and anti-CD20 antibody (rituximab) to inhibit the antibody production. The aim of introducing the ABO-incompatible kidney transplantation at the OUH was to increase the rate of living donor kidney transplantation without increasing rejection or mortality rates.. Retrospective evaluation. Eleven patients received ABO-incompatible kidney transplantation. The patients were followed for 3-26 months.. One patient had an antibody-mediated rejection, one patient suffered T-cell-mediated rejection, and one patient died of myocardial infarction with a functioning graft on the third post-operative day. Both rejections were treated effectively. Among the patients, the average serum creatinine level was 128 micromol/l.. The rejection and mortality rates for ABO-incompatible kidney transplantation at the OUH are similar to the results from ABO-compatible kidney transplantations performed at the OUH and at other hospitals.

Topics: ABO Blood-Group System; Adult; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Blood Group Incompatibility; Creatinine; Denmark; Female; Graft Rejection; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Rituximab; Tacrolimus

Drug-induced acute interstitial nephritis is a well-recognised and important reversible cause of acute renal failure. Peroxisome-proliferator activated receptor-gamma agonists, such as rosiglitazone, have been proven to be safe in chronic kidney disease patients. We describe a 65-year-old man with long-standing diabetes mellitus and hypertension, presenting with a five-day history of fluid overload and uraemic symptoms. There was no ingestion of analgesics, alternative medicine and other nephrotoxic drugs, the only new prescription being rosiglitazone, which was commenced during his last clinic follow-up two weeks prior to presentation. He required haemodialysis with minimal improvement in renal profile, despite cessation of the offending drug. Renal biopsy revealed findings consistent with acute interstitial nephritis. An episode of upper gastrointestinal bleeding with bleeding duodenal ulcer limited the use of steroids. He was treated with a course of mycophenolate mofetil which showed good gradual response and he remained stable with residual renal impairment.

Topics: Acute Kidney Injury; Aged; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Mycophenolic Acid; Renal Dialysis; Rosiglitazone; Thiazolidinediones

Among the causes of the nephrotic syndrome in renal allografts, minimal change disease is a rarity with only few cases described in the medical literature. Most cases described have occurred early in the post-transplant course. There is no established treatment for the condition but prognosis is favorable. We describe a case of minimal change disease that developed 8 years after a successful transplantation of a renal allograft in a middle-aged woman. The nephrotic syndrome was accompanied by deterioration of allograft function. Treatment with mycophenolate mofetil was successful in inducing remission and stabilizing allograft function.

Topics: Biopsy; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Nephrosis, Lipoid; Prodrugs; Remission Induction; Time Factors; Transplantation, Homologous

Herein we have described the case of a male renal transplant recipient who developed drug fever apparently related to sirolimus. He had been stable under an immunosuppressive regimen of tacrolimus and mycophenolate mofetil, but developed acute cellular rejection at 5 years after transplantation due to noncompliance. Renal biopsy showed marked interstitial fibrosis, and immunosuppression was switched from mycophenolate to sirolimus, maintaining low tacrolimus levels. One month later he was admitted to our hospital for investigation of intermittently high fever, fatigue, myalgias, and diarrhea. Physical examination was unremarkable and drug levels were not increased. Lactic dehydrogenase and C-reactive protein were increased. The blood cell count and chest radiographic findings were normal. After extensive cultures, he was started on broad-spectrum antibiotics. Inflammatory markers and fever worsened, but diarrhea resolved. All serologic and imaging tests excluded infection, immune-mediated diseases, and malignancy. After 12 days antibiotics were stopped as no clinical improvement was achieved. Drug fever was suspected; sirolimus was replaced by mycophenolate mofetil. Fever and other symptoms disappeared after 24 hours; inflammatory markers normalized in a few days. After 1 month the patient was in good health with stable renal function. Although infrequent, the recognition of drug fever as a potential side effect of sirolimus may avoid unnecessary invasive diagnostic procedures. Nevertheless, exclusion of other common causes of fever is essential.

Topics: Fever; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Radiography, Thoracic; Sirolimus; Treatment Outcome

A long-term female hemodialysis patient with end-stage renal disease due to Wegener's granulomatosis (WG) experienced a severe relapse when immunosuppressive therapy was switched from prednisone and cyclophosphamide to azathioprine maintenance therapy. Ten courses of protein A immunoadsorption therapy and switching immunosuppressive therapy to mycophenolate mofetil have proved to be very successful and free of side effects. The patient has fully recovered from all clinical WG symptoms and is still in remission ten months after the treatment.

Topics: Adult; Azathioprine; Cyclophosphamide; Female; Granulomatosis with Polyangiitis; Humans; Immunosorbent Techniques; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Prednisone; Remission Induction; Renal Dialysis; Staphylococcal Protein A

A 53-year-old man who underwent successful kidney transplantation for stage 5 chronic kidney disease presented to our clinic with intermittent painless gross hematuria. Urachal adenocarcinoma, stage III A by Sheldon system, was diagnosed after serial histopathologic and radiological studies. The patient was treated with extended partial cystectomy, en bloc resection of urachus and umbilicus, pelvic lymphadenectomy, and ileocystoplasty. There were no complications seen in this patient. Neither urachal adenocarcinoma recurrence, metastasis, nor de novo uroileal cancer developed during 48-month follow-up. His reconstructed bladder functioned efficiently, without compromising the transplanted kidney function. Our case demonstrated that conservative surgery and augmentation ileocystoplasty could be offered to kidney transplant recipients with localized urachal carcinoma.

Topics: Adenocarcinoma; Hematuria; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Mycophenolic Acid; Neoplasm Staging; Prednisolone; Tacrolimus; Urachus

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; Cyclosporine; Daclizumab; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

The active metabolite of mycophenolate mofetil (MMF), mycophenolic acid, inhibits the activity of the target enzyme inosine monophosphate dehydrogenase (IMPDH). The aim of this study was to correlate eight different single nucleotide polymorphisms of the IMPDH type II gene to the activity of the IMPDH enzyme to explain between-patient differences in IMPDH activity.. In a prospective study, we measured IMPDH activity, mycophenolic acid plasma concentrations, and eight polymorphisms of IMPDH type II in de novo kidney transplant recipients, 6 days posttransplantation while on MMF treatment. Polymorphisms in the IMPDH type II gene were only observed for the IMPDH type II 3757T > C (rs11706052) single nucleotide polymorphism. Ten of 101 patients (10%) were heterozygous and two of 101 patients (2%) homozygous for IMPDH type II 3757T > C. The allele frequency was 6.9%. The IMPDH activity over 12 h (AUC(act)) was 49% higher for patients with an IMPDH type II 3757C variant [n = 12 vs. n = 68; 336 (95% confidence interval: 216-521) vs. 227 (95% confidence interval: 198-260) hmicromol/s/mol adenosine monophosphate; P = 0.04]. The IMPDH activity measured before transplantation (Act(pre-Tx)) was not significantly different between IMPDH type II 3757TT wild-type and variant carrier patients (P = 0.99).. We report that the IMPDH type II 3757T > C polymorphism is associated with an increased IMPDH activity in MMF-treated renal transplant patients. This polymorphism explains 8.0% of the interpatient variability in IMPDH activity.

Topics: Adult; Area Under Curve; Cohort Studies; Female; Genetic Variation; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pharmacogenetics; Polymorphism, Single Nucleotide; Prospective Studies; Treatment Outcome

Pretransplant screening in living donor kidney transplantation includes human leukocyte antigen matching, and panel reactive antibody analysis, whereas T cell mediated anti-donor reactivity is not assessed routinely. We investigated T cell reactivity after living related kidney transplantation between two monocygotic twins and in consequence correlated the withdrawal of individual immunosuppressive medication with immunological findings.. Immunosuppression consisted of mycophenolate mofetil, glucocorticoid single shot, and induction therapy with antithymocyte immunoglobulin.. FACS analysis of recipient peripheral blood cells revealed a normal haemogram after transplantation, showing non-activated CD4 and CD8 cells. Mixed lymphocyte reaction did not reveal donor-specific T cell activity. IFN-gamma and IL-10 ELISA of supernatants of recipient cells cocultivated with donor cells support the lack of Th1 and Th2 cell differentiation.. Based on immunological findings on days 5 and 20 MMF-therapy was reduced and stopped. Immunological monitoring on day 90 confirmed the absence of immune reactions directed against donor tissue.

Topics: Aged; Antilymphocyte Serum; B-Lymphocytes; Blood Cell Count; Creatinine; Female; Glucocorticoids; Graft Survival; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-10; Kidney Failure, Chronic; Kidney Transplantation; Leukocytes, Mononuclear; Lymphocyte Culture Test, Mixed; Monitoring, Immunologic; Monocytes; Mycophenolic Acid; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells; Twins, Monozygotic; Withholding Treatment

Immunosuppressive therapy is essential for patients after renal transplantation, but it may have mutagenic side effects. The frequency of micronuclei (MN) assessed by the cytokinesis block assay is well established in the diagnosis of DNA damage.. We examined 79 patients before and after renal transplantation with the cytokinesis block assay. For MN evaluation, the criteria of the Human Micron Nucleus (HUMN) project were used.. Age and sex had no influence on the number of MN before transplantation. Patients with a shorter time on dialysis had fewer MN than patients with a longer time on dialysis. After 3 weeks of immunosuppressive therapy, the ability of cells to proliferate was reduced; therefore, only 36 patients could be analyzed. In these patients, MN frequency rose significantly. There was no linear relationship between MN after transplantation and age, sex, time on dialysis or graft function. The majority of patients (79%) were treated with cyclosporine A, mycophenolate mofetil and methylprednisolone when leaving the hospital. There was no difference between the different therapeutic schemes with regard to MN frequency after transplantation, but patients with mycophenolate mofetil showed less cellular proliferation. The function of the transplanted organ or the occurrence of rejection had no effect on MN frequency after transplantation.. In patients with renal transplantation, immunosuppressive therapy intensifies the genotoxic damage of the preceding chronic renal failure.

Topics: Adult; Cell Division; Cells, Cultured; Creatinine; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphocytes; Male; Methylprednisolone; Micronuclei, Chromosome-Defective; Middle Aged; Mutagens; Mycophenolic Acid; Steroids

10-30% of dialysis population awaiting renal transplantation is sensitized. Present desensitization protocols use intravenous immune globulins, rituximab, and plasmapheresis in various combinations; however, these regimens are unaffordable by many in developing countries. We tried desensitization with mycophenolate mofetil and plasmapheresis. Methods. Patients with high PRA titre (> or =50%) or positive crossmatch (>10%) were treated with MMF for a month before proposed transplant and were given five sittings of plasmapheresis. Results. 11 of 12 patients had normalization of PRA/crossmatch with this regimen and were successfully transplanted. One patient lost the graft due to graft vein thrombosis, and two patients died within three months after transplant due to septicemia and pulmonary embolism, respectively, with a functioning graft. No patient, including the two who died, developed clinical rejection over a mean follow-up of 10 months (range 1-16 months). Mean serum creatinine at last follow up was 1.1 mg/dL (range 0.9-1.3 mg/dL). Conclusions. Though the number of patients studied is small, we feel that highly sensitized patients awaiting living donor renal transplant should be tried on this simple and cost-effective regime before transplant. The more aggressive and expensive approaches incorporating IVIg and rituximab should be used only if this relatively low-cost regime is unsuccessful.

Topics: Adult; Cohort Studies; Combined Modality Therapy; Cost Savings; Cost-Benefit Analysis; Desensitization, Immunologic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Plasmapheresis; Preoperative Care; Transplantation Immunology; Treatment Outcome; Waiting Lists; Young Adult

To clarify the demographic data, outcomes and complications of renal transplantation in children at Srinagarind (university) Hospital.. The authors reviewed the medical records of children with end-stage renal disease (ESRD) who received renal transplantation at Srinagarind Hospital, Khon Kaen, between August 2001 and July 2008.. Eight male and seven female patients were identified Their mean age was 12.8 +/- 3.2 years (range, 5.0-17.6). The major cause of ESRD was a congenital anomaly of the kidneys (53%). All of the children received cadaveric transplantations and none received induction therapy. Triple immunosuppressive drugs comprising cyclosporine, prednisolone and mycophenolate mofetil were administered to 12 patients. Tacrolimus, instead of cyclosporine, was given to three patients who had received a renal transplant since January 2008. The median follow-up time was 15 months (3 to 82 months). The most frequent complication was urinary tract infection (40%). Acute graft loss was found in one patient (6.7%) due to graft infarction. Other complications included herpes viral infection, chronic rejection, acute rejection, severe gingival hyperplasia, myopathy, lymphocele and transitional cell carcinoma of the bladder. Two patients returned to dialysis due to graft infarction and chronic rejection, respectively. The mean serum creatinine at the last follow-up of the remaining cases was 1.2 +/- 0.5 mg/dL (range, 0.6-2.3). All of the patients survived. The 1- and 5-year graft survival rates were 93.3% and 86.7%, respectively.. The present study demonstrates the potential for successful outcomes of pediatric renal transplantation in this resource-limited area.

Topics: Adolescent; Age Factors; Cadaver; Child; Child, Preschool; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Intensive Care Units, Pediatric; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Retrospective Studies; Tacrolimus; Thailand

Although current therapies for pretransplant desensitization and antibody mediated rejection (AMR) have had some success, they do not specifically deplete plasma cells that produce antibodies to HLA. Bortezomib, a proteasome inhibitor, has been shown to induce plasma cell apoptosis and has been used in the treatment of AMR; however, there are no reported experiences in using this agent in pretransplant desensitization. We report using bortezomib in conjunction with Rituximab to desensitize a kidney transplant recipient on the waiting list. The patient's anti-HLA antibody titers (calculated PRA- (cPRA)) decreased from 57% to 31% prior to transplantation and the overall strength of his anti-HLA antibodies also decreased. He received a deceased-donor kidney to which he had a single low-level donor specific antibody that was undetectable post transplant. This case report demonstrates the potential safety of bortezomib therapy in treatment of highly sensitized patients awaiting kidney transplant and its association with decreased anti-HLA antibody levels.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Autoantibodies; B-Lymphocytes; Boronic Acids; Bortezomib; CD4-Positive T-Lymphocytes; Desensitization, Immunologic; Histocompatibility Testing; HLA-A Antigens; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Pyrazines; Rituximab; Waiting Lists

Bortezomib can be used to successfully treat acute kidney injury in the renal transplant allograft due to light chain cast nephropathy from recurrent multiple myeloma.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Biopsy; Bone Marrow; Boronic Acids; Bortezomib; Female; Humans; Immunoglobulin kappa-Chains; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Multiple Myeloma; Mycophenolic Acid; Protease Inhibitors; Pyrazines; Recurrence; Syndecan-1; Tacrolimus

Hepatitis C virus (HCV) infection is common among end-stage renal disease patients receiving hemodialysis and a kidney transplant. HCV-positive kidney transplant recipients have worse clinical outcomes than those who are HCV negative. The optimal immunosuppressive regimen in this group of patients remains uncertain.. Using data obtained from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients, we studied the impact of induction and maintenance immunosuppression on risk of patient death, with death-censored graft failure and death with a functioning graft as secondary endpoints. Cox regression analysis was used to estimate hazard ratios (HR) adjusted for donor, recipient, and transplant variables. A total of 3708 HCV-positive and 75,629 HCV-negative kidney transplant recipients were analyzed.. Patient survival was negatively affected by HCV-positive serology. Among HCV-positive kidney transplant recipients, a reduced HR for patient death was observed with the use of induction therapy (HR=0.75, 95% CI 0.61-0.90, P=0.003) and with the use of mycophenolate mofetil (HR=0.77, 95% CI 0.64-0.92, P=0.005).. In kidney transplant recipients with HCV-positive serology, the use of antibody induction did not negatively affect patient survival and the use of mycophenolate mofetil as part of maintenance immunosuppression was associated with better patient survival.

Topics: Adult; Cause of Death; Female; Follow-Up Studies; Graft Rejection; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Proportional Hazards Models; Retrospective Studies; Risk Factors; Survival Rate; Treatment Outcome; United States

Late introduction of mycophenolate mofetil (MMF) is used in renal transplant patients to allow calcineurin inhibitor (CNI) withdrawal. This change in treatment may alter the immunosuppressive load predisposing patients to infections. To assess this we have analysed infection rates in 30 consecutive patients with chronic allograft nephropathy commenced on MMF for CNI withdrawal. Methods and results. The study period was from 12 months pre-commencement to 12 months post-commencement. At commencement, patient mean age was 51.2 +/- 12.9 years and mean time post-transplant was 3170 +/- 2130 days. Estimated glomerular filtration rate (eGFR) at the start of the study period and at conversion was 30.7 +/- 12.1 ml/min and 23.1 +/- 9.9 ml/min, respectively. The mean dose of MMF post-conversion was 1575 +/- 428 mg/day. Estimated GFR had stabilized at 12 months post-conversion to 25.3 +/- 12.2 ml/min. There was a significant increase in infections following conversion: pre-conversion, 26.7% (8/30); post-conversion, 66.6% (20/30) (chi(2) = 24.5, P < 0.0005). There was an inverse correlation between eGFR at conversion and infection rates post-conversion (r = -0.379, P = 0.039). There were no hospitalizations for infection pre-conversion and 6 patients (20%) were hospitalized post-conversion, for a total of 285 days (7-107).. There is significant morbidity associated with an increased incidence of infection after late introduction of MMF at standard doses in renal transplant recipients. This risk may be related to GFR at the time of conversion.

Topics: Adult; Calcineurin Inhibitors; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid

Reversible posterior leukoencephalopathy syndrome (RPLS) is one of the important side effects of calcineurin inhibitors (CNIs). Magnetic resonance imaging (MRI) of the brain is useful for the diagnosis of RPLS, showing the edema primarily in the cortex and subcortical white matter of the posterior brain regions. Interruption of CNIs is essential for the treatment of patients with RPLS. Herein we have described 2 cases (1.7%) of RPLS induced by CNIs after kidney transplantation. The first case was a 56-year-old man with chronic renal failure due to diabetic nephropathy who received a living-related kidney transplantation in 2006. Initial immunosuppressive therapy consisted of cyclosporine, mycophenolate mofetil (MMF), prednisolone, and basiliximab. Four months after transplantation, he developed unconsciousness and paralysis. The second case was a 24-year-old woman with end-stage renal disease due to Alport syndrome who received an ABO-incompatible living-related kidney transplantation. Initial immunosuppressive therapy consisted of tacrolimus, MMF, prednisolone, and basiliximab. On postoperative day 3, she developed convulsions and unconsciousness. In both patients, RPLS was diagnosed with neurological symptoms and MRI findings at early stage of the disease, and they recovered rapidly from the disease by the interruption of CNIs. Our data demonstrated that early diagnosis and immediate interruption of CNIs were essential for the treatment of RPLS after kidney transplantation.

Topics: Adult; Brain; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Magnetic Resonance Imaging; Male; Middle Aged; Mycophenolic Acid; Nephritis, Hereditary; Posterior Leukoencephalopathy Syndrome

This retrospective study was done to assess the efficacy and safety of immunosuppression conversion on progression of chronic allograft nephropathy.. One hundred seventy-four cyclosporine-treated renal transplant recipients were studied. Patients were included if they had biopsy-proven chronic allograft nephropathy (mild to moderate) with a serum creatinine level of 300 micromol/L or less. The treatments groups were (1) mycofenolate mofetil and reduced-dosage cyclosporine (group MMF/CsA; n=132) and (2) azathioprine and reduced-dosage tacrolimus (group Aza/Tac; n=42). Patient records were checked for graft function, survival, and comorbidities after conversion.. Mean follow-up before conversion was 52.2 -/+ 31.1 and 47.9 -/+ 27.4 month in groups MMF/CsA and Aza/Tac, respectively. There was a significant deterioration of graft function in group Aza/Tac after 5 years (P < .05). Ten-year actuarial graft survival in group MMF/CsA was 38%; in group Aza/Tac it was 19% (P = .04). Nine patients started dialysis within 12 months. Tacrolimus-treated patients had a lower insignificant incidence of hyperlipidemia (P = .05) but a significantly higher incidence of diabetes mellitus (P = .04). There were no significant changes or differences in blood pressure between the groups.. Our results suggest that in patientswith chronic allograft nephropathy and deteriorating allograft function, cyclosporine minimization and addition of mycofenolate mofetil achieve favorable effects in retarding the decline of graft function. Further prospective studies with larger cohorts are needed for validation.

Topics: Adult; Azathioprine; Cohort Studies; Cyclosporine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Histocompatibility Testing; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Prospective Studies; Reoperation; Reproducibility of Results; Survival Analysis; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Mycophenolate mofetil (MMF) use may be associated with progressive multifocal leukoencephalopathy (PML). We conducted a retrospective cohort study of 32,757 renal transplant recipients using the United States Renal Data System kidney transplant files for the incidence, prognosis, and clinical features associated with PML occurring after kidney transplant. Subjects were transplanted from January 1, 2000 to July 31, 2004 and followed through December 31, 2004. The incidence density of PML in MMF users was 14.4 cases/100,000 person-years at risk versus 0 for non-MMF users (P=0.11) by log rank test. Factors significantly associated with PML were BK virus infection (22.2% vs. 1.1%), pretransplant transfusion (75% vs. 34%), panel reactive antibody more than 20% (56% vs. 14%), and use of antirejection medications in the first year (33% vs. 9.2%), all P less than 0.05. PML is rare in the renal transplant population. There was no significant association between PML and MMF, but MMF use in this cohort is too high to accurately assess an association.

Topics: Adult; Cohort Studies; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Male; Medicare; Middle Aged; Mycophenolic Acid; Postoperative Complications; Renal Replacement Therapy; Retrospective Studies; Survival Rate; United States

This retrospective study was conducted to assess the efficacy and safety of immunosuppression conversion on progression of chronic allograft nephropathy (CAN).. One hundred-seventy four cyclosporin (CsA)-treated renal transplant recipients were studied. Patients were included if they had a biopsy-proven CAN (mild to moderate) with serum creatinine < or =3.5 mg/dL. Patients were treated with either: (A) MMF/reduced dose CsA [MMF for azathioprine (Aza)] (n=132); (B) Aza/Tac for CsA (n=42). Patient records were checked for graft function and survival, co-morbidities after conversion.. Mean follow-up before conversion was 52.2+/-31.1 and 47.9+/-27.4 month in-group A and B, respectively. There was a significant deterioration of graft function in-group B after 5-years (P<0.5). Ten-year actuarial graft survival was 38% in-group A and 19% in-group B (P=0.04). Nine patients started dialysis within 12 months. Tacrolimus-treated patients had a lower insignificant incidence of hyperlipidemia (P=0.05), but a significantly higher incidence of diabetes mellitus (P=0.04).There was no significant change or difference in blood pressure between groups.. Our results suggest that in patients with CAN and deteriorating allograft function, CsA minimization and addition of MMF achieved favorable efficacies in retarding the decline of graft function. Further prospective studies with larger cohorts are needed for validation.

Topics: Adult; Azathioprine; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Survival; Humans; Hyperlipidemias; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Transplantation, Homologous; Treatment Outcome

The aim of this study is to examine the effect of mycophenolate mofetil (MMF) on epithelial-myofibroblast translation (EMT) in adenine-induced chronic renal failure (CRF) rat model and the role of vascular endothelial growth factor(VEGF) and inhibitor of differentiation (Id2 and Id3) in EMT in the rat kidney.. Sixty-four male Wistar rats were randomly assigned to the following groups: normal control (n = 16), CRF (n = 24) and MMF(n = 24). CRF was induced by gastric gavage of adenine (125 mg kg(-1) d(-1)) to rats for eight weeks. CRF rats were treated with MMF (15 mg kg(-1) d(-1)) as "MMF" group. The rats were sacrificed at week 2, 4, 6 and 8, respectively. Urinary protein and serum creatinine levels were measured, and the histopathologic degrees of interstitial fibrosis were evaluated in Masson-stained sections. Expressions of alpha-smooth muscle actin (alpha-SMA), transforming growth factor beta1 (TGFbeta1), VEGF and Id (Id2 and Id3) in the kidney tissue were assessed by immunohistochemistry, RT-PCR and/or Western blot methods.. The urinary protein level in MMF group was evidently lower than that in CRF group (P < 0.01), whereas no statistically significant difference was observed in serum creatinine level between the two groups. Renal interstitial fibrosis was reduced significantly with MMF treatment (P < 0.01). Expression of alpha-SMA in MMF group was lower than that in CRF rats at week 6, 8 (P < 0.01), while expression of TGFbeta1 was decreased markedly at week 2, 4, 6 (P < 0.01). The expressions of VEGF in MMF rats were increased significantly at week 6, 8 (P < 0.01), and Id2, Id3 in MMF rats were increased significantly at week 4, 6 (P < 0.05).. MMF may ameliorate chronic renal fibrosis and EMT in adenine-induced CRF rats. This effect of MMF on EMT is probably related to upregulation of VEGF, Id2 and Id3 expressions and suppressing overexpression of TGFbeta1 in renal tissue. The exact mechanism needs to be studied further.

Topics: Animals; Kidney; Kidney Failure, Chronic; Kidney Tubules; Male; Mycophenolic Acid; Rats; Rats, Wistar; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Hyperlipidemia following successful renal transplantation is a frequent and persistent complication. Several immunosuppressive agents including cyclosporine A (CyA), corticosteroids, and tacrolimus appear to have a significant pathogenetic role. The aim of this study is to investigate the differential effects of different immunosuppressive agents on lipids in renal transplant patients.. Two groups of renal transplant recipients, each treated with a different combination of immunosuppressive agents, were studied: Group A (n = 13), cyclosporine A, mycophenolate mofetil (MMF), steroids, and basiliximab; Group B (n = 13), tacrolimus, MMF, steroids, and daclizumab). Plasma lipids [cholesterol (CHOL), low-density lipoprotein (LDL)-CHOL, high-density lipoprotein (HDL)-CHOL, and triglycerides (TG)] were examined before transplantation and 1 and 6 months posttransplantation.. The patients treated with cyclosporine A-MMF showed a significant increase in mean cholesterol and mean LDL-cholesterol values at the 1-month posttransplantation follow-up compared with pretransplant levels (CHOL: 208.9 +/- 47.4 vs. 268.7 +/- 42.2 mg/dl, P = 0.004; LDL: 118.4 +/- 49.9 vs. 198.7 +/- 40.7 mg/dl, P = 0.002; pretransplant vs. 1 month, respectively). At 6 months, LDL-cholesterol levels were significantly elevated compared with pretransplant levels (LDL: 118.4 +/- 49.9 vs. 148.3 +/- 48.5 mg/dl, P = 0.034), whereas there was no significant change in the cholesterol level during the same period. In cyclosporine A-MMF-treated patients, plasma triglyceride levels were reduced at the 1- and 6-month follow-up (TG: 293.9 +/- 59.2 vs. 182.9 +/- 48.7 mg/dl, P = 0.03; 293.9 +/- 59.2 vs. 178.6 +/- 74.2 mg/dl, +/- = 0.023; pretransplant vs. 1 and 6 months, respectively). Patients receiving combined therapy with tacrolimus-MMF showed no significant changes in LDL-CHOL levels during the trial. Cholesterol levels at 6 months posttransplantation were significantly lower than the pretransplant measurements (CHOL: 182.9 +/- 44.4 vs. 162.3 +/- 37.2 mg/dl, P = 0.024; pretransplant vs. 6 months). A significant reduction in triglyceride level was documented at the 1-month follow-up followed by a subsequent decrease within 6 months (TG: 228.5 +/- 61.6 vs. 147.6 +/- 51.5 mg/dl, P = 0.005; TG: 228.5 +/- 61.6 vs. 130.4 +/- 54.7 mg/dl, P = 0.011; pretransplant vs. 1 and 6 months, respectively).. In posttransplant patients with stable renal function cyclosporine therapy is associated with increased cholesterol and LDL-cholesterol levels. Hyperlipidemia is less pronounced in patients given tacrolimus. Tacrolimus appears to an immunosuppressant agent with fewer and less severe adverse effects on lipid metabolism.

Topics: Adult; Cholesterol, LDL; Creatinine; Cyclosporine; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

Topics: Bone Marrow Transplantation; Child, Preschool; Directed Tissue Donation; Fanconi Anemia; Female; Graft Survival; Graft vs Host Disease; Hemibody Irradiation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Mycophenolic Acid; Siblings; Transplantation Chimera; Transplantation Conditioning; Vesico-Ureteral Reflux; Vidarabine

Two new diagnoses have been causing graft loss during long-term follow-up, namely, chronic nephropathy and anticalcineurinic toxicity. The advent of the mammalian target of rapamycin (m-TOR) obviates anticalcineurine toxicity and reduces posttransplant malignancy incidence with good inmunosuppressive potential. We examinated the renal and metabolic behavior in renal transplant recipients who required conversion from an anticalcineurinic (cyclosporine or tacrolimus) to an m-TOR inhibitor (everolimus) as part of their immunosuppressive maintenance therapy.. Twenty-one first renal transplant recipients had everolimus added to their inmunosuppressive therapy combined with an antimetabolite (mycophenolate mofetil or sodium mycophenolate). The mean age of the patients was 35 +/- 17 years (range, 6 to 65). The prevalence of male recipients was 57%; the overall mean weight, 64 kg (range, 48 to 95). All patients were hispanic with 15 transplants from cadaveric donors (71%). The mean follow-up posttransplant was 18 months (range, 3 to 40) and the mean follow-up on everolimus, 10 months (range, 2 to 22).. There was no mortality or graft loss, but there were 3 (17%) biopsy-confirmed acute rejection episodes. There were no significant changes in metabolic function pre- or postconversion. Regarding renal function, the mean creatinine serum showed a trend to decline: preconversion 1.7 mg/dL; postconversion 1.5 mg/dL. In 10 patients, it was possible to discontinue at least one antihypertensive medication (48%).. Everolimus was an effective medication to manage renal transplant patients. It produced metabolic stability and low myelotoxicity, despite combination with an antimetabolite (mycophenolic acid). Also, reduction of antihypertensive medications was an additional benefits for many patients.

Topics: Adolescent; Adult; Aged; Child; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Severe autoimmune myasthenia gravis is difficult to manage and may require immunosuppression with cyclosporine. However, cyclosporine dependency is associated with the risk of nephrotoxicity. Mycophenolate mofetil is a non-nephrotoxic alternative which should be considered to rescue cyclosporine-dependent, severe myasthenia gravis sufferers with renal impairment from progression to end-stage renal failure. However, the evidence is limited and studies have not assessed the outcome of a direct substitution in these cyclosporine-dependent patients. We study three such patients who successfully converted to mycophenolate mofetil, and briefly examine the evidence behind this option. We believe that total cyclosporine withdrawal is feasible, but strongly recommend overlapping mycophenolate mofetil treatment with cyclosporine.

Topics: Adult; Cyclosporine; Diabetic Nephropathies; Drug Evaluation; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Myasthenia Gravis; Mycophenolic Acid; Plasma Exchange; Prednisolone; Recurrence; Thymectomy

Immunosuppressive protocols in dual kidney transplantation (DKT) are based on calcineurin inhibitors (CNI). We wonder whether a CNI-free immunosuppression can improve outcome in older patients receiving a DKT with marginal donor organs. Thirty-six were treated with CsA, MMF and prednisone (CsA group) and 42 with rATG, SRL, MMF and prednisone (SRL group). Incidence of delayed graft function and acute rejection was 44% and 11% in the CsA group, and 40% and 8% in the SRL group. CMV infection incidence was low in both protocols. Three-year patient survival was 89% in the CsA and 76% in the SRL group. One- and 3-year graft survival after censoring for dead with a functioning allograft was 94.2% and 94% in CsA and 95% and 90% in SRL, respectively. Renal function was similar in both groups whereas proteinuria was higher in the SRL group. Uninephrectomy due to graft thrombosis or urinary-related complications was numerically higher in the SRL (21%) than in the CsA group (8%) (p = 0.13) and it was associated with renal failure and proteinuria. In DKT, a new induction immunosuppressive protocol based on rATG, SRL, MMF and prednisone does not offer any advantage in comparison to the old CsA, MMF and prednisone.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Cyclosporine; Delayed Graft Function; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Risk; Treatment Outcome

C-reactive protein (CRP) is a strong predictor of cardiovascular disease, all-cause mortality, and renal allograft loss. Little is known about the effects of immunosuppressive and cardiovascular risk-modifying drugs on CRP in renal transplant recipients.. We retrospectively identified stable patients with > or =1 highly sensitive CRP measurements between January 1 and August 31, 2005. Variables collected included patient demographics; transplant, dialysis, and cardiovascular disease-related variables; and medication profiles. Univariate correlations with CRP were assessed by unpaired Student t testing, analysis of variance, or chi analysis and followed by multivariate linear regression with stepwise backward elimination until a final stable model was attained.. CRP levels were obtained in 298 recipients. In univariate analysis, body mass index (P<0.0001) and systolic blood pressure (P=0.009) showed a positive correlation, whereas number of immunosuppressive drugs (P=0.05) and use of mycophenolate mofetil (MMF) (P=0.003) were negatively correlated with CRP levels. By multivariate analysis, only body mass index (P<0.0001) and MMF dose (P<0.0001) were independently and opposingly correlated with CRP. Mean CRP level was 5.18+/-5.7 mg/L in patients not taking MMF compared with 3.13+/-3.5 mg/L in those on 2000 mg per day (P=0.002).. MMF use correlates inversely with CRP levels in renal transplant recipients, suggesting that immunosuppressive regime design may alter allograft and cardiovascular disease risk in these patients. Prospective study of the effects of MMF on novel cardiovascular disease risk factors such as CRP is warranted.

Topics: Adult; Aged; Analysis of Variance; C-Reactive Protein; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies

A pilot study was performed on eight consecutive renal-transplant (RT) patients presenting with acute humoral rejection (AHR) to assess the efficacy of monoclonal anti-B cell antibodies, such as rituximab (375 mg/m weekly) for 3 to 5 consecutive weeks, in addition to plasma exchange (PE), steroids, mycophenolate mofetil, and tacrolimus. AHR was associated with increased serum creatinine, the appearance of donor-specific alloantibodies (DSA), and the presence of C4d in a transplant biopsy. After a follow-up of 10 months (range 7-23), patient and graft survivals were 100% and 75%, respectively. Renal function improved in six cases in which serum creatinine decreased from 297+/-140 to 156+/-53 micromol/L (P=0.015); graft loss occurred in two cases; and four patients had infectious complications. At last follow-up, DSA had disappeared or decreased in four cases. Rituximab therapy, in addition to PE, might be of benefit for RT patients presenting with AHR.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antibody Formation; Creatine; Female; Graft Rejection; Humans; Immunologic Factors; Immunosuppressive Agents; Infections; Isoantibodies; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Plasma Exchange; Rituximab; Steroids; Tacrolimus; Tissue Donors; Treatment Outcome

Calcineurin inhibitors (CNIs) are the cornerstone of immunosuppression after liver transplantation. However, CNI treatment is frequently associated with chronic renal failure (CRF). The reduction or interruption of CNI may reduce renal failure. We prospectively studied 49 liver recipients treated with CNI (tacrolimus, n = 14; cyclosporine, n = 35) who secondarily developed CNI-associated CRF and for whom mycophenolate mofetil (MMF) was introduced to reduce or withdraw CNI. The creatinine clearance (CCl; 42.9 +/- 14 ml/minute) increased significantly after CNI reduction (48.8 +/- 17 ml/minute after 1 year, 49.9 +/- 18 ml/minute after 2 years, and 58.4 +/- 20 ml/minute after 3 years, P < 0.0001). CCl decreased during the 2 years before CNI reduction at a rate of -5.6 +/- 5 ml/minute/year; for the 2 years after CNI reduction, CCl increased significantly by +3.2 +/- 4.3 ml/minute/year (P < 0.0001). Ten patients did not have improved renal function after 1 year, but the rate of decrease in CCl slowed after CNI reduction. Three parameters were identified as risk factors for unresponsiveness to CNI reduction: (1) low CCl at MMF introduction, (2) a high rate of CCl decrease during the 2 years before conversion, and (3) alcoholic cirrhosis. The type of CNI molecule used did not impair the renal response. None of the patients developed acute or chronic graft rejection after the reduction or interruption of CNI. In liver recipients with CRF, a reduction or withdrawal of CNI concomitantly with the introduction of MMF was safe and was associated with an improvement in renal function.

Topics: Adrenal Cortex Hormones; Adult; Aged; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Treatment Outcome

Idiopathic membranous nephropathy (IMN) is one of the most common causes of primary nephrotic syndrome in adults. However, it is a relatively rare entity in the pediatric population and there is a paucity of data about the incidence, prognosis, and optimal treatment of IMN in children and adolescents. We conducted this study to evaluate pediatric patients with IMN in order to clarify the presentation, response to therapy, and clinical outcome.. A retrospective chart review was performed on patients identified with biopsy-proven IMN between 1988-2005. Patients with systemic lupus erythematosus or hepatitis-related lesions were excluded. The following data were tabulated: age, gender, ethnicity, presenting clinical and laboratory findings, proteinuria in a first morning urine specimen, estimated glomerular filtration rate (GFRe), histopathology, type and duration of treatment, and clinical status at final evaluation.. 13 cases of IMN were identified out of 460 renal biopsies performed for evaluation of primary kidney disease during the study interval. Mean age was 9.6 +/- 4.6, gender 6 M:7 F, ethnicity 8 W:2 B:3 H. At the initial visit hematuria was present in 9 patients, edema in 5, nephrotic-range proteinuria in 5, and hypertension in 3. Mean urinary protein:creatinine ratio 3.3 +/- 2.5 and all patients had a normal GFRe. Classic glomerular findings of IMN were seen in all renal specimens, with concomitant interstitial changes in 2 cases. Treatment included an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in 11 cases. Most patients were also given immunosuppressive medications - prednisone in 10, a calcineurin inhibitor in 5, and mycophenolate mofetil or azathioprine in 3 patients. At the last follow-up, 42 +/- 35 months after the diagnostic biopsy, 7 children were hypertensive and the urine protein:creatinine ratio was 2.3 +/- 3.1. The mean GFRe was 127 +/- 57 mL/min/m2. Three patients had Chronic Kidney Disease Stage 3, all of whom were also hypertensive.. IMN is a rare but serious glomerulopathy in pediatrics. We estimate that it accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.

Topics: Adolescent; Biopsy; Child; Child, Preschool; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Male; Mycophenolic Acid; Prednisone; Prognosis; Proteinuria; Retrospective Studies; Time Factors; Treatment Outcome

Administration of the NO inhibitor N(wdelta)-nitro-L-arginine methyl ester (NAME) and a high-salt diet (HS) promotes severe albuminuria and renal injury, which regresses upon discontinuation of treatments.. We investigated whether these changes reappear after reinstitution of HS, and whether they are prevented by treatment with the antilymphocyte agent mycophenolate mofetil (MMF) or the AT-1 receptor blocker losartan (L). Adult male Munich-Wistar rats received NAME and HS. A control Group (C) received only HS. After 20 days, rats receiving HS and NAME exhibited severe hypertension and albuminuria. After a 30-day recovery period, hypertension was attenuated and albuminuria had virtually disappeared.. Rats were then distributed among the following groups: HS, receiving HS; NS, receiving a normal salt (NS) diet; HS-MMF, receiving HS and MMF; HS-LOS, receiving HS and L; HS-HDZ, receiving HS and hydralazine (HDZ). Sixty days later, NS rats showed only slight albuminuria and renal damage or inflammation. In contrast, HS rats developed severe hypertension, marked glomerulosclerosis with interstitial expansion and renal infiltration by macrophages and angiotensin II-positive cells. The group treated with losartan had lowered blood pressure and a lack of albuminuria or renal injury. MMF provided similar protection without altering blood pressure, suggesting a nonhemodynamic effect, a hypothesis reinforced by the finding that HDZ lowered blood pressure without preventing renal injury.. These results indicate that treatment with HS and NAME predisposes to the development of hypertension and renal injury upon salt overload, characterizing a new model of chronic nephropathy.. The response to MMF or L, but not HDZ, suggests a key role for inflammatory rather than hemodynamic factors.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Hydralazine; Hypertension; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Losartan; Male; Mycophenolic Acid; Nitric Oxide; Rats; Rats, Wistar; Sodium Chloride, Dietary

Although the prognosis for patients with renal lupus has improved, a small number still progress to renal failure. Studies from the USA have found it difficult to distinguish whether the higher rate of renal failure in African-Americans is due to genetic or socio-economic factors. Our aim was to identify ethnic and other factors in a UK lupus cohort that contribute to renal failure.. The University College London (UCL) Hospitals lupus cohort of 401 patients (Whites 64%, Blacks 19%), followed since 1978, has 127 patients with renal disease, of whom 21 have gone into renal failure. We determined the characteristics and possible causes of renal failure in this group. Black patients were disproportionately represented in the renal failure group (62% vs 19% for Whites).. Those in the renal failure group had persistently low C3 compared with the renal disease cohort. A high proportion of patients in the renal failure group were felt to be non-adherent to treatment.. Given that health-care for patients in the UK is free at the point of delivery, we postulate that in our cohort genetic factors rather than socio-economic status are likely to be more significant in causing renal failure. However, there may be cultural and other reasons for this, which requires further study.

Topics: Adolescent; Adult; Asian People; Black People; Chi-Square Distribution; Child; Cyclophosphamide; Disease Susceptibility; Ethnicity; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Patient Compliance; White People

The optimal effect of therapy with cyclosporine (CsA) seeks to minimize undesirable side effects while maximizing immunosuppression. This balance, depends on CsA exposure, which may be characterized by the area under the concentration-time-curve (AUC). Therefore, we tested the pharmacokinetic profile of microemulsion CsA as a superior approach to guide clinical immunosuppression after de novo simultaneous pancreas-kidney transplantations. We examined 10 consecutive pancreas-kidney recipients with type 1 diabetes and end-stage renal disease. All patients were treated with a regimen consisting of CsA, mycophenolate mofetil (MMF), and prednisone. Full (9-point) pharmacokinetic studies (C0, C1, C2, C3, C4, C6, C8, C10, C12) were performed on week 1 and during week 3 to examine CsA pharmacokinetic profiles. Mean AUC0-12 of 4431 +/- 2400 microg x h/L at week 1 remained stable at week 3 (5119 +/- 1190 microg x h/L). The C6 sampling time displayed the best correlation with AUC0-12 (r2 = 0.881), followed by C3 (r2 = 0.758). Our preliminary data after simultaneous pancreas-kidney transplantation support the hypothesis that C3 or C6 sampling is a more accurate predictor of the AUC0-12 than C0. The combination of two samplings, namely C3 + C6 (r2 = 0.938) or C2 + C6 (r2 = 0.955) proved excellent prediction of exposure after simultaneous pancreas-kidney transplantation.

Topics: Area Under Curve; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Emulsions; Humans; Immunosuppressive Agents; Intestinal Absorption; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Pancreas Transplantation; Postoperative Period; Prednisone; Regression Analysis; Reproducibility of Results

Topics: Abscess; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Biopsy, Fine-Needle; Caspofungin; Contraindications; Cyclosporine; Delayed Graft Function; Drug Interactions; Echinocandins; Fever of Unknown Origin; Gram-Negative Bacterial Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lipopeptides; Male; Middle Aged; Mycophenolic Acid; Peptides, Cyclic; Postoperative Complications; Prednisone; Pyrimidines; Radionuclide Imaging; Stenotrophomonas maltophilia; Surgical Wound Infection; Thyroiditis; Triazoles; Ultrasonography; Voriconazole

The serious shortage of cadaveric organs has prompted the development of ABO-incompatible live donor renal transplantation. We report our experience of the initial two live donor ABO incompatible renal transplants at our hospital. The first patient was a 55-year-old type A female who received a kidney from her AB type husband. The second patient was a 27-year-old type O male who received renal transplantation from his type A father. Preconditioning immunosuppressive therapy in the two patients with tacrolimus, mycophenolate mofetil and methylprednisolone was started 7 days before transplantation. During the period of preconditioning, double filtration plasmapheresis (DFPP) was employed to remove anti-A and -B antibodies. Laparoscopic splenectomy and renal transplantation were performed after the anti-donor ABO antibodies were reduced to a titer of 1:4. Rituximab, a humanized monoclonal anti-CD20 antibody, was administered to the second patient due to a rebound in the anti-A antibody titer during the preconditioning period. Under a tacrolimus-based immunosuppressive regimen, both patients recovered very well without any evidence of rejection. Serum creatinine levels were 1.0 and 1.4 mg/dL at 6 and 3 months after transplantation, respectively. These cases illustrate that with new immunosuppressive agents, DFPP and splenectomy, ABO-incompatible renal transplantation can be successfully conducted in end-stage renal disease patients whose only available live donors are blood group incompatible.

Topics: ABO Blood-Group System; Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Blood Group Incompatibility; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Rituximab; Splenectomy; Tacrolimus; Tissue and Organ Procurement; Transplantation Conditioning; Transplantation Immunology

A young female with essential hypertension developed progressive azotemia; renal biopsy showed hypertensive nephrosclerosis with considerable tubulointerstitial disease and cellular infiltration. The addition of mycophenolate mofetil (MMF) to her antihypertensive treatment resulted in a dramatic improvement of renal function during the following three months. When the patient discontinued MMF treatment, end-stage renal failure rapidly developed. This patient represents the first report of the beneficial use of MMF in non-immune chronic renal disease and demonstrates that significant functional improvement may be obtained with the addition of MMF to the treatment of hypertensive nephrosclerosis for patients in whom there is significant tubulointerstitial inflammatory infiltration.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Captopril; Drug Therapy, Combination; Female; Humans; Hydralazine; Hypertension; Kidney Failure, Chronic; Mycophenolic Acid; Nephrosclerosis; Treatment Outcome

Topics: Adult; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Mycophenolic Acid; Red-Cell Aplasia, Pure; Tacrolimus

MMF has been shown to decrease the incidence of acute rejection in children and adults at 1 and 3 yr. Other beneficial effects of MMF have been more difficult to demonstrate. Our open-labeled study presents a 5-yr data for patients and graft survival, allograft function, and growth in MMF-treated patients. The trial included 29 patients who were treated with MMF in combination with cyclosporine and methylprednisone. Patients were compared with a preceding group of 29 patients treated with AZA instead of MMF. Patient and graft survival rate 5 yr after transplantation were 97 and 90% in the MMF group vs. 93 and 83% in the AZA group (p: NS). Acute rejection was 20.6% in the MMF group vs. 58.6% in the AZA group (p < 0.01). Chronic rejection was 10.3% in the MMF group and 25% in the AZA group (p: NS). The changes in the creatinine clearance from baseline to 5 yr (Delta) were different between groups (-6.0 +/- 5.1 mL/min/1.73 m(2) in the MMF group vs. -22.2 +/- 7.6 mL/min/1.73 m(2) in the AZA group, p < 0.05). Also, the slope of 1/Scr showed a significant lower incidence of worsening renal function after the second year of renal transplantation (p < 0.0001) in the MMF group compared with the AZA group. Delta Height SDS in prepubertal patients was 0.3 +/- 0.4 SDS in the MMF group vs. -0.8 +/- 0.2 SDS in the AZA group (p < 0.05). This study shows that long-term MMF therapy has resulted in a decrease in acute rejection and was associated with a protection against renal function deterioration. The use of MMF enables a reduction in the dose of steroids and leads to a linear growth improvement of children after renal transplantation.

Topics: Adolescent; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Prospective Studies; Transplantation, Homologous

Mesangial IgA glomerulonephritis (MIgAGn) is the most common biopsied primary glomerulonephritis worldwide, with a poor long-term prognosis for renal function in over a third of all patients. No proven therapy currently exists for MIgAGn. Recent studies have suggested some benefit with mycophenolate mofetil (MMF), especially in hypertensive patients with kidney failure and proteinuria, though other studies have failed to corroborate these findings. We report eight adult patients with biopsy proven MIgAGn followed in a single hospital. They all received angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Compassionate use of MMF was based on the presence of clinical and analytical data suggesting a high risk of short- to medium-term progression to chronic renal failure. MMF treatment was stopped after two and three months in two patients who had advanced renal failure at the start of therapy because of disease progression and greater fluid retention. Several months later they both required dialysis and kidney transplantation. The mean duration of MMF therapy in the other six patients was 15 (range: 10-18) months. The mean serum creatinine concentration fell from 1.82 +/- 0.47 to 1.55 +/- 0.41 mg/dl (p = 0.04). Protein loss in 24-hour urine collection fell from 1.95 +/- 1.35 to 0.77 +/- 0.58 g/day (p = 0.02). These results in this low number of patients showed that treatment with MMF in high-riks patients with MIgAGn and early stage kidney failure generally stabilized the disease and reduced proteinuria. MMF was well tolerated and may be of some benefit in a subgroup of patients with MIgAGn and a poor prognosis.

Topics: Adult; Creatinine; Data Interpretation, Statistical; Disease Progression; Female; Follow-Up Studies; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Prospective Studies; Proteinuria; Renal Dialysis; Risk Factors; Time Factors; Treatment Outcome

In end-stage cardiomyopathy where concomitant chronic renal failure is a contraindication for cardiac transplantation (HTx), simultaneous heart and kidney transplantation (HKTx) may be the only feasible therapeutic option. Due to the increased donor shortage, the clinical outcome of combined HKTx patients on tacrolimus-based immunosuppression was assessed and compared with a group of HTx patients.. Three hundred forty-nine HTxs, including 13 (4%) combined HKTxs, were performed since 1995. Two hundred twenty-one HTx and all HKTx recipients received tacrolimus-based immunosuppression. Acute rejection episodes (AREs), infections, renal function and clinical outcome were evaluated. Pre-operative renal diagnoses for HKTx patients included cystic nephropathy (n = 4), glomerulonephritis (n = 4), cytostatica-induced nephropathy (n = 1), chronic rejection after renal transplant (n = 1), reflux nephropathy (n = 2) and chronic calcineurin-inhibitor -induced nephropathy after HTx (n = 1). Twelve patients (92%) were on hemodialysis pre-operatively, 1 underwent implantation of a left ventricular assist device (LVAD) before HKTx.. After 4.7 +/- 2 years, 92% of HKTx compared with 85% of HTx patients had survived (p = 0.42). Acute cardiac rejection episodes were more frequent in HTx than in HKTx patients (0.04 +/- 0.09 vs 0.02 +/- 0.04 ARE/100 patient-days; p = 0.07). Incidence of infection was comparable (0.3 +/- 0.2 vs 0.5 +/- 0.4 infection/100 patient-days). Freedom from transplant vasculopathy was 100% in the HKTx group compared with 71% in the HTx group after 4 years (p = 0.04).. Tacrolimus-based immunosuppression yields promising long-term results in HKTx and HTx. The incidence of transplant vasculopathy seems to be lower after HKTx than after HTx. If these results are secondary to a protective effect of tacrolimus-induced tolerance or of tolerance-associated co-transplantation they will need to be investigated in prospective multicenter trials.

Topics: Cardiomyopathy, Dilated; Comorbidity; Coronary Disease; Creatinine; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

Conversion from cyclosporine (CsA) to sirolimus (SRL) has mainly been done in clinical conditions warranting calcineurin inhibitor discontinuation. Little is known about the clinical outcome of conversion in renal transplant recipients without transplant dysfunction.. This prospective, open-label, multicentric pilot study evaluates the safety and efficacy of converting patients with stable renal function from CsA to SRL.. Forty stable patients on CsA, mycophenolate mofetil (MMF) (1.5 g/day), and steroids (ST) were converted at 7.6+/-1.4 months after renal transplantation. At 1 year, graft and patient survival was 100% and the incidence of acute rejection 5%. Calculated glomerular filtration rate (GFR) increased from 54+/-18 to 66+/-16 ml/min (P<0.0001). Blood pressure remained unchanged. A gradual increase in the incidence and severity of proteinuria was observed from month 6 onwards with de novo proteinuria in 30% of the patients at 1 year. Protein excretion was below 1 g/day in 12.5%, between 1 and 3 g/day in 17.5% and above 3 g/day in 7.5% of the proteinuric cohort (P=0.0043, compared to baseline). No predictors could be identified for the development of proteinuria. All patients had a reduction in protein excretion following renin-angiotensin blockade and were continued on SRL.. Conversion of stable renal transplant recipients from a CsA-MMF-ST to a SRL-MMF-ST regimen is safe and results in improved renal function but is associated with the development of proteinuria in 30% of the patients requiring renin-angiotensin blockade.

Topics: Adult; Aged; Creatinine; Cyclosporine; Diabetic Nephropathies; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Sirolimus

Mycophenolate mofetil (MMF) is an immunosuppressant that is widely used for prophylaxis of rejection in solid organ transplantation. In this study, we examined the effect of renal insufficiency on the pharmacokinetics of MMF, particularly on the free fraction of drug in renal transplant patients. Our study was performed on 10 patients with severe renal insufficiency (creatinine clearance [CrCl] <30 mL/min), and 10 control patients with preserved renal function (CrCl >90 mL/min). All the patients had received a cadaveric donor graft at least 1 year prior and were clinically stable under treatment with MMF and cyclosporine. For each patient, we determined 12-hour areas under the curve (AUC(0-12 h)) for the metabolites: mycophenolic acid (MPA), 7-O-mycophenolic acid glucuronide (MPAG), and the free non-protein-bound fraction of MPA (f-MPA). The two groups were matched for age, sex, and MMF dose. Mean AUC(0-12 h) values for MPA were similar in both groups. The renal insufficiency group showed a significantly increased AUC(0-12 h) for MPAG (1550 +/- 392 vs 3527 +/- 1130 microg.h/mL, P < .001) and increased trough and AUC(0-12 h) values for f-MPA (0.023 +/- 0.02 vs 0.094 +/- 0.07 microg/mL, P = .003, and 0.87 +/- 0.3 vs 1.52 +/- 0.8 microg . h/mL, P = .016, respectively). We proposed that these differences should be taken into account when deciding upon the dose of this drug for the subset of patients with impaired transplant function.

Topics: Area Under Curve; Biotransformation; Cadaver; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Tissue Donors

MMF (mycophenolate mofetil) has been proven to provide an effective immunosuppression by non-competitive selective reversible inhibition of IMPDH (inosine monophosphate dehydrogenase), the enzyme playing a crucial role in GTP biosynthesis. However, the exact metabolic changes induced by inhibition of IMPDH in target cells of the immune system have been the subject of recent debate. The aim of the present study was to evaluate whether MMF treatment produced sustained changes in the guanosine nucleotide pool of MNLs (mononuclear leucocytes) in vivo. Sixty-two renal failure patients were divided into three groups: chronic renal failure patients undergoing haemodialysis (CRF-HD; n=20) and two groups of patients after renal transplantation, the first on AZA (azathioprine; TN-AZA; n=23) and the second treated with MMF (TN-MMF; n=19). In addition, MNLs from 25 healthy subjects were analysed as controls. Anion-exchange HPLC was used to quantify purine and pyrimidine nucleotides in MNLs. We report a significant decrease in GTP and the total MNL guanine nucleotide pool in the TN-MMF group (P<0.05) compared with control, CRF-HD and TN-AZA groups, although no significant differences were found between any of the other groups. Adenine nucleotide concentrations in MNLs were decreased in the TN-AZA group, but not in the TN-MMF group compared with the CRF-HD group and controls. There were no differences in CTP concentrations, but UTP concentrations were decreased in the CRF-HD, TN-AZA and TN-MMF groups compared with controls. MMF caused a significant and sustained decrease in the guanine nucleotide pool in MNLs from renal transplant recipients. This decrease contrasts with the elevation in GTP reported in erythrocytes of MMF-treated patients.

Topics: Adolescent; Adult; Aged; Azathioprine; Child; Drug Administration Schedule; Enzyme Inhibitors; Female; Guanosine Triphosphate; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Failure, Chronic; Kidney Transplantation; Leukocytes, Mononuclear; Male; Middle Aged; Mycophenolic Acid; Postoperative Period; Purine Nucleotides; Pyrimidine Nucleotides

ABSTRACT. Anemia has long been known to be a complication of end-stage renal disease (ESRD), and it has been linked to cardiovascular morbidity and mortality. Although kidney transplant recipients (KTR) are prone to experiencing cardiovascular outcomes, little is known about the epidemiology of anemia in this population. With few exceptions, studies to date have not fully evaluated the associations between posttransplant anemia (PTA) and medications commonly used in KTR, particularly immunosuppressant drugs, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). The authors aimed to specifically investigate possible associations between these drugs and PTA. Detailed medical information was retrospectively collected on 374 consecutive KTR from our transplant clinic. Univariate/multivariate linear regression models were used to test for associations between hematocrit (HCT) and other covariates, and logistic regression models were used to detect independent predictors of PTA, defined as HCT <33%. The mean time since transplantation was 7.7 yr, and mean creatinine was 2.2 mg/dl. The prevalence of PTA was 28.6%. Ten percent of all patients were on erythropoietin therapy, but only 41.6% of patients whose HCT was <30 received this treatment. From multivariate analyses, the authors found that female gender and lower renal function were associated with lower HCT (both P < 0.001). Patients on ACEI had significantly lower HCT (P = 0.005) compared with patients without such treatment. In addition, a significant curvilinear dose-response relationship was found between ACEI dose and HCT. Among the immunosuppressant drugs, mycophenolate mofetil (P = 0.05) and tacrolimus (P = 0.02) were associated with a lower HCT. The authors conclude that PTA is prevalent and undertreated in KTR. Several medications that are possibly modifiable correlates of PTR deserve further study.

Topics: Adult; Anemia; Angiotensin-Converting Enzyme Inhibitors; Erythropoietin; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Prevalence; Retrospective Studies; Sex Distribution; Tacrolimus

Topics: Azathioprine; Cyclophosphamide; Data Interpretation, Statistical; Drug Administration Schedule; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Severity of Illness Index; Time Factors

Among the numeruos adverse side effects of tacrolimus (TAC), de novo thrombotic microangiopathy stands out as an infrecuente but severe complication. Renal dysfunction is the only alteration that should lead to suspicion of thrombotic microangiopathy, because the clinical features of intravascular hemolysis are not always found. The definitive diagnosis can usually be made with kidney biopsy. Patientes with TAC induced thrombotic microangiopathy usually promptly recover after treatment withdrawal or reduction in the dose of TAC and a short course of plasma therapy, but the risk of rejection increases. Switching from TAC to cyclosporine has also been tried with resolution of the hemolysis but thrombotic microangiopathy has been noted with both and this condition may later recur. We present a 29-year-old man who received a kidney-pancreas transplant for end-stage diabetic nephropathy. After initial induction with basiliximab, the immunosuppression consisted of prednisone, tacrolimus and mycophenolate mofetil. Twenty four days posttransplantation his renal function declined with a peak creatine level of 2.35 mg/dl. Laboratory studies showed thrombocytopenia and features of intravascular hemolysis. TAC associated hemolytic uremic syndrome was suspected and drug was immediately stopped and converted to sirolimus. Also he was treated with plasma infusion. The allograft biopsy showed focal glomerular and arteriolar acute thrombosis without evidence of rejection. Our experience demostrate that switching from tacrolimus to sirolimus could be an adecuate strategy for patients who develop FK506-associated de novo thrombotic microangiopathy without increase risk of acute rejection.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Duodenostomy; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Jejunostomy; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Male; Mycophenolic Acid; Pancreas Transplantation; Pancreatic Fistula; Plasma; Postoperative Complications; Prednisone; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Necrosis; Sirolimus; Skin; Treatment Outcome; Vasculitis, Leukocytoclastic, Cutaneous

Chronic renal failure triggered by calcineurin inhibitor (CNI)-based immunosuppression is a common complication after cardiac transplantation. Sirolimus and mycophenolate mofetil (MMF) are 2 newer immunosuppressive agents with no documented nephrotoxic side effects. This case report describes a patient with ongoing chronic renal failure 10 months after cardiac transplantation on cyclosporine-based immunosuppressive therapy. Conversion of the immunosuppressive regimen from cyclosporine to sirolimus and MMF resulted in freedom from acute rejection, excellent cardiac graft function and consistently improved renal function. This case illustrates the beneficial potential of sirolimus and MMF as CNI-free and safe long-term immunosuppression in a patient with chronic renal failure after heart transplantation.

Topics: Calcineurin; Calcineurin Inhibitors; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Sirolimus

The aim of this study was to study the incidence of chronic renal dysfunction in patients with more than 5 yr of follow-up following liver transplantation and to evaluate the benefit of decreasing cyclosporine A (CsA) dose combined with mycophenolate mofetil (MMF) on renal function and immune response in these patients. Between 1988 and 1994, 60 children were transplanted, and 86% survived >5 yr post-liver transplantation. Fourteen patients developed chronic renal dysfunction secondary to CsA toxicity as evaluated by renal biopsy. In 11 patients CsA dose was decreased to 40-90 mg/ml target levels and MMF 600 mg/m(2) twice daily was added to the immunosuppressive regimen. Plasma creatinine decreased (from 1.0 +/- 0.03 to 0.8 +/- 0.03 ng/dl, p < 0.007), creatinine clearance increased (from 66.8 +/- 3.0 to 99.2 +/- 6.3 ml/min/1.73 m(2), p < 0.002) and microalbuminuria decreased (from 21.0 +/- 8.6 to 3.6 +/- 1.1 mg/24 h, p < 0.05) after 12 months of CsA combined with MMF therapy. During combined therapy the proliferative, cytolytic response and cytotoxic antibodies showed no significant changes, whereas CD4/CD8 ratio increased (from 1.2 +/- 0.2 to 1.4 +/- 0.1, p < 0.05). Tumor necrosis factor-alpha secretion increased (p < 0.005) during MMF therapy. The release of interleukin-10 was strikingly augmented under both immunosuppressive regimens, but the release of transforming growth factor-beta and interferon-gamma did not change. Our findings indicate that initiation of MMF combined with reduced doses of CsA allowed the recovery of renal function with minor changes in the immune response.

Topics: Adolescent; Child; Cyclosporine; Cytokines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Interferon-alpha; Interferon-gamma; Interleukin-10; Kidney Failure, Chronic; Kidney Function Tests; Liver Function Tests; Liver Transplantation; Mycophenolic Acid; Time Factors; Transforming Growth Factor beta

Primary focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease in both children and adults. Our current treatments are suboptimal, and a significant percentage of cases are resistant to current therapy.. We performed an open-label, 6-month trial of the new immunosuppressive agent mycophenolate mofetil (MMF) in 18 biopsy-proven patients resistant to a course of corticosteroids therapy. Seventy-five percent had also failed to respond to a cytotoxic agent and/or a calcineurin inhibitor.. A substantial improvement in proteinuria was seen in 44% (8/18) of the patients by 6 months. This was sustained for up to 1 year post treatment in 50% (4/8) of this group. No patient had a complete remission. No deterioration in renal function was observed in any patient over the treatment period, but 3 progressed to chronic kidney failure during follow-up. Adverse effects were mild. Only 1 patient required a dose reduction due to an intercurrent infection.. MMF appears safe to use in this group of patients and did lower proteinuria in 44% of this cohort resistant to other forms of treatment. Relapses were common, suggesting more prolonged or combination therapy may be required. More rigorous trials utilizing this medication should be considered to further assess the risk-benefit ratio of treatment with MMF in patients with FSGS.

Topics: Adult; Aged; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Treatment Outcome

This study investigated the effect of St John's wort (SJW) extract on the pharmacokinetics of the immunosuppressants tacrolimus (TAC) and mycophenolic acid (MPA).. Ten stable renal transplant patients received 600 mg SJW extract for 14 days in addition to their regular regimen of TAC and mycophenolate mofetil.. Dose-corrected AUC((0-12)) of TAC decreased significantly from 180 ng/ml/h at baseline to 75.9 ng/ml/h after 2 weeks of SJW treatment. To maintain therapeutic TAC concentrations, dose adjustments from a median 4.5 mg/day at baseline to 8.0 mg/day under SJW treatment were required. Two weeks after discontinuation of SJW, TAC doses were reduced to a median of 6.5 mg/day. MPA pharmacokinetics remained unaffected by comedication with hypericum extract.. Administration of SJW extract to patients receiving TAC treatment can result in a serious drug interaction leading to markedly reduced TAC blood concentrations associated with the risk of organ rejection.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hypericum; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Phytotherapy; Probability; Prospective Studies; Sampling Studies; Statistics, Nonparametric; Tacrolimus; Transplantation Immunology; Treatment Outcome

Topics: Adult; Creatinine; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Function Tests; Liver Transplantation; Mycophenolic Acid; Postoperative Complications; Time Factors

In recent years an increasing number of cases with polyomavirus (PV)-nephropathy after renal transplantation were reported from several transplant centres. New, highly potent immunosuppressive drugs like tacrolimus or mycophenolate mofetil were accused as risk factors for this increase. However, data about the incidence of PV-nephropathy in correlation to different immunosuppressive therapy concepts are lacking.. All renal transplant biopsies performed at Hannover Medical School between 1999 and 2001 (n=1276) were immunohistochemically screened for the presence of PV-specific proteins. The results were correlated to the different immunosuppressive therapy protocols and patients with PV-nephropathy were compared with a matched control group.. PV-nephropathy was found in <1% of all investigated allograft biopsies (11/1276) and in approximately 1% of all patients (7/638), respectively. All patients being immunohistochemically positive for PV-specific proteins also showed the typical morphological changes of PV-nephropathy. Four out of seven patients with PV-nephropathy were under triple immunosuppression comprising tacrolimus and mycophenolate mofetil. Under this immunosuppressive therapy protocol an eight times higher incidence and a 13 times higher risk (multivariate odds ratio 12.7) of PV-nephropathy was observed in our patients compared with the control group.. PV-nephropathy is a rare but serious complication after renal transplantation. A small group of patients under intensive immunosuppression comprising tacrolimus in combination with mycophenolate mofetil has a significantly increased risk of acquiring this deleterious complication.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus; Polyomavirus Infections; Prospective Studies; Risk Factors; Tacrolimus; Tumor Virus Infections

A previous study has argued that mycophenolate mofetil (MMF) is associated with a reduced incidence of death with function when compared to azathioprine (AZA) in cadaveric renal transplantation. This study was designed to verify this result because methodological issues bring these findings into question.. The data used in this study was derived from records of renal transplants performed in 1995 and 1996 as recorded in the UNOS Scientific Renal Transplant Registry and supplied by the United States Renal Data System (USRDS). Univariate and multivariate survival analysis was used to compare rates of death with function. Covariate characteristics of the donor, recipient, procedures, early outcomes and the transplant centre were considered.. 12,251 recipients of cadaveric renal transplants were identified as having received either MMF or AZA, but not both. The relative risk of death with function calculated by the Kaplan-Meier method was 21% less for MMF patients (P=0.005). MMF had from 21% (P=0.008) to 24% (P=0.001) reductions in relative risk by multivariate methods.. The use of MMF is associated with a reduction in the incidence of death with a functioning graft in cadaveric renal transplantation. These results verify previous analyses.

Topics: Adolescent; Adult; Analysis of Variance; Azathioprine; Cadaver; Child; Child, Preschool; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Risk Factors; Survival Analysis

Acute intermittent porphyria (AIP) results from a deficiency of the porphobilinogen deaminase enzyme of heme biosynthesis. The disease is exacerbated by a wide variety of drugs. Only steroids and azathioprine (Aza) have so far been considered safe in patients with AIP, and cyclosporine is listed as contraindicated. From the transplantation point of view, it is well known that cyclosporine (CsA) is a superior immunosuppressive agent compared to azathioprine. This case report presents a female patient evaluated for renal transplantation. A test dose of CsA was given, and no symptoms of AIP occurred. Renal transplantation with a cadaveric donor was performed, and the patient was immunosuppressed with CsA, Aza, and prednisolone. Following three acute rejections, Aza was replaced by mycophenolate mofetil. Nevertheless, graft function deteriorated slowly, necessitating return to dialysis 3 years after transplantation. No symptoms of AIP were observed while the patient was on cyclosporine and/or mycophenolate mofetil therapy, and the authors conclude that these drugs can be safely administered to at least some patients with AIP.

Topics: Aminolevulinic Acid; Azathioprine; Creatinine; Cyclosporine; Drug Interactions; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Porphobilinogen; Porphyria, Acute Intermittent; Prednisolone; Renal Dialysis; Sweden; Treatment Outcome

Topics: Adult; Azathioprine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Time Factors; Tuberculosis

The aim of this study was to determine whether there has been an increase in the incidence or severity of wound-healing complications that can be attributed to the introduction of newer immunosuppressive drugs.. Consecutive series of adult kidney-only transplant recipients were selected from our Unified Transplant Database backward from September 2002. There were 513 patients divided into groups on the basis of their maintenance immunosuppression given for at least the first 30 days posttransplant. Group I (152) was given sirolimus, mycophenolate mofetil, and prednisone (SRL/MMF/P) between March 2000 and September 2002; group II (168) was given cyclosporine A (CsA)/MMF/P between January 1999 and July 2002; and group III (193) was given azathioprine (AzA)/CsA/P between January 1993 and December 1997. A classification system for wound-healing problems was developed, and each of the three groups was analyzed by univariate and multivariate analysis.. From groups III to II to I, there was a significant increase in mean age (42.4 vs. 49 years), percent of patients diabetic (17% vs. 29%), mean body mass index (BMI) (24.2 vs. 27.1 kg/m2), and percent BMI greater than 30 (13.5% vs. 27%). The cumulative percentage of all wound-healing problems between group I (19.7%) vs. group II (16.1%) and group III (15.6%) was not significantly different. The most significant risk factor was a recipient BMI greater than 30 (P=0.0012) and delayed graft function (P=0.0041).. During a 10-year period marked by changing recipient demographics, the introduction of MMF and SRL did not result in a significant increase in transplant wound-healing complications. The most significant risk factor associated with transplant wound-healing complications remains body weight, which was the major influence for each of the immunosuppressive drug combinations described.

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Sirolimus; Time Factors; Wound Healing

Topics: Adult; Antilymphocyte Serum; Azathioprine; Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prednisolone; Prednisone; Tacrolimus; Time Factors; Treatment Failure; Treatment Outcome

Infection due to cytomegalovirus (CMV) is the most frequent opportunistic infection following renal transplantation (RT). It is usually asymptomatic. Cytomegalovirus disease causes fever leucopenia, thrombocytopenia and slightly elevated transaminases. The development of severe invasive forms is uncommon nowadays with post-transplantation monitoring, prophylactic regimens in high-risk patients and early treatment with ganciclovir. We report two renal transplant recipients who presented with severe gastrointestinal bleeding as the first manifestation of CMV disease at 9 and 14 weeks after transplantation. In both patients repeated post-transplantation pp65 antigenemia monitoring was negative. One patient developed hypovolemic shock due to severe rectal bleeding; an atypical bleeding ulcer was detected in the ileocecal valve. The other patient presented with upper gastrointestinal hemorrhage from a bleeding duodenal ulcer. Histological and immunohistochemical study confirmed the diagnosis. Both patients were elderly and on triple therapy with tacrolimus, mycophenolate and prednisone. We discuss the role of mycophenolate and the new immunosuppressant agents as factors favoring a state of enhanced immunosuppression, which may facilitate the onset of severe atypical forms of CMV disease.

Topics: Aged; Cytomegalovirus; Cytomegalovirus Infections; Disease Susceptibility; Duodenal Ulcer; Gastrointestinal Hemorrhage; Humans; Ileal Diseases; Ileocecal Valve; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Postoperative Complications; Prednisone; Shock; Tacrolimus; Ulcer

Topics: Creatine; Cyclosporine; Diabetes Complications; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Stents; Ureteral Obstruction

Topics: Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Renal Replacement Therapy; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors; Treatment Failure

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Creatinine; Drug Administration Schedule; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Patient Selection; Postoperative Complications; Tacrolimus; Time Factors; White People

Mycophenolate mofetil (MMF) has been used successfully in patients with ANCA-associated vasculitis as maintenance therapy. Only transient and moderate side effects have been reported with a daily dose of 2 g. Since all the treated patients who have been reported so far had no or only moderate renal insufficiency when MMF was initiated, no data are available regarding side effects in patients with end-stage renal disease (ESRD).. Five ESRD patients with ANCA-associated vasculitis and a relapsing course of their disease were treated. All patients had pretreatment with cyclophosphamide for at least 17 months. MMF was initiated as a remission maintenance therapy, and started with a dose of 1 g/d. The aim was to increase the MMF dose to 2 g/d. Blood counts, liver enzymes and gastrointestinal side effects were monitored.. Four patients developed severe anemia, 2 requiring blood transfusion with permanent or temporary cessation of MMF treatment. One patient developed leukopenia. Gastrointestinal symptoms led to a dose reduction to 1 g/d (n = 2) or cessation of treatment (n = 1). Three patients remained on longer MMF treatment; however, their daily dose did not exceed 1 g.. MMF, a promising drug regarding maintenance therapy in ANCA-associated vasculitis, seems to have more side effects in ESRD patients, leading to dose reduction or even cessation of treatment. Therefore, in this patient group a lower dose and closer monitoring for side effects seems to be required compared to patients with no or moderate renal insufficiency.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Antineutrophil Cytoplasmic; Dose-Response Relationship, Drug; Female; Humans; Kidney Failure, Chronic; Leukocyte Count; Male; Middle Aged; Mycophenolic Acid; Recurrence; Time Factors; Vasculitis

The importance of HLA matching for renal transplantation outcomes has been appreciated for several decades. It has been hypothesized that as pharmacologic immunosuppression becomes stronger and more specific, the impact of HLA matching may be vanishing. Mycophenolate Mofetil (MMF) has been demonstrated to both decrease acute rejection and improve three-year graft survival. It is possible that with new immunosuppressive regimens containing MMF the relative effect of HLA matching may be altered. To determine the relative impact of HLA matching in patients on MMF we undertook an analysis of the United States Renal Transplant Data Registry (USRDS).. All primary, solitary renal transplants registered at the USRDS between January 1995 and June 1997, on initial immunosuppression that included either MMF or AZA were followed until June 1998. Primary study end points were graft and patient survival. Kaplan-Meier analysis was performed to compare AZA vs. MMF treated patients by HLA mismatch. Cox proportional hazard models were used to investigate the interaction between HLA mismatch and AZA versus MMF therapy on the study endpoints. All multivariate analyses were corrected for 13 potential confounding pretransplant variables including intention to treat immunosuppression.. A total of 19,675 patients were analyzed (8,459 on MMF and 11,216 on AZA). Overall three year graft survival was higher in the MMF group when compared to the AZA group (87% vs. 84% respectively P<0.001). For both AZA and MMF three-year graft survival improved with fewer HLA donor-recipient mismatches. Comparing zero antigen mismatches to six antigen mismatches, the relative improvement was comparable for both patients on AZA (92.4% vs. 80.6%) and MMF (95.2% vs. 82.9%). By Cox proportional hazard model the relative risk for graft loss decreased significantly in both the AZA and MMF treated patients with increased HLA matching.. The use of MMF does not obviate the benefits of HLA matching, while HLA matching does not minimize the benefits of MMF on long term graft survival. Our study would suggest that HLA matching and MMF therapy are additive factors in decreasing the risk for renal allograft loss.

Topics: Azathioprine; Cohort Studies; Drug Interactions; Female; Graft Survival; Histocompatibility Testing; HLA-A Antigens; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Proportional Hazards Models; Retrospective Studies; Transplantation, Homologous

Topics: Anti-Inflammatory Agents; Azathioprine; Cyclophosphamide; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Prednisolone; Risk Factors

Mycophenolate mofetil (MMF) acts as a prodrug for the immunosuppressive drug mycophenolic acid (MPA). It is rapidly converted to MPA following oral ingestion. MPA is metabolized to MPA glucuronide (MPAG), which is renally excreted. This study examines the pharmacokinetics of MPA and MPAG in patients with end-stage renal failure who were on hemodialysis (N = 10) or peritoneal dialysis (N = 10) treatment.. After an overnight fast, a single oral dose of 1 g MMF was given. Plasma concentrations of MPA and MPAG were measured from 0 (predose) to 36 hours after administration, using high-performance liquid chromatography (HPLC). The area under the concentration time curve (AUC) from 0 to 36 hours was calculated using the trapezoidal rule.. Mean (+/- SD) AUC for MPA was 55.7 +/- 32.6 mg/L.h for hemodialysis patients and 44.7 +/- 14.7 mg/L.h for peritoneal dialysis patients, which is similar to expected values for subjects with normal renal function. The mean (+/- SD) maximum plasma concentration (Cmax) for MPA was lower than would be expected for subjects with normal renal function (16.01 +/- 10.61 mg/L for hemodialysis, 11.48 +/- 4.98 mg/L for peritoneal dialysis). MPAG clearance was prolonged with AUC approximately five times what would be expected in subjects with normal renal function (1565 +/- 596 mg/L.h for hemodialysis, 1386 +/- 410 mg/L.h for peritoneal dialysis). There was no significant difference for any of the pharmacokinetic parameters between subjects on hemodialysis and those on peritoneal dialysis. Plasma concentrations of MPA and MPAG did not fall significantly during hemodialysis. No MPA was detectable in hemodialysis or peritoneal dialysis fluid, but small amounts of MPAG were detected in hemodialysis fluid in 1 out of 10 subjects and in peritoneal dialysis fluid in 3 out of 10 subjects.. The accumulation of MPAG may be responsible for the poor gastrointestinal tolerance of this drug in dialysis patients and probably limits the maximum dose of MMF that can be tolerated.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Dialysis Solutions; Female; Glucuronates; Glucuronides; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis

Anemia secondary to mycophenolate mofetil (MMF) was recently described in experimental animals. A clinical association between MMF and anemia has been observed, but there are no proven reports. We describe a girl with chronic graft failure who developed erythroid aplasia under immunosuppression with MMF. She showed prompt resolution when MMF was discontinued and a recurrence of this clinical course when MMF was restarted. As re-challenge with a medication is the most definitive approach for showing a direct relationship between the drug and the side effect, this case clearly demonstrates that MMF can cause erythroid aplasia.

Topics: Adolescent; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Red-Cell Aplasia, Pure

Topics: Antigens, CD; Azathioprine; Cell Differentiation; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Activation; Lymphocyte Subsets; Lymphocytes; Mycophenolic Acid; Tacrolimus

Myofibroblasts have been shown to play a pivotal role in the synthesis of extracellular matrix components in several animal models of renal fibrosis. The purpose of the present study was to investigate whether mycophenolate mofetil (MMF) reduces interstitial myofibroblast infiltration and collagen III deposition in 5/6 nephrectomized rats.. Forty-five Wistar rats underwent 5/6 renal ablation and received by daily oral gavage either vehicle (N = 20) or MMF (N = 25) during the 60 days following surgery. Groups of five treated and five untreated rats were killed at two, four, and eight weeks after subtotal nephrectomy. Four untreated and three treated rats were killed at week 12, one month after treatment withdrawal. At the time of sacrifice, proteinuria, plasma, and urine creatinine were determined. Immunohistochemistry was performed on renal tissue for alpha-smooth muscle actin (alpha-SMA), a cytoskeletal marker of myofibroblasts, for type III collagen, and for proliferating cell nuclear antigen (PCNA). Moreover, in order to study the in vitro effects of MMF on fibroblast proliferation, rat fibroblasts were cultured in the presence or absence of mycophenolic acid (MPA).. At all periods studied, MMF treatment improved renal functional parameters and progressively decreased remnant kidney hypertrophy and glomerular volume increment. Proliferating cells in renal tubules, interstitium, and glomeruli, as well as interstitial myofibroblast infiltration and interstitial type III collagen deposition, were also significantly reduced by MMF treatment. In addition, MPA exhibited a dose-dependent inhibitory effect on in vitro proliferation of rat fibroblasts.. Reduction of interstitial myofibroblast infiltration may be an important event by which MMF significantly prevents renal injury following subtotal renal ablation. Thus, our results suggest that MMF could be useful to limit the progression of chronic renal disease toward end-stage renal failure.

Topics: Actins; Animals; Cell Division; Cells, Cultured; Collagen; Creatinine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extracellular Matrix; Fibroblasts; Fibrosis; Kidney; Kidney Failure, Chronic; Mycophenolic Acid; Nephrectomy; Proliferating Cell Nuclear Antigen; Proteinuria; Rats; Rats, Wistar; Regeneration; Weight Loss

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Ischemia; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prednisolone; Radiography; Splanchnic Circulation; Tacrolimus

Topics: Adenosine Diphosphate; Arachidonic Acid; Collagen; Humans; Immunosuppressive Agents; In Vitro Techniques; Kidney Failure, Chronic; Mycophenolic Acid; Platelet Aggregation; Ristocetin; Uremia

African American renal transplant recipients have poorer graft survival. A study using the United States Renal Data Registry documented an improvement in graft survival for patients who took mycophenolate mofetil (MMF) compared with azathioprine (AZA). This analysis did not address the impact of MMF on African American renal transplant recipients. The present study aimed to quantify potential beneficial effects of MMF therapy on long-term renal allograft survival in African Americans. With the use of the United States Renal Data Registry, all adult Caucasian and African American patients who had received a primary renal transplant between 1988 and 1997 were analyzed by Kaplan-Meier analysis and Cox proportional hazard models. Primary study end points were death with a functioning graft and graft failure censored for death. A total of 57,926 patients were studied. For African Americans, 3-yr patient survival was 96.3 versus 93.2% (P<0.001) for MMF and AZA, respectively. Three-yr death-censored graft survival for African Americans was 85.8 versus 75.1% (P<0.001) for MMF and AZA, respectively. For Caucasians, 3-yr patient survival was 97.3 versus 93.2% for MMF and AZA, respectively. Three-yr death-censored graft survival for Caucasians was 90.1 versus 86.4% (P<0.001) for MMF and AZA, respectively. By multivariate analysis, MMF was associated with a significant reduction in the relative risk for all study end points in African Americans. MMF therapy is associated with both improved patient and death-censored graft survival in African American renal transplant recipients. This benefit is comparable to the benefit of MMF in Caucasian renal transplant recipients.

Topics: Adult; Azathioprine; Black or African American; Black People; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Risk Factors; Treatment Outcome; White People

Topics: Adult; Antilymphocyte Serum; Bilirubin; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid

Topics: Adult; Anemia; Antibodies, Viral; Azathioprine; Bone Marrow Cells; DNA, Viral; Drug Therapy, Combination; Erythrocyte Transfusion; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Parvoviridae Infections; Parvovirus B19, Human; Polymerase Chain Reaction; Postoperative Complications; Reticulocyte Count

Extensive renal ablation is associated with progressive sclerosis of the remnant kidney. Because lymphocytes and monocytes accumulate in the remnant kidney, it is likely that they play a role in the renal scarring. Therefore, we treated rats with 5/6 nephrectomy (5/6Nx) with mycophenolate mofetil (MMF), a drug that has an antiproliferative effect and that suppresses the expression of intercellular adhesion molecules.. Sprague-Dawley rats with 5/6Nx received MMF (30 mg. kg-1. day-1 by daily gastric gavage, N = 15) or vehicle (N = 16). Ten additional rats were sham operated. All rats were fed a 30% protein diet. Body weight, serum creatinine, and urinary protein excretion were determined weekly. Lipid peroxidation, as a measure of oxidative stress observed by urinary malondialdehyde determinations, was performed every two weeks. Histologic studies were done in the remnant kidney four weeks (9 rats from the vehicle-treated group, 7 rats from the MMF group, and 5 sham-operated rats) and eight weeks after surgery (the remaining rats). Glomerular volume, sclerosis in glomeruli (segmental and global) and interstitium (semiquantitative scale), infiltrating lymphocytes and macrophages (CD43- and ED1-positive cells), and expression of adhesion molecules (CD54, CD18, and CD11b) were analyzed.. MMF treatment prevented the progressive increment in serum creatinine and the proteinuria observed in the 5/6 nephrectomized rats during the eight weeks of observation (P < 0.01). Weight gain was comparable in the MMF-treated and sham-operated rats, whereas weight gain was decreased in untreated 5/6 nephrectomized rats. Excretion of malondialdehyde increased after surgery but returned sooner to control levels in the MMF-treated rats. Increments in glomerular size and mean arterial blood pressure induced by renal ablation were not modified by MMF treatment. Eight weeks after surgery, segmental sclerosis was present in 48.4 +/- 8.35% (+/- sd) glomeruli in the vehicle-treated group versus 25 +/- 10.5% in the MMF-treated group (P < 0.001). Interstitial fibrosis was reduced significantly with MMF treatment (P < 0.001). Infiltration with CD43- and ED1-positive cells in glomeruli and interstitium was two to five times lower in MMF-treated rats (P < 0.01). Expression of adhesion molecules CD18 and CD11b was similarly reduced.. MMF ameliorates the progressive renal damage in the remnant kidney after 5/6Nx. This effect is associated with a reduction in the infiltration of lymphocytes and monocytes, whereas glomerular hypertrophy and systemic hypertension are unchanged.

Topics: Animals; Blood Pressure; Cell Adhesion Molecules; Creatinine; Disease Models, Animal; Hypertension, Renal; Hypertrophy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Lymphocytes; Male; Monocytes; Mycophenolic Acid; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley

Chronic renal diseases progress to organ insufficiency, which may require replacement therapy within one to three decades even independently of the type of initial insults. In the majority of cases, the degrees of proteinuria and interstitial leukocyte infiltration and scarring are strictly correlated with the rate of disease progression. This study tests the hypothesis that excess intrarenal protein traffic may cause lymphocyte-dependent interstitial injury that, while not fully controlled by antiproteinuric therapy, can be further inhibited by concomitant immunosuppression. A primarily nonimmune model was used to reproduce progressive renal disease due to a critical loss of nephron mass. Angiotensin-converting enzyme (ACE) inhibitor limited proteinuria, interstitial inflammation, MHC class II antigen expression, and severe lesions. Combined treatment with ACE inhibitor and a specific antilymphocyte agent, mycophenolate mofetil, dramatically attenuated macrophage and T cell infiltration, MHC-class II overexpression, dendritic cells, and all manifestations of the disease. Evidence of lymphocyte-mediated renal injury in the setting of excess protein traffic provides the basis for combining ACE inhibition and immunosuppression to halt progression of proteinuric kidney disease and minimize the need for dialysis or transplantation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Lisinopril; Lymphocytes; Male; Mycophenolic Acid; Proteinuria; Rats; Rats, Sprague-Dawley

Nephrotoxicity is a frequently encountered adverse effect of calcineurin inhibitors (cyclosporine and tacrolimus)-combined immunosuppressive regimens.. We have compared the glomerular filtration rate in 14 patients who underwent lung transplantation, before and after replacement of azathioprine by mycophenolate mofetil and reduction of associated calcineurin inhibitors doses.. After a mean follow-up of 16+/-4 months with the modified immunosuppressive regimen, the mean glomerular filtration rate increased by 20% with no change in lung function.. By its strong immunosuppressive effect, mycophenolate mofetil allows the decrease of associated calcineurin inhibitor doses, with subsequent improvement of renal function without jeopardizing the transplanted lung.

Topics: Calcineurin Inhibitors; Cyclosporine; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lung Transplantation; Mycophenolic Acid; Tacrolimus

The aim of this study was to report the results of 50 transplantations of kidney and pancreas performed in the same surgical centre for chronic renal insufficiency of patients with insulino-dependent diabetes.. From 1989 to 1999, 50 pancreatic transplantations were consecutively performed, 48 combined with a kidney transplantation and two in patients having a functioning kidney graft. The whole pancreas was transplanted in the right iliac fossa through an extraperitoneal approach with duodeno-vesical bypass of exocrine secretion. The kidney was transplanted in the left iliac fossa through a different extraperitoneal approach. Immunosuppression protocol included Azathioprine replaced by Mycophenolate Mofetil since 1996, associated with corticotherapy and Ciclosporine replaced by FK 506 since 1997. Recipients were 32 women and 18 men (mean age: 37 +/- 5 years) treated by insulinotherapy since 23 +/- 6 years and receiving 35 +/- 10 insulin units per day. Peptide C was 0.33 +/- 0.35 mg/mL and serum creatinin 726 +/- 260 mumol/L.. One patient died on d10 from pulmonary artery thrombosis due to unknown drepanocytosis. The most frequent postoperative complications were leakage of duodeno-vesical anastomosis (n = 9) decreasing in frequency with experience, reoperated with preservation of the pancreatic graft in all cases and venous thrombosis of the pancreatic graft (n = 5) with a definitive loss of function. Secondary deaths occurred at 24, 36, 48, 50, 72 months with functioning grafts in two patients. With a mean 5-year follow-up, 44 patients were alive (88% of the whole series), 34 of them with two functional grafts (68% of the whole series) Sixteen pancreas grafts were lost: three by death of the patients, eight from surgical complications, four by rejection and one by transplantectomy of a functional graft.. Combined kidney and pancreas transplantation is now very efficient in the treatment of diabetic renal insufficiency. Total pancreas transplantation through an extraperitoneal approach seems to be the safest method. A very strict selection of both donors and recipients is necessary.

Topics: Adult; Azathioprine; Combined Modality Therapy; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Survival Analysis; Tacrolimus; Treatment Outcome

Methylprednisolone has been found to be significantly more suppressive than prednisolone (the pharmacologically active metabolite of prednisone) of mitogen-stimulated human lymphocyte proliferation. In this study, peripheral blood mononuclear cells (PBMC) from end stage renal disease patients were cultured with phytohemagglutinin (PHA) alone and with methylprednisolone and prednisolone individually, as well as each glucocorticoid (10(-7) mol/L) in combination with 300 ng/ml cyclosporine, 10 ng/ml tacrolimus, 25 microg/ml pentoxifylline, and 10(-7) mol/L mycophenolic acid. Under each experimental condition, the mean +/- SD % inhibition of PHA-stimulated 3H-thymidine incorporation was significantly greater with methylprednisolone than with prednisolone: methylprednisolone 55 +/- 17 versus prednisolone 28 +/- 14, p < 0.001; methylprednisolone + cyclosporine 76 +/- 18 versus prednisolone + cyclosporine 52 +/- 18, p < 0.001; methylprednisolone + tacrolimus 74 +/- 18 versus prednisolone + tacrolimus 50 +/- 20, p = 0.001; methylprednisolone + mycophenolic acid 69 +/- 14 versus prednisolone + mycophenolic acid 46 +/- 15, p < 0.001. These results confirm and extend previous observations and suggest that methylprednisolone might be more effective than prednisone in treatment protocols used to suppress allograft rejection.

Topics: Cells, Cultured; Cyclosporine; Drug Combinations; Enzyme Inhibitors; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lymphocytes; Methylprednisolone; Mycophenolic Acid; Pentoxifylline; Prednisolone; Tacrolimus

Mycophenolate mofetil (MMF) is rapidly hydrolyzed to its active metabolite mycophenolic acid (MPA), which is excreted by the kidney after undergoing glucuronidation to MPAG. MPAG has been shown to accumulate in patients with renal failure. MPA is extensively and avidly bound to human serum albumin. In vitro inhibition of the pharmacologic target, inosine monophosphate dehydrogenase, is dependent on free MPA. It has been demonstrated that high MPAG concentrations decrease MPA protein binding in vitro. In addition, the uremic state is associated with altered protein binding of many drugs.. We assessed free MPA, total MPA, and MPAG kinetics in a patient with renal failure receiving MMF for a pancreas transplant, who presented with signs of MMF toxicity. MPA, MPAG, and free MPA were measured by high performance liquid chromatography and a validated 14C-MPA ultrafiltration methodology.. The MPAG area under the concentration curve (AUC) in this patient was extremely high (5899 microg x hr/ml). The total MPA AUC of 36.8 microg x hr/ml was within the range usually obtained in stable renal patients. The free fraction of MPA and the free MPA AUC were markedly elevated (13.8% and 5.07 microg x hr/ml, respectively).. Patients with severe renal insufficiency may have markedly increased free MPA levels that may not be reflected in total MPA concentrations. These patients may be at increased risk for MMF-related toxicity.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glucuronates; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Pancreas Transplantation; Protein Binding; Serum Albumin

Renal transplantation is a treatment option that should be considered for the elderly (> or = 60 years old) with end-stage renal disease. Little is known regarding the use of tacrolimus (as induction and maintenance immunosuppression) in this age group. We report the outcome of kidney transplantation in 21 patients aged 60 years or more with tacrolimus. During the past few years in kidney transplant maintenance immunosuppressive regimens, we have revised our standard general protocol from cyclosporine to tacrolimus-based therapy for maintenance immunosuppression and for rescue therapy. We also introduced mycophenolate (RS-61443) while we have continued to use ATGAM/OKT3 as induction regimen in the immediate postoperative period. We treated these renal recipients with tacrolimus and steroids in combination with azathioprine or mycophenolate mofetil without antibody induction. This was well tolerated and not associated with a higher rate of rejection (20%) whereas the potential toxicity of antilymphocyte preparations was avoided.

Topics: Administration, Oral; Age Factors; Aged; Azathioprine; Cadaver; Cyclosporine; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Tacrolimus; Treatment Outcome