tacrolimus and Cytomegalovirus-Infections

The aim of this meta-analysis is to explore the effect of IL-2RA vs rATG on the rate of acute rejection, post-transplant infections, and graft as well as patient's survival in standard- and high-risk renal transplant patients receiving tacrolimus-based maintenance immunotherapy.. Random effects model was the method used for identifying risk difference. Confidence interval including the value 1 was used as evidence for statistically significant risk difference. Heterogeneity was assessed using Der Simonian analysis. Heterogeneity was evident at the level of P value < 0.1 RESULTS: The random effects model showed no significant differences in both acute rejection rates between IL-2RA and rATG induction therapies with relative risk of 1.24 graft survival with relative risk 0.90. Patient survival also did not demonstrate any significant difference with a relative risk of 1.19. Random effects for CMV infection showed a lesser tendency for CMV infection in IL-2RA group compared to ATG group the with a relative risk of 0.73.In subgroup analysis, the random effects model for acute rejection rates in high-risk transplants showed a higher risk of acute rejection in the IL-2RA group compared to rATG (relative risk equals 1.55) In standard-risk transplants, there were no significant differences between both groups with relative risk equals 1.02 CONCLUSIONS: This meta-analysis revealed no significant difference in patient and graft survival when using IL-2RA vs rATG with the tacrolimus-based maintenance immunosuppression era. However, subgroup analysis showed less incidence of rejection in high-risk renal transplant recipient's population using rATG compared to IL-2RA.

Topics: Antilymphocyte Serum; Basiliximab; Cytomegalovirus Infections; Daclizumab; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Transplantation; Maintenance Chemotherapy; Models, Statistical; Receptors, Interleukin-2; Survival Rate; Tacrolimus

Resistant cytomegalovirus (R-CMV) is an emerging problem in the renal transplantation population. The most frequent CMVs are high-resistance mutations (UL97 gene).. We describe our experience in management of R-CMV after renal transplant at our center (2012-2016).. We encountered 3 cases of R-CMV infection after renal transplant (all primary infections). All 3 patients received induction therapy with corticosteroids, tacrolimus, and mycophenolate mofetil. The first patient (basiliximab induction, preemptive CMV) developed CMV replication on day +53, which responded poorly both to standard-dose valganciclovir (vGCV) and high-dose ganciclovir (GCV) (creatinine clearance [CrCl] >70 mL/min; vGCV 900 mg twice daily for 50 days and GCV 7.5 mg/kg twice daily for 8 days). Hematologic toxicity occurred. The R-CMV test was positive and foscarnet (FOS) was initiated (90 mg/kg twice daily for 21 days). The second patient presented CMV infection (day +30, thymoglobulin induction, CMV prophylaxis), which was not controlled with the high dose (CrCl 23 mL/min; GCV 3.5 mg/kg twice daily and vGCV 900 mg twice daily), resulting in severe neutropenia. R-CMV was detected and FOS initiated (FOS 50 mg/kg twice daily for 7 days and 50 mg/kg every 2 days for 13 days). The third patient's infection occurred on day +22 (basiliximab induction, preemptive CMV). Standard-dose vGCV was uneffective (CrCl >70 mL/min, vGCV 900 mg twice daily) and it did not respond to the high dose (GCV 7.5 mg/kg twice daily and vGCV 2700 mg/d). Moderate hematologic toxicity occurred. R-CMV was diagnosed and FOS treatment begun (FOS 70 mg/kg per day for 2 weeks).. Resistant CMV infection may be severe due to viral infection and side effects of high-dose antiviral treatment. We presented 3 cases requiring the use of FOS in the absence of response or toxic effects from the usual treatment, with an optimal sustained response (temporary in case 2) and without serious side effects.

Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Antiviral Agents; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Multiple, Viral; Female; Foscarnet; Ganciclovir; Humans; Induction Chemotherapy; Kidney Transplantation; Male; Middle Aged; Mutation; Postoperative Complications; Recombinant Fusion Proteins; Tacrolimus; Valganciclovir; Virus Replication

A 31-year-old woman with systemic lupus erythematosus and lupus nephritis was treated with prednisone and immunosuppressants. After her lupus nephritis symptoms worsened, both high-dose steroid and cyclophosphamide pulse therapy were administered. The patient developed an intestinal perforation, and laparoscopic Hartmann's surgery was performed on the sigmoid colon. Serum Cytomegalovirus (CMV) antigen C7HRP was detected, and the patient was diagnosed with CMV colitis and underwent a colon resection. Severe hematochezia continued despite ganciclovir administration, and the patient underwent laparoscopic total colectomy and partial ileostomy. CMV enteritis should be considered in patients treated with prednisone and immunosuppressants and those who have abdominal pain and hematochezia. Immunocompromised patients with intestinal perforation due to CMV enteritis have a poor prognosis. We report a case with along with the results of a literature review.

Topics: Adult; Antiviral Agents; Betamethasone; Colitis; Colon, Sigmoid; Cytomegalovirus; Cytomegalovirus Infections; Enteritis; Female; Ganciclovir; Gastrointestinal Hemorrhage; Humans; Immunocompromised Host; Immunosuppressive Agents; Intestinal Perforation; Lupus Nephritis; Prednisolone; Tacrolimus

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

Diarrhea is a frequent but overlooked complication of kidney transplantation. Diarrhea is repeatedly neglected, often considered by patients and clinicians an unavoidable side effect of immunosuppressive regimens. It is, however, associated with a significant impairment in life quality. Severe and chronic posttransplant diarrhea may lead to dehydration, malabsorption, rehospitalization, immunosuppression, noncompliance, and a greater risk of graft loss and death. There is thus a need to optimize and standardize the management of posttransplant diarrhea with consistent diagnostic and therapeutic strategies. A recent study has suggested that the increased sensitivity of molecular tools might help in early pathogen identification and guidance of antimicrobial treatment. Most bacterial and protozoan infections are readily curable with appropriate antimicrobial agents; cryptosporidiosis and C. difficile infections may however be complicated by relapsing courses. In addition, identification of enteric viral genomes in stool has further reduced posttransplant diarrhea of unknown origin. Chronic norovirus-related posttransplant diarrhea, arising from the interplay of the virus and immunosuppressive drugs, has emerged as a new challenge in the field. Prospective and controlled studies are necessary to evaluate the efficacy and safety of innovative anti-norovirus therapeutics, as well as optimal immunosuppressive regimens, to enable viral clearance while preventing rejection and donor-specific antibody formation. This review seeks to provide a basis for the design of future clinical prospective studies.

Topics: Caliciviridae Infections; Clostridioides difficile; Cryptosporidiosis; Cytomegalovirus Infections; Diarrhea; Humans; Kidney Transplantation; Norovirus; Tacrolimus; TOR Serine-Threonine Kinases

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

Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus-associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non-renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment-related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy-proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis-dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post-HCT PVAN are provided.

Topics: Antiviral Agents; BK Virus; Cystitis; Cytomegalovirus Infections; Fatal Outcome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatorenal Syndrome; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Failure, Chronic; Lymphoma, Follicular; Male; Middle Aged; Myelodysplastic Syndromes; Nephritis, Interstitial; Polyomavirus Infections; Postoperative Complications; Reoperation; Tacrolimus; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous

The objective of this study was to conduct a meta-analysis of randomized controlled trials (RCT) to compare the effectiveness and safety of induction with and without antithymocyte globulin (ATG) combined with cyclosporine/tacrolimus-based immunosuppression in renal transplantation.. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane controlled trials register, Cochrane Renal Group Specialized Register of RCTs, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality, and then extracted data. Data were extracted for patient and graft survival, acute rejection, the incidence of Banff, cytomegalovirus (CMV) infection, leukopenia, and thrombocytopenia. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence intervals (CI).. Four RCTs (892 patients) were identified. The data showed that induction with ATG was more beneficial than no induction with ATG to reduce the incidence of chronic rejection (RR 0.70; 95% CI, 0.57-0.84) and acute rejection within 6 months (RR 0.68; 95% CI, 0.49-0.96) and at 12 months (RR 0.67; 95% CI, 0.50-0.89) as well as Banff II episodes (RR 0.53; 95% CI, 0.30-0.91), but increased the incidences of CMV infection (RR 1.61; 95% CI, 1.27-2.04) and leukopenia (RR 3.88; 95% CI, 2.80-5.38) and thrombocytopenia (RR 2.92; 95% CI, 1.77-4.04). There was no statistical difference between patient or graft survival rates at 6 and 12 months, as well as the incidences of Banff III or Banff I after transplantation.. Based on available data induction with ATG was more efficient to reduce the rate of acute rejection episodes and chronic rejection responses after renal transplantation, but was associated with increased side effects, particularly CMV infections. It is important to provide the most benefit for an individual patient.

Topics: Adult; Antilymphocyte Serum; China; Confidence Intervals; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Randomized Controlled Trials as Topic; Registries; Risk; Survival Rate; Survivors; Tacrolimus

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

Topics: Cyclosporine; Cytomegalovirus Infections; Diabetes Mellitus; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Tacrolimus

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

Thrombotic microangiopathy (TMA) is a rare but potentially lethal complication encountered in solid organ and bone marrow transplant recipients, requiring rapid recognition, diagnosis, and initiation of therapy. Several potential causes have been identified in this setting, including viral infections and medications.. We report a case of TMA in a liver transplant recipient with active cytomegalovirus (CMV) gastritis. A 41-year-old female presented 3 months after liver transplantation with a 5-week history of nausea, vomiting, anorexia, and diarrhea. CMV serology was donor seropositive and recipient seronegative (D+/R-). The immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and prednisone. Evaluation revealed CMV viremia with a high viral load and intravenous ganciclovir was started. A decline in hemoglobin and platelets with an increase in lactate dehydrogenase (LDH) warranted hematologic evaluation, which revealed findings consistent with microangiopathic hemolytic anemia. Ganciclovir and tacrolimus were discontinued. Intravenous immunoglobulin was administered and daily plasmapheresis was initiated. As the patient's blood counts and LDH started to improve, ganciclovir was cautiously reinstituted. The patient's gastrointestinal symptoms gradually resolved and her blood counts continued to improve with prolonged plasmapheresis (a total of 23 plasmapheresis sessions). Tacrolimus and possibly CMV infection were suspected to be the cause for her TMA, and cyclosporine was substituted.. TMA is an important entity in the differential diagnosis of acute hemolytic anemia in liver transplant recipients. Many cases seem to be medication-induced. However, in treatment-resistant or relapsing cases, a possibility of concomitant CMV infection should be considered.

Topics: Adult; Cytomegalovirus; Cytomegalovirus Infections; Female; Gastritis; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Liver Transplantation; Purpura, Thrombotic Thrombocytopenic; Tacrolimus

Clinical liver transplantation became an established therapy of end-stage liver disease since the first at least medium-term successful liver transplantation in 1967. Clinical studies have played a major part in improving peri- and postoperative therapy in liver transplantation. In this article clinical studies of major impact are presented. Main topics are studies dealing with immunosuppressants, improvements in surgical techniques, viral infections and tumor diseases. Controlled randomized multicentric studies are rare; most of the studies are unicentric. Further studies in the fields of reducing side effects of immunosuppression, the introduction of monoclonal antibodies and improvement of the therapy of viral hepatitis would be helpful. These studies should be controlled, randomized and multicentric.

Topics: Carcinoma, Hepatocellular; Cyclosporine; Cytomegalovirus Infections; Double-Blind Method; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Multicenter Studies as Topic; Postoperative Complications; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Tacrolimus

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

To describe the incidence of cytomegalovirus (CMV) infection/disease in kidney transplant recipients receiving an mTOR-inhibitor-containing immunosuppressive regimen without prophylactic CMV treatment.. This single-center retrospective cohort analysis included all de novo kidney transplant recipients (09/15/2015-07/31/2017) receiving 3 mg/kg single dose of rabbit antithymocyte globulin induction, tacrolimus, everolimus, and prednisone. Preemptive therapy was initiated only in patients deemed at higher risk for CMV infection: (a) D+/R- CMV patients; (b) after treatment for acute rejection (ARt); and (c) after everolimus discontinuation (EVRd).. Of 230 patients, there were no episodes of CMV disease among 217 (94%) without criteria to initiate preemptive therapy. Of 77 (33.5%) patients initiating preemptive therapy, 13 were D+/R-, 30 were ARt, and 34 were EVRd. The overall incidence of first CMV infection/disease was 6% (46.1% in D+/R-, 13.3% ARt [all patients had also discontinued everolimus], and 11.8% after early [<90 days] EVRd). The incidence of biopsy-proven acute rejection was 5.6%, and median glomerular filtration rate at month 12 was 47 mL/min/1.73m. This study suggests that everolimus-containing immunosuppressive regimen reduces the need for preventive strategies for CMV infection in the majority of kidney transplant recipients, reducing antiviral drug-associated toxicities and healthcare-related expenditures.

Topics: Adult; Antilymphocyte Serum; Brazil; Cytomegalovirus; Cytomegalovirus Infections; Everolimus; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisone; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases

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

There is no consensus on the best immunosuppressive regimen for elderly renal transplant recipients. The objective of this study was to assess cytomegalovirus infection incidence and kidney transplant outcomes in elderly recipients treated with mammalian target of rapamycin inhibitors sirolimus/ tacrolimus at low doses compared with those receiving tacrolimus/mycophenolate sodium.. In this single-center prospective randomized study (Trial Registration No. NCT02683291), kidney transplant recipients over 60 years of age were randomly allocated into 2 groups: tacrolimus-sirolimus (21 patients) and tacrolimus-mycophenolate (23 patients). Cytomegalovirus infection rate and patient survival, biopsy-proven acute rejection, and renal function at 12 months were assessed.. Cytomegalovirus infection rate was higher in the mycophenolate group (60.9%) than in the sirolimus group (16.7%; P = .004). The rates of biopsy-proven acute rejection, patient survival, graft survival, and estimated glomerular filtration rate over 12 months did not significantly differ between groups.. The incidence of cytomegalovirus infection was significantly lower in the sirolimus group. The use of tacrolimus combined with sirolimus in elderly kidney transplant recipients is safe.

Topics: Age Factors; Aged; Biopsy; Brazil; Calcineurin Inhibitors; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Risk Factors; Sirolimus; Tacrolimus; Time Factors; 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

There is no evidence of whether everolimus (EVR) reduces cytomegalovirus (CMV) events in patients receiving steroid-free regimens. Besides, studies evaluating a tacrolimus (TAC) and EVR regimen are limited to 1-year follow-up. In this single-center prospective randomized trial, the incidence of CMV and 3-year efficacy and safety outcomes of EVR were compared to those of mycophenolate sodium (MPS) in a steroid-free regimen based on low-exposure TAC. Both groups received rabbit anti-thymocyte globulin (r-ATG) induction (6 mg/kg) and the steroids were withdrawn at day 7. Maintenance immunosuppression consisted of TAC (4-7 ng/ml until month 3 and 2-4 ng/ml thereafter) plus EVR (3-8 ng/ml) in the EVR group (n = 59); and TAC (4-7 ng/ml during all follow-up) plus MPS (1440 mg) in the MPS group (n = 56). The EVR group presented with a lower incidence of CMV events (18.6% vs. 50%, P = 0.001). No differences were observed in biopsy-proven acute rejection (6.8% vs. 3.6%, P = 0.680),graft loss (0.0% vs. 1.8%, P = 0.487),death (6.8% vs. 1.8%, P = 0.365), or estimated glomerular filtration rate at 36 months (61.1 ± 25.4 vs. 66.3 ± 24 ml/min/1.73 m

Topics: Adolescent; Adult; Aged; Cytomegalovirus; Cytomegalovirus Infections; Everolimus; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Steroids; Tacrolimus; Transplant Recipients; Young Adult

Although tacrolimus (Tac) has immunosuppressive properties and exhibits promising efficacy against graft-versus-host disease (GVHD), little is known about Tac in the prophylaxis of GVHD after HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). In a multicenter randomized controlled trial, 174 patients received haplo-HSCT with GVHD prophylaxis involving short-term Tac (from -8days to +30days) or cyclosporine (CsA). The 100day cumulative incidences of acute GVHD (aGVHD) and grade III-IV aGVHD with the short-term Tac regimen and CsA regimen were 29.1 (19.5-38.7)% vs. 50.0(39.6-60.4)% (p=0.005) and 3.6(0.0-7.5)% vs. 13.5(6.1-20.9)% (p=0.027), respectively. There were no significant differences in the incidences of chronic GVHD (cGVHD), relapse and cytomegalovirus infection. Lymphocyte subset analysis showed that T cells decreased to lower levels on the short-term Tac regimen within 3 months of transplantation. The disease-free survival and overall survival on the short-term Tac and CsA regimens were 59.3 (48.9-69.7)% vs. 55.7 (45.3-66.1)% (p=0.696) and 65.1 (55.1-75.1)% vs. 61.4 (51.2-71.6)% (p=0.075), respectively. Our findings indicate that the short-term Tac regimen for GVHD prophylaxis in patients undergoing haplo-HSCT is associated with a low incidence and slight severity of aGVHD and did not increase the incidence of relapse and cytomegalovirus infection.

Topics: Acute Disease; Adolescent; Adult; Child; Cyclosporine; Cytomegalovirus Infections; Disease-Free Survival; Female; Graft vs Host Disease; Haplotypes; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Lymphocyte Subsets; Male; Middle Aged; Premedication; Recurrence; Survival Rate; Tacrolimus; 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

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in heart transplant (HTx). Our aim was to analyze the rate of CMV infection in HTx patients receiving treatment with cyclosporine (CsA) or tacrolimus (Tac). Ninety-five patients were randomized to receive either CsA (53.7%) or Tac (46.3%). We performed prophylaxis with valganciclovir in patients with the highest risk of CMV infection. We considered CMV infection as an increased viral load or the presence of CMV in histological samples. We analyzed baseline characteristics, CMV infection, and other complications. Event-free rates were calculated using the Kaplan-Meier method. There were no significant differences in baseline characteristics between both groups. CMV infection was detected in 31.6% of patients (in 66.7% due to asymptomatic replication). The group treated with Tac had a lower rate of CMV infection (15.9% vs. 45.1%, p = 0.002) and longer CMV infection-free survival time (1440 vs. 899 d, p = 0.001). No differences were observed in the complications analyzed in both groups. The independent risk factors for infection identified in the multivariate analysis were treatment with CsA and bacterial infections. This was the first study to demonstrate a lower rate of CMV infection in patients treated with Tac vs. those treated with CsA after HTx.

Topics: Adult; Antiviral Agents; Calcineurin Inhibitors; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Survival Rate; Tacrolimus; Valganciclovir

Cytomegalovirus (CMV) infection is one of the most common and important opportunistic infections following kidney transplantation. It causes significant morbidity and mortality. Valganciclovir (VGCV) is the drug of choice for prophylaxis to prevent CMV infection.. We conducted a post-hoc analysis of a randomized controlled trial in 187 kidney transplant recipients to evaluate the impact of VGCV dosing and renal function on the development of CMV infection.. The results demonstrate that the following variables were independent risk factors for the development of CMV infection: high-risk CMV serostatus (donor positive/recipient negative; hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.46-5.28, P = 0.002); anti-thymocyte globulin induction therapy (HR 2.1, 95% CI 1.08-4.07, P = 0.028); higher mean tacrolimus trough concentration (HR 1.4, 95% CI 1.09-1.74, P = 0.007); creatinine clearance <60 mL/min (HR 3.4, 95% CI 1.64-6.85, P = 0.001); and body weight >80 kg (HR 2.1, 95% CI 1.05-4.37, P = 0.037). VGCV dosing was appropriate for most patients, in those who did and did not develop CMV infection. These results strongly suggest that the currently recommended dose adjustments of VGCV dosing based on estimated renal function calculated using ideal body weight may underestimate the renal function of overweight patients and indirectly result in underexposure of overweight patients to VGCV. Based on these findings, further VGCV pharmacokinetic analyses are warranted in kidney transplant recipients with moderate-to-severe renal dysfunction.

Topics: Adult; Aged; Antibodies, Viral; Antilymphocyte Serum; Antiviral Agents; Body Weight; Creatinine; Cytomegalovirus; Cytomegalovirus Infections; Disease-Free Survival; Female; Ganciclovir; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Valganciclovir

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

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

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

This analysis of the Euro-SPK 001 study examined the occurrence and effect of cytomegalovirus (CMV) infection during the first 3 years after simultaneous pancreas-kidney (SPK) transplantation.. In this multicentre study, 205 SPK transplant patients were randomized to immunosuppressive treatment with tacrolimus (n = 103) or cyclosporin microemulsion [(ME), n = 102]. All patients received antibody induction therapy, mycophenolate mofetil and short-term corticosteroids. The choice of CMV prophylaxis and treatment was at the discretion of each investigator.. The overall incidence of CMV infection was 34%, with equal distribution in the tacrolimus and cyclosporin-ME groups. Fewer CMV infections occurred with ganciclovir (22%) than aciclovir (43% P = 0.007) or no prophylaxis (42%, P = 0.008). The rates of CMV infection according to donor and recipient CMV serological status were: D-/R- 11%; D-/R+ (40%, P = 0.004); D+/R+ (37%, P = 0.002); and D+/R- (52%, P<0.001). In the three at-risk subgroups, infection rates were lower among patients receiving ganciclovir (22%) than among those receiving aciclovir or no prophylaxis (64%; P<0.0001). Acute rejection was more common among CMV-infected patients (66 vs 41% without infection, P = 0.001) and in those not receiving ganciclovir prophylaxis. The 3-year actuarial rejection-free survival rate was 61.4% with ganciclovir and 42.2% with no prophylaxis or aciclovir alone (P = 0.002). No differences were observed in actuarial patient, kidney or pancreas survival between CMV and non-CMV infection groups.. Our findings confirm that the incidence of CMV infection is the same in tacrolimus- and cyclosporin-ME-treated SPK recipients. Ganciclovir prophylaxis effectively prevented CMV infection, especially in higher risk groups, and was associated with a reduced incidence of rejection compared with aciclovir/no prophylaxis.

Topics: Adult; Antibodies, Viral; Antiviral Agents; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Disease-Free Survival; DNA, Viral; Drug Therapy, Combination; Europe; Female; Follow-Up Studies; Ganciclovir; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Israel; Kidney Transplantation; Male; Pancreas Transplantation; Polymerase Chain Reaction; Risk Factors; Severity of Illness Index; Tacrolimus; Time Factors

The purpose of this study is to find out whether basiliximab administration will improve postoperative renal function by delaying the start of tacrolimus and decreasing of dosage requirement for tacrolimus in adult living donor liver transplantation (LDLT). Forty-five adult LDLT recipients were enrolled in the study. The induction group (n = 27) was given basiliximab 20 mg on days 0 and 4; tacrolimus administration was delayed until renal function improved. The control group (n = 18) did not receive basiliximab; tacrolimus was given on the first postoperative day. Trough levels of tacrolimus in the induction and control groups were aimed to be maintained at 5-10 ng/ml and 10-15 ng/ml during the first week after transplant, respectively. The median follow-up was 22 months (range 10-34 months). The preoperative conditions were poorer in the induction group (Child C, 56% vs. 33%, P = 0.01; UNOS 2a, 15% vs. 0%, P = 0.02). The intraoperative blood loss was also higher in the induction group than in the control group (median 2,180 ml vs. 495 ml, P < 0.01). The median delay in tacrolimus administration in the induction group was 36 hours (range 24-108 hours). Serum creatinine levels at second and third postoperative months were significantly lower in the induction group. The creatinine clearance rate in the induction group was higher at the third month posttransplant (median 72 vs. 57 ml/minute, P = 0.04). The incidence of renal insufficiency was significantly lower in the induction group at the third month posttransplant (26% vs. 67%, P < 0.01). Blood cholesterol level at the sixth month posttransplant was lower in the induction group (median 152 vs. 196 mg/dl P = 0.03). The incidences of acute cellular rejection, bacteremia, and cytomegalovirus (CMV) infection were similar in both groups. In conclusion, for pretransplant critical patients with more intraoperative blood loss, basiliximab induction could prevent early renal dysfunction by delaying the start of tacrolimus and reducing the dose requirement of tacrolimus without increasing graft rejection and infection. Furthermore, it also improved renal function as well as lowered cholesterol levels within 6 months after transplantation.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Creatinine; Cytomegalovirus Infections; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Recombinant Fusion Proteins; Tacrolimus; Treatment Outcome

Induction with monoclonal antibodies for prevention of acute cellular rejection (ACR) may avoid many of the adverse events associated with polyclonal antibodies. Basiliximab, a chimeric monoclonal antibody directed against the alpha-chain of the interleukin 2 receptor (CD25), has been extensively evaluated as an induction therapy for kidney transplant recipients, more frequently in combination with a cyclosporine-based regimen. In this study, we assessed the efficacy and safety of basiliximab in combination with a tacrolimus-based regimen after liver transplantation.. Fifty consecutive liver transplants (47 cadaveric donors; 3 living donors) were analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after transplantation) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/mL target trough levels) and a tapered dose regimen of steroids. Follow-up ranged from 404 to 1,364 days after transplantation (mean 799.89 days, SD+/-257.37; median 796 days).. A total of 88% of patients remained rejection-free during follow-up with an actuarial rejection-free probability of 75% within 3 months. The actuarial patient survival rate at 3 years was 88%, and the graft survival rate was 75%. Twelve (24%) patients experienced one episode of sepsis, requiring temporary reduction of immunosuppressive therapy. There were no immediate side effects associated with basiliximab and no evidence of cytomegalovirus infection or posttransplant lymphoproliferative disorder.. Basiliximab in combination with a tacrolimus-based immunosuppressive regimen is effective in reducing episodes of ACR and increasing ACR-free survival after liver transplantation. In addition, basiliximab does not increase the incidence of adverse effects or infections.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Basiliximab; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Survival; Hepatitis, Viral, Human; Humans; Liver Diseases; Liver Transplantation; Male; Middle Aged; Recombinant Fusion Proteins; Survival Analysis; Tacrolimus

We reviewed two groups of kidney transplant patients receiving neoral (Group I, 27 patients) or FK506 (Group II, 25 patients) as maintenance immunosuppression between December 1998 and May 2002. The recipient and donor demographics and induction therapy were comparable in both groups except for more highly sensitized patients in Group II. Acute rejection (AR) rate and timing were similar in both groups except for more steroid resistant AR in Group II (P=0.04). Infections rate was similar in both groups (25.9% in Group I and 36% in Group II; P=N.S.), but there were less viral infections in Group I (0%) than Group II (29%; 4 CMV). CMV infections were related to the presence in Group II of more CMV-negative recipients getting kidneys from CMV-positive donors. The metabolic profile was comparable between the two groups, except for a better HDL in Group II (48.2+/-7.6) versus Group I (45+/-2.2; P=0.021). Mean serum creatinine levels upon discharge, at 1, 3 and 6 months were: 1.62+/-0.32, 1.4+/-0.17, 1.39+/-0.14 and 1.4+/-0.14 in Group I and 2.15+/-0.5, 1.48+/-0.23, 1.41+/-0.21 and 1.23+/-0.11 in Group II, respectively. The 6 months actuarial patient and graft survival were identical in both groups (100 and 100%). Both calcineurin inhibitors are effective and safe in KT. The higher rate of AR in Group II was related to more highly sensitized patients and the higher CMV infections was due to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. The same study will be continued to evaluate the long term effects of both drugs.

Topics: Acute Disease; Adolescent; Adult; Aged; Creatinine; Cyclosporine; Cytomegalovirus Infections; Emulsions; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Tacrolimus

Topics: Adult; Cyclosporine; Cytomegalovirus Infections; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Postoperative Complications; Tacrolimus; Treatment Failure

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: Antilymphocyte Serum; Azathioprine; Bacterial Infections; Cytomegalovirus Infections; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Muromonab-CD3; Mycoses; Postoperative Complications; Prednisolone; Prospective Studies; Sepsis; Survival Rate; Tacrolimus; Time Factors

The recent U.S. multicenter randomized trial of FK506 versus cyclosporine (CsA) demonstrated equivalent patient and graft survival in patients treated with FK506 and statistically fewer rejection episodes in the first year posttransplant.. To determine if more effective posttransplant immunosuppression was associated with an increased risk of cytomegalovirus (CMV) or posttransplant lymphoproliferative disease (PTLD), we examined the incidence of these two opportunistic infections during 3 years of follow-up.. CMV infection occurred in 40 (19.5%) FK506 and 40 (19.3%) CsA-treated patients. The incidence of CMV disease was 9.3% in FK506 and 6.8% in CsA-treated recipients; the most common site of CMV disease was the gastrointestinal tract. A multivariate analysis of several risk factors demonstrated that a CMV- recipient of a CMV+ donor was at greatest risk for CMV infection. The incidence of posttransplant lymphoproliferative disease was equal in the two treatment arms: six CsA- and five FK506-treated recipients.. The results of this study suggest that the superior efficacy of FK506 in the prevention of acute rejection was not associated with an increased risk of CMV or posttransplant lymphoproliferative disease compared with CsA.

Topics: Cyclosporine; Cytomegalovirus Infections; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Multivariate Analysis; Opportunistic Infections; Postoperative Complications; Tacrolimus

Topics: Adult; Antilymphocyte Serum; Azathioprine; China; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Hepatitis B Surface Antigens; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Time Factors

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

This paper reports the histopathologic results of 2-year protocol biopsies from patients who were enrolled in the U.S. FK506 kidney transplant study .. Recipients of cadaveric kidney transplants were randomized to tacrolimus or cyclosporine therapy. Patients active in the trial at 2 years after transplantation were approached for a protocol biopsy. Biopsies were scored by the Banff classification in a blinded fashion by one pathologist.. A total of 144 patients (41.3% of those active at 2 years) had a 2-year protocol biopsy performed; 79 patients were treated with tacrolimus and 65 patients were treated with cyclosporine. Evidence of acute rejection was found in seven (8.9%) of the 2-year biopsies in tacrolimus-treated patients and six (9.2%) cyclosporine-treated patients. Chronic allograft nephropathy was found in 49 (62.0%) tacrolimus biopsies and 47 (72.3%) cyclosporine biopsies (P=0.155). There were no apparent histopathologic differences between the tacrolimus and cyclosporine biopsies. The occurrence of chronic allograft nephropathy was significantly higher in patients who received a graft from an older donor (P<0.01), who experienced presumed cyclosporine or tacrolimus nephrotoxicity (P<0.001), who developed a cytomegalovirus infection (P=0.038), or who experienced acute rejection in the first year after transplantation (P=0.045). A multivariate analysis showed that nephrotoxicity and acute rejection were the most significant predictors for chronic allograft nephropathy.. The occurrence of histologic acute rejection was rare at 2 years, confirming the absence of subclinical acute rejection in these late biopsies. A majority of the biopsies showed features consistent with chronic allograft nephropathy that was associated with acute rejection (particularly in cyclosporine-treated patients), nephrotoxicity, and cytomegalovirus infection in the first year. This suggests that nonimmunologic factors, such as drug-induced toxicity, may play an important role in chronic allograft nephropathy.

Topics: Adult; Aged; Biopsy; Cyclosporine; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Transplantation, Homologous

Topics: Antibodies, Monoclonal; Azathioprine; Cadaver; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Methylprednisolone; Patient Readmission; Survival Rate; Tacrolimus; Tissue Donors

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provide

Topics: Acute Disease; Adult; Cyclosporine; Cytomegalovirus Infections; Drug Resistance; Evaluation Studies as Topic; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Tacrolimus; Treatment Outcome

FK506 has been proven effective for prevention and treatment of liver allograft rejection. Herein, we compare FK506-based immunosuppression with an effective quadruple immunosuppressive regimen, including cyclosporine and antithymocyte globulin. The results of a single center participating in the European multicenter FK506 study are reported, including immunosuppressive efficacy as well as toxicity. One-year patient and graft survival was 96.7% and 90.0% for the CsA group and 90.2% and 88.5% for the FK506 group, which is not statistically different. The incidence and severity of acute rejection episodes during the first postoperative year was similar in both treatment groups with 34.4% and 33.3% for the FK506 and CsA treatment group, respectively. Immunosuppressive potency was better for the FK506 group compared with the CsA group according to the incidence of chronic rejection. Furthermore, 5 patients (8.3%) required conversion to FK506 for immunological reasons, i.e., refractory acute or chronic rejection. The incidence of moderate and severe neurotoxicity during the early postoperative period was higher in the FK506 group (21.3%) compared with the CsA group (11.7%), while the incidence of renal insufficiency and acute renal failure was similar (18.0% and 18.3% for the FK506 and CsA treatment groups, respectively). The incidence of CMV infection was significantly higher under treatment with CsA (25.0%) than with FK506 (6.6%) (P < or = 0.05), while the incidence of pneumonia (13.1% and 13.3%), cholangitis (29.5% and 26.7%), and urinary tract infection (39.3% and 28.3% for the FK506 and CsA treatment groups, respectively) was similar in both treatment groups. However, infection was more serious in some cases treated with FK506, and evolved as the main cause of death in the FK506 treatment group. Therefore, caution should be paid to over immunosuppression and toxicity in FK506-treated patients. Regarding the monitoring of FK506, FK506 plasma level failed to be a reliable indicator, and therefore we recommend measurement of whole blood FK506 levels. Our data indicate that immunosuppressive potency of FK506 is greater than that of CsA, especially concerning the incidence of chronic rejection.

Topics: Adolescent; Adult; Aged; Cyclosporine; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Opportunistic Infections; Renal Insufficiency; Survival Analysis; Tacrolimus; Transplantation, Homologous

One hundred and forty randomly selected liver transplant recipients were studied before and after primary orthotopic liver transplantation for the presence or absence of CMV enteritis. Following OLTx, 65 patients were treated with cyclosporine A and 75 were treated with FK506. The two groups were similar with regard to the incidence, location, and outcome of their upper gastrointestinal CMV infection. Prior to OLTx, only one patient had evidence of enteric CMV infection. The incidence of CMV enteritis post-OLTx was 27.7% in the CsA-treated group and 20% in the FK-treated group. During the first posttransplant month, no patient in the FK-treated group developed CMV enteritis, compared with 11.5% of the patients who were treated with CsA (P less than 0.05). Gastric CMV was found in over 80% of those positive for any organ in either group. In addition to CMV infection of the upper gastrointestinal tract, clinically evident CMV disease involved more nonenteric organs in the CsA-treated group than in the FK-treated group. In the CsA-treated group, CMV-negative patients had a statistically higher 1-year survival rate (100%) than CMV-positive patients (77.8%) (P less than 0.05). In the FK-treated group, no difference in survival was observed between CMV-positive or CMV-negative cases at 1 year. Of the patients on CsA, 20% received OKT3 for persistent rejection, as compared with 13% in the FK-treated group. The patients receiving both CsA and OKT3 had a higher rate of upper gastrointestinal CMV infection than did FK-treated patients who also received OKT3 therapy (38.5% versus 20%, respectively). Based upon these data, it can be concluded that (1) patients receiving FK have a lower incidence of enteric CMV infection; (2) following OLTx, upper gastrointestinal CMV infection presents later in FK-treated patients; (3) the stomach is the most frequently involved organ in the UGIT; (4) FK-treated liver recipients have less severe enteric CMV infection than do CsA-treated patients; (5) enteric CMV is not a major cause of mortality in liver transplant recipients; and (6) in patients receiving FK, those who require OKT3 therapy do not appear to be at a greater risk for the development of CMV enteritis than those who do not.

Topics: Adolescent; Adult; Aged; Cyclosporine; Cytomegalovirus Infections; Female; Gastrointestinal Diseases; Humans; Incidence; Liver Transplantation; Male; Middle Aged; Muromonab-CD3; Survival Rate; Tacrolimus; Time Factors

Topics: Acyclovir; Adult; Cyclosporine; Cytomegalovirus Infections; Female; Follow-Up Studies; Humans; Incidence; Liver Transplantation; Male; Tacrolimus

Cytomegalovirus (CMV) infection is the most common infection following pediatric liver transplantation (LT). Preemptive therapy (PET) is an approach to initiate antiviral treatment for asymptomatic early CMV viremia detected by surveillance testing. However, data on CMV infection after PET are scarce, and the optimal cut-off remains controversial. This study aimed to evaluate the incidence, risk factors, and consequences of CMV infection in pediatric LT using 2 different viral load (VL) cut-offs.. We retrospectively reviewed patients aged 0-18 years who underwent LT at Ramathibodi Hospital between March 2001 and August 2020. Demographic data, CMV infection, CMV treatment, and consequences of CMV infection were collected. CMV viremia was monitored by a quantitative nucleic acid amplification test. Clinical outcomes were compared after starting antiviral therapy at a low (>400 but <2000 IU/mL) and a high VL cut-off (≥2000 IU/mL).. A total of 126 patients were included. CMV infection was 71% (90/126), with an incidence rate of 5.5 per 1000 patient-day. Higher tacrolimus and prednisolone dosages were associated with CMV infection with an adjusted hazard ratio of 1.2 (95%CI 1.0-1.4, p = .02) and 2.4 (95%CI 1.9-3.4, p < .001), respectively. The consequences of CMV infection did not differ significantly for the low and high CMV VL cut-off groups.. CMV infection in LT recipients is common and is associated with higher tacrolimus and corticosteroid dosage. Additionally, using the CMV VL cut-off at 2000 IU/mL to initiate antiviral therapy is practical and effective in preventing CMV disease.

Topics: Antiviral Agents; Child; Cytomegalovirus; Cytomegalovirus Infections; Humans; Liver Transplantation; Retrospective Studies; Risk Factors; Tacrolimus; Viremia

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

PTLD is a clinical condition with high mortality. Monitoring EBV replication can be a useful tool to avoid the development of PTLD.. This was a retrospective analysis of 428 pediatric patients who underwent liver transplantation between 1989 and 2016. The patients were divided into 2 groups (transplanted before 2006, when PCR-EBV was not monitored, and after 2006, when PCR-EBV monitoring was started). Patients with continuous PCR measurements for EBV were evaluated for the impact of a reduction in immunosuppression or a change in immunosuppressants on the number of viral copies. A logistic regression model was applied to evaluate factors related to PTLD.. The prevalence of PTLD was 4.2%. After monitoring patients with PCR for EBV levels, a predominance of the most severe, monomorphic form of lymphoproliferative disorder was observed (p = .009). The PTLD mortality was 5%. There was a change in the PCR level after tacrolimus reduction (p = .002) and after tacrolimus exchange for mTOR (p = .008). The number of EBV copies was significantly higher (p = .029) in patients who developed PTLD. In the multiple regression model, seropositivity for CMV was an independent protective factor for lymphoproliferative disorder (OR=0.09; 95% CI 0.02-0.42), reducing the chance of having PTLD adjusted by serology for EBV by 91%.. Monitoring the EBV viral load by PCR seems to prevent the emergence of milder forms of lymphoproliferative disorder. Pretransplant seropositivity for CMV is a protective factor for PTLD.

Topics: Child; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Liver Transplantation; Lymphoproliferative Disorders; Polymerase Chain Reaction; Protective Factors; Retrospective Studies; Tacrolimus; Viral Load

Letermovir is a novel agent for the prevention of cytomegalovirus (CMV) infection and disease that, unlike traditional CMV DNA polymerase inhibitors, does not carry the risk of myelosuppression. The purpose of this study was to evaluate the safety, efficacy, and clinical application of letermovir for CMV prophylaxis in heart transplant (HT) recipients. Between November 1, 2019, and October 1, 2021, at a single, tertiary care hospital, 17 HT recipients were initiated on letermovir due to leukopenia while on valganciclovir. Fifteen (88%) had high-risk mismatch (CMV D+/R-). Median time on letermovir was 5 months (interquartile range, 2-8 months.) At the end of the study period, nine of 17 patients (52.9%) were still on letermovir and four of the 17 (23.5%) had successfully completed the prophylaxis window on letermovir and been switched to the pre-emptive strategy. One patient developed clinically significant CMV viremia in the setting of being unable to obtain medication due to insurance barriers but was later successfully restarted on letermovir. One patient was unable to tolerate letermovir due to symptoms of headache and myalgias. Two patients developed low-level non-clinically significant CMV viremia and were switched back to valacyclovir. All patients had tacrolimus dosages reduced at time of letermovir initiation to minimize the risk of supratherapeutic tacrolimus concentration. One patient required hospitalization due to symptomatic tacrolimus toxicity. For HT recipients who cannot tolerate valganciclovir, letermovir presents an alternative for CMV prophylaxis. Close monitoring for breakthrough CMV and calcineurin inhibitor levels is necessary. Larger studies are required to further delineate its use and help provide further evidence of its safety and efficacy.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Heart Transplantation; Humans; Tacrolimus; Transplant Recipients; Valganciclovir; Viremia

BACKGROUND The interaction of viral infection may be associated with increased morbidity after renal transplantation. This study aimed to identify the incidence and risk factors of viruria infections in renal transplant recipients. MATERIAL AND METHODS In this longitudinal study, 502 episodes recorded in 81 kidney transplant patients from 1/2019 to 12/2021 in a hospital in Vietnam were included. BK, JC polyomaviruses, CMV, EBV, and HSV were detected. Multivariable Cox regression analysis was performed to evaluate risk factors for the viruria infection. RESULTS Fifty-six patients (69.1%) had viruria co-infection. The incidence of JC, CMV, and BK infection was the most common viruria, with 67.9%, 61.7%, and 56.8%, respectively. Cox regression revealed that the risk factors for JC were single infection, dose of MMF (HR 1.002), corticoid (HR 1.02), hypertension (HR 1.65), and hematuria (HR 2.03); risk factors for CMV infection were male sex (HR 1.92) and eGFR (HR 0.98); risk factors for BK single infection were hypertension (HR 1.67), proteinuria (HR 3.80), higher tacrolimus trough level (HR 1.17), and dose of MMF (HR 1.002). Hypertension (HR 1.68), fasting plasma glucose (HR 1.13), proteinuria (HR 6.01), tacrolimus trough level (HR 1.12), and dose of MMF (HR 1.004) were independent risk factors for the viruria co-infection. CONCLUSIONS Kidney function was associated with the incidence of viruria. Higher tacrolimus trough level and dose of MMF were associated with higher risk of BK, JC, and co-infection.

Topics: BK Virus; Blood Glucose; Coinfection; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Humans; Hypertension; Kidney Diseases; Kidney Transplantation; Longitudinal Studies; Male; Polyomavirus; Polyomavirus Infections; Proteinuria; Risk Factors; Tacrolimus

Belatacept improves long-term graft survival, but control of some primary viral infections may be impaired. We evaluated the impact of belatacept and tacrolimus on cytomegalovirus (CMV) viral control, remission and relapse in CMV high-risk and moderate-risk recipients.. Using a multistate Markov model, we evaluated viral load state transitions of 173 kidney transplant recipients with at least one episode of viremia within 1 year after transplant: state 1, undetectable/low viral load; state 2, moderate viremia; and state 3, severe viremia.. Among high-risk recipients, belatacept-treated recipients exhibited a significantly higher probability of entering moderate viremia (.36; 95% CI = .31, .41) than tacrolimus-treated recipients (.20; 95% CI = .13, .29). The expected number of days in viremic states differed. High-risk belatacept-treated recipients persisted in moderate viremia for significantly longer (128 days, 95% CI = 110, 146) than did tacrolimus-treated recipients (70.0 days, 95% CI = 45.2, 100) and showed a trend of shorter duration in low/undetectable viral load state (172 days, 95% CI = 148, 195) than did tacrolimus-treated recipients (239 days, 95% CI = 195, 277). Moderate-risk recipients showed better viral load control and with no differences by immunosuppression.. High-risk belatacept-treated recipients showed defects in sustaining viral control relative to tacrolimus-treated recipients. Avoidance of initial use belatacept in high-risk recipients or development of modified management protocols should be considered.

Topics: Abatacept; Antiviral Agents; Chronic Disease; Cytomegalovirus; Cytomegalovirus Infections; Humans; Kidney Transplantation; Recurrence; Tacrolimus; Transplant Recipients; Viral Load; Viremia

Opportunistic infections remain a significant cause of morbidity and mortality after kidney transplantation. This retrospective cohort study aimed to assess the incidence and predictors of post-transplant DNA virus infections (CMV, EBV, BKV and JCV infections) in kidney transplant recipients (KTR) at a single tertiary centre and evaluate their impact on graft outcomes.. KTR transplanted between 2000 and 2021 were evaluated. Multivariate logistic regression analysis and Cox proportional hazard analyses were used to identify factors associated with DNA virus infections and their impact on allograft outcomes respectively. A sub-analysis of individual viral infections was also conducted to describe the pattern, timing, interventions, and outcomes of individual infections.. Data from 962 recipients were evaluated (Mean age 47.3 ± 15 years, 62% male, 81% white). 30% of recipients (288/962) had infection(s) by one or more of the DNA viruses. Individually, CMV, EBV, BKV and JCV viruses were diagnosed in 13.8%. 11.3%, 8.9% and 4.4% of recipients respectively. Factors associated with increased risk of post-transplant DNA virus infection included recipient female gender, higher number of HLA mismatch, lower baseline estimated glomerular filtration rate (eGFR), CMV seropositive donor, maintenance with cyclosporin (rather than tacrolimus) and higher number of maintenance immunosuppressive medications. The slope of eGFR decline was steeper in recipients with a history of DNA virus infection irrespective of the virus type. Further, GFR declined faster with an increasing number of different viral infections. Death-censored graft loss adjusted for age, gender, total HLA mismatch, baseline eGFR and acute rejection was significantly higher in recipients with a history of DNA virus infection than those without infection (adjusted hazard ratio (aHR, 1.74, 95% CI, 1.08-2.80)). In contrast, dialysis-free survival did not differ between the two groups of recipients (aHR, 1.13, 95% CI, 0.88-1.47).. Post-transplant DNA viral infection is associated with a higher risk of allograft loss. Careful management of immunosuppression and close surveillance of at-risk recipients may improve graft outcomes.

Topics: Adult; Cytomegalovirus Infections; Female; Humans; Kidney Transplantation; Male; Middle Aged; Polyomavirus Infections; Postoperative Complications; Retrospective Studies; Tacrolimus

We report 3 cases of patients with chronic ocular surface inflammatory disease who developed cytomegalovirus (CMV) corneal endotheliitis during immunosuppressant and steroid treatment.. This is a retrospective observational study analyzing the clinical characteristics and outcomes of 3 patients with ocular surface inflammatory diseases (2 with Mooren ulcer and 1 with idiopathic scleritis) who developed CMV corneal endotheliitis. All patients developed CMV corneal endotheliitis between 8 and 14 months of starting steroid and immunosuppressant treatment, including topical 0.1% tacrolimus. Decimal visual acuity, endothelial counts, and intraocular pressure were analyzed.. All patients received topical 0.5% ganciclovir after the diagnosis of CMV corneal endotheliitis, which improved endothelial inflammation. However, all patients developed irreversible mydriasis and required additional surgeries, including endothelial keratoplasty, cataract surgery, and glaucoma surgery. At the final follow-up (14-46 months post-CMV corneal endotheliitis onset), fair outcomes were achieved, as demonstrated by a mean decimal best-corrected visual acuity of 0.3 and a well-controlled intraocular pressure.. Topical steroids and immunosuppressants can induce fulminant CMV corneal endotheliitis with cataract progression and irreversible mydriasis. In these cases, early diagnosis and treatment, including topical 0.5% ganciclovir, glaucoma surgery, cataract surgery, and endothelial keratoplasty, are necessary for preserving the patient's vision.

Topics: Aged; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Drug Therapy, Combination; Endothelium, Corneal; Eye Infections, Viral; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Keratitis; Male; Retrospective Studies; 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

Valganciclovir is the preferred drug for cytomegalovirus (CMV) prophylaxis in solid organ transplantation. A limitation to its use is profound myelosuppression. Letermovir is a new agent approved for CMV prophylaxis in hematopoietic stem cell transplantation and is associated with less toxicity. This study aims to assess the effectiveness and safety of letermovir in solid organ transplantation.. A single-center, matched cohort study was performed on 31 transplant recipients who were converted from valganciclovir to letermovir from November 2017 to June 2020. The primary outcome was the rate of CMV breakthrough infections while on prophylaxis. Secondary outcomes included rate of leukopenia, doses of immunosuppression, rejection, non-CMV infection, and renal function. Statistical analyses of continuous variables included the student's t-test, ANOVA test, and Wilcoxon Signed Rank test. Categorical data were analyzed with chi-square test and Fisher's Exact test.. There was no difference in the rate of CMV breakthrough between patients on letermovir (8.7%) and valganciclovir (13.5%), (P = .7097). After conversion to letermovir, patients required lower tacrolimus doses at -3.34 mg (SD-1.3, P = .0273), between conversion and day 7. Transplant Infectious Disease The median difference in tacrolimus trough concentrations from conversion to day seven was 9.1 ng/ml [4.9, 16.95] (P = .0002). Leukopenia improved by 1.8 109/L [1.08, 4.85] (P < .0001).. Patients converted from valganciclovir to letermovir did not show an increased rate of CMV breakthrough compared to a historical, matched cohort of patients remaining on valganciclovir. A significant drug interaction was noted with tacrolimus, leading to a recommendation to reduce the dose by 40-50% upon initiation of letermovir.

Topics: Acetates; Antiviral Agents; Cohort Studies; Cytomegalovirus; Cytomegalovirus Infections; Drug Interactions; Humans; Organ Transplantation; Quinazolines; Tacrolimus

Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.

Topics: Adult; Antiviral Agents; Biopsy; Cytomegalovirus; Cytomegalovirus Infections; Humans; Kidney Transplantation; Liver; Lymphohistiocytosis, Hemophagocytic; Male; Tacrolimus; Tomography, X-Ray Computed

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

Published literature on predictors of polyomavirus (BKV) and cytomegalovirus (CMV) infections in simultaneous pancreas and kidney (SPK) transplant and their impact on allograft outcomes remain sparse. We hypothesize that BKV and CMV viremia infections decrease allograft survival in SPK. Identifying modifiable predictors of BKV and CMV may help tailor immunosuppression and improve allograft survival.. All SPK recipients at our institution between January 2000 and April 2016 were included (n = 757). Thirty-nine recipients had BKV only and 25 had CMV only, and infection occurred at median follow-up times of 217 and 163 days, respectively. Event density sampling was used to match recipients with BKV or CMV to up to 10 recipients without infection by age, sex, and HLA mismatch status, and these were followed for a median of 4.3 years after infection.. Older age (HR 1.49 for each decade; 95% CI: 0.95, 2.35; P = .083) and tacrolimus use (HR 20.6; 95% CI: 2.37, 179.53; P = .006) were associated with increased incidence of BKV, but not CMV, infection. Both BKV and CMV infections were associated with increased risk of allograft failure for both pancreas (BKV [HR 2.17; 95% CI 1.47, 3.208; P = .000], CMV [HR 1.7; 95% CI 1.077, 2.687; P = .023]) and kidney (BKV [HR 2.65; 95% CI 1.765, 3.984; P = .000], CMV [HR 2.07; 95% CI 1.295, 3.308; P = .002]).. Older age at time of transplant and tacrolimus may help predict BKV infection in SPK recipients.

Topics: Adult; Age Factors; Cohort Studies; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Incidence; Kidney Transplantation; Male; Pancreas Transplantation; Polyomavirus Infections; Risk Factors; Tacrolimus

Data binding the expression of Toll-like 4 receptor (TLR4), transplanted kidney (KT) function, and symptomatic CMV infection (CMV+) are scarcely available.. To investigate the relationship between TLR4 expression (TLR4ex) in patients who had a relapse of CMV and transplant function.. TLR4ex was measured in peripheral blood mononuclear cells of KT recipients. We compared TLR4ex among 30 CMV+ patients and 87 patients without CMV infection (CMVneg). At the beginning (day 0) TLR4ex, as well as concentrations of cyclosporin A and tacrolimus were determined. All patients, CMV+ and CMVneg patients were divided according to the respective median of TLR4ex into groups of low-TLR4 expression (L-TLR4ex) and high-TLR4 expression (H-TLR4ex). Estimated glomerular filtration rate (EGFR) was assessed on day 0 and after the follow-up (F-up). The magnitudes of EGFR change (ΔEGFR) were evaluated. Stable treatment along the F-up period (median 11.9 months) was applied.. TLR4ex of CMV+ in 67% was below median for all patients. For day 0, in CMV+: no link of TLR4ex with EGFR was found; TLR4ex was lower but day 0 EGFR did not differ from H-TLR4ex. In CMVneg, a GFR-TLR4ex link was present. Post F-up. In CMV+ with L-TLR4ex, EGFR declined, with no change in H-TLR4ex. In CMVneg with H-TLR4ex, EGFR increased, with no change in L-TLR4ex. Both regression and receiver operating characteristic curve analyses points out the impact of CMV+ and TLR4ex on eGFR and ΔEGFR.. In CMV+, low TLR4ex increases the risk of EGFR deterioration. In CMVneg, high TLR4ex raises the chance of EGFR improvement.

Topics: Adult; Cyclosporine; Cytomegalovirus Infections; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Kidney; Kidney Transplantation; Leukocytes, Mononuclear; Male; Middle Aged; Tacrolimus; Toll-Like Receptor 4

Little is known regarding optimal tacrolimus (TAC) trough levels after 1 year post-transplant in stable kidney transplant recipients (KTRs) who have not experienced renal or cardiovascular outcomes. This study aimed to investigate the effect of 1-year post-transplant TAC trough levels on long-term renal and cardiovascular outcomes and opportunistic infections in stable KTRs.. KTRs receiving TAC with mycophenolate-based immunosuppression who did not experience renal or cardiovascular outcomes within 1 year post-transplant were enrolled from a multicenter observational cohort study. Renal outcome was defined as a composite of biopsy-proven acute rejection, interstitial fibrosis and tubular atrophy, and death-censored graft loss. Cardiovascular outcome was defined as a composite of de novo cardiomegaly, left ventricular hypertrophy, and cardiovascular events. Opportunistic infections were defined as the occurrence of BK virus or cytomegalovirus infections.. A total of 603 eligible KTRs were divided into the low-level TAC (LL-TAC) and high-level TAC (HL-TAC) groups based on a median TAC level of 5.9 ng/mL (range 1.3-14.3) at 1 year post-transplant. The HL-TAC group had significantly higher TAC trough levels at 2, 3, 4, and 5 years compared with the levels of the LL-TAC group. During the mean follow-up of 63.7 ± 13.0 months, there were 121 renal outcomes and 224 cardiovascular outcomes. In multivariate Cox regression analysis, LL-TAC and HL-TAC were not independent risk factors for renal and cardiovascular outcomes, respectively. No significant differences in the development of opportunistic infections and de novo donor-specific anti-human leukocyte antigen antibodies and renal allograft function were observed between the two groups.. TAC trough levels after 1 year post-transplant remained at a similar level until the fifth year after kidney transplantation and were not directly associated with long-term outcomes in stable Korean KTRs who did not experience renal or cardiovascular outcomes. Therefore, in Asian KTRs with a stable clinical course, TAC trough levels higher than approximately 6 ng/mL might not be required after a year of kidney transplantation.

Topics: Adult; Cardiovascular Diseases; Cohort Studies; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Opportunistic Infections; Polyomavirus Infections; Renal Insufficiency; Republic of Korea; Tacrolimus

Variability in tacrolimus levels has been associated with increased rejection, graft loss, and de novo donor-specific antibody (dnDSA) development in kidney transplant recipients (KTRs); however, limited data on alemtuzumab induction or infection exist. We sought to determine the impact of tacrolimus variability in KTRs on dnDSAs, graft outcomes, and infections 3 years posttransplant after alemtuzumab induction.. Adult KTRs from January 1, 2013, to December 31, 2017, receiving alemtuzumab and tacrolimus-based immunosuppression at a single center were included. Tacrolimus variability was calculated using coefficient of variability (CV), and high CV was defined as ≥30%. Graft and infectious outcomes were assessed between high and low CV groups.. Two hundred fourteen KTRs were included. The median tacrolimus CV from 0 to 3 months and from 3 to 12 months was 28.1% and 25.8%, respectively. Recipients with high CV had decreased glomerular filtration rate at 3 and 12 months (67.7 ± 35.48 vs 80.7 ± 29.3, P = .01 and 70.9 ± 35.4 vs 83.3 ± 30.2, P = .015). High CV was also associated with increased cytomegalovirus viremia and disease (19.6% vs 9.3%, P = .046 and 6.4% vs 17.9%, P = .015). No difference in biopsy-proven acute rejection, survival, or dnDSA development at 3 years was observed.. High tacrolimus variability was associated with significantly reduced graft function and increased cytomegalovirus viremia and disease but not biopsy-proven acute rejection, survival, or dnDSA development.

Topics: Adult; Alemtuzumab; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Tacrolimus

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

We aimed to compare the early results of i.v. with p.o. TAC as a primary immunosuppressant in pediatric patients undergoing LT. This retrospective study enrolled 75 children who underwent LT and received TAC-steroid regimens as a primary immunosuppressant between September 2011 and October 2015 at our institution. Thirty-five recipients received TAC i.v. and 40 received TAC p.o. Early results were evaluated and compared, including ACR, EBV, or CMV infection; renal adverse effects; and hospital stay. Comparisons of 90-day post-transplant results showed that the rates of overall viral (74% vs 40% P < 0.002), EBV (46% vs 17.5% P < 0.008), and CMV (51% vs 30% P = 0.05) infections were significantly higher in the i.v. than in the p.o. group. Neither regimen has any adverse effects on renal function. There were no between-group differences in ACR incidence and severity, serum creatinine concentration, and hospital stay. Patient and graft survival rates at 3 months and 1 year did not differ significantly between the two groups. Compared with p.o. treatment, i.v. administration of high TAC concentration did not have beneficial post-transplant effects on ACR incidence and severity, while increasing the incidence of viral infections in pediatric LT.

Topics: Administration, Oral; Biopsy; Child; Child, Preschool; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Length of Stay; Liver; Liver Failure; Liver Transplantation; Male; Pediatrics; Postoperative Period; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome

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

Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects.. The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD.. All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed.. The study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers.. Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.

Topics: Cytomegalovirus Infections; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; France; Humans; Hypertension; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk; Skin Neoplasms; Tacrolimus; Time Factors

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

Cytomegalovirus (CMV) infection is a relevant cause of morbidity and mortality in transplantation patients. Its major incidence is in the first year and viral replication is related to acute rejection, survival reduction, and graft vascular disease.. This study aims to evaluate retrospectively whether a high dose of calcineurin inhibitors correlates with CMV-positive polymerase chain reaction (PCR), need for treatment, and death in cardiac transplantation patients.. This is a case-control study including patients who underwent transplantation between 2014 and 2016. They were separated into two groups (positive or negative PCR) and evaluated for dosage serum levels of cyclosporine and tacrolimus. Patients were classified with adequate dose of immunosuppressant or high dose, and was analyzed that there was any association with those and positive CMV-PCR, need for treatment for CMV, and deaths. For statistical analysis, the Student t test was used for the quantitative variables and the Fisher's Exact Test for qualitative variables. To show CMV-free survival, the Kaplan-Meier curve was used. The level of significance was set at 5%.. CMV-positive PCR in the sample was 72% for a total of 50 individuals. Positive PCR correlated with a high dose of calcineurin inhibitors in a statistically significant way (P = .002), as did a high dose of cyclosporine (P = .004); however, a high dose of tacrolimus had no such association (P = .17). When a high dose was assessed with a need for treatment, the chance of needing treatment increased more than eight times (P = .024; odds ratio = 8.25; 95% CI = 1.33 to 51.26), which was different from results found with high-dose tacrolimus (P = 1.0). However, no significant association was found in relation to deaths.. Tacrolimus serum levels showed no association with CMV-PCR, which was different from serum cyclosporine, which showed association with CMV-PCR positivity, increasing the need for treatment approximately 8-fold, without association with death.

Topics: Adult; Calcineurin Inhibitors; Case-Control Studies; Cyclosporine; Cytomegalovirus Infections; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; 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

Despite the high efficacy of mycophenolate mofetil (MMF)/tacrolimus-based multitarget treatment, risks of infections are a matter of concern. In the present study, we clarified the potential of multitarget therapy using mizoribine opposed to MMF.. A total of 36 patients with biopsy-proven lupus nephritis were treated with mizoribine, tacrolimus, and glucocorticoids and then retrospectively evaluated. To determine the efficacy, proteinuria remission (≤ 0.2 g/day), complete remission (Liu et al. in Ann Intern Med 162:18-26, 2015) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) remission rates, and the prednisolone dose at months 6 and 12 were evaluated. The associations between serum mizoribine/tacrolimus levels and clinical parameters were investigated. To assess safety, adverse events were inspected.. All patients could continue the original treatment regimen without withdrawal or exacerbations through month 12. At month 6, the proteinuria remission, complete remission, SLEDAI remission rates, and prednisolone dose were 69, 53, 36%, and 12.1 mg/day, respectively, whereas the values at 12 months were 92, 67, 50%, and 8.8 mg/day, respectively. The treatment was efficacious for every histologic type of nephritis and non-renal manifestations of SLE. Excluding one patient who was hospitalized due to upper respiratory tract infection, serious infections, including pneumonia and cytomegalovirus disease, were not observed. Higher trough tacrolimus levels were associated with normalization of complement, whereas higher peak mizoribine levels with prevention of cytomegalovirus viremia.. Our results suggest that multitarget therapy using mizoribine opposed to MMF is highly safe and effective through 12 months. The therapy may enable faster dose reduction of concomitant glucocorticoids.

Topics: Adolescent; Adult; Aged; Cytomegalovirus Infections; Female; Humans; Lupus Nephritis; Male; Middle Aged; Ribonucleosides; Tacrolimus; Young Adult

The aim of the present study was to describe the salivary shedding of human herpesviruses (HHV) in renal transplant recipients and to observe the oral manifestations in this group.. A prospective case-control study was conducted with a study group of 20 renal transplant recipients and a control group of 20 non-transplanted, immunocompetent individuals. Clinical examination evaluated the presence of drug-induced gingival overgrowth (DIGO), salivary flow, and caries. Stimulated saliva was collected from both groups, with HHV being detected by using real-time polymerase chain reaction.. The mean age of the study group was 45.90 ± 9.89 years, with 55% (11/20) being female, 60% (12/20) being Caucasian, 65% (13/20) having a deceased donor, and 70% (14/20) having used tacrolimus as the main immunosuppressive drug. Renal transplant recipients had shedding of more herpesviruses compared to the control group, with the exception of HHV-7. Statistical significance was found for herpes simplex virus-1 (HSV-1) (P = 0.017) and cytomegalovirus (P = 0.035). DIGO was observed in seven patients (35%), with 35% (7/20) presenting with decreased salivary flow and four (20%) reporting xerostomia.. Renal transplant recipients excreted herpesviruses more often than control individuals, especially HSV-1. Decreased salivary flow and xerostomia were more frequent in patients who used tacrolimus, whereas those who used cyclosporine had more cases of DIGO.

Topics: Brazil; Case-Control Studies; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Female; Herpes Simplex; Herpesviridae; Herpesviridae Infections; Herpesvirus 1, Human; Herpesvirus 4, Human; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prevalence; Prospective Studies; Real-Time Polymerase Chain Reaction; Roseolovirus Infections; Saliva; Tacrolimus; Virus Shedding

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

New-onset diabetes after transplantation (NODAT) is a significant co-morbidity following kidney transplantation. Lower post-transplant serum magnesium levels have been found to be an independent risk factor for NODAT in adult kidney transplant recipients.. We undertook a retrospective analysis of risk factors for NODAT in pediatric renal transplant recipients at our institution with the aim of determining if hypomagnesemia confers a significant risk of developing NODAT in this patient population.. A total of 173 children with a median age at transplantation of 7.0 (range 1.3-17.5) years were included. Hypomagnesemia was found to be a significant independent risk factor for NODAT (p = 0.01). High trough tacrolimus levels were also independently associated with NODAT (p < 0.001). There was no significant association between NODAT and body mass index at the time of transplantation, monthly cumulative steroid dose or post-transplant cytomegalovirus viremia (p = 0.9, 0.6 and 0.7, respectively).. This study identifies hypomagnesemia as a significant independent risk factor for the development of NODAT in pediatric renal transplant recipients. Given the clear association between hypomagnesemia and NODAT in both adults and children following renal transplantation, further studies are merited to clarify the etiology of this association and to examine the effect of magnesium supplementation on NODAT.

Topics: Adolescent; Body Mass Index; Child; Child, Preschool; Cytomegalovirus Infections; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Magnesium Deficiency; Male; Postoperative Complications; Retrospective Studies; Risk Factors; Steroids; Tacrolimus; Transplant Recipients

Living donor liver transplantation (LDLT) is now an established technique for treating children with end-stage liver disease. Few data exist about liver transplantation (LT) for exclusively young infants, especially infants of <3 months of age. We report our single-center experience with 12 patients in which LDLT was performed during the first 3 months of life and compare the results with those of older infants who underwent LT. All of the patients were treated at the National Center of Child Health and Development, Tokyo, Japan. Between November 2005 to November 2016, 436 children underwent LT. Twelve of these patients underwent LT in the first 3 months of life (median age, 41 days; median weight, 4.0 kg). The indications for transplantation were fulminant hepatic failure (n = 11) and metabolic liver disease (n = 1). All the patients received the left lateral segment (LLS) in situ to mitigate the problem of graft-to-recipient size discrepancy. A reduced LLS graft was used in 11 patients and a segment 2 monosegment graft was used in 1 patient. We compared the results with those of infants who were 4-6 months of age (n = 67) and 7-12 months of age (n = 110) who were treated in the same study period. There were significant differences in the Pediatric End-Stage Liver Disease score and the conversion rate of tacrolimus to cyclosporine in younger infants. Furthermore, the incidence of biliary complications, bloodstream infection, and cytomegalovirus infection tended to be higher, whereas the incidence of acute cellular rejection tended to be lower in younger infants. The overall cumulative 10-year patient and graft survival rates in recipients of <3 months of age were both 90.9%. LDLT during the first 3 months of life appears to be a feasible option with excellent patient and graft survival. Liver Transplantation 23 1051-1057 2017 AASLD.

Topics: Age Factors; Cyclosporine; Cytomegalovirus Infections; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Japan; Liver Failure, Acute; Liver Transplantation; Living Donors; Male; Retrospective Studies; Severity of Illness Index; Survival Rate; Tacrolimus

LT from ABO-I donors requires preconditioning regimens to prevent postoperative catastrophic AMR. NAC for HBL is known to cause myelosuppression leading to a reduction in the number and function of lymphocytes. We investigated this chemotherapy-induced myelosuppression in HBL patients listed for LT from ABO-I donors with reference to the kinetics of B, T cells, and anti-ABO blood type isoagglutinin titers. Between 2005 and 2015, of the 319 patients who underwent LDLT at our institute, 12 were indicated for unresectable HBL. Three patients with unresectable HBL who underwent LDLT from ABO-I donors are included in this study. Immunosuppression consisted of a standard regime of tacrolimus and low-dose steroids as in ABO compatible/identical LDLT. No additional preoperative therapies for B-cell depletion were used. Absolute lymphocyte counts, lymphocyte subsets (including CD20+ B cells, CD3+CD4+ T cells and CD3+CD8+ T cells), and anti-ABO blood type isoagglutinin titers were measured before LDLT and postoperatively. The median age at diagnosis was 19 months (range, 3-31 months). The median follow-up was seven months (range, 6-15 months). The median interval from the last NAC to LDLT was 33 days (range, 25-52 days). The median interval from LDLT to adjuvant chemotherapy was 28 days (range, 22-36 days). The counts of CD20+ B cells before LDLT were depleted to median 5 cells/mm(3) (range, 0-6 cells/mm(3)). There was a transient rebound in the CD20+ B cell counts on day seven (maximum of 82 cells/mm(3)) followed by a decline starting at 14 days after LDLT that was sustained for the duration of adjuvant chemotherapy. Anti-ABO blood type isoagglutinin titers were lowered to between 1:1 and 1:16 before LDLT and remained low for the duration of follow-up in this study. All of the three patients remained in good health without either acute cellular or AMR after LDLT. The B-cell depletion that occurs after cisplatin-based chemotherapy for HBL may help accomplish safe ABO-I LDLT in children without the use of additional conditioning regimens for prevention of AMR.

Topics: ABO Blood-Group System; Antigens, CD20; Antineoplastic Agents; B-Lymphocytes; Blood Group Incompatibility; CD3 Complex; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chemotherapy, Adjuvant; Child, Preschool; Cisplatin; Cytomegalovirus Infections; Female; Hepatoblastoma; Humans; Immunity, Innate; Immunosuppression Therapy; Infant; Liver Neoplasms; Liver Transplantation; Living Donors; Lymphocyte Subsets; Male; Risk; Rituximab; Tacrolimus; Transplantation Conditioning; Treatment Outcome

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

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

Tacrolimus impairs allo- and viral-specific T cell responses. Belatacept, a costimulation-based alternative to tacrolimus, has emerged with a paradoxical picture of less complete control of alloimmunity with concomitant impaired viral immunity limited to viral-naïve patients. To reconcile these signatures, bulk population and purified memory and naïve lymphocytes from cytomegalovirus (CMV)-seropositive (n=10) and CMV-seronegative (n=10) volunteers were studied using flow cytometry, interrogating proliferation (carboxyfluorescein succinimidyl ester dilution) and function (intracellular cytokine staining) in response to alloantigens or CMV-pp-65 peptides. As anticipated, T cells from CMV-experienced, but not naïve, individuals responded to pp-65 with a small percentage of their repertoire (<2.5%) consisting predominantly of mature, polyfunctional (expressing interferon gamma, tumor necrosis factor alpha and IL-2) T effector memory cells. Both CMV naïve and experienced individuals responded similarly to alloantigen with a substantially larger percentage of the repertoire (up to 48.2%) containing proportionately fewer polyfunctional cells. Tacrolimus completely inhibited responses of CMV- and allo-specific T cells regardless of their maturation. However, belatacept's effects were decreasingly evident in increasingly matured cells, with minimal effect on viral-specific triple cytokine producers and CD28-negative allo-specific cells. These data indicate that belatacept's immunosuppressive effect, unlike tacrolimus's, wanes on progressively developed effector responses, and may explain the observed clinical effects of belatacept.

Topics: Abatacept; Case-Control Studies; Cytomegalovirus; Cytomegalovirus Infections; Flow Cytometry; Humans; Immune Tolerance; Immunoconjugates; Immunologic Memory; Immunosuppressive Agents; Interferon-gamma; Isoantigens; Lymphocyte Activation; Peptide Fragments; Phosphoproteins; T-Lymphocytes; Tacrolimus; Viral Matrix Proteins

Pharmacokinetic monitoring of calcineurin inhibitors (CNIs) is unsatisfactory because, at comparable blood concentrations, side effects vary considerably. We recently confirmed the applicability of a pharmacodynamic (PD) assay that measures the suppression of CNI target genes, specifically the suppression of nuclear factor of activated T cells (NFAT)-regulated genes in liver transplant (LT) recipients. The aim of this prospective study was to prove the clinical reliability of this assay. Therefore, we quantified the residual gene expression (RGE) of NFAT-regulated genes and evaluated the association between the RGE of NFAT-regulated genes and the incidence of cytomegalovirus (CMV) infection.. In 20 LT recipients, 10 patients on cyclosporine (CsA) and 10 patients on tacrolimus (Tac) therapy, who presented with CMV infection, the RGEs of interleukin-2, interferon-γ (IFNγ), and granulocyte-monocyte colony-stimulating factor were measured and compared with the RGEs of these cytokines in 40 healthy dose-matched LT controls.. CsA-treated CMV patients demonstrated a lower RGE of all NFAT-regulated genes compared with controls (30 ± 17 vs. 44 ± 20, P = 0.067). For IFNγ, the level of significance was reached (26 ± 17 vs. 43 ± 17, P = 0.0125). Daily CsA dosage, CsA baseline (C0 ) and 2 h (C2 ) concentrations were comparable (CsA dosage 169 mg/day vs. 165 mg/day; CsA C0 94 μg/L vs. 85 μg/L; CsA C2 389 μg/L vs. 381 μg/L). In addition, Tac-treated CMV patients demonstrated a lower RGE of all NFAT-regulated genes compared with controls (68 ± 25 vs. 84 ± 22, P = 0.0769). Analogous to CsA-treated CMV patients, the level of significance was reached for IFNγ (61 ± 24 vs. 88 ± 29, P = 0.0154). Daily Tac dosage and Tac 1.5 h concentrations (C1.5 ) were comparable in both groups (Tac dosage 4 mg/day vs. 4 mg/day; Tac C1.5 8 μg/L vs. 10 μg/L), whereas Tac C0 concentrations were significantly higher in controls (Tac C0 4 μg/L vs. 6 μg/L, P = 0.0276).. Measuring the RGE of NFAT-regulated genes is appropriate to assess the risk of infections in LT recipients. Measuring the RGE of IFNγ is particularly suitable to assess the risk of CMV infection. PD monitoring of CNIs in LT recipients is an approach to individualize immunosuppression, which may help to reduce infectious complications.

Topics: Adult; Aged; Cyclosporine; Cytomegalovirus Infections; Female; Gene Expression Regulation; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; NFATC Transcription Factors; Risk Factors; Tacrolimus; Young Adult

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

Recurrence of cytomegalovirus (CMV) infection following solid organ transplantation causes mortality and morbidity in allograft recipients. The aim of this study was to evaluate prevalence and risk factors of recurrent CMV infection in kidney transplant patients.. Four hundred and twenty-seven consecutive kidney transplant recipients were included in this retrospective cohort study. Both donors and recipients were CMV seropositive. Recurrent CMV infection (symptomatic or asymptomatic) was defined as detection of CMV infection in a patient who has had previously documented infection and who had not have virus detected for an interval of at least 4 weeks during active surveillance.. Of 427 recipients, 71 (16.6%) had CMV infection, of which 19 (4.4%) were recurrent infection. Donor source, dialysis duration before transplantation, recipient and donor age and sex, and administration of antithymocyte globulin and prophylactic treatment ganciclovir were not associated with CMV infection or recurrence. The use of tacrolimus in the immunosuppressive regimen as compared to cyclosporine was an independent risk factor for CMV infection but not recurrent infection.. Intensive immunosuppressive regimen, such as using tacrolimus, might be associated with a higher risk for CMV infection, but this study was not able to document the same association for recurrent CMV disease. In patients receiving immunosuppressive regimens that include tacrolimus and antithymocyte globulin, prophylactic treatment for CMV disease with ganciclovir is recommended.

Topics: Adolescent; Adult; Aged; Antilymphocyte Serum; Antiviral Agents; Cytomegalovirus Infections; Female; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Recurrence; Retrospective Studies; Risk Factors; Secondary Prevention; Tacrolimus; Young Adult

The adenosine triphosphate assay using peripheral lymphocytes may be useful to evaluate the risks of acute rejection and infection in kidney transplant patients. We used the adenosine triphosphate assay to evaluate differences between recipients who were treated with cyclosporine- or tacrolimus-based immunosuppressive therapy.. Adenosine triphosphate levels were measured in peripheral CD4+ cells before and after transplant and were correlated with clinical outcomes in 45 kidney transplant recipients. These recipients received immunosuppressive therapy with either cyclosporine (23 patients) or tacrolimus (22 patients).. Adenosine triphosphate levels were significantly lower in the cyclosporine- than tacrolimus-based therapy groups from 2 to 6 weeks after transplant. Adenosine triphosphate levels were similar between these groups before and 1 week after transplant. The frequency of cytomegalovirus infection was greater in the recipients who received cyclosporine (17 patients [74%]) than tacrolimus (6 patients [27%]; P ≦ .003). The frequency of acute rejection episodes was similar between the cyclosporine and tacrolimus groups.. These observations suggest that cyclosporine-based immunosuppressive therapy causes excessive immunosuppression compared with tacrolimus-based therapy, evidenced by the lymphocyte adenosine triphosphate levels. The adenosine triphosphate assay using peripheral CD4+ cells may be a useful method for predicting the occurrence of cytomegalovirus infections in kidney transplant recipients.

Topics: Adenosine Triphosphate; Adult; Biomarkers; Calcineurin Inhibitors; CD4-Positive T-Lymphocytes; Cyclosporine; Cytomegalovirus Infections; Drug Monitoring; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Monitoring, Immunologic; Predictive Value of Tests; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

The mTOR inhibitor everolimus (EVL) can be used for calcineurin inhibitor-sparing immunosuppression in heart transplantation (HTx). However, comparable data regarding clinical outcomes in HTx recipients receiving EVL either with dosage reduction of cyclosporine A (CSA) or with dosage reduction of tacrolimus (TAC) is scarce. In a retrospective data analysis, we compared 5-year clinical outcomes in 154 maintenance patients receiving EVL with CSA (n=106) or TAC (n=48). The primary endpoint was a composite of death, graft loss and EVL discontinuation (treatment failure). Secondary endpoints were kidney function, cardiac rejection, cytomegalovirus infection and biochemical safety parameters. In the CSA and TAC group, the primary endpoint was reached by 59.8% and 53.1%, respectively (P=0.716). Five-year mortality was 30.4% (CSA group) and 23.13% (TAC group), respectively (P=0.371), and freedom from EVL discontinuation was 53.3% and 59.6% (P=0.566) in the respective groups. Covariate-adjusted relative risk of treatment failure was in the CSA group=1.28 (95% CI: 0.70-2.34; P=0.43) compared with the TAC group. The course of covariate-adjusted estimated glomerular filtration rate and freedom from cytomegalovirus infection was similar in the two groups (P=0.502 and P=0.476), whereas covariate-adjusted freedom from rejection was lower in the CSA group compared with the TAC group (P=0.023). Lipid status and blood cell counts were comparable between groups. In conclusion, data indicate that EVL plus reduced TAC is not superior to EVL plus reduced CSA regarding treatment failure and kidney function. However, compared with EVL plus reduced CSA, EVL plus reduced TAC seems to reduce cardiac rejections.

Topics: Calcineurin Inhibitors; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome

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

The study was conducted to assess serious infectious complications in five hand allograft recipients (four males, one female, age 40 ± 10 years), transplanted between 2006 and 2010. All donors and recipients were positive but one for cytomegalovirus (CMV) immunoglobulin G. All recipients received immunosuppressive therapy basiliximab, tacrolimus, mycophenolate mofetil and methylprednisolone. Until May 2013, there were four cases of severe infections requiring hospitalization. One patient developed CMV infection on the 28th postoperative day. Despite therapy with ganciclovir and prophylaxis with valganciclovir, reinfection episodes occurred both 4 weeks and 7 months later. The female recipient developed CMV infection 8 months after hand transplantation. After 3 weeks of ganciclovir treatment, the polymerase chain reaction results remained negative. We found that the CD4/CD8 T lymphocytes ratio differs in those two patients who had developed CMV disease in the past in comparison to the three remaining hand transplant recipients (mean 0.46 versus 1.7, respectively). Moreover, the ratio of patients who were CD4-8 negative to total T lymphocytes in CMV recovered patients was two-fold higher compared to the remaining recipients (10.0 versus 4.4, respectively). The female recipient was also hospitalized because of acute tonsillitis 25 months after hand transplantation, and successfully treated with amoxicillin clavulanate. The third recipient was hospitalized because of severe acute pain involving right lower limb, especially foot, 74 months after hand transplantation. After 48 hours, a painful vesicular rash occurred on the plantar as well as dorsal surface of right foot and herpes zoster was diagnosed. Immunosuppressive therapy after hand transplantation may be complicated by serious infections. CMV disease was associated with persistent alterations in T lymphocyte subsets.

Topics: Adult; Allografts; Antiviral Agents; Cytomegalovirus Infections; Female; Hand Transplantation; Humans; Immunosuppression Therapy; Male; Middle Aged; Poland; Postoperative Complications; Retrospective Studies; T-Lymphocyte Subsets; Tacrolimus; Transplantation, Homologous; Vascularized Composite Allotransplantation

The aim of this study is to evaluate whether the combination of the ImmuKnow assay (IMK) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for identifying the risk of morbidity and mortality in living donor liver transplantation (LDLT) patients, and also to investigate the optimal cutoff value of IMK level of immune status.. Sixty six LDLT patients, who were randomly screened by using IMK between March 2002 and June 2011, were divided into 2 groups: patients in whom at least 1 IMK value was <175 ng/mL (Group A, n=16) and patients in whom all IMK values were >175 ng/mL (Group B, n=50). Both donors and recipients were evaluated for the CYP3A5 genotype.. The frequencies of cytomegalovirus and bacterial infection in Group A were significantly higher than those in Group B (P<0.001). The short term mortality was 4 (25.0%) in Group A and none in Group B, and the IMK level in all four cases became <100 ng/mL at least one time before death. The rate of CYP3A5*1 allele (expressors) among recipients was significantly higher in Group A than in Group B (63.6% vs. 22.2%, P=0.0147). The rates of CMV infection and bacterial infection, and the IMK levels was significantly higher in recipients with expressors (p=0.0216, p=0.0332, and p=0.0433, respectively).. The combination of the IMK and CYP3A5 genotype assay is useful for monitoring immune status after LDLT, and the IMK level <100 ng/ml might be the critical level to make a recovery from the severe immunesupressive condition.

Topics: Adolescent; Adult; Aged; Bacterial Infections; Child; Child, Preschool; Cytochrome P-450 CYP3A; Cytomegalovirus Infections; Female; Genotype; Humans; Immunoassay; Immunosuppressive Agents; Infant; Infections; Liver Transplantation; Living Donors; Male; Middle Aged; Morbidity; Polymorphism, Single Nucleotide; Risk Factors; Tacrolimus; Young Adult

To establish a fluorescent quantitative PCR method (FQ-PCR) with TaqMan probe for simultaneous detection of polyomavirus (BKV) and cytomegalovirus (CMV) and to evaluate its clinical application in the renal transplantation recipients. The conservative sequences of BKV and CMV were targeted and amplified by nested PCR technique. The PCR products were cloned into the plasmids pcDNA3. 1(+). The recombinant plasmid containing target sequences of BKV and CMV were constructed as external standards. The TaqMan-based assay was optimized. For evaluating the assay, the sensitivity was determinated by diluted standard (5 X 103-10icopies/mL), and the specificity was verified by negative control and positive control, and the precision was assessed by intra-assay coefficient of variation (ICV) through detecting standard repeatedly (20 times). A total of 480 blood samples of renal transplantation recipients were used to detect BKV and CMV DNA simultaneously with FQ-PCR, and the concentrations of FK506 were measured by ELISA. The association of DNA copy and concentrations of FK506 was analyzed. The cloned target BKV and CMV DNA was confirmed by sequencing and analysis. The sensitivity of the FQ-PCR assay reached 5 X 103 copies/ml in detecting BKV or CMV DNA. Control DNA verified the assay specifically detecting target DNA. The precision of the assay to quantif target DNA copies was acceptable (Intra-assay CV was 3.44% for BKV and 2.23% for CMV; Inter-assay CV was 4. 98% for BKV and 3.76% for CMV;). Of 480 samples, 130 samples (27. 08%) were CMV DNA positive, significantly higher than the BKV DNA positive (13.33%, 64/480, P<0.05). The positive BKV or CMV DNA was found to be associated with high concentrations of FK506 (P<0. 05). In conclusion, the developed real-time PCR assay for detecting both CMV and BKV DNA simultaneously was s high sensitive, precise and time-effectiveand could be applied in the monitoring of the CMV and BKV infection in the renal transplantation recipients.

Topics: Adolescent; Adult; Aged; Conserved Sequence; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Polyomavirus; Polyomavirus Infections; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Sensitivity and Specificity; Species Specificity; Tacrolimus; Time Factors; Tumor Virus Infections; Viral Load; Young Adult

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

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

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

Cytomegalovirus (CMV) -specific immunity is often estimated by the number of in vitro CMV antigen-inducible interferon-γ-positive (IFN-γ(+) ) T cells. However, recent work indicates that simultaneous production of IFN-γ, tumour necrosis factor-α (TNF-α) and interleukin-2 (IL-2) (referred to as 'polyfunctionality') is more relevant for anti-viral protection. Here, we compared polyfunctionality of CMV-specific T cells (pp65 and IE-1 proteins) in 23 solid-organ transplant patients and seven healthy controls by flow cytometry. The proportions of TNF-α(+) /IFN-γ(+) /IL-2 cells among the activated cells were significantly reduced in transplant patients but not the frequencies of IFN-γ(+) CD8(+) T cells. Immunosuppression reduces polyfunctionality, which reflects the increased infection risk in this patient group.

Topics: Adolescent; Adult; CD8-Positive T-Lymphocytes; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Female; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-2; Lymphocyte Activation; Male; Middle Aged; Organ Transplantation; Tacrolimus; Tumor Necrosis Factor-alpha; Young Adult

Basiliximab is a recently developed immunosuppressive agent for the prevention of acute allograft rejection in renal transplant recipients. The combination use of basiliximab and a calcineurin inhibitor was suggested to be more effective in comparison to immunosuppressive therapy using calcineurin inhibitor without basiliximab. Cyclosporine has been generally administered with basiliximab for renal transplant recipients. However, in cases of tacrolimus-based immunosuppressive regimen, the clinical efficacy and safety of combined use of tacrolimus and basiliximab remains to be elucidated. This study evaluated the tacrolimus pharmacological efficacy using a lymphocyte immunosuppressant sensitivity test (LIST) with MTT assay procedures in 16 cases of renal transplant recipients treated by tacrolimus without basiliximab and in 13 cases treated by tacrolimus in combination with basiliximab. The rate of acute rejection episodes in the recipients treated with tacrolimus plus basiliximab was 1/13 (7.7%), whereas the rate in the recipients treated with tacrolimus without basiliximab was 6/16 (37.5%). The recipients were divided into two groups according to their peripheral blood mononuclear cell (PBMC) sensitivity to tacrolimus [i.e., including a tacrolimus high sensitivity group (IC(50) <1.0 ng/ml) and a low sensitivity group (IC(50) >1.0 ng/ml). In the recipients treated with tacrolimus without basiliximab, the rate of acute rejection episodes in the tacrolimus high sensitivity group was 1/10 (10.0%), which was significantly lower than the rate in the low sensitivity group of 5/6 (83.3%; p = 0.008). The incidence of cytomegalovirus infection was not significantly different between the tacrolimus high and the low sensitivity groups of the recipients treated with tacrolimus with and without basiliximab. Therefore, in the case of selected tacrolimus-based immunosuppressive therapy for renal transplant recipients, the tacrolimus pharmacological efficacy should be evaluated using LIST at a time just before the transplant procedure in order to accurately predict allograft rejection. The data also suggested that low tacrolimus sensitivity recipients should be treated with tacrolimus-based immunosuppressive therapy in combination with basiliximab.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Calcineurin; Calcineurin Inhibitors; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Leukocytes, Mononuclear; Male; Middle Aged; Recombinant Fusion Proteins; Tacrolimus

The present study was designed to determine the pharmacokinetic profiles of a once-daily formulation of tacrolimus (CAS 104987-11-3; TAC-once) in patients before and after introduction of renal transplantation. Pharmacokinetic parameters for tacrolimus were almost comparable among patients receiving TAConce before, 2 weeks after and 3 weeks after renal transplantation. Among various parameters, C(trough) correlated most closely with the area under the concentration-time curve during 24 h (AUCo-24) (R2 = 0.82, P < 0.001), while no consistent correlation was observed between AUCo_24 and concentrations at 2 h or 4 h, or the dose of TAC-once. The clinical outcomes such as the incidence of acute re-jection, renal tissue injury and cytomegalovirus infection were evaluated during the first 3 weeks and 3 months after transplantation, and the data were compared with the historical data obtained from patients who had received the conventional twice-daily formulation of tacrolimus (TAC-twice). There were no significant differences in the incidence of such clinical outcomes between the two groups. These findings suggest that C(trough) is useful for therapeutic monitoring of tacrolimus in patients receiving TAC-once. In addition, pharmacokinetics and clinical outcomes were comparable between TAC-once and TAC-twice formulations.

Topics: Adolescent; Adult; Area Under Curve; Chemistry, Pharmaceutical; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Treatment Outcome; Young Adult

The optimal balance between efficacy and toxicity of tacrolimus (Tac) treatment remains unsolved. The quantification of nuclear factor of activated T cell (NFAT)-regulated gene expression may provide a tool to monitor the individual susceptibility to Tac.. Expression of NFAT-regulated genes (interleukin-2, interferon-gamma, and granulocyte-macrophage colony stimulating factor) in peripheral blood from renal transplant patients (N = 73) was measured by quantitative real-time polymerase chain reaction (at C0, C1.5, and C4) and correlated to clinical endpoints in a 1-year observation period. In a subgroup (n = 10), NFAT expression was quantified over a 12-hour dose interval.. Median daily Tac dose of 73 stable renal transplant patients [median age 47 years (range 19-69 years)] was 5 mg (1-13), Tac trough (C0), 1.5-hour (C1.5) and 4-hour (C4) concentrations were 8.5 mcg/L (3-20), 20 mcg/L (4.7-50.4), and 14.5 mcg/L (4.5-37.5), respectively. The mean residual expression of all 3 NFAT-regulated genes was 21% at C1.5 (1-84) and 35% at C4 (2-88). The relative reduction of gene transcripts was inversely correlated with the individual Tac blood concentrations. Seven patients had cytomegalus virus viremia during the observation period, and their residual NFAT-regulated gene expression at C1.5 was significantly lower [13% (1-21) versus 26% (1-84), P = 0.02] compared with those without viremia despite comparable Tac blood concentrations (6.3 versus 8.6 mcg/L).. Monitoring of NFAT-regulated gene expression in Tac-treated transplant recipients provides a tool to assess the individual response to Tac, identify patients at the risk of developing cytomegalus virus viremia, and may, thus, help to select the optimal Tac dose with respect to safety and toxicity.

Topics: Adult; Aged; Aged, 80 and over; Cytomegalovirus; Cytomegalovirus Infections; Female; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-2; Kidney Transplantation; Male; Middle Aged; NFATC Transcription Factors; Real-Time Polymerase Chain Reaction; Tacrolimus; Viremia; Young Adult

In an earlier study, we were able to show that Tac monotherapy following 2 × 20 mg alemtuzumab induction is at least as effective as Tac-based triple-drug immunosuppression in cadaveric renal transplantation. We were interested to learn whether 1 × 30 mg of alemtuzumab is as effective as 2 × 20 mg. Patients of the initial study group (group A) received 20 mg alemtuzumab on days 0 and 2, and tac monotherapy from day 2 on. This group acted as control group for the new arm (group C), where patients were given only 1 × 30 mg alemtuzumab on day 0 followed by Tac monotherapy from day 2 on with the same target levels as in the control group. Frequency of rejection at 6 months was 15% in the control group compared to 6% in the study group and 20% at 12 months in group A versus 6% in group C (P = 0.034). Time to rejection was 4.9 months in group A and 0.8 in group C. One-year patient survival was 98.5% in both groups, graft survival 96.9% in group A, and 98.5% in group C. Safety profile was similar in both groups apart from more viral and bacterial infections in group C. Single shot alemtuzumab induction of 30 mg is as effective as 2 × 20 mg in cadaveric renal transplantation.

Topics: Adolescent; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neoadjuvant Therapy; Tacrolimus; Treatment Outcome

Though steroid withdrawal is done in many renal transplant recipients, some patients must restart steroids. Little report has investigated steroid withdrawal under pharmacodynamic monitoring. We assessed lymphocyte sensitivity to endogenous cortisol as a biomarker for determining the safety of steroid withdrawal in renal transplant patients, as we hypothesized that patients hyposensitive to cortisol could not be sufficiently immunosuppressed by their intrinsic cortisol as a substitute for the reduced or withdrawn steroid. Lymphocyte sensitivity to cortisol was examined in 30 long stable renal transplant recipients. Lymphocyte sensitivity to cortisol and its relationship with the clinical outcome after steroid reduction and withdrawal was investigated. The lymphocyte sensitivities to cortisol were estimated as IC(50) of lymphocyte blastogenesis. The lymphocyte proliferation rate for concentration of serum cortisol compared between incident and non-incident groups. Serum creatinine levels (S-Cr) increased in a significantly higher number of patients hyposensitive to cortisol (IC(50)≧10000 ng/ml) than in normally sensitive patients (IC(50)<10000 ng/ml). The incidences of steroid withdrawal syndrome and necessity for increasing steroid dose or restarting steroid administration were also higher in the patients hyposensitive to cortisol. The patients in whom the lymphocyte proliferation rate was less than 60% did not show increase in S-Cr, experience steroid withdrawal symptoms, or require an increase in the steroid dose or restart of steroid administration. The patients who have the normal IC(50) values of cortisol, can withdraw steroid more safely. The lymphocyte sensitivity to cortisol may be a useful biomarker for selecting patients who can sustain steroid withdrawal.

Topics: Adrenal Cortex Hormones; Adult; Biomarkers, Pharmacological; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Graft Rejection; Humans; Hydrocortisone; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lymphocytes; Male; Methylprednisolone; Middle Aged; Prednisolone; Receptors, Cell Surface; Steroids; Tacrolimus; Time Factors

Sixty-six adult patients with hematologic malignancies underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) without T cell depletion. The patients were preconditioned with a reduced intensity regimen, and tacrolimus was used for graft-versus-host disease (GVHD) prophylaxis. Successful engraftment occurred in 60 patients (90.1%) and graft rejection in only 4 patients (6.1%). Among the 60 engrafted patients, only 5 developed severe (grade III or IV) acute GVHD. Twenty patients, including 19 relapse-free patients were alive at a median follow-up of 48 months (range 6-77 months). The overall survival (OS) at 6 years was 29.3%. The OS of 45 patients < 60 years of age was 43.6%, which was superior to that of 21 patients who were 60 years of age and older (9.5%) (P < 0.01). The OS of 11 patients from human leukocyte antigen (HLA) 1 locus-mismatched donors (63.6%) was higher than that of 28 patients from HLA 3 loci-mismatched donors (12.5%) (P < 0.01). Organ injury and infection were the main causes of mortality. Notably, immunosuppressive therapy could be successfully stopped in 9 patients transplanted from HLA 2 or 3 loci-mismatched donors with a median duration of 45 months (range 5-71 months). These data suggest that haplo-HSCT is a promising treatment for patients who need urgent allogeneic transplantation but lack HLA-identical family donors.

Topics: Adolescent; Adult; Aged; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Graft vs Host Disease; Haplotypes; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Japan; Lymphocyte Count; Lymphocyte Subsets; Male; Middle Aged; Recurrence; Survival Analysis; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Young Adult

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

Routine prophylaxis for CMV with valganciclovir is common in adult recipients but data to support its use in children are scarce. The aim of this study was to compare the efficacy and safety of valganciclovir vs. ganciclovir in a pediatric cohort. We performed a retrospective analysis of 92 children after KTx and/or LTx. All children have received IV ganciclovir for two wk, and then oral ganciclovir (TID; n = 41) before 2004, or valganciclovir (OD; n = 51) thereafter. Treatment was given for three months in R+/D+ or R+/D- recipients and for six months in R-/D+. Patients were followed for one yr post transplant. Both groups were comparable in their demographic and transplant-related history. Symptomatic CMV infection/disease developed in 13.7% vs. 19.5% of valganciclovir and ganciclovir groups, respectively (P-NS). Time-to-onset of CMV infection was comparable in both groups (P-NS); rates of acute allograft rejection were similar in both groups (3.9% vs. 9.8%). Risk factors for CMV infection included young age, serostatus of R-/D+, and allograft from cadaver donor. No significant side effects were noted in both groups. As in adults, valganciclovir appears to be as efficacious and safe as oral ganciclovir. Valganciclovir should be considered as a possible prophylactic treatment for CMV in pediatric recipients of KTx or LTx.

Topics: Administration, Oral; Adolescent; Antiviral Agents; Child; Child, Preschool; Cytomegalovirus Infections; Disease-Free Survival; Drug Therapy, Combination; Female; Ganciclovir; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Liver Transplantation; Logistic Models; Male; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome; Valganciclovir

Cytomegalovirus (CMV) infection represents one of the most frequent opportunistic infections following solid-organ transplantation. The incidence and severity of CMV infection depend on the immunosuppressive regimen, the CMV serostatus of donor and recipient, and the type of transplant.. We evaluated CMV infection rates during the last 2 years in our center: March 2007 to March 2009. We enrolled 55 patients-13 females and 42 males-who underwent liver transplantation (OLT) due to hepatitis C virus (HCV) cirrhosis (n = 9), hepatitis B virus (HBV) cirrhosis (n = 5) HCC both on HCV and HBV cirrhosis (n = 37), or autoimmune disease (n = 4). Fifty percent of the patients received tacrolimus (TRL) and the others cyclosporine (CsA), both dosed according to weight. All patients received oral acyclovir (400 mg/td or less, adapted to renal function) as herpes simplex prophylaxis for 6 months. CMV prophylaxis prescribed CMV- hyperimmunoglobulin on postoperative days 1 and 7. CMV infection was monitored using polymerase chain reaction (PCR <1000 IU/mL) according to the following schedule: every week for the first month, every 2 weeks from month 2 to 3 and monthly from month 4 to 6. Patients were treated when three positive PCR results not affected by immunosuppressive dose reduction or when the PCR showed DNA greater than three times the limit of detection. CMV treatment stipulated valgancyclovir (900 mg twice daily) until three consecutive PCRs were negative or for 3 months dosed according to renal function. PCR was measured every 2 weeks during treatment.. Among the patients who were all D(+)/R(+) (CMV-Immunoglobulin G [IgG](+)/IgG(+)). 10 required treatment (18%) within 3 months from OLT. There subjects were prescribed TRL (n = 4) or CsA (n = 6). No renal impairment was observed among treated patients. Of those having the infection, one died due to other causes-sepsis from candida at 5 months after OLT.. CMV-hyperimmunoglobulin on postoperative days 1 and 7 did not confer protection for CMV among OLT patients. Preemptive treatment with intravenous gancyclovir plus valgancyclovir per os seemed to be useful and safe in infected patients requiring treatment.

Topics: Acyclovir; Antiviral Agents; Corticosterone; Cyclosporine; Cytomegalovirus Infections; Female; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Retrospective Studies; Tacrolimus

New-onset diabetes after transplantation (NODAT) is a frequent complication after liver transplantation and has a negative impact on both patient and graft survival. In analogy with the previous finding of an association between posttransplant hypomagnesemia and NODAT in renal transplant recipients, the relation between both pretransplant and posttransplant hypomagnesemia and NODAT was studied in liver transplant recipients (LTRs). One hundred sixty-nine adult LTRs (>18 years old) without diabetes who underwent transplantation between 2004 and 2009 were studied (mean age = 52.11 ± 12.6 years, proportion of LTRs who were male = 67.5%, body mass index = 25.5 ± 4.4 kg/m², proportion receiving tacrolimus = 90.0%). NODAT was defined according to the American Diabetes Association criteria. The association of NODAT with both pretransplant and posttransplant serum magnesium (Mg) was examined. Overall, 52 of 169 patients (30.8%) developed NODAT, and 57.7% of these (30 patients) were treated with antidiabetic drugs. Both pretransplant Mg levels and Mg levels in the first month after transplantation were lower in patients developing NODAT (P = 0.008 and P = 0.001, respectively). A multivariate regression model (adjusted for weight, pretransplant glucose levels, hyperglycemia in the first week after transplantation, gender, hepatitis C, and corticosteroid dosing) demonstrated both pretransplant Mg levels (hazard ratio = 0.844 per 0.1 mg/dL increase, 95% confidence interval = 0.764-0.932, P = 0.001) and posttransplant Mg levels (hazard ratio = 0.659, 95% confidence interval = 0.518-0.838, P = 0.001) to be independent predictors of NODAT together with age, biopsy-proven acute rejection, and cytomegalovirus (CMV) infection in the first year after transplantation. In conclusion, pretransplant hypomagnesemia and early posttransplant hypomagnesemia are independent predictors of new-onset diabetes after liver transplantation. Other risk factors are age, biopsy-proven acute rejection, and CMV infection.

Topics: Adult; Biomarkers; Case-Control Studies; Cytomegalovirus Infections; Diabetes Mellitus; Female; Graft Survival; Humans; Hyperglycemia; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Magnesium; Male; Metabolic Diseases; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Risk; Risk Factors; Tacrolimus; Young Adult

A retrospective review of pediatric lung transplant recipients at 14 centers in North America and Europe was conducted to characterize the epidemiology and the risk factors for cytomegalovirus (CMV) and to explore the impact of preventative antiviral therapy.. Data were recorded for 1 year posttransplant. Associations between CMV and continuous and categorical risk factors were assessed using Wilcoxon rank sum and chi-square tests, respectively. Associations between time to CMV and risk factors or survival were assessed by multivariable Cox proportional hazards models.. Within 12 months posttransplant, 172 of 577 subjects (29.8%) developed 218 CMV episodes (90 asymptomatic infection, 25 syndrome, and 103 disease). Forty-one subjects developed more than one episode of CMV. Donor or recipient CMV seropositivity was associated with increased risk of CMV episodes. Except for decreased prophylaxis in CMV D-/R- subjects, duration of prophylaxis did not vary by D/R serostatus. For CMV D+ subjects, not being on prophylaxis at the time of CMV episode increased the risk of CMV (D+/R+ hazard ratio 3.5, 95% confidence interval 1.4-8.4; D+/R- 1.9, 1.02-3.7). CMV was associated with increased mortality within the first posttransplant year among those with donor or recipient CMV seropositivity (hazard ratio 2.0: 95% confidence interval 1.1-3.6; P=0.024).. CMV remains a serious complication after pediatric lung transplant, and the impact of prophylaxis is complex.

Topics: Acute Disease; Bronchiolitis Obliterans; Child; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Europe; Female; Graft Rejection; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Incidence; Lung Transplantation; Male; Multivariate Analysis; North America; Retrospective Studies; Survival Analysis; Survivors; Tacrolimus

Risk of new-onset diabetes after transplant (NODAT) is well characterized for adults but much less understood in pediatric transplant. This study examines the incidence and risk factors of NODAT in pediatric renal transplant patients.. The incidence of NODAT over the first 3 years after transplant was examined with the United States Renal Data System data for primary renal transplant recipients (ages 0-21 years, transplanted between 1995 and 2004) with Medicare primary. Patients had no evidence of diabetes before transplant. We estimated the cumulative incidence rate and used Cox proportional hazards regression to identify the risk factors for NODAT. Propensity scores were calculated for immunosuppression choice to adjust for potential confounding factors.. Two thousand one hundred sixty-eight recipients with valid immunosuppression records and without pretransplant evidence of diabetes were included. Unadjusted, cumulative NODAT incidence at 3 years posttransplant was 7.1%. Significant factors for increased risk of NODAT included cytomegalovirus D+/R- serostatus (adjusted hazard ratio [aHR]=1.60), age 13 to 18 years (aHR=2.18), age 19 to 21 years (aHR=2.60), body mass index more than or equal to 30 kg/m (aHR=2.17), and use of tacrolimus (aHR=1.51). We failed to find any significant relationships between NODAT and graft failure or death.. Although the incidence of NODAT among patients aged 0 to 21 years is lower than that for adult patients, it is higher than suggested by earlier research and may represent an increase over time. The lack of association between NODAT and graft or failure death has important implications for posttransplant care. A clearer understanding of risk factors can help guide posttransplant monitoring and clinical decision making.

Topics: Adolescent; Age Factors; Body Mass Index; Child; Child, Preschool; Cytomegalovirus Infections; Diabetes Mellitus; Female; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Kidney Transplantation; Male; Proportional Hazards Models; Registries; Risk Assessment; Risk Factors; Tacrolimus; Time Factors; United States; Young Adult

To explore the etiopathogenesis, therapy and incidence of pulmonary infection in kidney transplantation recipients taking new immunosuppressant.. The clinical data from 752 kidney transplant recipients were retrospectively analyzed, who were divided into 3 groups according to the immunosuppressants administered, namely group A (CsA+MMF+Pred, n=226), group B (FK506+MMF+Pred, n=386) and group C (FK506+Rap+Pred, n=140). The incidence and mortality of pulmonary infection were recorded and the analysis of etiopathogenesis, diagnosis and therapy of pulmonary infection were carried out in the 3 groups.. Fifty-three patients acquired post-transplant pulmonary infection. The incidence of pulmonary infection was 7.08% (16/226) in group A, 7.25% (28/386) in group B and 6.43% (9/140) in group C. One patient died in group A and 2 in group B. Among the 53 patients, 24 had simple bacterial infection, 9 had cytomegalovirus infection, 1 had mycotic infection, 17 had combined infection, and 2 had unidentified pathogen infection. Of the pathogenic bacteria detected, 68.35% were Gram-negative.. Gram-negative bacteria are most likely responsible for pulmonary infection after kidney transplantation, which most possibly occurs within 6 months after kidney transplantation. Early diagnosis and early treatment are critical for decreasing the mortality of severe pneumonia and for improving the survival rate of the patients and grafts.

Topics: Adolescent; Adult; Aged; Cyclosporine; Cytomegalovirus Infections; Female; Gram-Positive Bacterial Infections; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases; Male; Middle Aged; Tacrolimus

The short-term results of kidney transplantation are mainly attributed to the use of calcineurin inhibitors (CNI). However, opportunistic infections and cytomegalovirus (CMV) infections remain frequent and occur in the case of overimmunosuppression. Measurement of the biological effects of CNI could provide clues to identify overimmunosuppressed kidney transplant recipients (KTR) who would subsequently develop CMV infection.. Forty-one KTR given cyclosporine (n=18) or tacrolimus (n=23) were followed up every week during 1 month, then every month during 11 months, by measuring the patient's whole blood ability to inhibit interleukin-2 (IL-2) gene transcription and by measuring the patient's intracellular T-cell IL-2, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) production in response to polyclonal activation.. Cytomegalovirus infection or disease occurred in 19 patients and was significantly associated with CMV serological status D+R- and D+R+ (HR=19.6 and 6.6, respectively, P=0.0001). Immunosuppressive treatment was associated with a long-lasting decrease of all cytokines produced by the patient's T-cells. However, none of these assays taken separately at any of the time points of the follow-up allowed to predict the occurrence of a subsequent CMV infection. We only observed a weak association between cumulative low levels of the percentage of TNF-alpha producing CD8+ T cells before CMV infection and its occurrence just afterwards (HR=1.39 for 1000 unit lower, P=0.04). However, this association did not remain significant after adjustment for CMV serological status.. This study suggests that immunological monitoring is not better than CNI whole blood levels for diagnosis of overimmunosuppression-induced CMV infection in KTR.

Topics: Adult; Area Under Curve; Calcineurin Inhibitors; Cyclosporine; Cytomegalovirus Infections; Drug Monitoring; Female; Flow Cytometry; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-2; Jurkat Cells; Kidney Transplantation; Male; Middle Aged; Monitoring, Immunologic; Predictive Value of Tests; Promoter Regions, Genetic; Prospective Studies; Reproducibility of Results; T-Lymphocytes; Tacrolimus; Time Factors; Transcription, Genetic; Treatment Outcome; Tumor Necrosis Factor-alpha

Thymoglobulin (rATG) has become the agent of choice for induction therapy in high immunological risk kidney transplant recipients. However, its optimal dosing in this subgroup has not been studied.. To evaluate the effect of total rATG dosing on graft outcomes in such patients, we conducted a retrospective cohort study of 96 adult patients who received repeat transplants (85%) or had panel reactive antibody more than 40% (19%) and were maintained on tacrolimus, mycophenolate mofetil, and steroid. Group 1 (n=33) received less than or equal to 7.5 and group 2 (n=63) received more than 7.5 mg/kg rATG. Graft and patient survival, incidence of acute rejection (AR), and 12-month serum creatinine (SCr) were examined.. The groups were comparable regarding demographics, donor source, retransplantation, panel reactive antibody, and human leukocyte antigen mismatch. Group 2 had more African Americans (44.4% vs. 21.2%, P=0.03). During the 25.4+/-18.0 months follow-up graft survival was 82.5% and 79.4%, respectively (P=0.54). Three in group 1 and four in group 2 died (P=0.65). The incidence of biopsy proven AR during the first 12-months did not differ between the groups (9.5% vs. 8.8%, respectively, P=0.9). SCr at 12 months was 1.6+/-0.7 in group 1 and 1.8+/-1.0 in group 2 (P=0.3). There was no independent association between rATG dose and graft survival (hazard ratio: 0.85, P=0.79, 95% CI: 0.26-2.7 for group 2 vs. 1) or 1-year SCr (regression coefficient=0.02 for ln(SCr), P=0.3; 95%CI: -0.01 to 0.6).. Our results suggest that in high risk kidney transplant recipients total rATG doses less than or equal to 7.5 mg/kg are safe and effective in achieving a low rate of AR and graft outcomes comparable to higher doses.

Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Antiviral Agents; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prednisone; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus

We evaluated the relevance of human cytomegalovirus (HCMV) monitoring with quantitative real-time polymerase chain reaction in 42 consecutive HCMV positive liver transplant patients, and we analyzed the factors that determined the treatment of the first episode of HCMV DNAemia. No patients received anti-HCMV prophylaxis. HCMV infection monitoring was assessed every 2 weeks until day 90 and thereafter at every 3 to 4 weeks until day 180. HCMV infection was detected among 27 patients (64%, ie, 92/380 samples). Of these, 12 had their first HCMV DNAemia treated with IV gancyclovir (group I), whereas the other 15 patients were not treated (group II). Immunosuppressive treatment was not modified in cases of HCMV DNAemia. The median time between transplantation to the first CMV DNAemia was 37 days in group I and 52 days in group II (NS). Median HCMV viral load, whatever the treatment group and whatever the time of DNAemia, was 3 log copies/mL (0.48 to 5.80). Median HCMV viral load of the first positive DNAemia was 3.45 log copies/mL (1.69 to 5.80) in group I and 2.70 log copies/mL (1.15 to 3.94) in group II (P = .01). Even though liver enzymes were increased in almost all patients presenting with HCMV infection, comparison of liver-enzyme levels and hematological parameters between the two groups at first HCMV viremia showed that alkaline phosphatase levels were significantly higher (P = .0011) and hemoglobin levels were significantly lower in group I patients (P = .0443). The only factor that predicted treatment for the first episode of HCMV DNAemia was an alkaline phosphatase level >150 UI/mL at the time of the first HCMV reactivation [odds ratio 20 (1.96 to 203.3); P = .01].

Topics: Adrenal Cortex Hormones; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Humans; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Polymerase Chain Reaction; Postoperative Complications; Retrospective Studies; RNA, Viral; Tacrolimus; Viral Load; Viremia

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

Topics: Acute Kidney Injury; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytomegalovirus Infections; Etoposide; Glomerulonephritis, Membranous; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Prednisone; Rituximab; Sepsis; Staphylococcal Infections; Tacrolimus; Transplantation Conditioning

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

Intestinal transplantation has developed to become the standard of care for patients with irreversible intestinal failure who are not responding to total parenteral nutrition. Once considered experimental, it has taken time and much effort for the procedure to become a clinical reality, with final acceptance primarily because of the vastly improved outcomes. Advances and novel modifications in immunosuppression have been at the forefront of these improvements. The authors review their evolutionary experience with intestinal transplantation, particularly relating changes in immunosuppression protocols to improved outcomes.. From July 1990 to December 2003, 122 children received 129 intestinal containing allografts (70 liver/intestine, 42 isolated intestine, 17 multivisceral). Mean age was 5.3 +/- 5.2 years, and 55% were boys. Indications for transplantation were mostly short gut syndrome. The allografts were cadaveric, ABO identical (except one), with no immunomodulation. Bone marrow augmentation was used in 29% of the recipients since 1995. T-cell lymphoctytotoxic crossmatch was positive in 24% cases. Immunosuppression protocols can be divided into 3 categories: (i) maintenance tacrolimus and steroids (n = 52, 1990-1995, 1997-1998); (ii) addition of induction therapy with cyclophosphamide (n = 16, 1995-1997) then daclizumab (n = 24, 1998-2001). A third immunosuppressive agent was added in either group where increased immunosuppression was indicated; (iii) pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy (n = 37, 2002-2003). In this later group, if clinically stable at 60 to 90 days posttransplantation, and no recent rejection, the tacrolimus was weaned by decreasing frequency of dosing.. The overall Kaplan-Meier patient/graft survival was 81%/76% at 1 year, 62%/60% at 3 years, and 61%/51% at 5 years. Survival continues to improve, with 1-year patient/graft survival being 71%/62%, 77%/75%, and 100%/100% for groups (i), (ii), and (iii), respectively. Acute intestinal allograft rejection has decreased markedly in group (iii). The rate of infectious diseases, such as cytomegalovirus and Epstein-Barr virus, is lowest in group (iii). Graft-versus-host disease has not significantly increased with the latest protocol. Most importantly, the overall level of immunosuppression requirements has decreased markedly, with most patients in group (iii) being on monotherapy. Of these, most had their monotherapy weaned down to spaced doses, something never systematically attempted or achieved in pediatric intestinal transplantation.. Intestinal transplantation has progressed markedly over the last 13 years. Although there have been modifications in all aspects of the procedure, the story of intestinal transplantation has been the evolution of successful immunosuppression regimens. Our latest pretreatment/induction conditioning and posttransplantation monotherapy strategy improves graft acceptance and lowers subsequent immunosuppression dosing requirements. It is expected this will overcome many of the complications related to the previously high immunosuppression requirements. Minimization of immunosuppression with avoidance of steroid therapy offers profound long-term benefits, especially in the pediatric population. The patients still remain challenging and complex in every aspect; however, these advances offer significant hope to both patients and caregivers alike.

Topics: Adolescent; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Child; Child, Preschool; Cyclophosphamide; Cytomegalovirus Infections; Daclizumab; Epstein-Barr Virus Infections; Female; Graft Rejection; Graft Survival; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Intestinal Diseases; Intestines; Male; Organ Transplantation; Survival Analysis; Tacrolimus; Transplantation Conditioning

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

Up to date, 24 hands/thumbs have been transplanted in 18 patients. We herein report on cytomegalovirus (CMV) infection, disease, and the adopted treatment.. Immunosuppression consisted of tacrolimus-based triple-drug therapy with antithymocyte globuline or CD25-receptor antagonist induction. Donor/recipient CMV match was negative/negative (n=8), negative/positive (n=3), positive/positive (n=3), positive/negative (n=3) and unknown in one case. Six patients (three +/-, two +/+, and one -/+) received gancyclovir i.v. followed by oral gancyclovir or valgancyclovir for prophylaxis.. Patient and graft survival at a mean follow-up of 42.9 months were 100% and 91%, respectively. Of all patients tested for CMV, 45.5% developed CMV infection or disease. Two patients that were given a CMV-positive graft showed very high viral loads (550 and 1200/200000 leukocytes) after transplantation. Gancyclovir treatment failed to permanently control CMV in 80% of the patients experiencing CMV infection. Those patients requiring more toxic second-line therapies (foscarnet/cidofovir) suffered from side effects such as nephrotoxicity, nausea, vomiting, and diarrhea.. CMV infection/disease complicated the postoperative course after composite tissue allograft (CTA) transplantation in five of nine recipients challenged with the virus. The close time correlation suggests an association between virus replication and rejection in some cases. CMV represents the major infectious threat in CTA transplantation. Therefore, CMV-mismatch should be avoided and prophylaxis with valgancyclovir and anti-CMV hyperimmunoglobulin should be mandatory.

Topics: Adolescent; Adult; Antibodies, Viral; Antigens, Viral; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Drug Therapy, Combination; Follow-Up Studies; Ganciclovir; Glucocorticoids; Graft Rejection; Graft Survival; Hand Injuries; Hand Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Tissue Donors

With improved cytomegalovirus (CMV) prophylaxis, CMV disease after liver transplantation has decreased dramatically, and patient and graft survival have improved. We examined the impact of CMV prophylaxis on biopsy proven rejection after orthotopic liver transplantation by analyzing data on 192 liver recipients over 5 years (1994-1999). Risk factors assessed for biopsy proven rejection including donor and recipient age, CMV serostatus; CMV prophylaxis; immunosuppression; bacteremia and blood product use were examined over a 2-year follow-up. Multivariate analysis of risk factors for rejection showed that bacteremia (HR 3.57, 95% CI 1.39-9.36, P=0.008), donor age (HR 1.20, 95% CI 1.06-1.36, per 10 year increase, P=0.004), and use of cyclosporine as initial immunosuppression compared to tacrolimus (HR 1.98, 95% CI 1.27-3.09, P=0.003) were associated with increased risk; ganciclovir prophylaxis for 3 months (HR 0.51, 95% CI 0.33 to 0.79, P=0.003) and recipient age (HR 0.78; 95% CI 0.63-0.96, for each 10 year increase, P=0.03) were associated with decreased risk. We conclude that, the use of CMV prophylaxis with ganciclovir significantly reduces the incidence of biopsy proven rejection in liver transplant recipients.

Topics: Antiviral Agents; Biopsy; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Humans; Immunization, Passive; Immunoglobulins; Immunoglobulins, Intravenous; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

We reviewed the outcome of three methods employed for living-related renal transplantation (RTx) in our institution to assess triple immunosuppressive regimens. Between January 1989 and July 2003, a total of 35 living-related RTxs were performed at our institution. The immunosuppressive regimen given to 16 patients (group A) was cyclosporine (CsA), steroid and azathoprine (AZ) that given to 9 patients (group B) was tacrolimus (TAC), steroid and AZ and that given 9 patients (group C) was TAC, steroid and mycophenolate mofetil (MMF). Graft survival rate, serum creatinine, proteinuria, acute rejection, chronic allograft nephropathy (CAN), cytomegalovirus (CMV) infection and drug-induced nephropathy were investigated. There was no significant difference in graft survival rate among the three groups. Although serum creatinine levels (mg/dl) at 3 months post-transplant were 1.22+/-0.37 in group A, 1.43+/-0.14 in group B, 1.30+/-0.34 in group C, respectively (p<0.05; A vs. B), there was no significant difference at 1 year post-transplant. Frequency of proteinuria in groups A, B and C was 75.0, 50.0, 25.0%, respectively (p<0.05; A vs. C). The incidences of acute rejection and CAN within 1 year post-transplant were, respectively, 56.3% and 43.8% in group A, 37.5% and 37.5% in group B; and, 25.0% and 12.5% in group C (NS). The incidence of drug-induced nephrotoxicity was 12.5, 50.0% and 37.5% in groups A, B and C, respectively (p<0.05; A vs. B). The triple immunosuppressive therapy including calcineurin inhibitors, especially the regime of TAC, MMF, and steroids decreased the frequencies of proteinuria and rejections, which deteriorated the long-term outcome in living-related RTxs.

Topics: Adult; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Tacrolimus; Treatment Outcome

The efficacy and safety of tacrolimus (FK506; Prograf) were determined in 28 adult kidney transplant patients (20 males and 8 females), aged 18-68 years (mean+/-S.D.: 46.9+/-4.03 years). Induction therapy was ATG-F (n=23), daclizumab (n=3), or none (n=2), and maintenance immunosuppression consisted of tacrolimus, combined with mycophenolate mofetil (MMF; n=26) or azathioprine (AZA; n=2) and prednisone (Pred). In seven patients, cyclosporine A microemulsion (Neoral) was replaced by tacrolimus for acute rejection (AR; three patients), slow graft function (SGF, two patients) and Neoral side effects (two patients). Acute rejection occurred in five patients (17.8%), three of whom were steroid-resistant treated with a second course of ATG-F. Infection occurred in 10 patients (35.7%) with a total of 15 infectious episodes, comprising bacterial (73%) and viral (27%) infections related to CMV. Other side effects related to tacrolimus were hypertension in four patients (14%) and post-transplantation hyperglycemia in nine patients (32%), three of whom required insulin therapy. In addition, hypercholesterolemia and hypertriglyceridemia occurred in six (21%) and eight patients (28.5%), respectively. The patient's hospital stay was 12.7+/-1.3 days (range: 8-24 days), and mean serum creatinine upon discharge, and at 1, 3 and 6 months following transplantation were: 2.1+/-0.5, 1.47+/-0.21, 1.41+/-0.53 and 1.23+/-0.11 mg/dl, respectively. The 6-month actuarial patient and graft survival rates were 100%. While tacrolimus is an effective calcineurin inhibitor for kidney transplantation (KT), severe acute rejection seen is related to highly sensitized patients, and the CMV infections noted were related to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. Longer follow-up with a larger patient sample is needed to fully assess both the efficacy and safety of tacrolimus, including its metabolic effects.

Topics: Acute Disease; Adolescent; Adult; Aged; Calcineurin Inhibitors; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Hyperglycemia; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Safety; Tacrolimus

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

Graft-versus-host disease (GVHD) is still a major problem in allogeneic bone marrow transplantation (BMT). Prophylactic regimens used against GVHD in unrelated BMT, including cyclosporine (CsA)-plus-methotrexate (MTX), CsA-plus-MTX-plus-prednisone, and tacrolimus (FK506)-plus-MTX, are still unsatisfactory (34-70% occurrence of grades II-IV GVHD). To address this problem, we examined the efficacy of FK506-plus-MTX-plus-methylprednisolone (mPSL) in 20 patients who underwent BMT from unrelated donors.. All patients received FK506 beginning the day before transplantation at a dose of 0.03 mg/kg per day by continuous intravenous (IV) infusion. MTX was administered at a dose of 10 mg/m(2) IV on day 1, and 7 mg/m(2) on days 3, 6, and 11. Intravenous administration of mPSL was started at a dose of 2 mg/kg per day on day 1. In the absence of acute GVHD, mPSL was gradually tapered from day 29.. Development of acute GVHD was almost completely suppressed (one patient with grade I, none with grades II-IV). However, the incidence and severity of chronic GVHD did not decrease. Eight of 12 patients with extensive chronic GVHD died of thrombotic microangiopathy or infection. A vigorous fluctuation (>100 U/mL per 10 days) of the soluble interleukin 2 receptor level in the serum after engraftment was highly related to the occurrence of chronic GVHD.. An FK506-plus(+)-MTX-plus(+)-mPSL prophylactic regimen could almost completely suppress acute GVHD but not chronic GVHD in unrelated BMT. In this GVHD prophylactic system, the extent of the change of soluble interleukin 2 receptor level may be a good predictor of development of chronic GVHD.

Topics: Acute Disease; Adolescent; Adult; Antigens, Viral; Bone Marrow Transplantation; Cause of Death; Chronic Disease; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Methotrexate; Methylprednisolone; Tacrolimus; Transplantation, Homologous

Topics: Cyclosporine; Cytomegalovirus Infections; Female; Humans; Immunosuppression Therapy; Incidence; Liver Transplantation; Male; Medical Records; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Kidney transplant recipients require careful follow-up in both the early (< 6 months) and late posttransplant periods. Monitoring should focus on graft function and the most common complications of immunosuppression therapy. Infections, especially CMV infection, require particular attention in the first few months after transplantation, when immunosuppression is most intense. In both the early and the late posttransplant periods, an emphasis should be placed on intensive management of CVD risk factors (e.g., hypertension, hyperlipidemia, cigarette smoking). Screening for malignancies known to occur with a high incidence after transplantation is also important. With the improved short-term survival rates brought about by new, potent immunosuppressive agents, emphasis has now shifted to the prevention and treatment of posttransplant complications in kidney transplant recipients. A heightened awareness of these complications, along with a cooperative effort between primary care physicians and transplant programs, offers the best hope for further improvement in outcomes after kidney transplantation.

Topics: Cardiovascular Diseases; Cyclosporine; Cytomegalovirus Infections; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Transplantation; Metabolic Diseases; Monitoring, Physiologic; Neoplasms; Risk Assessment; Sirolimus; Tacrolimus; Transplantation, Homologous

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: Antibodies, Monoclonal; Basiliximab; Child; Creatinine; Cyclosporine; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus

We describe a renal transplant recipient, with overimmunosuppression induced by the interaction of tacrolimus and fluconazole, who developed two severe diseases produced by two different viruses of the herpes group (cytomegalovirus [CMV] disease and posttransplant lymphoproliferative [PTLD] disease EBV-related). Detection of Epstein-Barr virus (EBV) DNA in the blood preceded the histological diagnosis of PTLD. Both diseases improved after changes in the immunosuppressive regime and treatment with ganciclovir. Because CMV infection is a risk factor in developing PTLD, and the clinical and endoscopic manifestations of both diseases could be become confused, PTLD should be excluded in EBV seronegative patients that develop CMV disease. The detection of the EBV genome in blood could help in the early diagnosis of PTLD in these patients.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Fluconazole; Ganciclovir; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppression Therapy; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Postoperative Complications; Tacrolimus

Acute cellular rejection, though mostly encountered during the first 3 months after liver transplant, may occur later on. Clinical features and outcome of children experiencing late cellular rejection (LCR) have not been described to date.. A total of 20 children who developed acute rejection 6 months or more after liver transplant were studied for history of early rejection, levels of immunosuppression, causes of low immunosuppression, viral infections, signs of autoimmunity, and HLA mismatch. All liver biopsies were reviewed. Fifteen patients with no history of LCR were randomly selected as controls.. Of 20 children 5 were appropriately immunosuppressed, although 15 were not. Causes of low immunosuppression were: unknown (seven), poor compliance (three), posttransplant lymphoproliferative disease, (two), hepatocellular carcinoma recurrence (one), tuberculosis (one), gastroenteritis (one). Of 20 patients early rejection occurred in 13 and cytomegalovirus infection in 5. At last follow-up 10 children have persistent graft dysfunction, of whom 5 have progressed to de novo autoimmune hepatitis, 2 to chronic rejection, one has persistent graft dysfunction with recurrent cytomegalovirus activation, one has hepatic artery thrombosis and one is likely to have persistent poor compliance. None of the 15 controls developed de novo autoimmune hepatitis or any other form of persistent graft dysfunction at the time of last follow-up.. Late cellular rejection in children is usually due to low or decreased immunosuppression and is associated with long-term complications. Prompt intervention to correct inadequate immunosuppression and careful follow-up of the other patients to identify other treatable conditions is essential.

Topics: Antibodies, Viral; Biopsy; Child; Cyclosporine; Cytomegalovirus Infections; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunoglobulin M; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

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

Topics: Adult; Cytomegalovirus Infections; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Sirolimus; Tacrolimus

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

The effects of the immunocompromised state after liver transplantation on the frequency of cytomegalovirus-specific cytotoxic T lymphocytes (CTL) were investigated in 93 patients by using HLA class I tetrameric complexes corresponding to HLA-A*0201, HLA-B*0702, HLA-B*0801, and HLA-B*3501 refolded with peptides from the ppUL83 matrix protein. ppUL83 CTL frequencies were suppressed during the first 6 months after transplantation. Patients with >1 HLA-restricted response detected had high correlation among ppUL83 CD8(+) CTL frequencies restricted by different HLA haplotypes (Spearman's rho=.67; P<.0001). There was an inverse correlation among levels of the calcineurin inhibitor, tacrolimus, and ppUL83 CD8(+) CTL frequencies (r=-.31; P=.005), which is consistent with the presence of a large proportion (70%) of activated (CD38(+)) ppUL83 CD8(+) CTL within the population of HLA class I tetramer-positive cells.

Topics: Adolescent; Adult; Aged; Antigens, Viral; Cells, Cultured; Cytomegalovirus; Cytomegalovirus Infections; Histocompatibility Antigens Class I; Humans; Immunocompromised Host; Immunosuppressive Agents; Interferon-gamma; Liver Transplantation; Longitudinal Studies; Lymphocyte Count; Middle Aged; Phosphoproteins; T-Lymphocytes, Cytotoxic; Tacrolimus; Time Factors; Viral Load; Viral Matrix Proteins

Topics: Administration, Oral; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Postoperative Complications; Recurrence; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

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

Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts (91%), with a follow-up of 23 months (range, 6 to 35 months). One episode (1.8%) of hepatic artery thrombosis was seen. The rate of acute cellular rejection was 14%. No extra treatment was administered in 3 of 8 patients, and the other 5 episodes responded to a single course of steroids. Cytomegalovirus infection occurred in 4 patients (7%). Renal function, glucose control, and lipid metabolism are near normal in 47 patients (84%) without additional medication. Steroid elimination is completed in 51 patients (91%). Bioavailability of SRL and TAC varied between transplant recipients, but trough levels strongly correlated with the area under the curve (r(2) = 0.82 and r(2) = 0.84, respectively). Simultaneous administration did not affect the PK profile of the drugs at this dose. The ratio of trough level to daily dose correlated between SRL and TAC. The synergistic effect seen in animal models also occurs in clinical liver transplant recipients on SRL-TAC combination immunosuppression. A low-dose combination of SRL and TAC should be compared with conventional immunosuppression in a multicenter, randomized, controlled trial.

Topics: Adolescent; Adult; Aged; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver; Liver Transplantation; Male; Middle Aged; Sirolimus; Tacrolimus

Topics: Adult; Child; Cytomegalovirus Infections; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Intestines; Postoperative Complications; Retrospective Studies; Stomach; Survival Rate; Tacrolimus; Time Factors; Transplantation, Homologous; Viscera

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

Topics: Actuarial Analysis; Adolescent; Adult; Child; Child, Preschool; Creatinine; Cytomegalovirus Infections; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infant; Kidney Transplantation; Living Donors; Middle Aged; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Tissue Donors

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

Small bowel transplantation has become a life-saving procedure for selected adults and children with intestinal failure who are intolerant to parental nutrition. There are few pediatric data available on the results of this procedure. In this article we review the background of intestinal transplantation, present the results from the University of Western Ontario in London, Ontario and the University of Miami in Miami, Florida, and discuss some future directions. The majority of successful transplants are fully functional, and these children are able to assume a normal diet.

Topics: Child; Child, Preschool; Cytomegalovirus Infections; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Intestine, Small; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Cytomegalovirus Infections; Ganciclovir; Humans; Liver Transplantation; Tacrolimus

Prior to the FK506 era, OKT3 was primarily used for treatment of steroid-resistant rejection. Initially FK506 has been used as a last treatment of refractory acute or chronic rejection. We provide strong evidence that the use of FK506 is more successful if rescue therapy is performed early instead of using it as the last resort. Between September 1988 and March 1995 a total of 600 liver transplantations were performed in 550 patients. Of these 550 patients, 426 received primarily cyclosporine A (CsA)-based immunosuppression. Of the 426 CsA patients, 70 (16.4%) required either FK506 (51.4%), or OKT3 rescue therapy (27.1%), or a combination of the two drugs (21.5%). The latter group of patients received first OKT3 and then FK506 rescue when OKT3 therapy failed. Treatment was initiated simultaneously (within 1 week) in 11 patients, and 4 patients received FK506 rescue later during the course of rejection. The highest success rates (88.9%) were observed in patients given FK506 rescue therapy. Retransplantation was necessary more often in patients receiving OKT3 than in those with FK506 rescue therapy (15.8% versus 5.5%, respectively). Retransplantation and death due to chronic rejection increased with the need for additional FK506 rescue therapy after OKT3 failure. This increase was most pronounced in patients receiving FK506 during the late course of rejection, reaching a failure rate of 75.0% (50. 0% of deaths were due to chronic rejection). The lowest incidence of cytomegalovirus infection and of infectious, neurologic, and renal complications was observed in the FK506 rescue group. We conclude that early FK506 rescue therapy may be the treatment of choice for acute steroid-resistant rejection.

Topics: Acute Disease; Acute Kidney Injury; Cause of Death; Cyclosporine; Cytomegalovirus Infections; Drug Resistance; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Methylprednisolone; Muromonab-CD3; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus

Until recently, FK 506 was used only for rescue therapy after pancreas transplantation. We report our initial experience with FK 506 for 67 pancreas recipients (treated between 1 May 1993 and 30 April 1995). Of these recipients, 49 (73%) received FK 506 for induction and maintenance therapy, 12 (18%) for rescue or antirejection therapy, and 6 (9%) for reasons other than rescue or antirejection therapy. In our induction and maintenance therapy group, 32 recipients (65%) underwent a simultaneous pancreas-kidney transplant (SPK), 8 (16%) a pancreas transplant alone (PTA), and 9 (19%) a pancreas after previous kidney transplant (PAK). Quadruple immunosuppression was used for induction; the median FK 506 starting dose was 4 mg/day p.o. and target levels were 10-20 ng/ml. The most common side effects were nephrotoxicity (16%) and neurotoxicity (14%); transient episodes of hyperglycemia were also noted (12%), in particular in the presence of concurrent rejection and infection episodes. A matched-pair analysis was done to compare graft outcome with FK 506 versus cyclosporin A (CsA). For SPK recipients, pancreas graft survival at 6 months was 79% with FK 506 versus 65% with CsA (P = 0.04), for PTA, 100% versus 63% (P > 0.35), and for PAK, 88% versus 33% (P > 0.01). Pancreas graft loss due to rejection at 6 months posttransplant was lower with FK 506 versus CsA. Two FK 506 recipients died from B-cell lymphomas (Epstein-Barr virus positive) at 6 and 7 months posttransplant. In our rescue or anti-rejection group, 5 recipients underwent SPK, 3 PTA, and 4 PAK. The mean average FK 506 dose was 10 mg/day p.o. and the mean average FK 506 blood level was 11 ng/ml. The most common side effects were nephrotoxicity (33%) and neurotoxicity (16%). Two recipients developed hyperglycemic episodes, of whom 1 has remained on insulin with good exocrine pancreas graft function. Graft survival at 6 months after conversion was 75% for SPK, 67% for PTA, and 50% for PAK. Only one graft was lost due to chronic rejection. Our single-center experience shows that FK 506 after pancreas transplantation is associated with: (1) a low rate of graft loss due to rejection when used for induction, in particular for solitary pancreas transplants, (2) a high rate of graft salvage when used for rescue, (3) a 1% rate of new-onset insulin-dependent diabetes mellitus, and (4) a 3% rate of posttransplant lymphoma. Further studies are necessary to analyze the long-term impact of FK 506 on pancreas transplan

Topics: Adult; Cyclosporine; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Male; Middle Aged; Pancreas Transplantation; Tacrolimus

Topics: Biopsy; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Humans; In Situ Hybridization; Liver Transplantation; Polymerase Chain Reaction; Predictive Value of Tests; Retrospective Studies; Tacrolimus

A retrospective cohort study was conducted to determine the incidence of major infectious complications after orthotopic liver transplantation and to compare outcomes in patients receiving either cyclosporine (CsA) or FK506 (tacrolimus) as primary immunosuppression. Of 133 transplants performed in 118 patients, 124 transplant episodes were evaluated. Cytomegalovirus (CMV) infection (INF) and disease (DIS), deep fungal infection (DFI), and intraabdominal bacterial infections (IAI) were catalogued. The overall incidences of major infectious outcomes were: CMV INF = 33%; CMV DIS = 19%; DFI = 15%; and IAI = 25%. Cox proportional hazard analysis identified donor seropositivity, OKT3 as secondary immunosuppression and initial intensive care unit (ICU) duration as risk factors for CMV INF and DIS in the overall population. Fungal colonization was the dominant risk factor associated with deep fungal infection. A choledochojejunostomy anastomosis, the number of cellular blood products transfused at the time of transplantation surgery, and prior CMV INF were independent risk factors for both fungal colonization and deep infection. The single risk factor identified for intraabdominal bacterial infections was the number of cellular blood products transfused at the time of surgery. In the Cox proportional hazards model the relative risk (RR) for each category of infection was lower in the FK506 group (CMV: RR = .87, 95% confidence interval [C.I.] = [.32-2.4]; DFI: .58 [.13-2.6]; IAI: .51 [.15-1.7]), but the effect was not statistically significant. Survival was similar in patients receiving FK506 or CsA. CMV INF and DFI were independent predictors of death for all patients. Risk factors identified for CMV INF and DIS support the findings of others. Higher intraoperative blood product requirements and complicated intraoperative or postoperative courses increase the risk for IAI or DFI. The development of effective strategies to prevent CMV and fungal infections in liver transplant recipients remains a priority for future endeavors.

Topics: Bacterial Infections; Candidiasis; Cohort Studies; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus

Topics: Antibodies, Viral; Cytomegalovirus Infections; Follow-Up Studies; Ganciclovir; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Kidney Transplantation; Liver Transplantation; Methylprednisolone; Postoperative Complications; Tacrolimus; Time Factors

Although initial experiences with FK 506 rescue therapy for acute hepatic allograft rejection have provided promising results, analysis of available data indicates that inferior results are obtained when FK 506 rescue therapy is initiated in the latter stages of rejection. Since its initial availability, we have applied an aggressive approach towards FK 506 rescue therapy based on early conversion and assiduous dosing. We have reviewed our experience with this approach in patients with refractory hepatic allograft rejection to provide an assessment of this approach. Sixteen patients were treated for corticosteroid and OKT3-resistant acute hepatic allograft rejection. Fourteen patients were treated for cellular rejection and 2 for humorally-mediated rejection. Median follow-up was 7.3 months posttransplant and 6.0 months post-initiation of FK 506 therapy. Median time to first rejection was 8 days and median time to FK 506 therapy was 29 days. Laboratory values at the time of initiation of FK 506 therapy included: mean serum bilirubin, 4.0 +/- 3.1 mg/dl and SGPT 136 +/- 105 U/l. Prior to FK 506 therapy, patients received an average of 35.5 +/- 19.1 mg/kg of bolus/taper corticosteroids (prednisone equivalent) and 11.25 +/- 4.8 days of OKT3 therapy. FK 506 therapy was successful in reversing all episodes of rejection. Median time to rejection reversal with FK 506 rescue therapy was 23 days (mean +/- SD, 27.6 +/- 16.7 days) in patients with cellular rejection. Time to rejection reversal was 26 and 28 days in the 2 patients with humoral rejection. Patient and graft survival at 6 months were 100%/100%, and 94%/94% at 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Liver Transplantation; Male; Methylprednisolone Hemisuccinate; Middle Aged; Muromonab-CD3; Risk Factors; Tacrolimus; Time Factors

Cytomegalovirus (CMV) is a major infectious complication of organ transplantation and its incidence is influenced by the type and intensity of immunosuppressive therapy employed. Using a new immunosuppressive agent FK506, CMV infection was observed in 30% and CMV disease in 15% of the 26 liver transplant recipients. Delayed onset of CMV disease was noted; the mean time to the occurrence of CMV disease being 137 days posttransplantation. No graft loss or mortality could be attributed to CMV infection. Mucocutaneous herpes simplex virus (HSV) infections were encountered in 19% of the patients, while no disease could be attributed to varicella zoster virus or Epstein-Barr virus (EBV). The contribution of FK506 to a decrease in viral morbidity and associated mortality bears further investigation.

Topics: Cytomegalovirus Infections; Follow-Up Studies; Graft Rejection; Graft Survival; Herpes Simplex; Herpes Zoster; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Incidence; Liver Transplantation; Male; Middle Aged; Tacrolimus; Time Factors

Topics: Adolescent; Age Factors; Child; Child, Preschool; Cytomegalovirus Infections; Graft Rejection; Graft Survival; Humans; Infant; Kidney Transplantation; Lymphoproliferative Disorders; Pennsylvania; Survival Rate; Tacrolimus; Time Factors; Tissue Donors; Treatment Outcome

Topics: Adult; Cytomegalovirus Infections; Graft Rejection; Hepatitis; Histocompatibility Testing; HLA-DR Antigens; Humans; Liver Transplantation; Muromonab-CD3; Tacrolimus; Tissue Donors

Topics: Acute Kidney Injury; Adrenal Cortex Hormones; Alanine Transaminase; Azathioprine; Bilirubin; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Liver Function Tests; Liver Transplantation; Muromonab-CD3; Prednisone; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Acyclovir; Antiviral Agents; Cytomegalovirus Infections; Foscarnet; Humans; Immunosuppression Therapy; Phosphonoacetic Acid; Retinitis; Retrospective Studies; Tacrolimus; Transplantation Immunology