mycophenolic-acid and Cytomegalovirus-Infections

Mizoribine (MZR) is widely used in Asia due to its high safety and low cost, and comparative studies of its safety and efficacy with the first-line drug mycophenolate mofetil (MMF) have been carried out. This paper aimed to compare the efficacy and safety of MZR and MMF in immunosuppressive therapy of renal transplantation by meta-analysis.. We searched randomized controlled trials (RCTs) comparing MZR versus MMF for renal transplantation in PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, WanFang Database, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Database (CBM). Articles were assessed for their risk of bias using the Cochrane Collaboration. Forest plots and funnel plots were also performed on the included articles.. A total of twelve studies with 1103 patients were selected in the analysis. No significant difference were observed between the MZR group and the MMF group for the rate of acute rejection (RR = 1.50, 95% CI 1.11 to 2.01,

Topics: Cytomegalovirus Infections; Gastrointestinal Diseases; Humans; Hyperuricemia; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Ribonucleosides

Cardiac allograft vasculopathy (CAV) is a common complication following heart transplantation (HT), resulting in diminished graft survival. The preferred strategy for preventing CAV is optimal medical management; however, for patients who develop CAV, delaying disease progression through effective medication management is equally important. A review of the literature regarding medication management of CAV was conducted via a search of the MEDLINE database. Studies were included if they were published in English, conducted in humans ≥ 18 years of age or older, and used noninvestigational medications. Immunosuppressive medications such as the antiproliferative mycophenolate, the calcineurin inhibitor tacrolimus, and the proliferation signal inhibitors sirolimus and everolimus have been shown to prevent the development of CAV. Certain cardiovascular medications, such as HMG-CoA reductase inhibitors (statins), gemfibrozil, calcium channel blockers, and angiotensin-converting enzyme inhibitors, have also demonstrated efficacy in preventing this disease process. Prevention of CAV has also been observed with prophylaxis against cytomegalovirus infection and antioxidant medications. Despite being commonly used in HT patients, neither antiplatelet agents nor glycemic control have proved effective at preventing CAV. Only sirolimus has been shown to arrest the progress of existing CAV.

Topics: Allografts; Antioxidants; Calcineurin Inhibitors; Cardiovascular Agents; Cytomegalovirus Infections; Everolimus; Graft Occlusion, Vascular; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus

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

Mycophenolate mofetil (MMF) is currently used for prophylaxis of acute rejection in solid organ transplantation. There have been diverging reports regarding an association between MMF and the risk of cytomegalovirus (CMV) infection. We reviewed the main published studies in an attempt to clarify the association between the use of MMF and the risk, frequency and severity of CMV infections. In a search of the Medline database with the terms "mycophenolate" and "cytomegalovir*", 42 articles were found to be relevant; among these, 29 articles were thoroughly analyzed. The first studies on MMF in renal transplantation already showed a tendency towards an association between this drug and the occurrence of CMV disease. Further studies were designed specifically to study this association; with the conclusion that an immunosuppressive regimen containing MMF increases the likelihood of CMV disease. Most studies were performed with kidney transplant recipients. We conclude that the use of MMF apparently increases the incidence of CMV disease in renal transplant patients; however, further studies are needed to confirm this association.

Topics: Cytomegalovirus Infections; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Liver Transplantation; Mycophenolic Acid; Risk Factors; Severity of Illness Index

Pediatric heart transplantation is a surgical therapy for dilated cardiomyopathy and for complex congenital heart defects with low pulmonary artery resistance. However, it is still discussed as controversial because of uncertain long-term results. We report our experience with pediatric heart transplantation in a heterogeneous population.. Since 1988, 50 heart transplants were performed in 47 patients (30 with dilated cardiomyopathy, 17 with congenital heart disease). Mean age was 9.4 +/- 6.9 years (range, 4 days to 17.9 years). Twenty-three patients had a total of 36 previous operations. Clinical outcome was evaluated retrospectively.. Perioperative mortality was 6% due to primary graft failure. Late mortality (12%) was caused by acute rejection (n = 2), pneumonia (n = 2), intracranial hemorrhage (n = 1), and suicide (n = 1). Mean follow-up was 5.24 +/- 3.6 years. Actuarial 1, 5, and 10 year survival was 86%, 86%, and 80% and improved significantly after 1995 (92% [1 year]; 92% [5 years]). There was no significant difference between patients with dilated or congenital heart disease (1 year: 86% vs 82%; 5 years: 83% vs 74%; 10 years 83% vs 74%; p = 0.62). Three patients with therapy resistant acute or chronic rejection and assisted circulation underwent retransplantation and are alive. Freedom from acute rejection after 5 years was 40% with primary cyclosporine immunosuppression regime and 56% with tacrolimus. Since the introduction of mycophenolate mofetil, freedom from acute rejection increased to 62%. All survivors are at home and in good cardiac condition.. Pediatric heart transplantation is the treatment of choice for end-stage dilated cardiomyopathy as for congenital heart disease with excellent clinical midterm results. It is a valid alternative to reconstructive surgery in borderline patients. However, further follow-up is necessary to evaluate the long-term side effects of immunosuppressants.

Topics: Adolescent; Antiviral Agents; Bacterial Infections; Cardiomyopathy, Dilated; Child; Child, Preschool; Cyclosporine; Cytomegalovirus Infections; Extracorporeal Membrane Oxygenation; Female; Follow-Up Studies; Ganciclovir; Germany; Graft Rejection; Heart Defects, Congenital; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Immunosuppressive Agents; Life Tables; Lymphoma, Non-Hodgkin; Male; Mycophenolic Acid; Pneumonia, Pneumocystis; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Survival Rate; Tacrolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Vascular Resistance; Virus Diseases

To evaluate the safety of mycophenolate mofetil (MMF) versus azathioprine (Aza) in renal transplantation, we compared their side effects using evidence-based methods.. Medline, Embase, Cochrane library, and Chinese Biomedicine database (CBM) were searched to select randomized clinical trials that had one group using MMF and another group using Aza as an immunosuppressive drugs. Safety analysis consist of the following factors: diarrhea, abdominal pain, vomiting, nausea, constipation, CMV infection, leukopenia, anemia, thrombocytopenia or skin malignancy. RevMan 4.11 software was used for the systematic review analysis.. Twenty trials including 6387 patients were identified. The diarrhea incidence with MMF (3 g/d) was higher than for Aza at 1 and 3 years (P < .05). Diarrhea on MMF (2 g/d) was higher than for Aza within 6 months (P < .05). CMV infection incidence on MMF (3 g/d) was higher than for Aza's at 3 years (P < .05), but MMF (2 g/d) did not show a statistical significance compared with Aza. Leukopenia incidence on MMF (3 g/d) was higher than that on Aza, whereas the incidence with MMF (2 g/d) was not significantly different from Aza. Skin malignancy incidence showed no statistical difference between MMF 3 g/d, MMF 2 g/d, or Aza.. The use of MMF is associated with slight increases in gastrointestinal adverse effects, some hematologic adverse events, and CMV infections compared with Aza. Larger sample sizes of randomized controlled trials are needed to evaluate the safety of MMF.

Topics: Azathioprine; Cytomegalovirus Infections; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Mycophenolic Acid; Pain; Postoperative Complications; Randomized Controlled Trials as Topic; Retrospective Studies; Safety; Skin Neoplasms; Time Factors; Vomiting

B19 virus infection with persistent anaemia has been reported in organ transplant recipients. Detection of B19 virus DNA in serum is the best direct marker of active infection.. The present study evaluated the incidence and clinical role of active B19 virus infection in renal transplant recipients presenting with anaemia.. Forty-eight such recipients were investigated by nested PCR on serum samples. The controls were 21 recipients without anaemia. Active HCMV infection was also investigated as a marker of high immunosuppression.. In 11/48 (23%) patients B19 virus DNA was demonstrated in serum versus only 1/21 (5%) of the controls. Ten of these 11 patients had already been seropositive at transplantation and active infection occurred in eight of them during the first 3 months after transplantation. The remaining patient experienced a primary infection 9 months after transplantation. Eight (73%) of these 11 patients displayed a concomitant HCMV infection and four (36%) showed increasing serum creatinine levels but none developed glomerulopathy; 3/11 (27%) recovered spontaneously from anaemia whereas 8/11 (73%) needed therapy. In conclusion, the relatively high occurrence (23%) of B19 virus infection in patients presenting with anaemia, suggests that it should be considered in the differential diagnosis of persistent anaemia in renal transplant recipients. Presence of the viral DNA should be assessed early from transplantation and the viral load should be monitored to follow persistent infection and better understand the relation between active infection and occurrence of anaemia, and to assess the efficacy of IVIG therapy and/or immunosuppression reduction in clearing the virus.

Topics: Anemia; Antibodies, Monoclonal; Antibodies, Viral; Antilymphocyte Serum; Basiliximab; Cyclosporine; Cytomegalovirus Infections; Diagnosis, Differential; Disease Susceptibility; DNA, Viral; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Interleukin-1; Kidney Transplantation; Male; Mycophenolic Acid; Parvoviridae Infections; Parvovirus B19, Human; Phosphoproteins; Polymerase Chain Reaction; Postoperative Complications; Prednisone; Recombinant Fusion Proteins; Retrospective Studies; T-Lymphocytes; Tacrolimus; Viral Load; Viral Matrix Proteins; Viremia; Zidovudine

Topics: Cell Division; Chronic Disease; Cytomegalovirus Infections; Graft Rejection; Humans; Immunosuppressive Agents; Isoantibodies; Muscle, Smooth, Vascular; Mycophenolic Acid

Mycophenolate mofetil (MMF) is an immunosuppressive agent that exerts relatively selective antiproliferative effects on T and B lymphocytes. Efficacy has been demonstrated in large-scale randomised studies, but the use of MMF is complicated by gastrointestinal upset and is associated with an increased incidence of tissue-invasive cytomegalovirus (CMV) disease. The gastrointestinal tract is a well recognised site for invasive CMV disease, and it has therefore been hypothesised that the abdominal pain commonly seen with MMF is related to CMV infection. This has only been tested in a single small uncontrolled study, where abdominal pain was associated with the presence of CMV on endoscopic biopsy. In contrast, the toxicity profile in 85 patients with psoriasis who had received relatively high dosages of mycophenolic acid, the active moiety of MMF, for up to 13 years showed that the incidence of gastrointestinal upset fell dramatically over time. We can find little evidence that CMV disease explains the gastrointestinal adverse event profile associated with MMF, and instead support the contention that high local concentrations of MMF have a direct toxic effect on cells of the small intestine. We do not recommend any changes to current policy on CMV prophylaxis in patients receiving MMF, although we recognise that some severe gastrointestinal adverse effects may be CMV-associated. The use of trough plasma concentration monitoring, divided doses and a gradually increasing dosage schedule may be of value in limiting toxicity.

Topics: Cytomegalovirus Infections; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Mycophenolic Acid; Pain; Risk Factors

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Marrow Transplantation; Cytomegalovirus; Cytomegalovirus Infections; Daclizumab; Drug Therapy, Combination; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Immunosuppressive Agents; Mycophenolic Acid; Virus Activation

Kidney transplantation (KT) outcomes have significantly improved with calcineurin inhibitors (CNIs) administration. In recent years, the dose of CNIs has been reduced, and everolimus (EVR) has been used in combination with CNIs to avoid complications from the long-term use of CNIs. However, T-cell immune responses to these protocols have not been fully evaluated. This study evaluated the anti-donor T-cell responses to our CNI-sparing regimen.. Fifty-five de novo KT patients were enrolled. Three months after KT, the patients were randomly assigned to either the EVR group, which received low-dose cyclosporine (CsA) (n = 28), or the standard-exposure CsA control group (n = 27), which was treated with both mycophenolate mofetil and methylprednisolone. Graft function, adverse events, and immunologic status were evaluated 3 years after KT. Mixed lymphocyte reaction (MLR) assays were performed to evaluate anti-donor T-cell responses in KT patients.. Both groups maintained graft function well, but total cholesterol levels tended to increase annually in the EVR group. The incidence of cytomegalovirus (CMV) infection tended to be lower in the EVR group, regardless of the CMV serologic status. Immunologic evaluation by MLR assay showed that anti-donor T-cell responses were adequately maintained in both groups.. EVR starting 3 months after KT can reduce the trough levels of CsA without affecting graft function or compromising the immunosuppressive effects. The EVR combination protocol is expected to reduce CNI toxicity and improve long-term prognosis after KT.

Topics: Antibodies; Calcineurin Inhibitors; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid

The reported association of mTOR-inhibitor (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in kidney transplant recipients (KTR) who are CMV seropositive (R+) remains unexplained.. The incidence of CMV infection and T-cell profile was compared between KTRs treated with mTORis and mycophenolic acid (MPA), and. In KTRs who were R+ and treated with MPA, both. Severe CMV replication is associated with a dysfunctional T-cell profile and mTORis improve T-cell fitness along with better control of CMV. A dysfunctional T-cell phenotype could serve as a new biomarker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment.. Proportion of CMV Seropositive Kidney Transplant Recipients Who Will Develop a CMV Infection When Treated With an Immunosuppressive Regimen Including Everolimus and Reduced Dose of Cyclosporine Versus an Immunosuppressive Regimen With Mycophenolic Acid and Standard Dose of Cyclosporine A (EVERCMV), NCT02328963.

Topics: Aged; Anti-Bacterial Agents; Antigens, CD; Cell Culture Techniques; Cytomegalovirus Infections; Female; Humans; Kidney Transplantation; Leukocyte Immunoglobulin-like Receptor B1; Male; Middle Aged; MTOR Inhibitors; Mycophenolic Acid; Programmed Cell Death 1 Receptor; T-Lymphocyte Subsets

Cytomegalovirus (CMV) persists as the most frequent opportunistic infection among solid organ transplant recipients. This multicenter trial aimed to test whether treatment with everolimus (EVR) could decrease the incidence of CMV DNAemia and disease. We randomized 186 CMV seropositive kidney transplant recipients in a 1:1 ratio to receive EVR or mycophenolic acid (MPA) in association with basiliximab, cyclosporin, and steroids and 87 in each group were analyzed. No universal prophylaxis was administered to either group. The composite primary endpoint was the presence of CMV DNAemia, CMV treatment, graft loss, death, and discontinuation of the study at 6 months posttransplant. In the modified intent-to-treat analysis, 42 (48.3%) and 70 (80.5%) patients in the EVR and MPA groups reached the primary endpoint (OR = 0.21, 95% CI: 0.11-0.43, p < .0001). Fewer patients of the EVR group received treatment for CMV (21.8% vs. 47.1%, p = .0007). EVR was discontinued in 31 (35.6%) patients. Among the 56 patients with ongoing EVR treatment, only 7.4% received treatment for CMV. In conclusion, EVR prevents CMV DNAemia requiring treatment in seropositive recipients as long as it is tolerated and maintained.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Everolimus; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Transplant Recipients

Once-daily extended-release tacrolimus (TACER) is commonly administered following kidney transplantation (KTx); however, its optimal dosage remains unknown.. In this multi-center, randomized controlled trial, 62 living donor KTx recipients were assigned to either standard-exposure (SE; n = 32) or low-exposure (LE; n = 30) TACER (Graceptor®, Astellas Pharm Inc.) groups. All patients received basiliximab and mycophenolate mofetil (MMF). The primary outcomes were acute rejection, graft/patient survival, and the secondary outcomes were incidence of cytomegalovirus infection, and de novo donor-specific antibodies (dnDSA) production.. The tacrolimus trough level and estimated area under the blood concentration-time curve (eAUC) were significantly higher in SE than in LE (SE vs. LE; 1 year: 5.0 ± 0.9 ng/ml and 206.9 ± 26.8 ng h/ml vs. 3.4 ± 1.0 ng/ml and 153.9 ± 26.4 ng h/ml; 2 years: 4.8 ± 1.0 ng/ml and 204.9 ± 30.1 ng h/ml vs. 3.8 ± 0.9 ng/ml and 164.4 ± 27.0 ng h/ml). In contrast, the dosage and eAUC of MMF did not differ between groups. Two-year graft and patient survival rates were 100% in both groups, and acute rejection rates were 0% and 10% in the SE and LE, respectively (p = 0.11). The mean estimated glomerular filtration rates did not differ between the groups. Cytomegalovirus infection was slightly lower in the LE (SE: 12.5% and LE: 6.7%, p = 0.37). In the LE, four cases of dnDSA were noted within 2 years of transplantation; no case was observed in the SE (p = 0.034).. Although the LE TACER regimen showed similar rates of acute rejection, as well as graft and patient survival compared with SE after KTx, LE was significantly more associated with dnDSA. Further investigation of its long-term effect on graft survival is warranted. (University Hospital Medical Information Network Clinical Trials Registry ID: UMIN000033089).

Topics: Cytomegalovirus Infections; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Mycophenolic Acid; Tacrolimus

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

We sought to determine whether conversion from tacrolimus/mycophenolate mofetil (TAC-MMF) into tacrolimus/mTOR inhibitor (TAC-mTOR) immunosuppression would reduce the incidences of BK and CMV viremia after kidney/pancreas (KP) transplantation.. In this single-center review, the TAC-mTOR cohort (n = 39) was converted at 1 month post-transplant to an mTOR inhibitor and reduced-dose tacrolimus. Outcomes were compared to a cohort of KP recipients (n = 40) maintained on TAC-MMF.. At 3 years post-transplant, KP survivals and incidences of kidney/pancreas rejection were equivalent between mTOR and MMF-treated cohorts. (P = ns). BK viremia-free survival was better for the mTOR vs MMF-treated group (P = .004). In multivariate analysis, MMF vs mTOR immunosuppression was an independent risk factor for BK viremia (hazard ratio 12.27, P = .02). Similarly, mTOR-treated recipients displayed better CMV infection-free survival compared to the MMF-treated cohort (P = .01). MMF vs mTOR immunosuppression (hazard ratio 18.77, P = .001) and older recipient age (hazard ratio 1.13 per year, P = .006) were independent risk factors for CMV viremia. Mean estimated GFR and HgbA1c levels were equivalent between groups at 1, 2, and 3 years post-transplantation.. Conversion from TAC/MMF into TAC/mTOR immunosuppression after KP transplantation reduced the incidences of BK and CMV viremia with an equivalent risk of acute rejection and similar renal/pancreas function.

Topics: Adult; BK Virus; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Polyomavirus Infections; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Tumor Virus Infections; Viremia; Young Adult

To investigate the potential influence of variants in genes involved in the calcineurin pathway on the efficacy and toxicity of calcineurin inhibitors in renal transplantation.. Twenty-three polymorphisms in thirteen genes were tested in 381 renal transplant recipients receiving ciclosporin (n = 221) or tacrolimus (n = 160) and mycophenolate mofetil. Data were collected prospectively over the first year post-transplantation.. Multivariate survival analyses revealed no genetic associations with biopsy proven acute graft rejection and serious infections. Donor-recipient Cytomegalovirus mismatch was the only variable associated with serious infection.. This large exploratory study casts doubts on the potential interest of genetic biomarkers related to CNI pharmacodynamics but associations with other phenotypes in transplantation deserve further studies.

Topics: Adult; Calcineurin; Cyclosporine; Cytomegalovirus Infections; Female; Genetic Association Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pneumocystis carinii; Pneumocystis Infections; Polymorphism, Single Nucleotide; Prospective Studies; Risk; Signal Transduction; Tacrolimus

This study compared the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate and no CMV pharmacological prophylaxis. We randomized 288 patients to receive a single 3 mg/kg dose of antithymocyte globulin, tacrolimus, everolimus, and prednisone (r-ATG/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (BAS/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (BAS/MPS, n = 101). The primary end-point was the incidence of first CMV infection/disease in the intention-to-treat population at 12 months. Patients treated with r-ATG/EVR showed a 90% proportional reduction (4.7% vs. 37.6%, HR 0.10, 95% CI 0.037-0.29; p < 0.001), while those treated with BAS/EVR showed a 75% proportional reduction (10.8% vs. 37.6%, HR 0.25, 95% CI 0.13-0.48; p < 0.001) in the incidence of CMV infection/disease compared to BAS/MPS. There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 15.8%, p = 0.403), wound-healing complications, delayed graft function, and proteinuria. Mean estimated glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p = 0.021). In de novo kidney transplant recipients receiving no pharmacological CMV prophylaxis, reduced-dose tacrolimus and everolimus was associated with a significant reduction in the incidence of CMV infection/disease compared to standard tacrolimus dose and mycophenolate (ClinicalTrials.gov NCT01354301).

Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Treatment Outcome

In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Research Design

Everolimus (EVR) in heart and renal transplant (RTx) recipients may be associated with a decreased incidence of cytomegalovirus (CMV). A detailed analysis of the association between EVR versus mycophenolic acid (MPA) and CMV events has not been reported. CMV data from 2004 de novo RTx recipients from three-randomized, prospective, EVR studies A2309 (N = 833), B201 (N = 588) and B251 (N = 583) were retrospectively analyzed to identify differences between two EVR dosing groups and MPA. EVR groups received 1.5 mg/day, or 3 mg/day with either standard (SD-CsA) or reduced dose cyclosporine (RD-CsA). Controls received MPA with SD-CsA. CMV prophylaxis was as per center practice. CMV incidence (infection/syndrome, disease, viremia) was captured per local center evaluations. Kaplan-Meier analyses demonstrated that freedom from CMV viremia and infection/syndrome was significantly greater for EVR versus MPA for recipients without CMV prophylaxis. Among recipients who received prophylaxis, freedom from viremia was greater for EVR 3.0 mg; freedom from infection/syndrome was greater for EVR 3.0 and 1.5 mg. Although freedom from organ involvement was numerically greater for EVR, it was not statistically significant. This analysis documents significant reductions in the incidence of CMV infection/syndrome and viremia in EVR-treated de novo RTx recipients, especially those who did not receive CMV prophylaxis versus MPA.

Topics: Adult; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Everolimus; Female; Ganciclovir; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Sirolimus; Viremia

Secondary cytopenias are serious complications following hematopoietic cell transplantation. Etiologies include myelotoxic agents, viral infections, and possibly transplant-related factors such as the intensity of the conditioning regimen and the source of stem cells.. We retrospectively analyzed data from 2162 hematopoietic cell transplant recipients to examine the effect of these factors on overall cytopenias occurring after 28 days in hematopoietic cell transplantation.. Advanced age of the patient, recipient cytomegalovirus seropositivity, unrelated donor status, human leukocyte antigen mismatch and lower doses of transplanted CD34(+) cells (≤ 6.4×10(6)/kg) significantly increased the risk of cytopenias after day 28. Non-myeloablative hematopoietic cell transplantation had protective effects on anemia and thrombocytopenia after day 28 (adjusted odds ratio 0.76, probability value of 0.05 and adjusted odds ratio 0.31, probability value of <0.0001, respectively) but not on overall or ganciclovir-related neutropenia. This lack of protection appeared to be due to the use of mycophenolate mofetil in the majority of recipients of non-myeloablative hematopoietic cell transplants. Peripheral blood stem cells did not confer protection from cytopenias when compared to bone marrow.. Elderly patients appear to be more prone to cumulative toxicities of post-transplant drug regimens, but non-myeloablative conditioning, optimized human leukocyte antigen matching, and higher doses of CD34(+) cell infusions may reduce the risk of cytopenia after day 28.

Topics: Adult; Age Factors; Aged; Anemia; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Thrombocytopenia; Time Factors; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous

Cytomegalovirus (CMV) is a major cause of infectious complications following cardiac transplantation, severely affecting short- and long-term outcomes. A 12-month, multicenter, randomized, open-label study in de novo cardiac transplant patients was undertaken to compare the efficacy, renal function, and safety of everolimus plus reduced cyclosporine versus mycophenolate mofetil (MMF) plus standard cyclosporine (ClinicalTrials.gov NCT00150046). CMV-specific data was prospectively collected on infections, laboratory evidence, CMV syndrome, and CMV disease. In total, 176 patients were randomized (everolimus 92; MMF 84). Use of CMV prophylaxis was similar between groups (everolimus 20.8%; MMF 24.0%). Patients in the everolimus arm had a significantly lower incidence of any CMV event (8.8% versus 32.5% with MMF, P<0.001), CMV infection as an adverse event (4.4% versus 16.9%, P=0.011), laboratory evidence of CMV (antigenemia 7.7% versus 27.7%, P<0.001; polymerase chain reaction assay 2.2% versus 12.0%, P=0.015), and CMV syndrome (1.1% versus 8.4%, P=0.028). In the donor (D)+/recipient (R)+and D-/R+ subgroups, even after adjusting for use of prophylaxis, the CMV event rate remained significantly lower with everolimus than with MMF (P=0.0015 and P=0.0381, respectively). In conclusion, de novo cardiac transplant recipients experienced lower rates of CMV infection, CMV syndrome, or organ involvement on an everolimus-based immunosuppressant regimen compared with MMF.

Topics: Adult; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Kidney Function Tests; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Treatment Outcome

An effective host immune response, critical for successful control of Cytomegalovirus (CMV) disease in solid organ transplant recipients, is affected by intensity and type of immunosuppressive therapy. We used information prospectively captured in the VICTOR-trial to investigate the impact of immunosuppressive therapy on short- and long-term outcomes of CMV treatment in organ transplant recipients. Dual, as compared to triple, immunosuppressive therapy ([odds ratios] OR of 2.55; 95% CI: 1.51-4.60; p = 0.002), lower blood concentrations of calcineurin inhibitors (OR of 5.53; CI: 1.04-29.35; p = 0.045), and longer time since transplantation (OR of 1.70; CI: 1.01-2.87; p = 0.047) all showed better early (Day 21) CMV DNAemia eradication. We observed no effect of the intensity of the immunosuppressive therapy on overall rates of viral eradication or recurrence. The type of calcineurin inhibitor (tacrolimus/cyclosporine) or use of mycophenolate did not affect treatment efficacy, although both tacrolimus and mycophenolate treated patients showed a lower rate of virological recurrence OR 0.51 (95% CI: 0.26-0.98; p = 0.044) and OR 0.45 (95% CI: 0.22-0.93; p = 0.031), respectively. Lower total intensity of immunosuppressive therapy was associated with more effective early, but not overall, CMV DNAemia eradication by valganciclovir/ganciclovir therapy. Both mycophenolate and tacrolimus (rather than cyclosporine) therapy seem to be associated with reduced risk of recurrence.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Cytomegalovirus Infections; DNA, Viral; Female; Ganciclovir; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Organ Transplantation; Secondary Prevention; Tacrolimus; Treatment Outcome; Valganciclovir

Immunosuppressive regimens have lowered the rate of kidney rejection, but with increasing immunodeficiency-related complications. New cytomegalovirus (CMV) prophylaxis also has become available. The impact of these 2 developments on CMV diseases has not been well evaluated. We conducted a randomized trial comparing a drug regimen common in the 1980s, cyclosporin A (CsA) with azathioprine (Aza), with a drug combination used most today, tacrolimus (Tac) with mycophenolate mofetil (MMF), and we analyzed CMV risk factors in kidney transplant patients.. The 300 patients included in the trial underwent the same universal prophylaxis and preemptive therapy. CMV events and risk factors were prospectively recorded.. With preventive and preemptive strategies combined for 3 months, CMV replication was detected in 32.6% and CMV disease in 18.1% of patients. Multivariate analysis on risk factors for CMV disease were CMV donor (D)/recipient (R) matching and first month renal function (risk ratio [95% confidence interval]: 1.02 [1.01; 1.04]; P=0.011), but not the immunosuppressive regimen (P=0.35). The D+/R- combination increased the risk of CMV disease by a factor of 9 (P<0.0001) when compared with D-/R- status, and a factor of 3.5 (P<0.0001) when compared with all CMV-positive recipients. Despite the 50% rate of CMV disease in the D+/R- group, no asymptomatic CMV replication was detected with the preemptive strategy.. With modern immunosuppression, a sequential quadritherapy with Tac/MMF, and a 3-month CMV prevention strategy, the risk for CMV disease remains close to that with CsA/Aza. A CMV-negative recipient transplanted from a CMV-positive donor (D+/R-) remains a major risk factor, calling for better CMV prophylaxis or matching in negative recipients. Preemptive strategy thus appeared inefficient for this high-risk group. Transplant recipients with altered renal function should also be considered at risk.

Topics: Adult; Antiviral Agents; Azathioprine; Chemoprevention; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Ganciclovir; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Renal Insufficiency; Risk Factors; Tacrolimus; Treatment Outcome

The incidence of severe graft-vs-host disease (GVHD) in unmanipulated human leukocyte antigen (HLA) 2-3 antigen-mismatched bone marrow transplantation (BMT) using cyclosporine and methotrexate as GVHD prophylaxis is 80% to 90%. We investigated whether pharmacological GVHD prophylaxis consisting of four drugs, including a steroid, effectively suppressed GVHD in this transplantation setting.. Thirty patients who had hematologic malignancies at an advanced stage or with poor prognosis underwent allogeneic BMT using a myeloablative preconditioning regimen consisting of cyclophosphamide (60 mg/kg x 2), total body irradiation (8-10 Gy), and fludarabine (30 mg/m(2) x 4) with or without cytosine arabinoside (2 g/m(2) x 4), and GVHD prophylaxis consisting of a combination of tacrolimus, methotrexate, mycophenolate mofetil, and methylprednisone (2 mg/kg). Early therapeutic intervention for GVH reaction or grade I GVHD was performed, and steroid was slowly tapered.. All patients achieved donor-type engraftment. Neutrophil (>0.5 x 10(9)/L) and platelet (>20 x 10(9)/L) engraftment was achieved on day 13 and on day 30, respectively. Seventeen patients (56.7%) had no GVHD. Eleven patients (36.7%) developed grade II-III acute GVHD. Seven patients (23.3%) died of transplant-related toxicity, including fungal or viral infections and thrombotic microangiopathy, and four patients died of disease progression. Estimated relapse rate at 3 years was only 20.9%. The probability of survival at 3 years was 49.9%.. These data suggest that, in unmanipulated HLA-haploidentical allogeneic BMT, this GVHD prophylactic regimen, which includes methylprednisolone 2 mg/kg, and early therapeutic intervention for GVH reaction suppress the incidence of severe GVHD to an acceptable level, while preserving the graft-vs-leukemia effect.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematologic Neoplasms; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Incidence; Living Donors; Methotrexate; Methylprednisolone; Mycophenolic Acid; Myeloablative Agonists; Postoperative Complications; Tacrolimus; Transplantation Conditioning; Whole-Body Irradiation

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

We report the 5-year outcomes from a randomized prospective trial in primary adult renal allograft recipients, designed to evaluate calcineurin inhibitor (CNI)-free immunosuppression on kidney transplant function.. Sixty-one patients were randomized to either sirolimus (n=31) or cyclosporine (n=30) after basiliximab induction and mycophenolate mofetil (MMF) with steroids. Sirolimus was concentration controlled at 10-12 ng/mL for at least 6 months.. After 5 years, sirolimus-MMF-steroids compared to cyclosporine-MMF-steroids provides similar patient survival (87.1 vs. 90%, P=0.681), acute rejection rates (12.9 vs. 23.3%, P=0.22), total cholesterol (209.1 vs. 204.3 mg/dL, P=0.973), urine protein/creatinine ratios (0.398 vs. 0.478 mg/dL, P=0.72), and overall medical and surgical morbidity (P=NS). Although unadjusted patient survival was similar, sirolimus based CNI-free patients had longer death censored graft survival (96.4 vs. 76.7%, P=0.0265), higher glomerular filtration rate (GFR) by the abbreviated Modified Diet in Renal Disease (66.7 vs. 50.7 cc/min, P=0.0075), and fewer graft losses from chronic allograft nephropathy. The Banff chronic scores at two years were strong predictors of 5-year GFR. At 5 years, there were six de novo (three solid organ, three skin) cancers in the CNI group and only two de novo (one skin, one leukemia, no solid organ) cancers in the sirolimus group (P=NS).. This study of low to moderate risk patients demonstrates that excellent 5-year kidney transplant outcomes can be achieved without CNI drugs, when therapeutic drug monitoring of sirolimus is employed. The application of CNI drug avoidance protocols to high-risk recipients (retransplants, highly sensitized, etc.), extrarenal allograft recipients, or alternative drug regimens such as steroid or MMF elimination should be subjected to controlled trials.

Topics: Acyclovir; Adult; Aged; Antiviral Agents; Calcineurin Inhibitors; Cyclosporine; Cytomegalovirus Infections; Female; Ganciclovir; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Survival Analysis; Treatment Outcome

Prior retrospective studies have suggested that tacrolimus monotherapy is an option associated with excellent outcomes and reduced toxicities.. We conducted a prospective, randomized, 2-center study of tacrolimus combination therapy vs monotherapy. From April 16, 2004, to September 15, 2005, 58 adult heart transplant patients were studied. All received oral tacrolimus, mycophenolate mofetil, and corticosteroids. Patients were then randomized to a group where mycophenolate was maintained (COMBO) or to a group where it was discontinued (MONO) 14 days post-transplant. Corticosteroids were rapidly withdrawn in both groups between 8 and 12 weeks.. The primary end point (mean 6-month International Society of Heart and Lung Transplantation biopsy score) was 0.44 +/- 0.04 in the MONO group and 0.60 +/- 0.05 in the COMBO group (p = 0.013, unpaired Student's t-test). The freedom from rejection grade of 2R or higher at 6 and 12 months was 93.3% with MONO and 92.9% with COMBO (p = NS).. Tacrolimus monotherapy appears to be safe and efficacious in heart transplant recipients and is not associated with excess rejection in the first year post-transplant. Further studies of this approach are warranted.

Topics: Adrenal Cortex Hormones; Adult; Aged; Cytomegalovirus Infections; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Tacrolimus; Treatment Outcome

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.

Topics: Adult; Antiviral Agents; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Heart-Lung Transplantation; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Patient Selection; Postoperative Complications; Sirolimus; Treatment Outcome; United States

Secondary hypogammaglobulinemia after heart transplantation may follow immunosuppressive therapy with the resultant increased risk of infections, including cytomegalovirus (CMV) disease. There is limited information on the use of intravenous immunoglobulin replacement therapy (IVIG) in heart-transplanted patients with hypogammaglobulinemia and CMV disease. We present data on five consecutive heart-transplanted patients with relapsing CMV disease, four of whom developed gastrointestinal disease. The immunosuppressive regimen included prednisone, cyclosporine A, azathioprine, mycophenolate mofetil, tacrolimus and antithymocyte globulin (ATG). Evaluation revealed CMV antigenemia. All the patients had been treated with intravenous ganciclovir. In addition, hyperimmune CMV immunoglobulin was administered in three patients. Significantly reduced levels of immunoglobulin G (IgG) were observed in the patients as compared with 15 heart-transplanted individuals without CMV disease [mean IgG levels: 323+/-18 and 639+/-63 mg/dl, respectively (p=0.003)]. IVIG [FLEBOGAMMA], 200-400 mg/kg every 21 days with the goal of maintaining normal serum IgG levels, was added for the treatment of CMV disease. Selected batches with the highest anti-CMV titers were set apart for the treatment of the patients. IVIG treatment, in combination with antiviral therapy, proved able to control CMV disease. There was a favorable clinical response and the patients became free of gastrointestinal symptoms. Detection of CMV antigens was negative after treatment. During IVIG therapy no immediate or delayed adverse effects were observed. Even if our survey was limited to five cases, the results suggest that addition of IVIG to antiviral chemotherapy might improve outcome in heart-transplanted patients with hypogammaglobulinemia and CMV disease.

Topics: Agammaglobulinemia; Antilymphocyte Serum; Antiviral Agents; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Ganciclovir; Heart Transplantation; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisone; Recurrence; Tacrolimus

A large-scale, controlled clinical study has shown that enteric-coated mycophenolate sodium (EC-MPS) is therapeutically equivalent to mycophenolate mofetil (MMF) in de novo renal transplant patients. Safety and efficacy outcomes from an open-label extension of this core study (n = 122) were compared to those of the MMF arm of two well-controlled randomized studies (RAD B251, n = 141, and RAD B201, n = 150) for the 12- to 36-month posttransplant period. During this period, 33 (27%) EC-MPS patients experienced one or more drug-related adverse event. Sixteen patients (13%) discontinued the extension study due to adverse events. The incidence of all safety parameters was similar in the EC-MPS patients and the MMF-treated patients in the RAD B201 and RAD B251 studies during the 12- to 36-month posttransplant period, as was the frequency of adverse events, infections, malignancies, and hematological abnormalities. During the 24 months of the EC-MPS extension study, four patients died and two lost their graft. Biopsy-proven acute rejection (BPAR) occurred in four patients (3.3%). BPAR, graft loss, and death occurred in a similar proportion of MMF-treated patients in the RAD B201 and RAD B251 studies during months 12 to 36 posttransplant. These findings confirm the safety and efficacy of EC-MPS in maintenance transplant patients at least 1 year posttransplant and suggest that outcomes with EC-MPS are comparable to MMF in this population when used in combination with CsA-ME and steroids.

Topics: Adult; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Hematologic Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Postoperative Complications; Tablets, Enteric-Coated; Time Factors

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

Chronic allograft nephropathy (CAN) is the main cause of graft failure after the first year of transplantation. This prospective, centrally randomized, open-label study was conducted to examine the possibility that mycophenolate mofetil (MMF) can prevent the emergence of CAN. The incidence of biopsy-proven CAN at 1 year was compared between two cyclosporine-based regimens comprising either mycophenolate mofetil (MMF) or azathioprine (AZA). The AZA group (n = 34) and the MMF group (n = 37) were balanced for all baseline characteristics of donors and recipients, the pre-existence of renal lesions on donor biopsy, the incidence of delayed graft function and acute rejection. Based on an intent-to-treat analysis, the number of patients with CAN at 1 year post-transplantation was significantly reduced in the MMF group (17/37-46%) compared with the AZA group (24/34-71%) (p = 0.03). When observed data were considered, 56/71 (78.8%) patients had a 1-year biopsy, and the number of patients with CAN was significantly lowered in the MMF group (9/29-31%) compared with the AZA group (17/27-63%) (p = 0.01). These results suggest a beneficial effect of MMF on the incidence of CAN at 1 year post-transplantation.

Topics: Adolescent; Adult; Aged; Azathioprine; Chronic Disease; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Transplantation, Homologous

Topics: Acute Disease; Azathioprine; Creatinine; Cytomegalovirus Infections; Drug Therapy, Combination; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Transplantation, Homologous

Black American heart transplant recipients receiving cyclosporine-based primary immunoprophylaxis suffer higher rates of allograft rejection with hemodynamic compromise, infections, and posttransplant coronary artery disease. We examined the hypothesis that a combination of tacrolimus and mycophenolate mofetil "resurrects" clinical outcome of black Americans to those seen in white heart transplant recipients.. Sixty-three adult primary heart transplant recipients were included in this study. Twenty black American and 21 white patients who received tacrolimus-based primary immunoprophylaxis were enrolled in this prospective, observational parallel cohort investigation. A separate group of 22 black American patients were randomly allocated to receive cyclosporine-microemulsion-based primary prophylaxis and served as the control population for assessing outcomes in the black American group. Adjunctive immunosuppression included mycophenolate mofetil and corticosteroids. The primary end-point was the freedom from allograft rejection requiring treatment at 1 year. Secondary end-points included rejection with hemodynamic compromise, and patient or graft survival. Adverse events evaluated included development of infections requiring hospitalization and nonimmunological outcomes including hyperlipidemia, hypertension, and diabetes mellitus (new onset or worsened).. Tacrolimus-treated black American patients had greater freedom from allograft rejection requiring treatment at 1 year than those treated with cyclosporine (64% vs. 37%, P=0.01). No differences were noted between tacrolimus-treated black Americans and whites in the primary end point (64% and 67% respectively, P=nonsignificant [NS]). Tacrolimus-based immunosuppression was associated with better 1-year survival in black Americans compared with cyclosporine (95% vs. 73%, P=0.04), and this end point was similar to that achieved in tacrolimus-treated white heart transplant recipients (95%). No differences in infection rates were noted among either group. Cyclosporine-treated black Americans suffered more hyperlipidemia and worse hypertension than tacrolimus-treated patients.. Compared with cyclosporine, an immunosuppressive strategy using tacrolimus in black Americans achieves superior efficacy with regard to allograft rejection, higher allograft survival, and similar safety. Furthermore, tacrolimus-based immunosuppression is similar in immunological efficacy and safety in black Americans and in white heart transplant recipients.

Topics: Adult; Aged; Black or African American; Black People; Body Weight; Creatinine; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Hemodynamics; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous; Treatment Outcome; White People

Topics: Adult; Azathioprine; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Herpesviridae Infections; Herpesvirus 7, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Polymerase Chain Reaction; Postoperative Complications; Prednisolone; Recurrence; Virus Activation

Topics: Acute Disease; Acyclovir; Antiviral Agents; Cadaver; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Emulsions; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Muromonab-CD3; Mycophenolic Acid; Prednisone; Reoperation; Time Factors; Treatment Outcome

Topics: Age Factors; Aged; Aged, 80 and over; Cadaver; Cytomegalovirus Infections; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Pilot Projects; Postoperative Complications; Prospective Studies; Survival Rate; Tissue Donors; Transplantation, Homologous

Mycophenolate Mofetil (M MF) is a new immunosuppressive agent with proven efficacy for the prevention of kidney allograft rejection. However, only little experience is available with the use of MMF in liver transplant recipients.. In this prospective, controlled trial the efficacy and safety of MMF and Azathioprine (AZA) were compared in a Neoral based quadruple immunosuppressive regimen after orthotopic liver transplantation.. Between 12/96 and 12/98 57 adult patients were enrolled in the study at the University of Hamburg. 28 patients were randomised to MMF, 29 patients to AZA in combination with equivalent doses of lymphocyte antibodies, Neoral and methylprednisolone.. After a median follow-up of 10+/-3.2 months patient or graft survival did not differ significantly between the MMF and AZA group. However, MMF treated patients experienced less frequently acute rejection episodes (MMF: 6/28; 21.4% versus AZA: 13/29; 44.8%) (p=0.06). Furthermore, thrombocytopenia (MMF: 6/28; 21.4% versus AZA: 14/29; 48.3%) (p<0.05) and leukopenia (MMF: 2/28; 7.1% versus AZA: 6/29; 20%) (p=0.14) were less often observed under MMF compared to AZA. The incidence of serious bacterial infections and cytomegalovirus infections was almost identical in both groups. These preliminary data suggest that after liver transplantation primary immunosuppression with MMF is advantageous over AZA with regard to safety and efficacy.

Topics: Adult; Antilymphocyte Serum; Azathioprine; Corticosterone; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Survival Analysis; Transplantation, Homologous

Topics: Antilymphocyte Serum; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Patient Selection; Postoperative Complications; Prospective Studies; Reoperation; Safety; Survival Rate; Time Factors

Mycophenolate mofetil (MMF) combined with conventional cyclosporine and steroids doses efficiently prevents acute rejection in kidney transplants. However, this regimen has been associated with an increased incidence of cytomegalovirus (CMV) disease and leukopenia, specially in patients receiving MMF at 3 g/d, suggesting that the combination of two powerful immunosuppressants carries the risk of overimmunosuppression. For this reason, we treated a group of patients with MMF 3 g/d combined with low cyclosporine and steroids doses. Eighty-two kidney transplants performed at two centers and enrolled in the European Mycophenolate Mofetil Cooperative Study were randomized to receive: A) placebo (n = 27); B) MMF 2 g/d (n = 27); and C) MMF 3 g/d (n = 28). In this double blind study all patients received cyclosporine and steroids at conventional doses. Fifteen kidney transplants enrolled in an MMF open pharmacokinetic study were treated with MMF 3 g/day combined with low cyclosporine and steroid doses (group D). Efficacy was evaluated as the incidence of biopsy proven acute rejection, and safety focused on CMV disease and leukopenia. Patients receiving MMF showed a low incidence of biopsy proven rejection (B) 18.5%; C) 10.7%; and D) 13.3%). Patients of group C had a high incidence of CMV disease (35.7%) when compared with the other groups (lower than 8%). Incidence of leukopenia was higher in patients treated with MMF (B) 25.9%; C) 39.3%; and D) 40%) than in placebo treated patients (7.4%). Patients in group (C) displayed leukopenia mainly in the context of CMV disease, while patients of group (D) had leukopenia not related to CMV infection. All patients of group (D) who presented leukopenia recovered after MMF reduction dose, while in group (C) there were 5 out of 28 patients who required MMF withdrawal. We propose that a reasonable approach to take advantage of a powerful non-nephrotoxic immunosuppressant such as MMF, could be the administration of this drug at 3 g/d from the time of transplantation combined with low CsA and steroid doses.

Topics: Adult; Analysis of Variance; Anti-Inflammatory Agents; Clinical Trials as Topic; Cyclosporine; Cytomegalovirus Infections; Double-Blind Method; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Leukopenia; Male; Middle Aged; Mycophenolic Acid; Prednisone; Survival Analysis

The success of liver transplantation in this decade has become the stimulus to extend the donor and recipient pool. Reducing early posttransplant morbidity to maintain our success, as we expand our frontiers, has led us to focus on balanced testing of multidrug immunosuppression regimens.. A prospective trial in orthotopic liver transplantation using Mycophenolate Mofetil and an identical steroid taper with randomization of patients to Neoral (N) or Tacrolimus (FK) is the basis of this report. This was an intent-to-treat study designed to compare the 6-month primary endpoints of rejection and infection and to compare the 6-month secondary endpoints of liver function, renal function, bone marrow function, hypertension, and serum cholesterol levels.. Ninety-seven patients completed the 6-month follow-up period (N=49, FK=48). The actual 6-month patient and graft survival rates were 98% and 94%, respectively. There was no difference in the number of patients with rejection episodes (N=11, FK=8) (P=0.61). There were 24 infections (3 cytomegalovirus) in the FK group and 30 infections (9 cytomegalovirus) in the N group. The cholesterol levels at 6 months were not significantly different (P=0.07) between the groups. The other secondary 6-month endpoints were not significantly different, except total bilirubin, which was lower in the FK arm (P=0.02).. The use of Mycophenolate Mofetil with N or FK and an identical steroid taper after orthotopic liver transplantation is associated with excellent graft and patient survival, and at 6 months, only 191% of the patients experienced rejection, with a 48% overall infection rate.

Topics: Adolescent; Adult; Aged; Cholesterol; Cyclosporine; Cytomegalovirus Infections; Female; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Risk Factors; Tacrolimus

Mycophenolate mofetil (MMF) is a new immunosuppressive drug that selectively inhibits de novo purine synthesis. It has been tested in three large double-blind controlled trials for the prevention of rejection in renal transplant patients. These studies indicate that the use of MMF dramatically decreases the incidence of biopsy-proven rejection, the use of multiple courses of steroids for rejection, and the use of antilymphocyte preparations for treatment of rejection. The drug was well tolerated with an acceptable safety profile. The main side effects were gastrointestinal (nausea, vomiting, diarrhea), but seldom resulted in the cessation of drug therapy. Hematologic side effects similar to those with azathioprine occurred and were reversible. There was a slight increase in CMV-invasive disease with the use of MMF, but no deaths. Rates of malignancy were within published ranges for transplant recipients. Mycophenolate mofetil is a safe and efficacious drug for prevention of rejection in kidney transplant recipients.

Topics: Antilymphocyte Serum; Azathioprine; Cytomegalovirus Infections; Diarrhea; Double-Blind Method; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Nausea; Neoplasms; Opportunistic Infections; Placebos; Purines; Safety; Steroids; Vomiting

The kinetics of early and late cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation using various methods of graft-versus-host-disease (GVHD) prophylaxis are poorly defined. We retrospectively compared CMV reactivation and disease among 780 seropositive patients given HLA-matched peripheral blood stem cell (PBSC) grafts and calcineurin inhibitor plus posttransplantation cyclophosphamide (PTCy; n = 44), mycophenolate mofetil (MMF; n = 414), or methotrexate (MTX; n = 322). Transplantation occurred between 2007 and 2018; CMV monitoring/management followed uniform standard practice. Hazards of CMV reactivation at various thresholds were compared. Spline curves were fit over average daily viral load and areas under the curve (AUC) within 1 year were calculated. PTCy and MMF were associated with an increased risk of early (day ≤100) CMV reactivation ≥250 IU/mL after multivariate adjustment. The viral load AUC at 1 year was highest with MMF (mean difference = 0.125 units vs MTX group) and similar between PTCy and MTX (mean difference = 0.016 units vs MTX group). CMV disease risk was similar across groups. There was no interaction between GVHD prophylaxis and CMV reactivation on chronic GVHD risk. Despite PTCy-associated increased risk of early CMV reactivation, the CMV disease risk by 1 year was low in HLA-matched PBSC transplant recipients. In contrast, MMF was associated with higher overall CMV viral burden in the 1 year posttransplant. Although different mechanisms of immunosuppressive agents may affect CMV reactivation risk, effective prevention of GVHD may reduce corticosteroid exposure and mitigate infection risk over time.

Topics: Cytomegalovirus Infections; Graft vs Host Disease; Humans; Immunosuppressive Agents; Methotrexate; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Retrospective Studies

The risk of infectious complications among patients with pemphigus managed by rituximab is yet to be precisely elucidated.. To evaluate the risk of infections in patients with pemphigus managed by rituximab vs. first-line corticosteroid-sparing agents [azathioprine and mycophenolate mofetil (MMF)].. A global population-based cohort study compared patients with pemphigus initiating rituximab (n = 963) vs. azathioprine or MMF (n = 963) regarding the risk of 26 different infections. Propensity score matching was conducted to optimize comparability.. During the initial 12 months following treatment, patients under rituximab experienced elevated risk of COVID-19 [hazard ratio (HR) 1.82, 95% confidence interval (CI) 1.06-3.14; P = 0.028], parasitic diseases (HR 3.22, 95% CI 1.04-9.97; P = 0.032) and cytomegalovirus (CMV) infection (HR 1.63, 95% CI 1.04-2.58; P = 0.033). When evaluating infections developing ≥ 12 months after drug initiation, rituximab was associated with greater risk of pneumonia (HR 1.45, 95% CI 1.00-2.10; P = 0.047), COVID-19 (HR 1.87, 95% CI 1.49-2.33; P < 0.001), osteomyelitis (HR 2.42, 95% CI 1.11-5.31; P = 0.023), herpes simplex virus (HR 2.06, 95% CI 1.03-4.11; P = 0.037) and CMV (HR 1.63, 95% CI 1.07-2.49; P = 0.023) infections.. Within the first 12 months after treatment, patients under rituximab experience an elevated risk of COVID-19, parasitic and CMV infections. Rituximab is associated with pneumonia, osteomyelitis and viral diseases even beyond the first year after therapy. Pneumococcal vaccine and suppressive antiviral therapy should be considered even 1 year following therapy. There is no signal for elevated risk of tuberculosis, hepatitis B virus reactivation, Pneumocystis jiroveci pneumonia and progressive multifocal leukoencephalopathy.

Topics: Azathioprine; Cohort Studies; COVID-19; Cytomegalovirus Infections; Humans; Immunosuppressive Agents; Mycophenolic Acid; Pemphigus; Rituximab

There is a scarcity of long-term data on steroid-free immunosuppression using alemtuzumab in pediatric kidney transplantation (KTx). This study examines long-term outcomes with alemtuzumab without steroid maintenance therapy in pediatric KTx.. From July 2005 to June 2015, 71 pediatric KTx recipients received alemtuzumab without steroid maintenance. They were followed from 4.1 to 14.1 years post KTx.. Patient survival: One child expired with a functioning graft from post-transplant lymphoproliferative disorder (PTLD). Patient survival was 98.6%. Graft survival: Eighteen grafts were lost (16 from chronic rejection). Graft survival at 5 and 10 years was 92.3% and 61.3%, respectively. Rejection: Twenty-three (32.4%) patients were free from T-cell-mediated rejection (TCMR), 16 (22.5%) had >3 episodes. Sixteen (22.5%) were treated for antibody-mediated rejection (AMR). Infection: Twenty-three children developed Epstein-Barr virus (EBV), 5 developed cytomegalovirus (CMV), and 20 developed BK virus infection. Four (5.6%) developed PTLD. Twenty-two (31.0%) required treatment for neutropenia. Growth parameters: Mean height and weight increased by 0.56 and 0.69 SDS (standard deviation score), respectively. Body mass index increased by 5.1 kg/m. Alemtuzumab, without corticosteroid maintenance, offers 98.6% patient survival at 14 years with five and 10-year graft survival of 92.3% and 61.3%, respectively. TCMR and AMR requiring treatment were 67.4% and 22.5%, respectively. CMV, EBV, and BK viremia rates were 7.0%, 32.4%, and 28.2%, respectively. Thirty-one percent were treated for neutropenia; 5.6% developed PTLD. There were improvements in growth parameters and blood pressure.

Topics: Adolescent; Alemtuzumab; Child; Child, Preschool; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Kidney Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus

To compare everolimus (EVR) plus low-dose tacrolimus (TAC) with mycophenolic acid (MPA) plus standard-dose TAC with regards to rates of cytomegalovirus (CMV) disease in de novo kidney-transplant recipients (KTRs).. This single-center retrospective study included 187 de novo KTRs; 59 patients (31.6%) received EVR/low-dose TAC (group 1); 128 patients (68.4%) received MPA with standard-dose TAC (group 2). All received anti-thymocyte globulins as the induction therapy, and steroid-sparing strategy. Valganciclovir prophylaxis was mandatory for CMV D+/R- KTRs (seronegative recipients of a seropositive donor) in both groups and for R+ seropositive recipients (only in group 2).. The 2-year incidence of CMV disease was low and comparable between groups: 6.8% and 7.0% in groups 1 and 2, respectively (p = 0.94). There was no statistical difference in CMV serostatus (p = 1). However, CMV disease tended to be less frequent, though not statistically different, in R+ KTRs receiving EVR without prophylaxis (3.7% vs. 8.5% in groups 1 and 2, respectively) and in patients without EVR discontinuation (2.6% vs. 6.9% in patients who did not discontinue MPA (p = 0.29). Two-year graft function was good and comparable between groups (median eGFR of 54.2 and 53.0 mL/min in groups 1 and 2, respectively; p = 0.47); incidence of immunological events was low. Significantly more patients in group 1 discontinued EVR because of adverse events than patients that discontinued MPA in group 2 (35.6% in group 1 vs. 10.2% in group 2; p < 0.001).. Everolimus plus low-dose TAC given to de novo KTRs was associated with low rates of CMV disease, especially in R+ patients with no CMV prophylaxis.

Topics: Adult; Aged; Cytomegalovirus Infections; Drug Combinations; Everolimus; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus

Post-transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV-specific T-cell anergy. In the ATHENA-study, de-novo everolimus (EVR) with reduced-exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA-study completing the 12-month visit on-treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV-specific CD4 T cells were determined after stimulation with CMV-antigen, and cytokine-profiles and various T-cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC-treated patients had CMV-infections, no such events were reported in EVR-treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV-specific T cells, their median expression of CTLA-4 and PD-1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA-4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV-specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR-treated patients retained CMV-specific T-cell functionality, which may contribute to enhanced protection against CMV infections.

Topics: Adult; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Everolimus; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; T-Lymphocytes; Tacrolimus; Treatment Outcome

Modern immunosuppressive regimens in paediatric kidney transplant recipients have contributed to improved long-term allograft survival, but at the expense of an increased incidence of viral infections. Here, we describe, for the first time, the incidence, risk factors and clinical outcome of CMV, EBV, BKV and JCV viraemia in a cohort of paediatric allograft recipients treated with a corticosteroid-minimisation immunosuppressive regimen (CMR).. We retrospectively analysed 98 children treated with a CMR (basiliximab induction, corticosteroids until day 4, long-term tacrolimus and mycophenolate mofetil), who received a kidney transplant in our centre between 2009 and 2019.. Over the first 4 years post-transplant, the incidences of viraemia were as follows: CMV, 25.5%; EBV, 52.0%; JCV, 16.3%; BKV, 26.5%. Younger children at time of transplant were more likely to develop EBV and BKV viraemia. EBV viraemia was also associated with a regimen involving corticosteroids, but lacking MMF. Recipient CMV serology predicted the development of EBV, BKV and CMV viraemia. Fifty-six percent of CMV viraemia episodes in high-risk patients occurred whilst the graft recipients were still receiving anti-viral prophylaxis or within 3 months of cessation. There was no difference in graft function at latest follow-up between those with and without viraemia.. Judicious monitoring of viraemia, coupled with timely clinical intervention, can result in similar long-term outcomes for graft recipients compared to controls. The high incidence of CMV viraemia observed within a short period of cessation of anti-viral prophylaxis supports an extension of the length of prophylactic treatment in high-risk allograft recipients.

Topics: Adrenal Cortex Hormones; Child; Cytomegalovirus Infections; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Retrospective Studies; Viremia

In our population, anti-thymocyte globulin (ATG) of 1 mg/Kg/day for 4 days is used; which permits not using valgancyclovir (VGC) prophylaxis in some renal transplant recipients (RTR) with moderate risk (R+), to reduce costs. This study aimed to determine the incidence and risk of developing cytomegalovirus (CMV), with or without prophylaxis, when exposed to low doses of ATG or basiliximab (BSL).. A retrospective cohort included 265 RTR with follow-up of 12 months. Prophylaxis was used in R-/D+ and some R+. Tacrolimus (TAC), mycophenolate mofetil, and prednisone were used in all patients. Logistic regression analysis was performed to estimate the risk of CMV in RTR with or without VGC.. Cytomegalovirus was documented in 46 (17.3%) patients: 20 (43.5%) with CMV infection, and 26 (56.5%) with CMV disease. Anti-thymocyte globulin was used in 39 patients (85%): 32 R+, six D+/R-, and one D-/R-. ATG was used in 90% (27 of 30) of patients with CMV and without prophylaxis. The multivariate analysis showed an association of risk for CMV with the absence of prophylaxis (RR 2.29; 95% CI 1.08-4.86), ATG use (RR 3.7; 95% CI 1.50-9.13), TAC toxicity (RR 3.77; 95% CI 1.41-10.13), and lymphocytes at the sixth post-transplant month (RR 1.77; 95% CI 1.0-3.16).. Low doses of ATG favored the development of CMV and a lower survival free of CMV compared with BSL. In scenarios where resources for employing VGC are limited, BSL could be an acceptable strategy.

Topics: Adult; Antilymphocyte Serum; Antiviral Agents; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Female; Ganciclovir; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Retrospective Studies; Risk Factors; Tacrolimus; Transplant Recipients; Valganciclovir

mTOR inhibitors exert a preventive effect on cytomegalovirus (CMV) disease in CMV seropositive (R+) kidney transplant recipients, but their impact during the curative treatment of CMV disease in high-risk kidney transplant recipients has not been investigated. We aimed to evaluate the efficacy and tolerance of mTOR inhibitors compared with mycophenolic acid in 63 consecutive kidney transplant recipients (80% of D+R-) suffering from CMV disease with a persistent or a recurrent CMV DNAemia. In this monocentric retrospective study, 16 had their treatment converted to mTOR inhibitors and 47 did not. The Kaplan-Meier curves did not show any significant differences in CMV DNAemia eradication (77% vs. 88% respectively; hazard ratio (HR), 1.648 [95% confidence interval (CI), 0.913-2.973]; log-rank test, P = .132), DNAemia recurrence (36% vs. 47%; HR, 1.517 [95% CI, 0.574-4.007]; log-rank test, P = .448) and CMV clinical recurrence (17% vs. 27%; HR, 1.375 [95% CI, 0.340-5.552]; log-rank test, P = .677) between patients who received mTOR inhibitors and those who did not. These results were confirmed in uni- and multivariate time-dependent Cox regressions. In summary, conversion from mycophenolic acid to mTOR inhibitors seems inadequate for improving CMV clearance or in better preventing CMV recurrences during severe or persistent CMV disease.

Topics: Adult; Aged; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Female; Humans; Immunophenotyping; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Protein Kinase Inhibitors; Retrospective Studies; TOR Serine-Threonine Kinases

Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.

Topics: Acute Disease; Adult; Beclomethasone; Chronic Disease; Cidofovir; Cytomegalovirus Infections; Etanercept; Female; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infliximab; Japan; Male; Middle Aged; Mycophenolic Acid; Off-Label Use; Postoperative Complications; Registries; Transplantation, Homologous; Virus Diseases

The association between immunosuppressive therapy or cytomegalovirus (CMV) infection and detection of de novo donor-specific antibody (dnDSA) at 1 year after transplantation was evaluated. The impact of dnDSA positivity at 1 year after transplantation on long-term death-censored renal graft survival was also evaluated. One hundred and sixty adults receiving living renal allografts were studied. Inclusion criteria were renal graft survival for at least 1 year and a standard regimen of immunosuppressive therapy with tacrolimus, mycophenolate mofetil (MMF), steroids, and basiliximab. DSA were measured retrospectively by the Luminex assay. The coefficient of variation (CV) was calculated and receiver operating characteristic (ROC) analysis was employed to clarify the association of tacrolimus with development of dnDSA. Seven of the 160 patients (4.4%) were positive for dnDSA. The intra-patient minimum trough level of tacrolimus (cutoff value: 3.2 ng/mL) was associated with development of dnDSA. Discontinuation of MMF and treatment of CMV infection were more frequent in patients with dnDSA than in those without dnDSA. In multivariate analysis, a low trough level of tacrolimus, discontinuation of MMF, and treatment of CMV infection within 1 year after transplantation were independently associated with detection of dnDSA at 1 year. In patients with or without dnDSA at 1 year, the 10-year allograft survival rate was 51.4 versus 87.9%, respectively (P = 0.002). A lower tacrolimus trough level, discontinuation of MMF, and treatment of CMV infection were associated with dnDSA positivity. Further investigation is needed to determine whether a new immunosuppressive regimen that avoids these factors can reduce dnDSA positivity.

Topics: Adult; Aged; Basiliximab; Cytochrome P-450 CYP3A; Cytomegalovirus Infections; Female; Humans; Immunosuppressive Agents; Isoantibodies; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polymorphism, Genetic; Tacrolimus; Young Adult

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; 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

The complex interaction between cytomegalovirus (CMV) infection and acute rejection after kidney transplantation is well recognized.. This single center retrospective cohort analysis investigated the incidence and risk factors associated with CMV infection after treatment for acute rejection (tAR) in kidney transplant recipients receiving only CMV preemptive therapy. Of the 938 kidney transplants performed between 04/30/2014 and 04/30/2015 we identified 87 (9.3%) that were treated for acute rejection within the first year.. Most patients (64%) received rATG induction therapy followed by tacrolimus in combination with azathioprine (67%) or mycophenolate (33%) and corticosteroids. The incidence of CMV infection/disease after tAR was 47%, of which 73% occurred within 30 days. Using multivariable logistic regression analysis, eGFR at 1 month (OR = 0.98; 95% CI, 0.97-0.99; P = 0.007) and timing of tAR (OR = 0.98; 95% CI, 0.96-0.99; P = 0.021) were independently associated with CMV infection/disease after tAR.. In this cohort of kidney transplant recipients receiving tacrolimus-based immunosuppressive and preemptive CMV therapy, almost 50% developed CMV infection/disease after tARin the first year of transplantation. Early rejection and poor initial renal function were risk factors associated with CMV infection or disease.

Topics: Adult; Aged; Allografts; Antibiotic Prophylaxis; Antilymphocyte Serum; Antiviral Agents; Azathioprine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Factors; Tacrolimus; Young Adult

The effectiveness of everolimus (EVR) for ABO-incompatible (ABOi) kidney transplantation is unknown. We evaluated outcomes of conversion from steroid to EVR in ABOi kidney transplant recipients.. We performed a retrospective observational cohort study of 33 de novo consecutive adult ABOi living donor kidney transplant recipients. Desensitization was performed using 0 to 4 sessions of plasmapheresis and 1 to 2 doses of 100 mg rituximab according to the anti-A/B antibody titer. ABOi recipients were administered a combination of tacrolimus, mycophenolate mofetil, and methylprednisolone. Diabetic patients were converted from methylprednisolone to EVR at 1 to 15 months post-transplantation to prevent diabetes progression. Graft outcomes, hemoglobin A1c (HbA1c) levels, and cytomegalovirus infection rates were compared between the EVR (n = 11) and steroid (n = 22) groups.. Mean postoperative duration was 814 and 727 days in the EVR and steroid groups, respectively (P = .65). Between the 2 groups, graft survival rate (100% vs 95.5%, P > .99), acute rejection rate (9.1% vs 18.2%, P = .64), and serum creatinine levels (1.46 mg/dL vs 1.68 mg/dL, P = .66) were comparable. Although HbA1c levels were elevated in the steroid group (5.47%, 5.87%; P = .003), no significant deterioration was observed in the EVR group without additional insulin administration (6.10%, 6.47%; P = .21). Cytomegalovirus infection rate was significantly lower in the EVR group than in the steroid group (18.2% vs 63.6%, P = .026).. Conversion from steroid to EVR in ABOi kidney transplant recipients maintained excellent graft outcomes and avoided diabetes progression and cytomegalovirus infection.

Topics: Adult; Aged; Blood Group Incompatibility; Cohort Studies; Cytomegalovirus Infections; Diabetes Complications; Diabetes Mellitus; Drug Substitution; Everolimus; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Plasmapheresis; Retrospective Studies; Rituximab; Steroids; Tacrolimus

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that T-cell-depleting agents should be used only for kidney transplant (KT) recipients at high immunologic risk. However, the effects of thymoglobulin induction therapy in low-immunologic risk KT recipients on tacrolimus, mycophenolic acid, and steroid have not been elucidated yet.. We retrospectively collected 6 months postoperative clinical data, for low-immunologic risk KT recipients at Soonchunhyang University Hospital. Recipients were divided into thymoglobulin and basiliximab groups, based on the induction agent used. Low-immunologic risk recipients were defined as those with panel-reactive antibody level <30% at the time of kidney transplantation. The incidence of biopsy-proven acute rejection and borderline change was compared between the two groups.. Of the 46 low-immunologic risk patients, 25 received thymoglobulin. The incidence of biopsy-proven acute rejection was 0% (n = 0) and that of borderline change was 8% (n = 2) in the thymoglobulin group. The basiliximab group had a significantly higher incidence of rejection (23.8%; n = 5; P = .015) and borderline change (42.9%; n = 9; P = .006). No significant difference in estimated glomerular filtration rate was found between the two groups at 6 months after kidney transplantation. Cytomegalovirus (CMV) infection occurred more frequently in the thymoglobulin group than in the basiliximab group. All patients with CMV infection in both groups were effectively treated with pre-emptive intravenous ganciclovir therapy.. In low-immunologic risk KT recipients who received tacrolimus, mycophenolic acid, and steroid therapy, thymoglobulin induction therapy significantly reduced the incidence of biopsy-proven acute rejection and borderline change compared with basiliximab induction therapy.

Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Induction Chemotherapy; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Recombinant Fusion Proteins; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome

To report a case of probable donor-derived cytomegalovirus (CMV) infection after keratolimbal allograft (KLAL) transplantation.. Observational case report.. A 41-year-old man with a history of aniridic keratopathy and limbal stem cell deficiency underwent KLAL in his right eye. Preoperatively, he was negative for CMV IgG and IgM. Postoperatively, he was maintained on tacrolimus and mycophenolate mofetil for systemic immunosuppression; he was also on prophylactic valganciclovir (for CMV) and trimethoprim/sulfamethoxazole (for pneumocystis pneumonia) for 1 month. Approximately 5 weeks postoperatively, he developed a nonproductive cough, rhinorrhea, and dyspnea. His condition did not improve with oral azithromycin or levofloxacin. He developed worsening symptoms over the next 2 weeks despite therapy. The serum CMV polymerase chain reaction was positive, and he was readministered valganciclovir with subsequent resolution of symptoms.. We present the first case of CMV disease in a seronegative patient who received a presumed CMV-seropositive donor KLAL. Similar to solid organ transplantation, prophylactic and therapeutic management of CMV infection is necessary in the setting of systemic immunosuppression.

Topics: Adult; Allografts; Antiviral Agents; Corneal Diseases; Cytomegalovirus Infections; Drug Therapy, Combination; Eye Infections, Viral; Ganciclovir; Humans; Limbus Corneae; Male; Mycophenolic Acid; Stem Cell Transplantation; Tacrolimus; Tissue Donors; Valganciclovir

Universal prophylaxis and preemptive therapy are used to prevent cytomegalovirus (CMV) disease post-transplantation. Data regarding which strategy is superior are sparse, especially in high-risk recipients (donor CMV seropositive (D+) and recipient CMV seronegative (R-)).. This retrospective, single-center cohort study included recipients who underwent kidney transplantation between 2009 and 2015. The incidence of CMV infection/disease and patient and graft outcomes were analyzed and compared between high-risk recipients (D+/R-) and intermediate-risk recipients (D+/R+ or D-/R+), all managed with preemptive therapy.. Of 118 kidney transplant recipients, 21 were high-risk and 97 were intermediate-risk. Over a median follow-up period of 3 years, asymptomatic CMV infection developed significantly more frequently in high-risk patients than in intermediate-risk patients (38.1% vs. 16.5%, p=0.04), and CMV disease developed in a similar manner (28.6% vs. 3.1%, p<0.01). Among high-risk patients, CMV infection developed within the first 3 months post-transplantation and CMV disease within the first 9 months post-transplantation. Kaplan-Meier analysis showed no difference in the probability of mortality (log-rank p=0.63) or graft loss (log-rank p=0.50) between the patient groups. Graft rejection occurred more frequently in high-risk than in intermediate-risk patients, but the difference was not significant (log-rank p=0.24).. These results suggest that further studies on universal prophylaxis in high-risk patients are needed to elucidate whether preventing CMV infection/disease during the early post-transplant period leads to better outcomes, especially in terms of reducing graft rejection.

Topics: Adult; Antibodies, Monoclonal; Antiviral Agents; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Retrospective Studies; Ribonucleosides; Risk Factors; Rituximab; Tacrolimus; Tissue Donors; Treatment Outcome

Modern immunosuppressive regimens, although associated with improved 1-year graft survival, are associated with adverse effects, including opportunistic infections, diabetes mellitus after transplantation, cardiovascular complications, and de novo malignancies.. To determine the short-term (12 months) cost-effectiveness of everolimus (EVR) versus mycophenolate sodium (MPS) in kidney transplant recipients receiving induction therapy, tacrolimus, prednisone, and no prophylaxis for cytomegalovirus infection.. A Markov state transition model was designed. Data from a single-center prospective trial were used along with data from the center's medical bills database. The target population comprised adults with low immunological risk submitted to first ABO-compatible transplantation with kidneys recovered from living or deceased donors. The time horizon was 12 months. The interventions included tacrolimus and prednisone plus a single 3-mg/kg dose of rabbit antithymocyte globulin (ATG) and EVR or basiliximab (BAS) and EVR or BAS and MPS. The clinical outcomes considered for this analysis were cytomegalovirus infection/disease, acute rejection, graft dysfunction, surgical complications, graft loss, and life-years gained.. ATG/EVR was cost-saving compared with BAS/MPS on all evaluated outcomes; BAS/EVR outperformed BAS/MPS on most of the evaluated outcomes. Results were confirmed by sensitivity analysis.. Compared with MPS, EVR is an alternative immunosuppressive agent that is able to provide resource-saving to the health care provider with effectiveness gains for the patient.

Topics: Animals; Cost-Benefit Analysis; Cytomegalovirus Infections; Economics, Pharmaceutical; Enzyme Inhibitors; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Prospective Studies; Rabbits

Cytomegalovirus (CMV) is a risk factor for patient and graft survival after kidney transplantation.. We retrospectively analyzed risk factors for CMV infection in 348 patients who received a kidney transplant donated after brain death (n = 232) or by living donation (n = 116) between 2008 and 2013. Of the 348 patients analyzed, 91 received a mammalian target of rapamycin inhibitor (mTORi)-based immunosuppressive regimen. A total of 266 patients were treated with standard immunosuppression (Group 1) consisting of basiliximab induction, calcineurin inhibitor (CNI), and either mycophenolic acid (MPA, n = 219) or everolimus (EVE) (n = 47). We also included 82 patients who received more intense immunosuppression (Group 2) with lymphocyte depletion, CNI, plus either MPA (n = 38) or EVE (n = 44). Only patients in the high-risk constellation received CMV prophylaxis in Group 1, while all patients in Group 2 received prophylaxis for 6 month.. The overall rate of CMV infections was low with 10.1% in all patients. Despite the different prophylaxis strategies applied, no difference was seen in CMV infections between Group 1 (10.9%) and Group 2 (13.6%). A multivariate analysis revealed that patients on EVE had fewer CMV complications compared with patients on MPA (P = 0.013, odds ratio [OR] 4.8, confidence interval [CI] 1.4-16.5). Donor and recipient age >65 years was an independent risk factor (P = 0.002, OR 3.2, CI 1.5-6.7) for CMV infections. Patients with CMV infections had significantly worse graft function after 2 years (P = 0.001).. CMV is a significant risk factor for long-term graft outcome. Patients treated with EVE developed fewer CMV complications compared to patients on MPA. The use of mTORi is useful in patients at high risk of developing CMV infections.

Topics: Adult; Aged; Cohort Studies; Cytomegalovirus; Cytomegalovirus Infections; Everolimus; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Retrospective Studies; TOR Serine-Threonine Kinases

It is known that several viruses can alter or modulate the transcriptional and translational activity of host cells to obtain a rapid and efficient replication. In particular, Human Cytomegalovirus (HCMV) can interact with host cell at multiple levels, even modulating the expression of small signaling molecules called microRNAs. Especially, human miRNA mir-146a expression seems to be downregulated by HCMV infection in vitro. The aim of this study was to evaluate mir-146a expression in kidney transplant patients during HCMV infection. Sixty-four serum samples from 22 kidney transplant patients were analyzed and subdivided in three groups (high viral load, low viral load, and absent viral load). Mir-146a expression for each sample has been evaluated by a specific stem-loop Real Time polymerase chain reaction, and a statistical analysis was performed. Expression levels of mir-146a were similar among the three groups tested showing no statistical significant difference. Results obtained did not confirm data previously reported in literature, but the change of mir-146a expression levels has to be more clearly defined as it could not be directly caused by virus replication.

Topics: Aged; Cytomegalovirus; Cytomegalovirus Infections; Female; Ganciclovir; Gene Expression Regulation; Graft Rejection; Host-Pathogen Interactions; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; MicroRNAs; Middle Aged; Mycophenolic Acid; Tacrolimus; Viral Load

Mizoribine (MZR) is an immunosuppressive agent that exhibits a less potent immunosuppressive effect at doses up to 3 mg/kg/d. We investigated whether high-dose MZR is effective and safe for renal transplant patients in conjunction with cyclosporine (CsA), basiliximab, and corticosteroids. Ninety Japanese renal transplant patients were administered MZR (6 mg/kg/d), CsA (7 mg/kg/d), prednisolone (maintenance dose, 10 mg/d), and basiliximab (20 mg/body). They were compared with a control group of 81 renal transplant patients who received mycophenolate mofetil (MMF; 1500 mg/d), CsA, prednisolone, and basiliximab. The 2-year patient and graft survival rates were 98.9% and 97.8% in the MZR group and 98.8% and 97.5% in the MMF group, respectively. The rejection rate within 2 years after transplantation was 21.1% in the MZR group and 16.0% in the MMF group; the difference was nonsignificant. None of the MZR group developed cytomegalovirus (CMV) disease, whereas 12.3% of the MMF group contracted CMV (P < .0001). CMV viremia developed in 28.9% of the MZR group vs 46.9% of the MMF group (P < .0001); their peak antigen levels were 20.4 ± 44.1 and 252.8 ± 527.0 (P < .01). Furthermore, the incidence of gastrointestinal disorder, hyperlipidemia, and blood disorder was significantly lower in the MZR group than in the MMF group. The combination of high-dose MZR with CsA, basiliximab, and corticosteroids not only provides satisfactory immunosuppression but is also associated with a low incidence of CMV infection and gastrointestinal and blood disorders.

Topics: Adult; Aged; Anemia; Antibodies, Monoclonal; Basiliximab; Case-Control Studies; Cyclosporine; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Glucocorticoids; Humans; Immunosuppressive Agents; Japan; Kidney Transplantation; Leukopenia; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Prednisolone; Recombinant Fusion Proteins; Ribonucleosides; Viremia; Young Adult

In elderly kidney transplant (KT) recipients, the incidence of acute rejection is decreased, while that of fatal infections is increased. There are currently no guidelines for an upper age limit for KT, which is very difficult to determine. Here we examined several cases of elderly KT recipients.. We evaluated 127 KT patients treated at our department between 2003 and 2012 and followed them for 3 years post-transplant. The subjects were divided into two groups by age: ≥60 years (elderly group; n = 24); and <59 years (non-elderly group; n = 103). The presence or absence of acute rejection and infection, dose of immunosuppressive drugs, trough calcineurin inhibitor level, renal function, and graft and patient survival rates were retrospectively examined.. Our basic immunosuppressive regimen was a combination of calcineurin inhibitor, methylprednisolone, mycophenolate mofetil, and basiliximab. At 1 year post-transplantation, the average tacrolimus and cyclosporine dose and trough levels were not significantly different. The mean dose of mycophenolate mofetil in the elderly group at 1 year post-transplantation was significantly lower than that of the non-elderly group. The incidences of cytomegalovirus infection and acute rejection during follow-up did not differ significantly between groups. There were no significant differences in creatinine level between the two groups. In the elderly group, the graft survival rates at 1 and 5 years were 100% and 95.4%, respectively, while those in the non-elderly group were 98.1% and 92.5%, respectively.. Using our current immunosuppressive protocol, the outcomes of patients in the elderly group were considered acceptable.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Calcineurin Inhibitors; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Graft Survival; Humans; Immunosuppressive Agents; Japan; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Retrospective Studies; Transplant Recipients

Topics: CD4-Positive T-Lymphocytes; Cyclophosphamide; Cytomegalovirus; Cytomegalovirus Infections; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mycophenolic Acid; Pneumonia; Retrospective Studies; Rheumatic Diseases; Risk Factors

We retrospectively reviewed 242 patients who received related donor myeloablative peripheral blood hematopoietic cell transplantation. We compared patients who received mycophenolate (MMF)/cyclosporine (CSA) (n = 71), to historical controls who received methotrexate (MTX)/CSA (n = 172). There were no differences in overall survival, nonrelapse mortality, and relapse. The MMF/CSA group had significantly faster neutrophil and platelet engraftment: medians of 13 versus 18 days and 10 versus 14 days, respectively (P = 0.001). The cumulative incidence of acute graft versus host disease (GVHD) (Grades, 2-4) was significantly lower in the MMF/CSA group (45.1 vs. 74.4%, P < 0.001). The MMF/CSA group showed a lower incidence of skin (51.5 vs. 72.1%, P < 0.001) and liver acute GVHD (11.3 vs. 54.2%, P < 0.001) and a higher incidence of lung (42.2 vs. 19.0%, P = 0.045), eye (59.7 vs. 30.1%, P < 0.001), and mouth (72.8 vs. 56.4%, P = 0.001) chronic GVHD but only eye chronic GVHD was confirmed in propensity score matching (PSM) analysis. The incidence of cytomegalovirus (CMV) viremia was higher in the MMF/CSA group (55.8 vs. 39.6%, P < 0.001) but this was not confirmed in PSM analysis. MMF/CSA was identified as an independent favorable factor for acute GVHD (P < 0.001, hazard ratio, 0.41) but as a possible adverse risk factor for CMV viremia as this was not found to be statistically significant in PSM analysis. MMF/CSA in myeloablative matched related donor peripheral blood stem cell transplant is not inferior as GVHD prophylaxis in comparison with MTX/CSA and is associated with faster engraftment but a potentially higher risk of CMV viremia.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Retrospective Studies; Survival Analysis; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous

Data on the incidence, timing, and risk factors for herpes zoster (HZ) in heart transplant (HT) recipients are limited.. We determined HZ incidence rates and actuarial estimates of time to first HZ episode in 314 HT recipients at our institution from 1995 to 2010. We developed Cox models to assess potential risk factors for HZ in HT.. Median age at HT was 54 (range, 17-71) years; 237 (76%) were male. There were 60 episodes of HZ in 51 patients, with an overall incidence rate of 31.6 cases (95% confidence interval [CI], 23.5-41.6)/1000 person-years. Although most cases occurred during the first post-HT year, cumulative HZ incidence was 0.078 at 1, 0.15 at 5, and 0.20 at 10 years. Many patients had substantial HZ morbidity, including 14% with HZ ophthalmicus and 45% with post-herpetic neuralgia. Adjusting for age, gender, and acute cellular rejection episodes, exposure to mycophenolate mofetil (MMF) was an independent risk factor for HZ (adjusted hazard ratio [HR] 2.18; 95% CI, 1.20-3.96; P = 0.01), while ganciclovir-based cytomegalovirus prophylaxis reduced HZ risk (adjusted HR 0.09; 95% CI, 0.01-0.71; P = 0.02). Although age and female gender increased HZ risk, the magnitude of their effect was not statistically significant in Cox models.. HZ is common and morbid after HT, particularly with MMF exposure. Ganciclovir prophylaxis is effective in reducing the short-term risk of HZ, but the steady incidence of cases for years post HT makes long-term HZ prevention challenging. Augmenting varicella zoster virus immunity post HT with vaccines warrants further exploration.

Topics: Adolescent; Adult; Age Factors; Aged; Antiviral Agents; Cardiomyopathies; Cohort Studies; Cytomegalovirus Infections; Female; Ganciclovir; Graft Rejection; Heart Defects, Congenital; Heart Transplantation; Herpes Zoster; Herpes Zoster Ophthalmicus; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Neuralgia, Postherpetic; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sex Factors; Time Factors; Young Adult

Cytomegalovirus (CMV) is a common infection after myeloablative allogeneic hematopoietic stem cell transplant (M-alloHSCT). Achievement of complete donor T-cell chimerism (CDC-T) post transplant is a measure of immune reconstitution. We investigated the association between CDC-T post M-alloHSCT and the incidence of CMV viremia.. We retrospectively reviewed all CMV and chimerism results of 47 patients for the first 6 months post M-alloHSCT. CDC-T was analyzed as a time-varying covariate for association with post M-alloHSCT CMV viremia.. CMV viremia occurred in 15 (32%) and CDC-T was achieved in 38 (81%) recipients within the first 6 months post M-alloHSCT. On univariable analysis, increased CMV viremia was seen among patients with CDC-T (hazard ratio 2.81 [P = 0.07, 95% confidence interval = 0.93-8.52]). A 30-day landmark analysis showed that the incidence of CMV viremia at 6 months (regardless of recipient CMV serostatus) was 50% among those who had achieved CDC-T by day 30, and 23% among those who had not (P = 0.06).. We conclude that shorter time to CDC-T may be associated with higher risk of CMV viremia. If confirmed in a larger cohort, this might be a marker for risk stratification in the management of CMV in this population.

Topics: Adolescent; Adult; Aged; Busulfan; Chimerism; Cohort Studies; Cyclophosphamide; Cyclosporine; Cytomegalovirus Infections; DNA; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Proportional Hazards Models; Retrospective Studies; T-Lymphocytes; Tacrolimus; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Viremia; Young Adult

Neutropenia after kidney transplant is an adverse event usually treated with a dosage reduction of mycophenolic acid. We evaluated the efficacy and safety of substituting mycophenolic acid with everolimus in patients with persistent neutropenia after kidney transplant.. This study was a retrospective analysis. A total of 17 patients who were initially treated with mycophenolic acid (1912 ± 196 mg/d), calcineurin inhibitors, and methylprednisolone for kidney transplant were included.. In 15 patients, neutropenia occurred within the first 3 months (during valganciclovir administration), and in 2 patients between the fourth and sixth month after transplant. One hundred eighteen episodes of neutropenia were recorded, originally treated by reducing the dosage of mycophenolic acid (765 ± 390 mg/d) and administering granulocyte colony-stimulating factor. Three patients experienced acute rejection 5 to 10 days after reducing the dosage of mycophenolic acid, and they were successfully treated with pulse steroids. Five patients developed cytomegalovirus infection 108 ± 65 days after the onset of neutropenia. After replacing mycophenolic acid with everolimus, episodes of neutropenia were observed in 6 patients. In 1 patient, discontinuing everolimus was necessary after 1.5 months of treatment. In 5 patients with cytomegalovirus infection, neutropenia subsided after termination of valganciclovir treatment. In the remaining 11 patients, no episodes of neutropenia were observed. No episodes of acute rejection occurred, and renal function remained stable during a followup of 47 ± 30 months (estimated glomerular filtration rate [eGFRMDRD6]: 45 ± 14 mL/min/1.73 m2→47 ± 22 mL/min/1.73 m2].. Replacing mycophenolic acid with everolimus appears to be a safe and effective alternative treatment in neutropenic renal transplant recipients.

Topics: Adult; Cytomegalovirus Infections; Drug Substitution; Drug Therapy, Combination; Everolimus; Female; Ganciclovir; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Retrospective Studies; Risk Factors; Sirolimus; Steroids; Time Factors; Treatment Outcome; Valganciclovir

Topics: Antibodies, Monoclonal; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Female; Ganciclovir; Glomerulonephritis, IGA; HIV Seronegativity; Humans; Immunosuppression Therapy; Inflammation; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prednisolone; Recombinant Fusion Proteins; Renal Dialysis; Renal Insufficiency; Sinusitis; Tacrolimus; Valganciclovir

A time-to-event model was developed to study the predictive factors of immunosuppressive efficacy in renal transplant patients and to investigate longitudinal calcineurin inhibitor (CNI) and mycophenolic acid (MPA) coexposures and patient characteristics as potential covariates. The efficacy end point included acute rejection (AR), graft loss, and death. Data from 222 patients were analyzed: 23 events were observed in 126 patients receiving cyclosporine as compared with 15 events in 96 patients receiving tacrolimus (P = 0.61) in the first 2 years posttransplantation. Each 1-mg·h/l increase of MPA area under the plasma concentration vs. time curve was associated with a 4% decreased risk of an event (hazard ratio (HR) = 0.96; 95% confidence interval (CI): 0.93-0.99). The onset of cytomegalovirus infection/disease significantly increased this risk (HR = 10.9; 95% CI: 6.5-21.7). Within the observed ranges, CNI exposures were not significantly associated with efficacy (i.e., AR, graft loss, and death). This work advocates the avoidance of unnecessary high CNI dosing and puts forward new arguments for MPA concentration monitoring.

Topics: Calcineurin Inhibitors; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Logistic Models; Models, Biological; Multicenter Studies as Topic; Mycophenolic Acid; Randomized Controlled Trials as Topic; Tacrolimus

Cytomegalovirus (CMV) infection is an important complication in organ and bone marrow recipients as well as patients infected with HIV. Although screening and prophylaxis have been defined in these patients, there are few data about the frequency of CMV disease in glomerular diseases treated by immunosuppression.. We recruited 133 patients with glomerular diseases treated by immunosuppression between 2006 and 2013. Patients who had any symptoms suggestive of CMV disease were screened for viral DNA. Immunosuppressive treatments were as follows: Group 1, steroid only; Group 2, steroid with cyclophosphamide (CP); Group 3, steroid with cyclosporine A; and Group 4, steroid with mycophenolate mofetil or azathioprine.. Patients developing CMV and non-CMV disease were compared for age, sex, renal pathology, hypertension, diabetes, baseline creatinine, and estimated glomerular filtration rate, and immunosuppressive regimen. At follow-up, 55 patients were tested for CMV disease during immunosuppressive treatment. Twenty-six patients had CMV DNA positivity of 1,112-205,500 copies/mL. Patients with CMV disease were all seen within the first 5 months of immunosuppressive treatment, and the disease was observed most commonly (14 patients, 53 %) in the first 2 months of treatment. Multiple regression analysis revealed that high baseline creatinine levels, older age, and use of steroids with CP were independent risk factors for development of CMV disease.. CMV disease is not an uncommon complication in patients with glomerular diseases treated by immunosuppression. Further prospective studies and prophylaxis should be addressed in future studies, including particular groups of patients.

Topics: Adult; Azathioprine; Biopsy; Cyclophosphamide; Cyclosporine; Cytomegalovirus Infections; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Real-Time Polymerase Chain Reaction; Retrospective Studies; Risk Factors; Turkey

We report a case of a 52-year-old woman, on immunosuppressive treatment with mycophenolate due to a history of giant cell myocarditis (GCM), who presented with new-onset severe blood-tinged diarrhoea after a cytomegalovirus (CMV) primoinfection. An extensively prolonged mycophenolate-related colitis was seen after withdrawal of mycophenolate due to an intestinal Epstein-Barr virus (EBV) infection-a rarely seen event itself. We postulate that colonic toxicity was triggered by CMV infection and perpetuated by intestinal EBV replication/infection.

Topics: Colitis; Cytomegalovirus Infections; Diarrhea; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Severity of Illness Index

Topics: Antiviral Agents; Azathioprine; Colitis; Cytomegalovirus Infections; Diarrhea; Female; Ganciclovir; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Treatment Outcome

To investigate the factors in association with colorectal disorders in adult renal transplant recipients.. A retrospective cohort study was carried out with clinical, microbiological and management data regarding diarrhea in 513 renal transplant recipients from Jan. 2007 to Dec. 2012.. Of the 513 patients, 118(23.00%) with no history of ulcerative colitis, were found to have diarrhea after kidney transplantation. In the 118 patients, diarrhea was probably caused by administration of immunosuppressive agents in 65 cases (55.08%), in 30 cases (25.42%) diarrhea was antibiotics associated, and in 23 cases (19.49%) it was due to infections, including bacterial, fungal and viral infections. Diarrhea occurred soon after transplantation in most cases. Of the 118 patients, the symptom of diarrhea occurred in the first 1 month in 84 cases (71.19%), and in the next 5 months in 16 cases (13.56%), and the other 18 cases (15.05%) occurred after 180 days after transplantation. Of the 118 patients, 84 cases (71.19%) were relieved or cured after proper diets, the symptomatic therapy or the adjust meat of the doses of immunosuppressive agents: 18 cases (15.25%) needed to use or adjust the antibiotics , 16 cases (13.56%) had to stop mycophenolate mofetil and convert to other drugs.. Immunosuppressive agents, antibiotics and infection are the common causes of diarrhea after kidney transplantation. The outcome is good with appropriate conservative management.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Child; Cyclosporine; Cytomegalovirus Infections; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Mycoses; Retrospective Studies; Tacrolimus; Young Adult

Tremendous breakthrough in solid organ transplantation was made with the introduction of calcineurin inhibitors (CNI). At the same time, they are potentially nephrotoxic drugs with influence on onset and progression of renal graft failure. The aim of this study was to evaluate the outcome of a conversion from CNI-based immunosuppressive protocol to sirolimus (SRL) in recipients with graft in chronic kidney disease (CKD) grade III and proteinuria below 500 mg/day.. In the period 2003-2011 24 patients (6 famale and 18 male), mean age 41 +/- 12.2 years, on triple immunosuppressive therapy: steroids, antiproliferative drug [mycophenolate mofetil (MMF) or azathiopirine (AZA)] and CNI were switched from CNI to SRL and followe-up for 76 +/- 13 months. Nine patients (the group I) had early postransplant conversion after 4 +/- 3 months and 15 patients (the group II) late conversion after 46 +/- 29 months. During the regular outpatient controls we followed graft function through the serum creatinine and glomerular filtration rate (GFR), proteinuria, lipidemia and side effects.. Thirty days after conversion, in all the patients GFR, proteinuria and lipidemia were insignificantly increased. In the first two post-conversion months all the patients had at least one urinary or respiratory infection, and 10 patients reactivated cytomegalovirus (CMV) infection or disease, and they were successfully treated with standard therapy. After 21 +/- 11 months 15 patients from both groups discontinued SRL therapy due to reconversion to CNI (10 patients) and double immunosuppressive therapy (3 patients), return to hemodialysis (1 patient) and death (1 patient). Nine patients were still on SRL therapy. By the end of the follow-up they significantly improved GFR (from 53.2 +/- 12.7 to 69 +/- 15 mL/min), while the increase in proteinuria (from 265 +/- 239 to 530.6 +/- 416.7 mg/day) and lipidemia (cholesterol from 4.71 +/- 0.98 to 5.61 +/- 1.6 mmol/L and triglycerides from 2.04 +/- 1.18 to 2.1 +/- 0.72 mmol/L) were not significant. They were stable during the whole follow-up period. Ten patients were reconverted from SRL to CNI due to the abrupt increase of proteinuria (from 298 +/- 232 to 1639 +/- 1641/mg day in 7 patients), rapid growth of multiple ovarian cysts (2 patients) and operative treatment of persisted hematoma (1 patient). Thirty days after reconversion they were stable with an insignificant decrease in GFR (from 56.10 +/- 28.09 to 47 +/- 21 mL/min) and significantly improved proteinuria (from 1639 +/- 1641 to 529 +/- 688 mg/day). By the end of the follow-up these patients showed nonsignificant increase in the serum creatinine (from 172 +/- 88 to 202 +/- 91 mmol/L), decrease in GFR (from 56.10 +/- 28.09 to 47 +/- 21 mL/day) and increased proteinuria (from 528.9 +/- 688 to 850 +/- 1083 mg/min).. In this small descriptive study, conversion from CNI to SRL was followed by an increased incidence of infections and consecutive 25-50% dose reduction in the second antiproliferative agent (AZA, MMF), with a possible influence on the development of glomerulopathy in some patients, which was the major reason for discontinuation of SRL therapy in the 7 (29%) patients. Nine (37.5%) of the patients experienced the greatest benefit of CIN to SRL conversion without serious post-conversion complications.

Topics: Adult; Azathioprine; Biomarkers; Calcineurin Inhibitors; Creatinine; Cytomegalovirus Infections; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Renal Insufficiency, Chronic; Sirolimus; Time Factors; Treatment Outcome

Data on how different immunosuppressive drugs affect cytomegalovirus (CMV)-specific T-cell responses may help guide more rational modification of immunosuppression in patients with CMV replication. We assessed the in vitro effects of individual standard and novel immunosuppressive drugs on a broad range of CMV-specific T-cell responses.. Peripheral blood mononuclear cells from healthy CMV-seropositive donors were preincubated with serial dilutions of tacrolimus, mycophenolate (MPA), sirolimus, tofacitinib, and belatacept. CMV-pp65 or CMV-pp72 peptide pools were used for stimulation. CMV-specific cytokine (Th1 and Th2) and chemokine responses were determined (a total of 5400 measurements). P<0.01 was set as significant.. After CMV stimulation, dose-dependent suppression of Th1, Th2, and chemokines was seen, but significant differences between drugs were present. For example, tacrolimus was more potent in inhibiting CMV-specific Th1 cytokines versus Th2, whereas MPA preferentially inhibited Th2 cytokines. In a comparison of the relative potency of each drug at different dosing ranges, tacrolimus had the strongest Th1 inhibitory effect (median inhibition of interferon-γ at 97.5%; P=0.004-0.008) followed by sirolimus (median inhibition at 82.4%). The remaining agents (MPA, belatacept, and tofacitinib) had less apparent dose-dependent effects on interferon-γ (belatacept median inhibition at 21.5%; P=0.004 vs. tacrolimus).. Immunosuppression-specific and dose-dependent reductions in CMV-specific cytokine release were observed with significant differences in Th1 versus Th2 profiles and in relative potency of the drugs.

Topics: Abatacept; Adult; Cytokines; Cytomegalovirus; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Humans; Immunoconjugates; Immunosuppressive Agents; In Vitro Techniques; Middle Aged; Mycophenolic Acid; Piperidines; Pyrimidines; Pyrroles; Sirolimus; T-Lymphocytes; Tacrolimus; Th1 Cells; Th2 Cells; Transcriptome

In an earlier study, we compared the duration of kidney graft survival between two groups of recipients; one on triple (cyclosporine, prednisone and mycophenolate mofetil) and the other on quadruple (cyclosporine, prednisone, mycophenolate mofetil, and sirolimus) immunosuppressive therapy.. The aim of this study was to examine the impact of antiviral and statin therapy on graft longevity.. One hundred five kidney allograft recipients were preoperatively assessed for serological markers of infection with various viral agents. All patients were on a prophylactic antiviral regimen of acyclovir and gancyclovir. Seventeen patients were on a statin. Patients were monitored for viral infections and graft rejection or loss for period of 3 years posttransplantation.. We detected a high preoperative prevalence rate of IgG immunoglobulins versus the latency-establishing Herpesviridae viruses. Two patients who were preoperatively IgG positive for CMV had cytomegalovirus disease after transplantation. One patient who was preoperatively IgG positive for VZV had shingles after the surgery. No other confirmed viral infections were reported. Thirteen of 88 patients (14.77%) whose treatment regimen did not include a statin suffered a rejection episode or lost the graft whereas 1 of 17 patients (5.88%) on a statin had a rejection episode.. The low rate of viral infections observed in our study population supports the utility of prophylactic administration of antiviral agents to transplant recipients. However, statins seem to have a protective effect on graft longevity (odds ratio [OR] = 0.361, 95% confidence interval [CI] = 0.044-2.957).

Topics: Adult; Anti-Inflammatory Agents; Antiviral Agents; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Herpes Zoster; Herpesvirus 3, Human; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Sirolimus; Transplantation, Homologous

We have used low doses of mizoribine (MZ) or mycophenolate mofetil (MMF) as induction and maintenance immunosuppressants, but since 2009 have employed a high dose of MZ. We reviewed the efficacy and side effects of MZ compared with MMF. It is difficult to compare graft survivals between these periods because of different patient demographics, though the high dose of MZ cohort showed no significant difference from MMF. High doses of MZ serum to prevent acute rejection episodes as the induction and maintenance therapy. MZ controlled with blood concentrations showed less side effects, suggesting that high MZ doses could be safely used for an induction and maintenance antimetabolite.

Topics: Adolescent; Adult; BK Virus; Child; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Herpes Zoster; Humans; Immunosuppressive Agents; Japan; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Retrospective Studies; Ribonucleosides; Treatment Outcome; Young Adult

Beneficial effects of protocols using minimal steroid exposure have been recently reported. The purpose of this study was to evaluate the outcomes of kidney transplantation recipients who received immunosuppression protocols with early steroid withdrawal (ESW) at our center.. We retrospectively studied 84 kidney transplant recipients who had received ESW immunosuppressive protocols at our center from March 2005 to December 2010. The immunosuppressive regimen was a combination of calcineurin inhibitors (tacrolimus/cyclosporine), methylprednisolone, which was tapered and discontinued within 2 months, mycophenolate mofetil, and basiliximab (postoperative days 0 and 4). We compared the outcomes of our ESW recipients with those of a historical control group (February 2003 to January 2005; n = 18).. Clinical acute rejection episodes were observed in 15 (17.9%) and 5 (27.8%) cases in the ESW and control groups, respectively. Cytomegalovirus infection occurred in 12 (14.3%) and 5 (27.8%) cases in the ESW and control groups, respectively. The creatinine levels at 1 year after transplantation were 1.3 ± 0.4 mg/dL and 1.3 ± 0.5 mg/dL in the ESW and control groups, respectively. In the ESW group of 84 recipients, actuarial patient survival at 1 year was 94.0%. In the historical group of 18 recipients, the actuarial patient survival at 1 year was 100% (P = .76). In the ESW group the graft survival rate at 1 year was 95.2%. In the historical group, graft survival rate at 1 year was 100% (P = .65). There were no significant differences in the parameters between the groups.. The outcomes from this study were considered to be acceptable; however, the possibility of improving the protocols exists.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; Cyclosporine; Cytomegalovirus Infections; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Japan; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Retrospective Studies; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Mycophenolate mofetil (MMF) is used for immunosuppression in myasthenia gravis (MG). Although there are numerous data on associated infection and prophylaxis in transplant patients who are on MMF, data in MG remains lacking. We report two elderly seropositive MG patients who developed cytomegalovirus (CMV) enteritis and Epstein-Barr virus (EBV) encephalitis while on MMF for 5months and 1year, respectively. Chronic MMF therapy in MG patients may trigger life-threatening infections including CMV and EBV diseases, especially in the elderly. Similar to the practice in transplant patients, viral serology testing and appropriate prophylactic regimen with antiviral agents should be considered, particularly in older MG patients.

Topics: Aged, 80 and over; Antiviral Agents; Cytomegalovirus Infections; Encephalitis, Viral; Enteritis; Epstein-Barr Virus Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Myasthenia Gravis; Mycophenolic Acid; Opportunistic Infections

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cytomegalovirus Infections; Female; Humans; Middle Aged; Mycophenolic Acid; Remission, Spontaneous; Scleroderma, Diffuse

Cytomegalovirus (CMV) infection remains a major problem in recipients with heart transplantation (HTx), because it may play a significant role in the development of cardiac allograft vasculopathy, which is one of the major causes of death after HTx. Valganciclovir (VGC) is effective for the treatment of CMV infection, but is often associated with neutropenia, especially when used with mycophenolate mophetil (MMF). We experienced an HTx recipient with positive CMV antigenemia who suffered progressive neutropenia after administration of VGC. We switched MMF to everolimus (EVL) and assay for CMV antigenemia was constantly negative even after discontinuation of VGC. In all other 14 HTx recipients who received EVL for any reason, we found that assay for CMV antigenemia remained negative throughout the period of EVL administration. Considering the prophylactic effect on CMV, EVL can not only be an alternative to rescue from comorbidity, but might also be indicated earlier especially in CMV-seronegative HTx recipients.

Topics: Adult; Antigens, Viral; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Substitution; Drug Therapy, Combination; Everolimus; Ganciclovir; Heart Transplantation; Heart-Assist Devices; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Neutropenia; Opportunistic Infections; Sirolimus; Valganciclovir

Topics: Adult; Aged; Biopsy; Colitis; Colon; Cytomegalovirus Infections; Female; Gastritis; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Stomach

Topics: Antigens, Viral; Colitis; Colonoscopy; Cytomegalovirus; Cytomegalovirus Infections; Diagnosis, Differential; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Methylprednisolone; Mycophenolic Acid; Nocardia Infections; Opportunistic Infections; Pneumatosis Cystoides Intestinalis; Respiratory Tract Infections

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Cytomegalovirus Infections; Esophageal Diseases; Female; Foscarnet; Humans; Immunocompromised Host; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Ulcer

To describe a case of cytomegalovirus (CMV) viremia and colitis in a patient on mycophenolate mofetil (MMF) monotherapy for birdshot chorioretinopathy.. Case report.. Retrospective chart review.. Treatment with MMF 1.5 g twice daily for 5 years led to leucopenia and a CD4 count of 299, which resulted in active CMV infection.. Treatment with MMF alone may put otherwise immune-competent individuals at risk for opportunistic CMV infection. Greater awareness of this association may allow for better monitoring, earlier detection, and treatment of future cases.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Birdshot Chorioretinopathy; CD4 Lymphocyte Count; Chorioretinitis; Colitis; Cytomegalovirus Infections; Drug Therapy, Combination; Ganciclovir; Humans; Immunosuppressive Agents; Leukopenia; Male; Mycophenolic Acid; Prednisone; Treatment Outcome; Valganciclovir; Viremia

The reasons for kidney allograft failure subsequent to pancreas after kidney (PAK) are multifactorial; therefore, we examined these factors to identify a meaningful risk assessment that could assist in patient selection.. Five transplant centers in New England collaborated for this multiinstitutional retrospective study of 126 PAK transplantation recipients who had a functioning pancreas allograft 7 days after transplantation. Host factors (age at pancreas transplant, gender, body weight, glomerular filtration rate at 3 months pre-PAK and at 3-, 6-, 9-, and 12-month post-PAK, presence of proteinuria, pre- or post-PAK kidney rejection, pancreas rejection, cytomegalovirus disease, and HbA1C at 6-month post-PAK) and transplant factors (time to PAK, use of induction antibody therapy, and combinations of immunosuppressive medications) were assessed in both univariate and multivariate analyses for the primary outcome of kidney allograft failure.. Of the variables assessed, factors associated with kidney allograft loss after PAK include impaired renal function in the 3 months before PAK, proteinuria, the occurrence of a post-PAK kidney rejection episode, and interval between kidney and pancreas transplantation more than 1 year.. In our analysis, post-PAK kidney allograft loss was strongly associated with glomerular filtration rate less than 45 mL/min pre-PAK, K to P interval of over 1 year, pre-PAK kidney rejection episode, and pre-PAK proteinuria. Diabetic candidates for PAK with any of these conditions should be counseled regarding the risk of post-PAK renal transplant failure.

Topics: Adult; Antilymphocyte Serum; Body Weight; Cytomegalovirus Infections; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Predictive Value of Tests; Proteinuria; Renal Replacement Therapy; Risk Assessment; Time Factors; Treatment Failure; Treatment Outcome

Cytomegalovirus (CMV) infection is not only a common complication after liver transplantation but also a significant contributing factor to morbidity and mortality. We investigated whether preemptive therapy can prevent CMV syndrome or tissue-invasive CMV disease in an endemic area. Preemptive therapy was initiated when more than 10 positive CMV pp65 antigen-positive cells per 400,000 white blood cells were detected, regardless of clinical manifestations. Intravenous ganciclovir as preemptive therapy was administered daily for 10 to 14 days until negative results were achieved. The incidence of initial CMV antigenemia and CMV syndrome during the posttransplantation period was 49.7% (353/710) and 5.2% (37/710), respectively. One hundred eight-two patients (51.6%) received ganciclovir as preemptive therapy. Patients with CMV antigenemia who received preemptive therapy had high Model for End-Stage Liver Disease score, repeat operation, renal dysfunction, infection, low hemoglobin concentration, low platelet count, low albumin concentration, high international normalized ratio, high total bilirubin value, high aspartate transaminase concentration, and high CMV peak titer. Cytomegalovirus syndrome and tissue-invasive CMV disease were more common in these patients. The survival curve in patients without CMV syndrome was better than that in those with CMV syndrome (P=.000). Patients with more than 10 pp65 antigen-positive cells per 400,000 white blood cells should be treated aggressively with an antiviral agent as preemptive therapy because CMV infection is common in CMV-endemic areas and patients with CMV syndrome demonstrate poor survival rates.

Topics: Adult; Cadaver; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Endemic Diseases; Female; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Korea; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Tissue Donors

Topics: Aged; Colitis; Crohn Disease; Cytomegalovirus Infections; Diagnosis, Differential; Diarrhea; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Mycophenolic Acid; Opportunistic Infections; Weight Loss

The authors report on a 55-year-old female patient after R1 resection of a malignant thymoma with spindle type epithelial cells (WHO type A, Masaoka stage III) referred for further therapy of an ulcerative colitis. At that time, both adjuvant radiation and cytostatic therapy were not applicable due to severe activity of the ulcerative colitis. Under immunosuppressive treatment with azathioprine and steroids, the patient developed cytomegalovirus (CMV) enteritis which was triggered by therapy-induced leukopenia. After a switch from azathioprine to mycophenolatmofetil (MMF) treatment and administration of cidofovir because of nonresponse to ganciclovir and incompatibility of foscarnet sodium (Foscavir), the patient clinically improved. In addition, the patient was treated with immunoglobulins every 3-4 weeks because of antibody deficiency. At present, 3.5 years after R1 resection, the patient still has no clues of a remaining tumor mass under current immunosuppressive therapy. Ulcerative colitis is also in complete remission stage.. This case indicates the very rare features of a syndrome with thymoma and antibody deficiency which was first described by Robert Good. Furthermore, the impact of immunosuppressive therapy and management of opportunistic infections on the course of this disease is obvious.

Topics: Agammaglobulinemia; Antiviral Agents; Azathioprine; Cidofovir; Colitis, Ulcerative; Cytomegalovirus Infections; Cytosine; Enteritis; Female; Humans; Immunization, Passive; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Leukopenia; Middle Aged; Mycophenolic Acid; Neoplasm Staging; Opportunistic Infections; Organophosphonates; Postoperative Complications; Syndrome; Thymectomy; Thymoma; Thymus Neoplasms

An increased incidence and magnitude of leukopenia during concomitant treatment with valganciclovir (VGC) and mycophenolate mofetil (MMF) has been reported.. To evalute the incidence and severity of leukopenia and neutropenia among liver recipients treated with VGC and related factors.. Retrospective analysis of clinical and analytical data related to leukopenia (<3000 leukocytes/mm(3)) and neutropenia (<900 neutrophils/mm(3)) in liver transplant patients who were treated with VGC from 2003 to 2007. We examined the influence of concomitant administration of MMF and development of subsequent infections.. Among 209 liver transplants, 40 treatments with VGC were prescribed in 37 patients (17.7%), 12 of which (30%) were associated with MMF. The patients has an average age of 49.7 +/- 12.7, body mass index (BMI) of 27.28 +/- 5.17, and Model for End-stage Liver Disease Score (MELD) 12.45 +/- 7.5. The daily average dose of VGC was 1440 +/- 446.5 mg and MMF, 1454.5 +/- 350.3 mg. We observed a decrease of 30% in initial leukocyte count (5353.7 +/- 2706.6) and 40% in neutrophil count (3600 +/- 2182.1). With no relationship to total dose or BMI-adjusted dose of VGC nor concomitant administration of MMF. The initial leukocyte count was significantly lower (4411 +/- 1930 vs 6206 +/- 3053; P = .03) and underwent a main drop (2344.7 +/- 1974.3 vs 898.1 +/- 2435.6; P = .04) when leukopenia developed. In the induced neutropenia group, previous leukocyte count (3797.1 +/- 1223.9 vs 5683.9 +/- 2829.3; P = .01), MELD (18.7 +/- 8.8 vs 11.1 +/- 6.6; P = .01), and the creatinine pretreatment (1.44 +/- 0.4 vs 1.09 +/- 0.3; P = .01) were significantly different. Subsequent infections induced by the leukopenia were not observed.. In our series, the concomitant use of VGC and MMF was not associated with a greater incidence of leukopenia and/or neutropenia than VGC administration alone. Previous leukocyte count was associated with them. MELD and renal dysfunction are factors related to severe neutropenia. Leukopenia was not associated with a greater incidence of infections.

Topics: Adult; Antiviral Agents; Body Mass Index; Creatinine; Cytomegalovirus Infections; Female; Ganciclovir; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Leukocyte Count; Leukopenia; Liver Failure; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Retrospective Studies; Risk Factors; Valganciclovir

This study was designed to evaluate the impact of daclizumab monoclonal antibody on early and late kidney graft survival.. From 2007 to 2008, 57 kidney transplant recipients were followed for a mean of 9.3 months. Twenty-three patients received 1 mg/kg daclizumab 24 hours before and 14 days after transplantation. In contrast, 34 patients (controls) did not receive daclizumab. The same immunosuppressive protocol was administered to all participants: oral prednisolone, mycophenolate mofetil, and cyclosporine. Delayed graft function (DGF), acute rejection, prednisolone pulses and/or antithymoglobulin (ATG), cytomegalovirus (CMV) infection, urinary tract infection (UTI), as well as early and late graft function were compared between the two groups.. The mean age in cases and controls was 39.7 and 37.1 years, respectively. The occurrence of DGF was 4% versus 3%; reversible acute rejection, 16% versus 14.5%, and irreversible acute rejection 0% versus 9% (P < .05) for treated versus control groups, respectively. ATG was used in 21% versus 23%, and pulse prednisolone 26% versus 20%, respectively. In case and control groups, the mean creatinine levels were 1.4 mg/dL versus 1.35 mg/dL at discharge. At last follow-up, it was 1.35 mg/dL versus 1.2 mg/dL, respectively. CMV infection occurred in 30% versus 35%, and UTI in 17% versus 19% of treated versus controls, respectively.. The prophylactic administration of daclizumab improved early graft survival and prevented irreversible acute rejection.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Creatinine; Cyclosporine; Cytomegalovirus Infections; Daclizumab; Delayed Graft Function; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisolone; Treatment Outcome; Urinary Tract Infections; Young Adult

Upper gastrointestinal (GI) bleeding remains a significant cause of mortality and morbidity among renal transplant recipients. We retrospectively analyzed the records of patients who received renal transplantations between January 2001 and July 2007 using mycophenolate mofetil (MMF) in their immunosuppressive regimens. The following data were recorded for those subjects with upper GI bleeding during the first month after transplantation (group B, cases): age, sex, acute rejection episodes, pretransplant upper GI endoscopic findings, Helicobacter positivity, and cytomegalovirus (CMV) seropositivity. The same parameters were studied among a group of patients, who did not have a history of upper GI bleeding (group A, controls). A statistical analysis was performed to ascertain potential risk factors. Among 523 patients (311 females, 212 males) of age range 7 to 58 years, 27 (5.2%) had upper GI bleeding: 13 males and 14 females of mean age 44 +/- 12 years. The most frequent endoscopic finding was erosive gastritis (n = 13; 48.1%) followed by duodenal ulcers. Binary logistic regression analysis comparing the 2 groups showed that acute rejection episodes (P = .015) and active CMV infection (P = .046) were the most prominent risk factors for upper GI bleeding during the first month after renal transplantation.

Topics: Adult; Antibodies, Viral; Cytomegalovirus Infections; Female; Gastrointestinal Hemorrhage; Helicobacter Infections; Humans; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies

In old recipients of renal allografts from old donors, benefits of calcineurin-inhibitors (CNI) are curtailed by nephrotoxicity. Intending to improve the outcome of these recipients, we analyzed a CNI-free immunosuppressive regimen consisting of anti-thymocyte globulin (ATG), basiliximab, mycophenolate mofetil (MMF) and steroids. Kidney allograft recipients with low immunological risk (panel reactive antibodies <30%) were eligible for this study. Immunosuppression induction included ATG (4 mg/kg, day 0), basiliximab (20 mg, day 0 + 4) and steroids, followed by MMF (TL 2-6 microg/ml) and steroid maintenance treatment. Patient and graft survival rates respectively were 89.3% and 85.4% (12 months), and 86.6% and 76.8% (24 months). Delayed graft function occurred in 44.6%. S-creatinine at 12 months was 1.85 +/- 0.94 mg/dl. Thirty patients (53.6%) showed biopsy-proven rejections (6x Banff 3, 13x Banff 4I and 16x Banff 4II), 77% of which were steroid-sensitive, 23% required antibody treatment. After 12 months, 83% of the patients had an MMF-based immunosuppression, 43% were CNI-free. Cytomegalovirus (CMV) infections occurred in 28, tissue-invasive disease in three patients. Despite acceptable renal graft survival and function in some of patients with marginal organs, high incidences of rejections and CMV infections suggest the feasibility of CNI-avoidance using an MMF-based protocol only in carefully selected patients.

Topics: Aged; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Calcineurin Inhibitors; Cytomegalovirus Infections; Delayed Graft Function; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Histocompatibility; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins

Cytomegalovirus (CMV) is the most common viral infection after transplantation. Valganciclovir (VGC) is established for prophylaxis and treatment of CMV infections, but leukopenia which appears in 10% to 13% (severe in 4.9%) is the principal side effect. We have recently noted an increased incidence of leukopenia and severe neutropenia among our renal transplant patients and thought to identify the associated factors. We conducted a retrospective analysis of all kidney transplantations performed between January 2005 and December 2006. All patients received mycophenolate mofetil (MMF), tacrolimus, and steroids. VGC was used for targeted prophylaxis and preemptive therapy of CMV infection, with doses adjusted to renal function. Of the 64 patients undergoing renal transplantation 13 (20.3%) developed leukopenia within 3 +/- 2 months after transplantation with severe neutropenia in 5 (7.8%). All patients were on MMF and VGC (VGC 605 +/- 296 mg/d). Leukopenia was significantly associated with simultaneous liver-kidney transplantation and with second kidney transplantations (P < .01). The incidence of leukopenia was higher among patients under VGC since day 1 of transplantation (P = .008) with maximal incidence observed among patients prescribed 900 mg/d as opposed to those on lower doses (P < .01). There was no increase in CMV infection among patients with a low dose of VGC. No patient developed clinical CMV disease. In conclusion, VGC prophylaxis was associated with an increased frequency of leukopenia on MMF-tacrolimus treated patients or regimens. Low-dose VGC for CMV prophylaxis appeared to be as effective as high-dose treatment, and associated less frequently with leukopenia and neutropenia.

Topics: Antiviral Agents; Cytomegalovirus Infections; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Mycophenolic Acid; Neutropenia; Postoperative Complications; Valganciclovir

Anemia remains frequent in the first month following renal transplantation and is a risk factor for cardiovascular accidents. The purpose of this study was to analyze the prevalence of anemia during this period notably among different immunosuppressive treatment groups.. In this study, we entered the patients who had received a renal allograft in our transplant unit from 1993 to 2003, including patients who had received azathioprine (AZA) from 1993 to 1996 and mycophenolate mofetil (MMF) from 1996 to 2003. No patient received rHu-erythropoietin after transplantation during that period. A mathematical model normalized the hemoglobin (Hb) threshold level at which blood transfusion was decided and Hb on admission.. One hundred and eighty-eight patients on AZA and 223 on MMF were included in the analysis. The mean age +/- SD was 41 +/- 12 years in the AZA group, and 45 +/- 12 years in the MMF group (P < .006). Before the transplantation, Hb was higher in the MMF group (11.4 +/- 1.9 vs 10.2 +/- 2 g/dL, P < .0001). After normalization at a threshold level of transfusion of 7 g/dL, transfusions were more frequent among the MMF group (72% vs 48%, P < .0001). Double therapy with MMF (1500 mg/d) + steroids or therapy with MMF (750 mg/d) + tacrolimus + steroids increased the risk of transfusion compared to the AZA group. MMF (750 mg/d) + cyclosporine conferred a similar risk of transfusion compared with the AZA group.. MMF alone or in association with tacrolimus is associated with an increased risk of anemia and transfusion in the immediate posttransplantation period.

Topics: Adult; Anemia; Azathioprine; Blood Transfusion; Cytomegalovirus Infections; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Postoperative Complications; Postoperative Period; Retrospective Studies

Topics: Adult; Antibodies, Viral; Cyclophosphamide; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Disease Susceptibility; Female; Humans; Immunocompromised Host; Immunoglobulin M; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Nephrotic Syndrome; Prednisone

Cytomegalovirus (CMV)-associated leucopenia in heart transplant patients is poorly characterized.. We conducted a retrospective analysis of timing, degree, and type of leukopenia in four groups of patients: cases (n=20); controls (n=20); subclinical early infection (n=21), and subclinical late infection (n=22). In the cases, white blood cells (WBC) count at diagnosis was compared to prediagnosis; and cases were compared to controls. Subclinical cases (early and late) were identified by measurement of CMV DNA in peripheral blood mononucleocytes, and WBC was compared to those of the cases and controls.. First, in human heart transplant recipients the total leukocyte count decreased prior to the time of diagnosis of CMV disease: cases: 5.4+/-2.1 x 10/microL vs. 3.7+/-2.1x10/muL (P<0.01); subclinical early: 8.1+/-4.1 x 10/microL vs. 6.9+/-1.6 x 10/microL (P<0.01). Second, the leukocyte populations most reduced during CMV disease are the neutrophils: 4.4 x 10/microL (78%) to 2.5 x 10/microL (69%) (P<0.05), and monocytes 0.6 x 10/microL (11%) to 0.3 x 10/microL (7.5%) (P<0.05). Third, the reduction in leukocyte count that occurs during CMV disease appears to be independent of immunosuppressive therapy (using cyclosporine A, mycophenolate mofetil, or azathioprine and prednisone). Finally, subclinical CMV infection in stable long-term heart transplant patients without disease is unassociated with a reduction in the leukocyte count.. Aside from implications for early diagnosis, CMV-associated decrease in monocytes is important because viral infections like Epstein-Barr virus cause monocytosis. The absence of leucopenia in subclinical late infections is a new important finding.

Topics: Adult; Aged; Azathioprine; Case-Control Studies; Cohort Studies; Cytomegalovirus; Cytomegalovirus Infections; Diagnosis, Differential; DNA, Viral; Female; Heart Transplantation; Hemoglobins; Humans; Immunosuppressive Agents; Leukocyte Count; Leukopenia; Male; Middle Aged; Mycophenolic Acid; Platelet Count; Retrospective Studies

Mycophenolic acid dose modifications after renal transplantation seem to adversely affect renal allograft outcome. The aim of this retrospective study was to examine the effect of mycophenolic acid dose modifications on renal function 1 year after transplantation and to determine the factors predictive of those dose modifications within the first year after renal transplantation.. All 130 patients at our institution who were treated de novo between January 2002 and April 2003 with either a mycophenolate mofetil-based or an enteric-coated mycophenolate sodium-based therapy and who had a functioning renal allograft 1 month after transplantation were included in this study.. Fifty-seven patients (43.8%) underwent a dose modification during the first year after transplantation. One, 3, 6, and 12 months after transplantation, renal function was significantly improved in the patients who did not receive a dose modification. A mycophenolic acid dose that 1 year after transplantation was less than the initial dose received just after transplantation was an independent factor associated with deteriorating renal function. Sirolimus immunosuppression, Cytomegalovirus infection, and pretransplant lymphocyte counts were independent factors associated with mycophenolic acid dose modifications within the first year after kidney transplantation.. Modification of the mycophenolic acid dose may adversely affect renal function 1 year after transplantation.

Topics: Adult; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Infections; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies

Collaboration of the Dutch centers for kidney transplantation in children started in 1997 with a shared immunosuppressive protocol, aimed at improving graft survival by diminishing the incidence of acute rejections. This study compares the results of transplantations in these patients to those in a historical reference group. Ninety-six consecutive patients receiving a first kidney transplant were treated with an immunosuppressive regimen consisting of mycophenolate mofetil, cyclosporine and corticosteroids. The results were compared with those of historic controls (first transplants between 1985 and 1995, n = 207), treated with different combinations of corticosteroids, cyclosporine A and/or azathioprine. Cytomegalovirus (CMV) prophylaxis was prescribed to high-risk patients in the study group, and only a small proportion of the reference group. The graft survival at 1 yr improved significantly: 92% in the study group, vs. 73% in the reference group (p < 0.001). In the study group 63% of patients remained rejection-free during the first year; in the reference group 28% (p < 0.001). After statistical adjustment of differences in baseline data, as cold ischemia time, the proportion of LRD, preemptive transplantation, and young donors, the difference between study and reference group in graft survival (RR 0.33, p = 0.003) and incidence of acute rejection (RR 0.37, p < 0.001), as the only factor, remained statistically significant, indicating the effect of the immunosuppressive therapy. In the first year one case of malignancy occurred in each group. CMV disease occurred less frequently in the study group (11%) than in the reference group (26%, p = 0.02). As a new complication in 4 patients bronchiectasis was diagnosed. A new consensus protocol, including the introduction of mycophenolate mofetil, considerably improved the outcome of pediatric kidney transplantation in the Netherlands, measured as reduction of the incidence of acute rejection and improved graft survival.

Topics: Adolescent; Adrenal Cortex Hormones; Azathioprine; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Cyclosporine; Cytomegalovirus Infections; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Netherlands; Outcome Assessment, Health Care; Time Factors

To establish guidelines for avoiding the side effects of mycophenolate mofetil (MMF) in renal transplant recipients with tacrolimus (TAC)-based immunosuppression, the relationship between the daily dose of MMF and the occurrence of side effects was analyzed in this study. The frequency of side effects was investigated retrospectively in 28 renal transplant recipients treated with immunosuppression (men 14 : women 14, age: 33.0+/-12.4 years, weight: 50.9+/-10.7 kg). Cytomegalovirus (CMV) infection and diarrhea were the most frequent side effects in the early transplant phase (from transplantation to 3-month biopsy) in the recipients. In 18 recipients, excluding the recipients with risk factors for CMV infection (ABO-incompatible transplantation, donor (+)/recipient (-) CMV serostatus, etc.), no significant correlation was shown between the daily dose of MMF and the occurrence of CMV infection in the two-sample t-test. On the other hand, the daily dose in the diarrhea group (33.2+/-4.3 mg/kg/day, n = 5) was significantly higher than that in the no-diarrhea group at 30 days (28.4+/-3.7 mg/kg/day, n = 23, p < 0.05) and 90 days (25.7+/-4.4 mg/kg/day, n = 21, p < 0.005) after transplantation, respectively. The receiver-operating characteristic (ROC) curve also revealed that the risk of diarrhea increased with a daily MMF dose higher than 30 mg/kg/day. In conclusion, to decrease the risk of diarrhea in the early transplant phase in renal transplant recipients with TAC-based immunosuppression, the daily dose of MMF should not be more than 30 mg/kg/day.

Topics: Adolescent; Adult; Child; Cytomegalovirus Infections; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; ROC Curve

In order to evaluate whether immunosuppressive agents such as mycophenolate mofetil (MMF) and azathioprine would differently influence the outcome of the renal transplants, we prospectively analyzed the incidence of acute rejection episodes, cytomegalovirus infection within the first 6 months following renal transplantation and 5 yr graft survival rate after minimizing influences of donor factors by grafting the same cadaveric donor kidney. There was no significant difference in sex, HLA mismatch, cold ischemic time, and patients' weight between the two groups. Contrary to the previous studies which demonstrated that MMF could lower the incidence of acute rejection episodes and improved graft survival rate, the two groups showed no significant difference in the incidence of acute rejection episodes and 5-yr graft survival rate as well. This discrepancy in these results might explain that donor factors could be important to cadaveric renal transplantation. Thus, we suggest that the influences of donor factors should be considered in further clinical studies of cadaveric renal transplantation.

Topics: ABO Blood-Group System; Adult; Azathioprine; Body Weight; Cadaver; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunophenotyping; Immunosuppressive Agents; Ischemia; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Time Factors; Tissue Donors; Treatment Outcome

There is a paucity of data examining the efficacy of valganciclovir (VGC) for cytomegalovirus (CMV) prophylaxis in kidney transplant patients, particularly with regard to utilization of a risk-stratified dosing regimen. Eighty adult African-American (AA) renal allograft recipients transplanted from November 3, 2001 to May 28, 2003 and followed for 22 +/- 8 months received VGC once daily for 90 d post-transplant dosed according to donor/recipient (D/R) serostatus: high risk (D+/R-) received 900 mg (n = 12); moderate risk (D+/R+, D-/R+) received 450 mg (n = 60); and low risk (D-/R-) received no prophylaxis (n = 8). Thymoglobulin or basiliximab was used for induction, and mycophenolate mofetil, prednisone, and either tacrolimus or sirolimus for maintenance immunosuppression. Only six patients (7.5%) developed symptomatic CMV infection diagnosed by pp65 antigenemia, three in the high-risk (25%) and three in the moderate-risk (5%) group (p = 0.02). All patients were on tacrolimus for at least 3 months prior to diagnosis. There were no cases of tissue-invasive disease, resistance to treatment, or recurrence. D+/R- serostatus was the only significant independent predictor for CMV infection using multivariate analysis (odds ratio 10.5; p = 0.04). Thymoglobulin induction was not associated with CMV infection. None of 43 patients who were exposed to sirolimus for >30 d developed CMV infection, vs. six of 37 who were not (p = 0.006). We conclude that VGC dosed according to D/R serostatus provides safe and effective CMV prophylaxis in AA renal allograft recipients.

Topics: Adult; Aged; Antibodies, Monoclonal; Antigens, Viral; Antilymphocyte Serum; Antiviral Agents; Basiliximab; Black or African American; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Ganciclovir; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Phosphoproteins; Prednisone; Recombinant Fusion Proteins; Retrospective Studies; Risk Assessment; Serologic Tests; Sirolimus; Tacrolimus; Valganciclovir; Viral Matrix Proteins

In nonheart-beating donor (NHBD) kidney transplants, immunosuppressive management is difficult mainly because of the high incidence of acute tubular necrosis. This has meant that since the start of our NHBD transplant program, several immunosuppression regimes have been used. The aim of this retrospective study was to evaluate the results obtained over 7 years using different treatment protocols. A total of 172 consecutive NHBD transplants performed between April 1996 and December 2002 were treated as follows: G-I (n = 21), cyclosporine (8 mg/kg/day) plus azathioprine plus steroids; G-II (n = 65), low-dose cyclosporine (5 mg/kg/day) plus mycophenolate plus steroids; G-III (n =17), low-dose tacrolimus (0.1 mg/kg/day) plus mycophenolate plus steroids; and G-IV (n = 69), daclizumab plus low-dose tacrolimus plus mycophenolate plus steroids. Delayed graft function rates were 76.2%, 72.3%, 76.5%, and 42%, respectively, for the four groups (P = 0.000). Rejection-free patient rates were 76.2%, 46.2%, 35.3%, and 71% (P < 0.001). Vascular rejection rates were 19%, 30.8%, 52.9%, and 18.8%, (P = 0.025). Two-year graft survival was 71.4% in group I, 95.4% in group II, 94.1 in group III, and 93.8% in group IV (P =0.004). Patient survival was worse in group I (75.2% in group I, 100% in group II, 100% in group III, and 96.7% in group IV at 2 years; P < 0.001). The use of daclizumab and low-dose tacrolimus could be effective at lowering the incidence of delayed graft function in NHBDT, with no negative repercussions on acute rejection.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Creatinine; Cyclosporine; Cytomegalovirus Infections; Daclizumab; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Lipid Metabolism; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Steroids; Survival Rate; Tacrolimus; Tissue Donors

Although most of the published papers had not found increase in the incidence of CMV disease in kidney transplant recipients treated with mycophenolate mofetil (MMF), we had feeling from everyday practice that after its introduction number of patients with CMV disease has increased. To test this hypothesis, we performed retrospective analysis of our database, comparing the incidence of CMV disease in patients treated with azathioprine (AZA) and patients treated with MMF. CMV disease was defined as CMV antigenemia (positive CMV pp65 determined by ELISA test) plus any of the following: decrease leucocytes or platelets, increased transaminases, increase in serum creatinine. The azathioprine treated group (AZA group) included 280 patients (132 female) treated for 17,672 months with AZA + Cyclosporine A (CyA) + steroid, or AZA + steroid, while the MMF group included 219 patients (112 female) treated for 5079 months with MMF + CyA + steroid, or MMF + steroid. There was no difference in acute rejection episodes between the AZA and the MMF group. The AZA group had 51 CMV disease episodes (1 episode per 346.5 treatment months), and the MMF group experienced 43 episodes (1 per 118.1 months) (P < .01). Mean onset of CMV disease was 32.65 +/- 47.69 (SD) months after transplantation in the AZA group, and 3.72 +/- 4.43 in the MMF group. There was no difference between two treatment groups regarding the donor-recipient CMV status mismatch. Despite having the increased incidence of CMV disease, MMF group had less severe disease compared to AZA group with decrease in leukocyte count in 11.6% vs 15.7% of episodes, decrease in platelet count in 20.9% vs 21.6%, elevation of transaminases in 18.6% vs 29.4% respectively, and finally increase in serum creatinine greater than 20% in 51.2% in MMF vs 74.5% in AZA group. Five patients from the AZA group experienced CMV pneumonitis with the mortality rate of 80%. Only one patient from the MMF group had CMV pneumonitis, and he survived. According to our results, patients treated with MMF have increased risk for development of CMV disease. However, the disease course is less severe, and less frequently accompanied with deterioration of renal function in comparison to the AZA group.

Topics: Adrenal Cortex Hormones; Azathioprine; Cadaver; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Time Factors

The impact of a prednisone-free immunosuppressive regimen was evaluated in simultaneous pancreas-kidney (SPK) recipients. Patient and graft survivals, rejection rates and the incidence of CMV disease were determined. Two hundred consecutive SPK transplant recipients received tacrolimus-based immunosuppression with (n = 100) or without (n = 100) chronic prednisone therapy. Patients were induced with lymphocyte depleting antibodies or IL-2 receptor blockers and received prophylactic antiviral therapy. Patient and graft survivals and rejection rates were not statistically significantly different between treatment groups. Two-year cumulative incidence of CMV in recipients in the prednisone-free protocol was reduced (7.2% vs. 16%; p = 0.15). Considering only recipients at highest risk (D+/R- or D+R+), incidence of CMV disease in the prednisone-free group (n = 61) compared to the steroid-treated group (n = 48) was reduced from 36% to 18% (p < 0.05). Multivariate analysis confirmed the independent effect of prednisone treatment on the incidence of CMV (RR 2.3; p = 0.04). In the prednisone-free protocol, incidence of CMV was less frequent in recipients receiving induction with Campath versus rabbit antilymphocyte globulin (2.4% vs. 12.6%; p = 0.14). Eliminating prednisone immunotherapy did not adversely affect outcomes and was associated with a reduced rate of CMV in SPK recipients of organs from sero-positive donors.

Topics: Adolescent; Adult; Antibiotic Prophylaxis; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prednisone; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus

We investigated relationships between cytomegalovirus (CMV) seropairing and CMV prophylaxis on graft outcome in recipients of solid organ transplants. Transplants carried out from 1985 to 2002 and reported to the Collaborative Transplant Study were analyzed. In cadaver kidney recipients, CMV prophylaxis was significantly associated with improved graft survival only in the seronegative-recipient/seropositive-donor combination (at 3 years: 79.4% with prophylaxis vs. 73.5% without prophylaxis; RR 0.80, p < 0.0001). Among patients who had a functioning graft at 1 year, significantly fewer patients who received CMV prophylaxis received rejection treatment in the preceding year (26.3%), compared with patients who did not receive prophylaxis (32.4%) (p = 0.0001), suggesting an inhibitory effect of CMV prophylaxis on acute rejection. Significant improvements in graft survival after CMV prophylaxis were found also in CMV-negative recipients of CMV-positive heart, and lung or heart-lung transplants, but not liver transplants. The age of the recipient had a differential effect on graft and patient survival after CMV prophylaxis. Use of antilymphocyte antibodies or mycophenolate mofetil was not associated with an enhanced CMV effect on graft outcome. These results may contribute to a better understanding of the influence of pretransplant CMV serology on the effect of CMV prophylaxis.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antigens, Viral; Antilymphocyte Serum; Antiviral Agents; Child; Child, Preschool; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Middle Aged; Mycophenolic Acid; Organ Transplantation; Survival Rate

Aspergillus infection is a rare but devastating complication following organ transplantation with high mortality rate. Aspergillus fumigatus is the most common cause of invasive aspergillosis. This fungus is present in the environment worldwide. Aspergillus infection is mainly acquired by inhalation of spores and several nosocomial infections in transplant recipient have been associated with construction work at hospitals. Risk factors for invasive aspergillosis include administration of steroid boluses, history of cytomegalovirus infection, neutropenia and prolonged antibiotic use after transplantation. Successful treatment depends on three factors: early diagnosis, aggressive antifungal therapy and decrease or removal of immunosuppression. Amphotericin deoxycholate has been the standard treatment for many years but lipid preparations for amphotericin are now used due to their significantly fewer adverse effects. A number of new antifungal drugs are now being developed including new azoles such as voriconazol and echinocandin. Invasive aspergillosis has a high mortality rate more than 95% when cerebral dissemination is demonstrated. We report the case of a 47 years old woman who received a cadaveric renal graft and developed pulmonary aspergillosis with fulminant cerebral dissemination two months later. The diagnosis of pulmonary aspergillosis was by culture isolation obtained from bronchioalveolar lavage. Removal of immunosuppresive agents and liposomal amphotericin B therapy were started shortly after admission. Brain CT scan performed on the 12th day showed cerebral dissemination. The recipient died two days later. Our patient had several risk factors such as the administration of steroid boluses and cytomegalovirus infection. Invasive aspergillosis must be always included in the differential diagnosis of fever and pulmonary disease in the renal transplant recipient.

Topics: Amphotericin B; Aspergillosis; Aspergillus fumigatus; Cross Infection; Cyclosporine; Cytomegalovirus Infections; Fatal Outcome; Female; Fever; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Liposomes; Lung Diseases, Fungal; Middle Aged; Mycophenolic Acid; Neuroaspergillosis; Neutropenia; Polycystic Kidney, Autosomal Dominant; Prednisone; Risk Factors

Mycophenolate mofetil (MMF) is a more potent immunosuppressive drug than azathioprine or mizoribine in combination with cyclosporine (CsA) and steroids. Recently, basiliximab (BA), an interleukin-2 receptor antagonist, has become available in Japan. The purpose of this study was to evaluate the efficacy of an extremely low CsA dose immunosuppressive protocol with MMF versus MMF plus BA after renal transplantation (RTx).. Between September 2001 and March 2003, we performed 79 RTx with CsA-based immunosuppression, including nine from cadavers and 70 from living donors with 15 ABO-incompatible RTx. Immunosuppression consisted of methylprednisolone (MP), CsA and MMF (group 1; n = 24) versus added BA during the induction phase (group 2; n = 55). In group 2, MP was withdrawn on postoperative day 14. Supplementary MP, muromonab-CD3, or gusperimus was administered if rejection was suspected clinically or diagnosed by biopsy.. The incidence of biopsy-proven acute rejection (AR) was significantly higher among group 1 than group 2 patients (P < .05). CsA C2 levels in group 1 were significantly higher than group 2 at each time (P < .01). The incidence of infection was comparable. Patient and graft survival rates in group 1 were 100% and 100%; in group 2, they were 98% and 98%, respectively.. The short-term results of RTx were favorable in both the MMF, and the MMF plus BA immunosuppression. In addition, BA significantly reduced the number of AR episodes. Early steroid withdrawal in recipients receiving BA induction was not associated with an increased risk of AR.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Postoperative Complications; Recombinant Fusion Proteins; Retrospective Studies; Tissue Donors

The present report describes use of nucleic acid sequence-based amplification (NASBA) technology to detect pp67 mRNA of cytomegalovirus (CMV) in transplant patients in India. In our experience, pp67 mRNA assay was an accurate, rapid, and effective diagnostic tool to detect active CMV disease in 40.7% (50/123) of symptomatic transplant cases. This assay also allowed us to monitor CMV therapy. As part of the immunosuppressive regimen mycophenolate mofetil was found to increase the risk of developing CMV disease. All positive cases with this assay were subjected to antiviral therapy, with complete remission of the disease. At our center CMV NASBA assay has become the gold standard for the diagnosis of CMV disease in transplant patients.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Humans; Immunosuppressive Agents; India; Kidney Transplantation; Mycophenolic Acid; Phosphoproteins; Risk Factors; RNA, Messenger; Self-Sustained Sequence Replication; Time Factors; Viral Matrix Proteins

Topics: Acute Disease; Antiviral Agents; Azathioprine; Bile Duct Diseases; Bile Ducts, Intrahepatic; Cytokines; Cytomegalovirus Infections; Drug Therapy, Combination; gamma-Globulins; Ganciclovir; Graft Rejection; Heart Transplantation; Hepatitis, Viral, Human; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Models, Biological; Mycophenolic Acid; Postoperative Complications; Ursodeoxycholic Acid

Mycophenolate mofetil (MMF) is a drug which decreases the frequency of renal transplantation rejection. However, cytomegalovirus infections are a common feature of this treatment leading the physicians to prescribe antiviral prophylactic drugs like valacyclovir. During this association, neutropenia occur and the cause of this adverse effect is difficult to define. This report presents a case of neutropenia in a woman treated with MMF and valacyclovir. As the duration of the valacyclovir treatment exactly corresponds to the neutropenia duration, and the mycophenolate trough levels increased with the neutrophil count, the responsibility of this neutropenia was ascribed to valacyclovir. However, an examination of the literature for cases of neutropenia led to the suspicion of an interaction between MMF and valacyclovir. Mycophenolate may increase intracellular concentrations of valacyclovir up to haematotoxic levels. This mechanism may explain the interaction and further research is needed to confirm this interaction.

Topics: Acyclovir; Antiviral Agents; Cytomegalovirus Infections; Drug Interactions; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Neutropenia; Valacyclovir; Valine

Recent reports have demonstrated the efficacy of interleukin-2-receptor blockers in lowering the incidence of early acute rejection. The present study aimed to test the hypothesis that the use of daclizumab induction (DAC) plus low-dose tacrolimus, mycophenolate mofetil, and steroid diminishes the incidence of delayed graft function (DGF) in renal transplants from non-heart-beating donors (NHBD).. We compared the incidence of DGF and rejection in 185 renal transplants from NHBD treated as follows: Group-I: quadruple sequential therapy with antithymocyte globulin, cyclosporine, azathioprine, and steroids (n=22); Group-II: cyclosporine (8 mg/kg/d) plus azathioprine plus steroid (n=26); Group-III: low-dose cyclosporine (5 mg/kg/d) plus mycophenolate mofetil plus steroid (n=68); Group-IV: low-dose tacrolimus (0.1 mg/kg/d) plus mycophenolate mofetil plus steroid (n=17); and Group-V: DAC plus low-dose tacrolimus plus mycophenolate mofetil plus steroid (n=43).. The incidences of DGF were 72.7% in Group-I, 73.1% in Group-II, 69.1% in Group-III, 76.5% in Group-IV, and 44.2% in Group-V. Acute rejection was higher in Group-IV.. The combination of DAC, low-dose tacrolimus, mycophenolate mofetil, and steroids is effective in lowering the incidence of DSF in NHBD kidney transplant recipients without any increase in acute rejection.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cytomegalovirus Infections; Daclizumab; Drug Therapy, Combination; Graft Rejection; Graft Survival; Heart Arrest; Humans; Immunoglobulin G; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Tissue Donors

Estimation of anti-CMV-IgG and anti-CMV-IgM is considered a relatively inexpensive screening tool of CMV status. The aim of study was to estimate how the immunosuppressive protocol influence serum anti-CMV IgG and IgM concentration in renal graft recipients and to estimate the adequacy of anti-CMV-IgG concentration and anti-CMV-IgM index as screening parameters of active CMV disease in patients receiving different immunosuppression. The study group consisted of 33 patients with clinical signs of CMV disease who received one of three types of immunosuppression: (1) azathioprine (Aza) + cyclosporine (CyA) + prednisone (Pr), 20 patients; (2) mycophenolate mofetil (MMF) + CyA + Pr, eight patients; tacrolimus (Tac) + MMF, five patients. Patients were enrolled when the pp65-antigen (pp65) of PBL was positive within 1 to 5 months after transplant (75 patients tested). The IgM-i in the Aza + CyA + Pr group was higher than in MMF + CyA + Pr group (2.73 + 1.8 vs 1.08 +/- 1.07, P =.021). The IgM-i in the Aza + CyA + Pr group was higher than in Tac + MMF (2.73 +/- 1.8 vs 0.78 +/- 0.69; P =.014). There was no difference in IgM-i between MMF + CyA + Pr and Tac + MMF. There was no difference in relative increase of IgG-c among all groups but there was a difference in relative increase of IgM-i between Aza + CyA + Pr and MMF + CyA + Pr groups (6.7 +/- 9.4 vs 2.3 +/- 5.9; P =.007) and between Aza + CyA + Pr and MMF + Tac groups (6.7 +/- 9.4 vs 0.6 +/- 0.54; P =.003). Immunosuppressive protocols including MMF exert an inhibitory influence on B-cell response and synthesis of anti-CMV-IgM. It makes the anti-CMV-IgM index an inadequate rough screening diagnostic parameter of active CMV disease.

Topics: Antibody Formation; Azathioprine; B-Lymphocytes; Cytomegalovirus Infections; Humans; Immunoglobulin G; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Prednisone; Retrospective Studies

To evaluate the efficacy of quadruple therapy with cyclosporine (CsA), methotrexate (MTX), mycophenolate mofetil (MMF) and low-dose antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis in unrelated donor hematopoietic stem cell transplantation (URD-HSCT).. Thirteen patients with leukemia received URD-HSCT, of whom 11 had HLA genotypes and 2 had mismatch for 1 genetic locus. Another 11 leukemia patients all serologically matched underwent related donor (RD)-HSCT. Total body irradiation (TBI) plus cyclophosphamide (CTX) was adopted in 19 cases and modified BuCY conditioning regimen (hydroxyurea, busulfan, Ara-C, Cyclophosphamide ) in the other 5 cases. All the patients received CsA+MTX protocal for GVHD prophylaxis, and in those undergoing URD-HSCT, additional MMF and low-dose ATG were used.. The incidence and severity of regimen-related toxicity differed little between unrelated and related transplantation. Acute GVHD (aGVHD) occurred in 46.2% of the patients undergoing URD- HSCT and in 55.6% of those with RD-HSCT, respectively. Four patients had chronic GVHD (cGVHD), in the 7 ones who could be followed up after URD-HSCT; 6 of the 9 patients with RD-HSCT developed cGVHD postoperatively. One patient with URD-HSCT died of hemorrhagic cystitis and another with RD-HSCT died of cytomegalovirus (CMV) pneumonia. The at one-year disease-free survival rate was 87.5% and 90.9% in patients with unrelated and related transplantation respectively. Significant difference was not noted in the positivity rate of CMV antigen between the patients receiving URD-HSCT or RD-HSCT.. CsA+MTX in combination with MMF and low-dose ATG may decrease the incidence and severity of aGVHD without increasing transplant-related mortality or CMV infection.

Topics: Adolescent; Adult; Antilymphocyte Serum; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Male; Methotrexate; Middle Aged; Mycophenolic Acid

Background. In this retrospective single center study we have evaluated the relation between the immunosuppressive regimen and the incidence and characteristics of cytomegalovirus (CMV) infection in the setting without CMV prophylaxis from 1989 through 1998. Methods. All (470) first cadaveric renal transplantations in nonsensitized (PRA < 60%) patients were analyzed. Immunosuppression consisted of cyclosporine A (Sandimmune) and prednisolone from 1989 through 2-1993 (S; 189 patients), of cyclosporine microemulsion (Neoral) and prednisolone from 3-1993 through 5-1997 (N; 200 patients) and of mycophenolate mofetil, Neoral and prednisolone from 5-1997 until 1998 (M; 81 patients). The CMV pp65-antigenemia was measured routinely at least once weekly from day 10 till 12 weeks after transplantation or until pp65-antigenemia became negative. No CMV-prophylaxis was given. Results. By changing from Sandimmune to Neoral and by adding mycophenolate mofetil, respectively, we observed a higher frequency of especially secondary CMV infections (S vs. N vs. M, respectively, 28 vs. 50 vs. 63%, P = 0.026; S vs. N, P = 0.027; S vs. M, P = 0.015; and N vs. M, n.s). The CMV infections lasted longer (median duration antigenemia S vs. N vs. M, respectively, 3 vs. 5 vs. 7 weeks, P = 0.0003; S vs. N, P < 0.002; S vs. M, P < 0.001; and N vs. M, P < 0.05). Viral load was higher in M (median maximal pp65-antigenemia S vs. N vs. M, respectively, 19 vs. 14.5 vs. 73, P < 0.01; S vs. N, n.s.; S vs. M, P < 0.001 and N vs. M, P < 0.01). Conclusions. The use of Neoral and the addition of mycophenolate mofetil caused significant changes in the incidence, duration and viral load of CMV infections.

Topics: Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Phosphoproteins; Postoperative Complications; Prednisolone; Retrospective Studies; Viral Load; Viral Matrix Proteins; Viremia

Topics: Creatinine; Cyclosporine; Cytomegalovirus Infections; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Retrospective Studies; Time Factors; Treatment Failure

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: Adult; Age Factors; Antigens, Viral; Antilymphocyte Serum; Cytomegalovirus Infections; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tissue Donors

Topics: Adolescent; Antibodies, Monoclonal; Basiliximab; Child; Child, Preschool; Creatinine; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Follow-Up Studies; Ganciclovir; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Prednisone; Recombinant Fusion Proteins; Safety; Tacrolimus; Time Factors

New antiviral agents and practice guidelines have been implemented to address cytomegalovirus (CMV) infection in organ transplantation. We hypothesized that such measures would reduce rates of symptomatic CMV infection, CMV disease, and CMV seroconversion and associated complications in renal transplant and simultaneous pancreas-kidney transplant recipients. We analyzed the impact of CMV in 1,424 renal transplant and simultaneous pancreas-kidney transplant recipients, transplanted at our center between January 1, 1994 and June 30, 1999. Most patients received quadruple sequential immunosuppression with high-dose acyclovir (800 mg four times daily) for 12 weeks as prophylaxis. High-risk patients (donor CMV-positive/recipient CMV-negative) received ganciclovir (500 to 1,000 mg three times daily) beginning in 1998, again for 12 weeks. One hundred and one renal transplant (9.0%) and 40 simultaneous pancreas-kidney transplant (13.4%) recipients experienced symptomatic CMV infection or CMV disease. Donor CMV-positive/recipient CMV-negative patients had the greatest rates of CMV infection or CMV disease (25.2%; P = 0.0001 versus all other categories). The impact of CMV on outcomes was evaluated in a proportional hazards model. Symptomatic CMV infection or CMV disease increased the risk for subsequent rejection (relative risk, 2.11; P = 0.003) and non-CMV infection (relative risk, 2.24; P = 0.001). To determine if the effects of ganciclovir were masked by pre-1998 data, CMV infection and CMV disease rates for ganciclovir-treated patients (n = 62) were censored at 1 year and compared with acyclovir-treated patients (n = 287). Ganciclovir was associated with trends toward lower rates of infection and disease. It also delayed the time to infection or disease. Serologic testing in high-risk patients also showed late seroconversion, with 20% of patients seroconverting by 6 months, 12 weeks after the prophylaxis period. These data suggest that despite better prophylaxis strategies, CMV remains an important pathogen in renal transplant and simultaneous pancreas-kidney transplant recipients. This finding may require reassessment of prophylaxis strategies and the development of alternative or novel anti-CMV regimens.

Topics: Acyclovir; Adult; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Administration Schedule; Female; Ganciclovir; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Transplantation Conditioning

Topics: Antilymphocyte Serum; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Reoperation; Retrospective Studies; Risk Factors; Sirolimus; Steroids; Treatment Failure

Mycophenolate mofetil (MMF) is increasingly used for prophylaxis and therapy of GVHD in allogeneic stem cell transplantation. In some recent reports of use of MMF in solid organ transplantation a high incidence of CMV disease has been described. We evaluated the frequency and course of active CMV infection in patients who received MMF compared to those who did not receive MMF after allogeneic stem cell transplantation. We retrospectively analyzed 48 adult patients who consecutively underwent unmanipulated allogeneic bone marrow (n = 15) or peripheral stem cell transplantation (n = 33) from HLA-compatible family donors (n = 30) or unrelated donors (n = 18) from February 1997 to September 2000 at our institution. Only patients who were evaluable for the first 100 days were included in this analysis. Sixteen patients received MMF post transplant (MMF+). CMV-antigenemia was monitored by CMV-pp65 antigen. CMV-antigenemia occurred in 14 patients and was virtually only observed in CMV-IgG+ recipients (13/23, 56%). CMV-IgG+/MMF+ patients developed a higher incidence of CMV-antigenemia (8/9, 89%) compared to the CMV-IgG+/MMF- patients (5/14, 35%; P < 0.05). Moreover, five of six patients with persistent or recurrent CMV-antigenemia received MMF. No patient in either group developed CMV disease or died of CMV-related complications. In multivariate analysis including MMF treatment, unrelated vs related donor, GVHD, CMV-serostatus of the donor and stem cell graft type, only MMF treatment was found to be a significant risk factor for both overall and complicated CMV infection.

Topics: Adult; Antigens, Viral; Cytomegalovirus Infections; Drug Evaluation; Graft vs Host Disease; Humans; Immunosuppressive Agents; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Retrospective Studies; Risk; Stem Cell Transplantation; Transplantation, Homologous

The incidence of CMV infection in pediatric renal transplant recipients has increased as immunosuppression levels deepen following the use of newer immunosuppressive agents. It has been thought that 3-5 months of anti-CMV prophylaxis offers sufficient protection for these patients. We present a case of late-onset fatal CMV disease in a pediatric renal transplant recipient who received prolonged anti-CMV prophylaxis while on "quadruple" immunosuppression with daclizumab, mycophenolate, tacrolimus, and prednisone. Our case has prompted us to reassess CMV surveillance, prophylaxis, and immunosuppression levels in our pediatric renal transplant patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child, Preschool; Cytomegalovirus Infections; Daclizumab; Drug Therapy, Combination; Fatal Outcome; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Care; Prednisone; Risk Factors; Tacrolimus

Mycophenolate mofetil (MMF) has been increasingly used after liver transplantation (LT) in adults. We report our preliminary experience with MMF as rescue therapy after pediatric LT.. A total of 19 children received MMF for 21 indications. Median age at LT was 30 months (range 7-149). The median initial oral dose of MMF was 23 mg/kg/day (range 12-43) orally. Median follow-up after initiation of MMF therapy was 642 days (range 229-1606).. 1) EFFICACY: MMF was indicated for rejection or insufficient immunosuppression in 16 cases, with normalization of both liver function tests and liver histology in 10 (62%). MMF was successfully used in one patient with post-LT immmune hepatitis and one patient with corticodependence. In three patients with renal function impairment, MMF allowed reduction of cyclosporine A or tacrolimus blood levels, without subsequent rejection. 2) Tolerance: Six patients (32%) experienced eight side effects, mainly gastrointestinal and hematological, which resolved after cessation of MMF in five cases and dose reduction in three. One case of posttransplant lymphoproliferative disease (PTLD) occurred under MMF therapy (5.2%). Four patients had EBV primary infection, while under MMF therapy, without subsequent PTLD. Three patients had CMV primary infection, and five CMV reactivation, under MMF therapy. Seven remained asymptomatic, and one presented with CMV enteritis.. These preliminary results suggest that MMF is an effective and safe immunosuppressant in pediatric LT recipients. Its use is hampered by frequent gastrointestinal and hematological side-effects. MMF does not seem to increase the risk of PTLD nor CMV disease.

Topics: Burkitt Lymphoma; Child; Child, Preschool; Cytomegalovirus Infections; Female; Graft Rejection; Herpesvirus 4, Human; Humans; Liver Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Salvage Therapy

Mycophenolic acid (MPA), the active form of the immunosuppressive agent mycophenolate mofetil (MMF), was found to markedly potentiate the anti-herpesvirus activity of the novel anti-herpesvirus agent A-5021, (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine. For example, at a concentration of 1 microg/ml MPA, the activity of A-5021 against HSV-1, HSV-2 and TK(-) HSV-1 increased by a factor of 130, 14 and > or = 189, respectively. Exogenously added guanosine reversed this potentiating effect, suggesting that a depletion of the endogenous dGTP pools enhanced the inhibitory effect of the 5'-triphosphate metabolite of A-5021 on the viral DNA polymerase. The combined effect of A-5021 and MPA on the growth of uninfected Vero cells was additive rather than synergistic. The combination of topically applied MMF (5%) with 0.05% A-5021 (a subactive concentration) completely protected against HSV-1-induced cutaneous lesions in hairless mice, whereas therapy with either compound used alone had no protective effect. These findings may have implications for those transplant recipients that receive MMF as (part of) their immunosuppressive therapy and that develop intercurrent herpesvirus infections for which they need treatment.

Topics: Animals; Antiviral Agents; Cell Line; Chlorocebus aethiops; Cytomegalovirus; Cytomegalovirus Infections; Drug Synergism; Drug Therapy, Combination; Guanine; Herpes Simplex; Herpesvirus 1, Human; Humans; Mice; Mice, Hairless; Microbial Sensitivity Tests; Mycophenolic Acid; Vero Cells

The impact of tacrolimus (TAC), mycophenolate mofetil (MMF) and steroid immunosuppression on cytomegalovirus (CMV) infection in combination with ganciclovir prophylaxis in simultaneous kidney-pancreas transplantation (SKPT) has not been well studied.. A retrospective analysis was made of 75 SKPTs performed between 1 January 1996 and 7 January 1999. All patients received ganciclovir for 3 months, but CMV donor (D)+ / recipient (R)- patients received ganciclovir for 6 months.. 16/74 (22%) were CMV D+/R-, 25 (33%) D+/R+, 16 (22%) D-/R+, and 17 (23%) D-/R- (1 patient with unknown donor serology was excluded). The mean time to CMV infection was 198 days post-transplant. The incidence of either CMV infection or tissue invasive CMV disease was 16/74 (22%), including 9 (12%) with CMV infection and 7 (10%) CMV disease. The one-year patient, kidney, and pancreas graft survival rates were 91%, 89%, and 83%, respectively. The mean follow-up was 29 months (minimum of 12 months). CMV infection was not associated with an increased incidence of graft failure or mortality. The D+/R- group had the highest incidence of CMV infection (44%) compared with the other serologic groups (17%, P=0.02). Concurrent CMV and rejection occurred more frequently in the D+/R- than the other serologic groups (25% vs. 7%, P=0.03). The D-/R- group had the best outcomes, with no CMV infection, improved kidney graft survival at the end of follow-up (82% vs. 72%, P=0.04) and the highest event-free survival (no CMV infection, rejection, or graft loss) when compared to the other groups (76% vs. 33%, P<0.01).. Compared to previous studies, ganciclovir prophylaxis delayed the onset and reduced the severity of CMV infection in patients receiving TAC, MMF, and steroids. Despite ganciclovir prophylaxis, CMV seronegative patients receiving CMV D+ organs had worse outcomes than seronegative recipients receiving CMV D- organs.

Topics: Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibiotic Prophylaxis; Antiviral Agents; Cytomegalovirus Infections; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Pancreas Transplantation; Prednisone; Severity of Illness Index; Survival Analysis; Tacrolimus

Ganciclovir, which is used to treat cytomegalovirus (CMV) infection, has been shown in rodent models to abolish CMV-mediated chronic cellular damage and endothelial cell proliferation; when associated with mycophenolate mofetil (MMF), it has been shown to increase its anti-herpes virus activity. This study tested the hypothesis that kidney graft recipients who received antirejection prophylaxis with MMF and who were treated with ganciclovir for a declared CMV disease could be protected from chronic graft dysfunction. Investigated was the impact of ganciclovir-treated CMV diseases in consecutive first kidney recipients according to their immunosuppressive therapy. The azathioprine (Aza)-treated group (Aza group) included 319 patients. The MMF-treated group (MMF group) included 126 patients. CMV disease was clinically defined and confirmed by virological proof of CMV infection and was treated for at least 14 d with ganciclovir. Despite having the same incidence (21.6% in the Aza group versus 24.6% in the MMF group) and severity, CMV disease was significantly associated with graft loss independent of acute rejection episodes or other factors when tested in a Cox proportional model in the Aza group only (P < 10(-4)). It was shown for the first time that patients whose CMV disease is treated with ganciclovir while they are on MMF therapy are protected from the long-term deleterious consequences of CMV disease on graft survival, independent of acute rejection. It is suggested that the enhanced anti-herpes virus activity of ganciclovir by MMF could contribute to this reported effect, which may represent a significant contribution of MMF efficacy to graft survival.

Topics: Acute Disease; Adolescent; Adult; Aged; Antiviral Agents; Azathioprine; Chronic Disease; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Ganciclovir; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications

In the paper the authors tried to identify factors influencing prevalence and clinical course of cytomegalovirus (CMV) infection in kidney transplant patients. The study was performed in the group of 100 patients after cadaveric kidney transplant followed up in the Chair and Department of Nephrology, Collegium Medicum, Jagiellonian University in Krakow. CMV infection was demonstrated to occur more frequently and significantly earlier in the patients administered prednisone, cyclosporin A and mycophenolate mofetil, compared to the group treated with standard triple-drug-therapy (prednisone, cyclosporin A, azathioprine) or double-drug-therapy (prednisone, cyclosporin A). Higher serum levels of cyclosporin A did not increase prevalence of the infection but urged its onset. Risk for CMV infection was however higher in the group of patients treated for acute rejection episodes, especially with antilymphocyte preparations. No differences were shown in the immunological matching within HLA-A, -B and -DR antigens between the patients without features of CMV Infection and those treated for its active form. The infection occurred significantly more frequently in the recipients with HLA-A1 antigen than in those with HLA-A9 and -DR7. In patients with delayed transplanted kidney functioning, time of the infection onset and a number of its episodes were similar to the remaining population, however severity of the clinical course positively correlated with the duration of acute tubular necrosis (ATN). CMV infection occurred slightly more frequently in patients requiring transfusions compared to those not administered blood preparations. Among patients with AB blood type, active CMV infection occurred statistically less frequently, whereas in those with other blood types percentage of patients with/without CMV infection were comparable.

Topics: Adolescent; Adult; Aged; Azathioprine; Cadaver; Cyclosporine; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prevalence; Risk Factors; Time Factors; Transplantation, Homologous

The emergence of a resistant strain is a theoretical threat after extensive use of antiviral drugs. We report the emergence of a ganciclovir-resistant cytomegalovirus (CMV) strain in a kidney transplant recipient during oral ganciclovir maintenance treatment. The patient was treated by oral ganciclovir for 2 months after successful treatment of CMV primary infection by intravenous ganciclovir. He developed a new episode of CMV infection with no clinical response to intravenous ganciclovir. The CMV isolate exhibited both phenotypic and genotypic resistance to ganciclovir. The CMV isolate was constituted of a mixture of strains, with and without a mutation at codon 460 of the UL97 gene. The clinical condition improved when mycophenolate mofetil (MMF) was discontinued, and a short course of intravenous globulin was added to ganciclovir. The emergence of the CMV strain could be secondary to more potent immunosuppression provide by MMF or subtherapeutic level obtained during oral ganciclovir treatment. We believe that ganciclovir resistance must be part of the differential diagnosis when a patient relapses or fails to respond to ganciclovir treatment.

Topics: Administration, Oral; Adult; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Microbial; Drug Therapy, Combination; Ganciclovir; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Recurrence

The impact of cytomegalovirus (CMV) infection post-transplantation is in part influenced by the degree of immunosuppression. While mycophenolate mofetil (MMF) does not increase the overall incidence of CMV infection, we have questioned whether or not it increases its severity. Using a case control study design in which 29 renal transplant patients developed CMV disease [17 (59%) of which received azathioprine (AZA) and 12 (41%) received MMF], increases in the frequency of organ involvement with CMV (58 vs. 18%; p = 0.03) and in the number of organs involved with CMV were noted in the MMF versus the AZA group (2.0 vs. 1.0; p = 0.015). These results indicate that the increased immunosuppressive activity of MMF impacts the morbidity of CMV infection, thus warranting the use of effective anti-CMV preventive regimens while patients are treated with MMF.

Topics: Acyclovir; Adult; Antiviral Agents; Azathioprine; Case-Control Studies; Cohort Studies; Cytomegalovirus Infections; Enteritis; Female; Ganciclovir; Hepatitis, Viral, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Mycophenolic Acid; Pneumonia, Viral; Risk Factors; Severity of Illness Index

Mycophenolate mofetil (MMF) is increasingly used for immunosuppression after renal transplantation (RTx). The aim of our study was to investigate if the use of MMF has resulted in an increase in the frequency and severity of primary cytomegalovirus (CMV) infections.. Retrospective study of adult RTx patients who were CMV seronegative and who received a kidney of a CMV seropositive donor in the period 1992-1997 (n=84). Twenty-four of these patients were treated with MMF (in combination with cyclosporin and prednisone; MMF+) and the other 60 were the control group (cyclosporin and prednisone; MMF-). No CMV prophylaxis was given. CMV infection was defined as CMV seroconversion of IgG antibodies. CMV disease was defined as CMV infection and fever in combination with one or more of the following: leukocytopenia, thrombocytopenia, elevated alanine aminotransferase, or histological evidence of tissue invasive disease.. The incidence of primary CMV infections was similar in both groups (MMF+, 75%; MMF-, 63%). CMV disease was more frequent in the MMF+ group than in the MMF- group (67 vs 30%, P<0.05). In the patients with CMV disease, the use of MMF did not affect severity of symptoms, frequency of tissue invasive disease, or frequency or duration of treatment with ganciclovir.. Addition of MMF to the immunosuppressive therapy after RTx did not result in an increase of primary CMV infections.However, these CMV infections led more often to CMV disease in patients treated with MMF than in those without MMF.

Topics: Adult; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Retrospective Studies

Ganciclovir prophylactic regimens have been shown to be effective in renal transplant recipients at risk for primary (donor seropositive/recipient seronegative) and secondary (recipient seropositive) cytomegalovirus (CMV) disease. However, in addition to serologic factors, the type and intensity of the administered immunosuppression is a strong risk factor for CMV disease. Since January 1995, we have utilized a potent immunosuppressive protocol selectively in recipients at high risk for immunologic graft loss, defined as retransplant recipients, recipients with delayed graft function, non-Caucasian recipients, and recipients suffering from acute rejection. Between January 1995 and December 1996, 110 consecutive renal transplants were performed in recipients who were either CMV seropositive or received an allograft from a CMV-seropositive donor. All recipients received ganciclovir prophylactic therapy for 3 months post-transplant. Group I (N = 43) consisted of recipients at high-immunologic risk for graft loss as defined above. These recipients were treated with an intense anti-rejection immunotherapeutic regimen consisting of Cellcept, Neoral, and prednisone, with the frequent addition of antilymphocyte antibody therapies and intravenous methylprednisolone. The remaining 67 recipients (group II) were treated with a less intense immunotherapeutic regimen consisting of azathioprine, Neoral, and prednisone. The incidence and severity of CMV disease and the patient and allograft survival were compared. The incidence of CMV syndrome was greater in group I (28%) compared with group II (7%), and was statistically significant (p < 0.05). The 1-yr patient and graft survival were similar, 95 and 91%, respectively, for group I compared with 97 and 97%, respectively, for group II. These data suggest that 3 months of ganciclovir prophylactic therapy is significantly less effective for the prevention of CMV disease in renal transplant recipients at high risk for acute rejection treated with an intense immunotherapeutic regimen. These data suggest that more effective prevention of CMV disease in these high-risk recipients will require the addition of other anti-viral agents, such as immunoglobulin preparation to the prophylactic regimen.

Topics: Adult; Antilymphocyte Serum; Antiviral Agents; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Ganciclovir; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Methylprednisolone; Mycophenolic Acid; Prednisone; Risk Factors

Topics: Adult; Antibodies, Viral; Antigens, Viral; Antilymphocyte Serum; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin M; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polymerase Chain Reaction; Postoperative Complications; Reproducibility of Results

Despite their well-known side-effects, corticosteroids (Cs) are currently used after kidney transplantation. Avoidance of Cs may improve patient quality of life and eventual long-term survival. We report on a regimen using antithymocyte globulin (ATG) and mycophenolate mofetil (MMF) for induction, and cyclosporin (CsA) plus MMF for maintenance treatment of recipients of primary kidney transplantation.. We studied 11 consecutive, non-sensitized renal transplant patients (nine cadaver and two living donors). Initial immunosuppression consisted of ATG (1.5 mg/kg/day, i.v.) given for 10 days and MMF (1.0 g/b.i.d.). CsA (8 mg/kg, in two divided doses) was started on post-operative day 11. Cs were only allowed in the case of MMF discontinuation, for the treatment of acute rejection, and in the event of recurrence of the primary glomerulonephritis.. All patients completed the entire 10-day ATG course. Main side-effects included fever (>38 degrees C) and serum sickness, observed in 73 and 27% of the patients respectively. The incidence of acute rejection was 27% (three of 11 patients). In two patients with acute rejection, serum sickness was concomitantly diagnosed and renal histology was partially compatible with immune-complex disease. The remaining patient had two episodes of low-grade rejection. All rejection episodes were rapidly reversed. Two patients (18%) were treated with ganciclovir for cytomegalovirus (CMV) infection. Two patients (18%) are currently receiving Cs for recurrence of the native glomerulonephritis and two rejection episodes respectively. All patients are currently alive with functioning kidneys (average follow-up of 8.4 months; average creatinine level of 128 micromol/l).. This pilot study suggests that ATG induction in combination with MMF and delayed introduction of CsA, in the absence of Cs, is not well tolerated in recipients of kidney transplants. An earlier introduction of calcineurin inhibitors and/or a shorter course of ATG may reduce the incidence of fever and serum sickness secondary to ATG.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Antilymphocyte Serum; Biopsy; Cyclosporine; Cytomegalovirus Infections; Drug Administration Schedule; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Pilot Projects; Postoperative Complications

Topics: Adult; Antiviral Agents; Creatinine; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Oliguria; Postoperative Complications; Prednisolone; Ureter; Ureteral Diseases; Urothelium

The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described.. Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described.. Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposi's sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant.. We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.

Topics: Adolescent; Adult; Cytomegalovirus Infections; Female; Glycated Hemoglobin; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Tacrolimus; Transplantation, Homologous

Mycophenolate mofetil (MMF) has been shown to have promise in short-term liver transplantation graft rescue studies. The purpose of this study was to evaluate the long-term efficacy and safety of MMF in liver transplant patients who had failed cyclosporine (CsA)-based conventional immunosuppression.. Nineteen orthotopic liver allograft recipients were converted from azathioprine to MMF in combination with CsA and prednisone in this prospective, open-labeled, single-center, graft rescue, pilot study. Six patients were taken off CsA when MMF was initiated. A 4-year patient follow-up is reported here. Patients were considered to have failed CsA-based immunosuppression either for refractory rejection, chronic rejection, or severe CsA neurologic toxicity.. Twelve patients had complete histologic resolution, two had partial resolution, and three had worsening of their rejection. Thirteen patients had a complete biochemical response; one had a partial response and four had worsening of their rejection. Two patients had no histologic and one no biochemical follow-up. Of the six patients treated with MMF and prednisone alone, four had complete resolution of rejection without recurrence. The majority of adverse reactions were gastrointestinal [nausea and/or vomiting (n=5); diarrhea (n=8); gastritis, duodenitis, or esophagitis (n=4); and ulcers (n=2)] or bone marrow suppressive [leukopenia (n=9), anemia (n=6), and thrombocytopenia (n=5)].. MMF seems to be an effective alternative immunosuppressive in patients failing CsA-based conventional therapy. MMF may be of particular benefit in patients who do not tolerate CsA or tacrolimus. The long-term safety profile is similar to that of other immunosuppressives.

Topics: Adult; Cytomegalovirus Infections; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft vs Host Disease; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Treatment Outcome

Abdominal pain occurs frequently in renal transplant recipients receiving mycophenolate mofetil (MMF) therapy. The cause of this abdominal pain has not been fully elucidated, but may involve local irritation, as well as inhibition of rapidly dividing cells of the gastrointestinal (GI) tract. This milieu of inflammation and added immunosuppression is conducive to activation of cytomegalovirus (CMV). We therefore sought to find the prevalence of active CMV in patients presenting with abdominal pain on maintenance MMF therapy. All patients receiving a renal transplant at our center from March 1, 1997, to September 1, 1997, were studied. Any patient presenting with midepigastric pain for greater than 3 days underwent esophagogastroduodenoscopy (EGD) with biopsy. CMV was diagnosed by the presence of inclusion bodies and immunohistochemical studies. Ten patients presented with persistent midepigastric pain; nine of these patients had evidence of GI CMV. Patients who were CMV negative and received an allograft from CMV-positive donors and those with leukopenia were at significantly increased risk for the development of abdominal pain. In our study population, the majority of patients on maintenance MMF therapy who presented with persistent midepigastric pain had evidence of active CMV infection in the upper gastrointestinal tract.

Topics: Abdominal Pain; Adult; Cytomegalovirus Infections; Digestive System; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Logistic Models; Male; Mycophenolic Acid; Prevalence; Risk Factors

Mycophenolate mofetil (MMF) is a new immunosuppressive drug used in combination with cyclosporin A (CsA) or tacrolimus and prednisone to prevent rejection of renal allografts in both adult and pediatric recipients. It has been shown in several large studies that MMF significantly decreases the incidence of acute rejection in adults and has acceptable adverse effects. In this retrospective study, we compare the incidence of adverse events between pediatric and adult renal allograft recipients. Twenty-two children and 37 adult renal allograft recipients were included in the study. The initial dose of MMF was 1.5 g b.i.d. for the adult patients and ranged from 15 to 30 mg/kg/d for the pediatric patients. All patients received p.o. acyclovir as prophylaxis for cytomegalovirus (CMV). The two groups were similar regarding gender distribution and graft source. Acute rejections occurred in 10 of the 22 pediatric patients (45%) and in nine of the 37 adults (24%), p = NS. The incidence of infections was similar in both groups except for the occurrence of CMV (n = 5), which was seen only in adults. The incidence of GI symptoms was significantly higher in the pediatric population (54.5% vs. 21.6%; p = 0.02). Significant weight loss was seen more often in the smaller pediatric patients (weight < or = 15 kg) compared to the larger pediatric patients, 60% vs. 11.7%, p = 0.05. Among the patients who had significant GI symptoms 50% of the adults and 75% of the pediatric recipients required either dose reduction or, most commonly, discontinuation of the MMF. The need to discontinue MMF was significantly higher in the pediatric patients, especially in those that weighed less than 15 kg. We suggest the possibility that the optimum dose, dosing interval or preparation of MMF has not yet been established for pediatric patients. One should therefore monitor pediatric patients closely, especially the small ones, to avoid significant nutritional problems and other adverse GI events.

Topics: Acute Disease; Acyclovir; Adolescent; Adult; Age Factors; Antiviral Agents; Body Weight; Child; Child, Preschool; Cytomegalovirus Infections; Data Interpretation, Statistical; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Male; Mycophenolic Acid

Topics: Antigens, Viral; Antilymphocyte Serum; Azathioprine; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Fluorescent Antibody Technique, Indirect; Heart Transplantation; Humans; Immunosuppressive Agents; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies

It has been well documented that a regimen of mycophenolate mofetil (MMF), cyclosporine (CsA), and prednisone (Pred) reduces the incidence of acute rejection in renal transplant recipients, as compared with previous regimens based on azathioprine (AZA), CsA, and Pred. In the general renal transplant patient population, immunosuppressive regimens that include MMF are usually well tolerated. It is not clear whether this holds true for older transplant recipients, who may be more susceptible to complications from the greater immunosuppression conferred by MMF.. We retrospectively analyzed our geriatric renal transplant population (age >60 years, 1990-1998) and compared a cohort of 46 patients treated with AZA, Pred, and CsA to a cohort of 45 patients treated with MMF, Pred, and CsA.. There were no significant differences between the groups with regard to pretransplantation demographics. Patient and graft survival during the first year was not significantly different between the groups. During the first year of follow-up, we observed 27 infections requiring hospitalization in 15 patients in the MMF-treated group as compared with 10 infections in 7 patients in the AZA-treated group. A Cox proportional hazard model accounting for the above mentioned covariates isolated MMF versus AZA as a significant risk factor for the occurrence of serious infectious events (all: P<0.01; cytomegalovirus, fungal: P<0.01).. We conclude that an immunosuppressive regimen of MMF, CsA, and Pred seems to be correlated with an increased incidence of infectious adverse events as compared with AZA, CsA, and Pred in elderly patients.

Topics: Aged; Azathioprine; Cohort Studies; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Mycoses; Postoperative Complications; Prednisone; Retrospective Studies; Survival Rate; Time Factors

Topics: Adult; Antiviral Agents; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Ganciclovir; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Retrospective Studies; Risk Factors; Survival Rate; Treatment Failure

Topics: Antilymphocyte Serum; Creatinine; Cyclosporine; Cytomegalovirus Infections; Drug Monitoring; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Steroids; Time Factors; Urinary Tract Infections

Three multicenter studies have shown that the addition of mycophenolate mofetil (MMF) to an immunosuppressive regime consisting of cyclosporin A (CSA) and prednisone (PRED) decreases the incidence of acute rejection episodes when compared with azathioprine (AZA) or placebo (1-3). In those patients receiving 3 g/d of MMF, the highest dose used in the studies, there was a trend towards an increased incidence of cytomegaloviral sepsis (CMV). We postulated therefore that MMF may represent an independent risk factor for the development of CMV infection in patients receiving renal allografts and MMF at our institution. Having altered the triple drug regime from CSA, AZA (2-2.5 mg/kg/d) and PRED to CSA, MMF (2 g/d) and PRED in July 1995, we elected to study all patients undergoing kidney transplantation for the 33-month period January 1994-September 1996, by undertaking a case control analysis to determine independent risk factors for the development of CMV infection, as defined by CMV viremia or tissue-invasive CMV. Three CMV disease-free control patients were matched to each case, these patients having been randomly selected from the entire pool of patients in the observation period. There were 31 CMV case patients and 102 control patients. Univariate analysis indicated that gender, a concomitant pancreas transplant, acute rejection and CMV seropositivity in the donor were risk factors. However, multivariate analysis indicated that only acute rejection and donor CMV seropositivity were independently linked (p < 0.05) to CMV disease in this sample. Specifically, the odds ratio (OR) for CMV disease between MMF and AZA was 1.0 (95% confidence interval (CI): 0.46-2.18). Therefore, in this case control study we find no evidence that MMF at a dose of 2 g/d is an independent risk factor for primary CMV viremia or tissue invasion in renal allograft recipients.

Topics: Adult; Azathioprine; Case-Control Studies; Cyclosporine; Cytomegalovirus Infections; Female; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Male; Mycophenolic Acid; Opportunistic Infections; Prednisone; Risk Factors

40 recipients of first cadaver kidney transplants were given perioperative donor vertebral bone marrow infusions (DBMC), compared with 100 controls who did not receive donor bone marrow. The immunosuppressive regimen included OKT3, Tacrolimus, and steroid maintenance therapy, and, in some patients, newly introduced mycophenolate mofetil. This report describes the 24-mo actuarial follow-up and several immunological monitoring studies including sequential measurements of donor bone marrow lineage subset chimerism by the recently reported PCR-flow assay. This is a sensitive in situ PCR detection system for donor versus recipient histocompatibility genes as well as cell surface CD epitope markers using flow cytometry. The results indicate (a) the stabilization of the donor CD3+ and CD34+ cells in recipient peripheral blood at levels below 1% between 6 mo and 1 yr postoperatively, with a 10-fold higher level of donor cell chimerism of these lineages in recipient iliac crest marrow; (b) significantly lower levels of chimerism in peripheral blood up to 6 mo postoperatively in patients who had early acute (reversible) rejection episodes compared with those who did not; (c) a higher degree of chimerism seen in patients who were class II MHC HLA DR identical with their donors; (d) the identification of a high proportion of the donor bone marrow derived CD3 dimly staining subset of T cells (to which regulatory functions have been ascribed) in recipient peripheral blood and especially in recipient bone marrow; and (e) an unexpectedly increased susceptibility to clinically significant infections (primarily viral), and even death in the DBMC-infused group, compared with controls, but no graft losses because of rejection in the DBMC-infused group. Mixed lymphocyte culture assays showed a trend toward a greater number of nonspecifically low reactors in the DBMC group, as well as a greater number of nonspecifically high reactors in the controls (P = 0.058). The autologous mixed lymphocyte reaction also indicated a trend towards nonspecific immune activation in the DBMC group. Finally, anti-cytomegaloviral IgG antibody reactivity was significantly inhibited in the DBMC group 4-6 mo postoperatively (P = < 0.05). In the controls, there were no donor cell lineages detected by PCR-flow in the peripheral blood. These rather unexpected findings, indicating a more depressed cellular and humoral immune capacity in the DBMC cadaver kidney transplant recipients in this relatively ea

Topics: Adolescent; Adult; Aged; Antigens, CD34; Bone Marrow Transplantation; Cadaver; CD3 Complex; Child; Cytomegalovirus Infections; Flow Cytometry; Follow-Up Studies; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; HLA-DR Antigens; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Polymerase Chain Reaction; T-Lymphocyte Subsets; Tacrolimus; Transplantation Chimera

Topics: Colitis; Colon; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Prednisone; Serologic Tests

PHARMACOKINETIC STUDIES. Eleven patients undergoing orthotopic liver transplantation (OLT) received mycophenolate mofetil (MMF) orally for prevention of rejection. Additional immunosuppressives used were cyclosporine (CsA) and steroids. Doses ranged from 3.5 to 4.5 g/d. Pharmacokinetic studies were performed between 11 d and 6 months after OLT. The Cmax and Tmax for mycophenolic acid (MPA) were 3.6-35.2 micrograms/mL and 0.5-4 h, respectively, and did not significantly change over 6 months. Oral clearance of MMF (dose of MMF/area under the curve for MPA) between d 11 and d 17 was significantly lower compared with d 21. Biliary diversion did not affect clearance. RESCUE THERAPY. Twenty-three patients with steroid- and OKT3-resistant acute rejection were converted to MMF (2-3.5 g/d) at a mean of 20 wk after OLT. Twenty-one patients responded, 14 with resolution of rejection and 7 with improvement. Sixteen patients remained on the drug. Eight patients had 14 infections, with cytomegalovirus (CMV) being the most common. The most common adverse events were diarrhea (4 patients) and leukopenia (3 patients). Four patients with chronic rejection all failed to improve after conversion to MMF. DOSE ESCALATION STUDIES--PRIMARY THERAPY. Seventeen patients received 3.5-5.0 g of MMF per d orally with reduced-dose CsA and prednisone as primary prophylaxis of rejection after OLT. Target CsA levels were 125-175 (whole-blood high-performance liquid chromatography). Two patients were terminated from the study for possible study drug-related reasons: pancreatitis in one and unsatisfactory response in the other. Gastrointestinal side effects were the most common (10 patients), including gastritis, esophagitis, and duodenal ulcer. Two patients developed leukopenia and/or pancytopenia. Of 5 culture-proven infections, 2 were CMV. After 3 months of follow-up, 7 of 17 patients had no rejection. Of 10 patients with rejection, 7 were treated with pulse steroids and 3 required OKT3. DUAL THERAPY WITH MMF AND STEROIDS. Four patients with rejection and unacceptable toxicity secondary to either CsA or FK-506 were treated with MMF 2-4 g/d and 20 mg of prednisone. After 325-500 d of follow-up, 3 had resolved their rejection episode and 1 had recurrent rejection and was restarted on low-dose CsA. CONCLUSION. MMF is a promising new immunosuppressive agent for both treatment of established rejection and primary rejection prophylaxis after OLT. More studies are needed to define its role furth

Topics: Administration, Oral; Adolescent; Adult; Cyclosporine; Cytomegalovirus Infections; Diarrhea; Female; Follow-Up Studies; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Leukopenia; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Recurrence

Topics: Clinical Trials as Topic; Costs and Cost Analysis; Cytomegalovirus Infections; Diarrhea; Drug Interactions; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Mycophenolic Acid; Organ Transplantation; Transplantation Immunology