Cyclosporine-based Immunosuppressive Regimen Research Articles

P.135: Comparison between tacrolimus-based and cyclosporine-based maintenance immunosuppressive regimens in kidney transplant recipients with functioning grafts beyond 15 years.

P.135: Comparison between tacrolimus-based and cyclosporine-based maintenance immunosuppressive regimens in kidney transplant recipients with functioning grafts beyond 15 years.

P.134: Assessment of tacrolimus-based vs. cyclosporine-based maintenance immunosuppressive regimens among living donor kidney transplant recipients with low immunological risk: Single centre experience.

P.134: Assessment of tacrolimus-based vs. cyclosporine-based maintenance immunosuppressive regimens among living donor kidney transplant recipients with low immunological risk: Single centre experience.

Antidonor T-Cell Responses Are Not Attenuated in Elderly Kidney Transplant Recipients.

Although the number of kidney transplants among elderly patients has been steadily increasing, no specific recommendations have been established for treatment of elderly patients. In general, elderly recipients are considered to be at lower risk of cell rejection and require less intense immunosuppression than younger recipients. However, a recent report from Japan reported that chronic T-cell-mediated rejection was more frequent in elderly living-donor kidney transplant recipients. In this study, we investigated the effects of aging on antidonor T-cell responses in living-donor kidney transplantrecipients. We retrospectively evaluated 70 adultliving-donor kidney transplantrecipients with negative crossmatches and cyclosporine-based immunosuppressive regimens. To evaluate antidonor T-cell responses, serial mixed lymphocyte reaction assays were performed.We compared results in elderly (≥65 years) versus nonelderly recipients. Regarding donor characteristics, elderly recipients were more likely than nonelderly recipients to receive a transplant from their spouse. The number of mismatches at the HLA-DRB1 loci was significantly higher in the elderly group than in the nonelderly group. As a result, the proportion of patients with antidonor hyporesponsiveness in the elderly group did not increase over the postoperative course. Antidonor T-cell responses in elderly living-donor kidney transplant recipients were not attenuated over time. Thus, caution is required regarding the imprudent reduction of immunosuppressants in elderly living-donor kidney transplant recipients. A rigorously designed, large-scale, prospective study is required to validate these results.

Effects of late cyclosporine withdrawal on renal graft function and survival.

Attempts to discontinue calcineurin inhibitors (CNIs) early after renal transplantation without conversion to an alternative immunosuppressive have failed due to high rates of acute rejection. Data on "late" CNI withdrawal are lacking so far. We carried out a matched case-control study on the effects of CNI withdrawal on graft loss and mortality in 90 patients (1500 screened) with advanced graft dysfunction (serum creatinine > 3.5mg/dl) and a cyclosporine-based triple immunosuppressive regimen at the Charité University Hospital, Berlin. Cyclosporine was withdrawn at a mean of 54.0 ± 32.8months post-transplant in 45 subjects. Whereas estimated glomerular filtration rate (eGFR) did not significantly differ between the groups at this time (12.4 ± 2.7 vs. 14.7 ± 8.9 in the control group, p = 0.08), it was significantly higher in subjects undergoing withdrawal after 120months (Δ 4.1ml/min; p < 0.001). In a Cox regression analysis adjusted for age, gender and eGFR, patients with CNI withdrawal showed better survival rates for the combined endpoint death/graft loss (hazard ratio, HR [95% confidence interval]: 0.19 [0.12-0.33], p = 0.001) compared to matched controls. The survival benefit was significant for the endpoints death (p = 0.01) and graft loss (p = 0.001). CNI withdrawal was associated with improved survival rates in patients with advanced graft dysfunction in this retrospective analysis.

Tacrolimus-Induced Hyponatremia in Lung Transplant Recipients: A Case Series.

BackgroundLung transplant recipients are treated with a 3-drug immunosuppressive regimen that consists of a calcineurin inhibitor, an antiproliferative agent, and a corticosteroid. Calcineurin inhibitors are the backbone of this regimen, and tacrolimus is used more often than cyclosporine, because tacrolimus is the more potent of the two agents. Tacrolimus-induced hyponatremia has been described among kidney transplant recipients, but not among lung transplant recipients.MethodsWe conducted a retrospective chart review of patients who underwent lung transplant at our institution and went on to develop severe hyponatremia.ResultsWe identified 5 lung transplant recipients who developed severe hyponatremia after lung transplantation (median nadir, 117 mEq/L; interquartile range, 116-119 mEq/L). Time to development of hyponatremia ranged from 3 to 85 days posttransplant. Hyponatremia persisted in these patients despite fluid restriction, salt tablets, diuretics, and fludrocortisone therapy. Hyponatremia resolved in 3 patients and significantly improved in 2 patients after they were switched from a tacrolimus-based immunosuppressive regimen to a cyclosporine-based regimen.ConclusionTransitioning from a tacrolimus- to a cyclosporine-based immunosuppressive regimen may resolve or improve severe hyponatremia in lung transplant recipients.

FOXP3 rs3761549 polymorphism predicts long-term renal allograft function in patients receiving cyclosporine-based immunosuppressive regimen

AimThe present study was conducted to determine the effect of FOXP3 single nucleotide polymorphisms (SNPs) on clinical outcomes in CsA-treated renal transplant patients. MethodsA total of 166 renal transplant patients with at least 5years of follow-up were included. SNPs of FOXP3 gene (rs3761547, rs3761548, rs3761549, rs2232365 and rs2280883) were detected by Taqman probe technique. The associations of SNPs with acute rejection, CsA-induced nephrotoxicity, pneumonia and post-transplantation estimated glomerular filtration rate (eGFR) were explored. ResultsPatients with rs3761549 T/TT genotype showed a more rapid decline in the eGFR level during the 5years following transplantation than those with the C/CC genotype (24.0% vs. 6.3%, P=0.004). All the SNPs and site-site interaction were not related to the occurrence of acute rejection, nephrotoxicity, and pneumonia. ConclusionsFOXP3 rs3761549 was significantly correlated with the renal allograft function. It could be used to predict and improve the outcome of renal transplant patients taking CsA as an immunosuppressant.

Study on pure red cell aplastic lymphocyte subsets characteristics and the effect of cyclosporin A

Objective To detect and analyse acquired pure red cell aplasia (PRCA) T lymphocyte subsets distribution and to assess its condition and cyclosporine immune function of T lymphocytes subsets. Methods Flow cytometry was applicated to detect peripheral blood T lymphocyte subsets of acquired PRCA patients before and after 3 months of treatment with cyclosporine-based immunosuppressive regimen and normal controls. Results Among 22 patients, 17 cases of blood returning normal (three cases of bone marrow returning normal), the total effective rate was 95.5 % (3 cases of cure, 14 cases of remission, 4 cases of improvement, 1 case of ineffectiveness). Th (CD3+ CD4+) cells and Th/Ts ratios in acquired PRCA patient group were lower than those in the normal control group, while Ts (CD3+ CD8+) cells was higher than that in the normal control group, the differences were statistically significant (P< 0.05). After 3 months of treatment, Th cells and Th/Ts ratio were higher than those before, and Ts cells were decreased compared with the previous (P< 0.05). Conclusion Disorders of T lymphocyte subsets in acquired PRCA patients lead to immune dysfunction, however, cyclosporine can improve T lymphocyte subsets in patients with imbalance, which is an effective way to treat the disease with significant curative effect and mild adverse reactions. Key words: Acquired pure red cell aplastic; T lymphocytes; Cyclosporine

Parasitic Infections in Solid Organ Transplantation

Parasitic Infections in Solid Organ Transplantation

Interleukin-2 receptor antibody does not reduce rejection risk in low immunological risk or tacrolimus-treated intermediate immunological risk renal transplant recipients

The use of interleukin-2 receptor antibody (IL-2Ra) induction has been associated with reduced rejection rates in renal transplant recipients. However, the effect of IL-2Ra induction on graft and patient outcomes in renal transplant recipients with differing immunological risk remains unclear. Using Australia and New Zealand Dialysis and Transplant Registry, renal transplant recipients in Australia between 1995 and 2005 were included. Recipients were stratified into low immunological risk (primary grafts with < or = 2 human leucocyte antigen (HLA)-mismatches and panel-reactive antibody (PRA) < 10%) or intermediate immunological risk (subsequent grafts or >2 HLA-mismatches or PRA > 25%) recipients. Recipients receiving T-cell depletive induction therapy or steroid and/or calcineurin-free inhibitor regimens were excluded. Outcomes analysed included the presence of rejection at 6 months, estimated glomerular filtration rate at 1 and 5 years, graft and patient survival. 218 of 1220 (18%) low-risk and 883 of 3204 (28%) intermediate-risk recipients received IL-2Ra. In intermediate-risk recipients, IL-2Ra induction was associated with a 26% reduction in the incidence of acute rejection; but this benefit was restricted only to recipients initiated on cyclosporine-based immunosuppressive regimens. In contrast, the use of IL-2Ra in low-risk recipients was not associated with reduced rejection risk. There was no association between IL-2Ra induction and other graft or patient outcomes in both low- and intermediate-risk recipients. This registry analysis suggests that IL-2Ra induction may be associated with a reduction in rejection risk in cyclosporine-treated intermediate immunological risk recipients, but not in low-risk renal transplant recipients.

Everolimus Versus Azathioprine in a Cyclosporine and Ketoconazole–Based Immunosuppressive Therapy in Kidney Transplant: 3-Year Follow-up of an Open-Label, Prospective, Cohort, Comparative Clinical Trial

In cyclosporine-based protocols, everolimus is more effective than azathioprine to reduce acute rejection. Ketoconazole may reduce cyclosporine and everolimus requirements. We compared kidney transplant patients treated with everolimus or azathioprine in a ketoconazole- and cyclosporine-based immunosuppressive regimen. This open-label, prospective trial of low immunologic risk patients. Included one group ( n = 11) who received everolimus (target blood level, 3–8 ng/mL) and the other ( n = 11) azathioprine (2.0–2.5 mg/kg/d). Both received steroids, ketoconazole, and cyclosporine with C 0 targets (ng/mL) in the everolimus group of 200–250, 100–125, and 50–65 for months 1 and 2 and thereafter and in the azathioprine group of 250–300 in month 1, 200–250 in month 2, 180–200 until month 6, and 100–125 thereafter. Their baseline characteristics were similar. Two biopsy-proven acute rejections occurred in each group. Three-year graft and patient survival in both groups was 100%. Creatinine clearances at months 6, 12, 24, and 36 were 63.7 ± 25.4, 58.9 ± 24.9, 56.0 ± 22.9, and 57.0 ± 27.6 in the everolimus group versus 72.6 ± 20, 68.6 ± 21.3, 71.4 ± 23.2, and 68.4 ± 19.2 in the azathioprine group (NS for every comparison). Major complications were rare and similar in both groups. Five patients in the everolimus group received simvastatin versus 4 in the azathioprine cohort ( P = .53). The average cyclosporine doses to achieve targets were 0.8–1.2 mg/kg in the everolimus group and 1.6–2.2 mg/kg in the azathioprine group. The average everolimus dose after month 2 was 0.75–0.9 mg/d. We concluded that with cyclosporine, ketoconazole, and steroids, everolimus was as effective and safe as azathioprine. Cyclosporine reduction with everolimus did not influence graft survival or function at 3 years.

Parasitic Infections in Solid Organ Transplant Recipients

Parasitic Infections in Solid Organ Transplant Recipients

A Cyclosporine-Based Immunosuppressive Regimen May Be Better Than Tacrolimus for Long-Term Liver Allograft Survival in Recipients Transplanted for Hepatitis C

Rapid recurrence of severe hepatitis C (HCV) after liver transplantation is a major barrier to survival of the transplanted liver. While cyclosporine (CsA) in vitro has been shown to suppress HCV replication, an effect is not seen with tacrolimus (Tac). Evidence is inconsistent whether or how this translates to clinical practice. To expand the evidence on this issue, we analyzed graft survival and histological outcomes after liver transplantation for HCV hepatitis. Methods Using our longitudinal database (1991 onward) graft outcomes for all liver transplant recipients with HCV were evaluated (105 grafts in 97 patients). Severe activity, severe fibrosis, and graft survival were analyzed. All liver biopsies were scored (blinded) according to the Ludwig scale. Immunosuppression was based on prednisone and a calcineurin inhibitor (Tac n = 89, 85%; CsA n = 15, 14%). Comparisons of outcomes using CsA versus Tac therapy were done using survival analysis via the log-rank test. Results Graft survival was significantly better in the CsA group. Although there was no apparent difference in severe activity (grade 2), there was a statistically significant difference in graft survival without fibrosing cholestatic hepatitis ( P = .01) and a trend toward a difference in fibrosis-free survival ( P = 0.1). The rate of sustained response to antiviral therapy was twice as high in the CsA group, 50% versus 22% ( P = 0.16; NS). Conclusions Graft survival in liver transplant recipients with HCV may be greater with CsA-based immunosuppression. There may also be a lower rate of fibrosing cholestatic hepatitis in this group.

Prevalence of Anemia in Renal Transplant Patients: Results From MOST, an Observational Trial

Introduction Anemia is one of the most common complications of chronic renal disease. However, the incidence or prevalence of anemia in kidney transplant recipients has not been well studied. The aim of this study was to assess the prevalence of anemia in renal transplant in early and late posttransplant period and the influence of drugs (immunosuppressive and antihypertensive). Methods MOST is an observational, prospective trial of renal transplant receiving cyclosporine-based immunosuppressive regimen under condition of normal practice in de novo or maintenance recipients. We analyzed the Spanish data from 397 de novo recipients and 2102 maintenance recipients. Results In maintenance recipients mean hemoglobin levels were 12.8 ± 1.6 g/dL (13.2 ± 1.7 in men and 12 ± 1.4 in women); 22.73% of men and 20.19% of women were found to be anemic. There was a significant correlation between hemoglobin and graft function ( r = .14, P < .0001). The percentage of patients with anemia increased with the severity of chronic renal disease according to the KDOQI classification. Therapy with mycophenolate mofetil was also associated with a higher likehood of anemia as compared with other immunosuppressive therapies (azathioprine or sirolimus). There were no differences with angiotensin-converting enzyme inhibitors or ARB II. In de novo patients postransplant anemia was a frequent complication during the first 3 to 6 months. In patients with delayed graft function the recovery of anemia was slower. Conclusion The prevalence of anemia in transplant recipients was remarkably high, especially in the early postransplant period, and appeared associated with impaired renal function and with immunosuppressive treatment.

Transplantation of pediatric kidneys to adult recipients: An analysis of 13 cases

Introduction The shortage of cadaveric donors for kidney transplantation has prompted many centers to expand the criteria used for donor selection to increase the organ supply. The use of cadaveric pediatric kidneys has been suggested as a means to overcome the shortage. However, some studies indicate that kidneys from pediatric donors show inferior results to those from adult donors. In this retrospective study we examined the outcome of kidney transplantation using cadaveric pediatric donors. Materials and methods From October 1990 to May 2002, 13 adult patients received pediatric renal transplants including two that were transplanted en bloc. The patients were divided into two groups based upon donor age: group I donors were 18 months to 6 years old; the seven recipients were of mean age 47.3 years. Group II donors were 7 to 15 years old; the six recipients were of mean age 43.6 years old. Cyclosporine-based immunosuppressive regimens were used in both groups. Results The patient survival rate was 85.7% in group I and 100% in group II. The graft survival rates at the first and third posttransplant year in group I were 71.4% (5/7) and 57.1% (4/7) and in group II, 66.7% and 50%, respectively. The frequency of urinary complications in group I was 28.5% (2/7) and in group II 33.3% (2/6). There was one case of venous thrombosis in group II. Conclusion Pediatric renal grafts may be used with reasonable safety. However, surgical complications remain a significant problem especially with younger pediatric grafts.

Insulin Resistance after Renal Transplantation

Cardiovascular disease is a prevalent and serious complication after solid organ transplantation. Treatment with glucocorticoids is associated with increased risk for diabetes mellitus, insulin resistance, weight gain, hypercholesterolemia, and hypertension, all shown to be independent risk factors for cardiovascular disease. We sought to test the hypothesis that tapering of prednisolone (TAP) the first year after renal transplantation improves insulin sensitivity (IS), and to assess the effect of complete steroid withdrawal (SW) on IS in patients on a cyclosporine-based immunosuppressive regimen. All patients (n = 57) completed two consecutive hyperinsulinemic euglycemic glucose clamp procedures, a TAP group (n = 34) and a control group (n = 12) at 3 and 12 mo after transplantation, and a SW group (n = 11) before and 5 mo after SW. The IS index (ISI) was calculated as the glucose disposal rate divided by mean serum insulin the last 60 min of the clamp. In the TAP group, the mean (range) daily prednisolone was reduced from 16 (10 to 30) to 9 (5 to 12.5) mg accompanied by an average increased ISI of 24% (P = 0.008). In contrast, no significant change in ISI was observed in the control group (0%, P = 0.988). In the SW group, withdrawal of 5 mg prednisolone did not influence mean ISI significantly (-8%, P = 0.206). Lowering daily prednisolone toward 5 mg/d has beneficial effects on insulin action after renal transplantation, but withdrawal of 5 mg prednisolone may not influence IS significantly.

Cyclosporine Minimization and Cost Reduction in Renal Transplant Recipients Receiving a C2-Monitored, Cyclosporine-Based Quadruple Immunosuppressive Regimen

Targeting 2-hr postdose cyclosporine (C2) levels to 1,000 to 1,700 mg/dL during the first 6 months after renal transplantation is recommended for triple immunosuppressive regimens. This trial determines whether lower C2 levels could be targeted safely in de novo kidney transplant recipients under a quadruple regimen compared with a similar cohort monitored with trough (C0) levels. This single-center, sequential, cohort-designed trial included patients who received Thymoglobulin, corticosteroids, an antimetabolite, and cyclosporine monitored by C2 (n=50) or C0 (n=50). Cyclosporine was tapered to maintain the C2 between 1,000 and 1,200 ng/mL months 0 to 3 and between 600 and 1,000 ng/mL thereafter and C0 between 250 and 350 ng/mL months 0 to 3 and between 100 and 250 ng/mL thereafter. Baseline patient and donor characteristics were similar. There were no differences in graft survival (100% C2 vs. 100% C0), acute rejection (4% C2 vs. 6% C0), allograft function, or adverse events at 6 months. C2 levels were lower than the suggested guidelines throughout the study (33% lower at 1 month and 48% lower at 6 months). Lower cyclosporine doses were achieved in the C2 arm compared with the C0 arm by 1 month and were sustained throughout the trial, which translated into an average cyclosporine cost savings of USD $773 in the C2 arm during the 6-month period (P<0.001). With a quadruple immunosuppressive regimen and lower C2 targets than recommended for triple therapy, safe and effective cyclosporine minimization was achieved. Lower cyclosporine doses were achieved in C2-monitored patients compared with C0-monitored patients, translating into lower immunosuppressive costs.

The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patients.

Cyclosporine is extensively metabolized by cytochrome-P450 3A (CYP3A) enzymes in the liver and intestine including the CYP3A5 isoenzyme. CYP3A5 is also expressed in the kidney and has been implicated in blood pressure regulation. Appreciable expression of CYP3A5 occurs in carriers of the CYP3A5*1 allele, while the CYP3A5*3 allele is associated with low expression. We tested whether the presence of the CYP3A5*1 allele in renal transplant recipients and in donor kidneys influences cyclosporine dose requirements, blood pressure and long-term graft survival in renal transplant patients during chronic treatment with a cyclosporine-based immunosuppressive regimen. We studied 399 Caucasian patients from our single-center registry with stable graft function for more than 10 weeks after transplantation. The genotypes for CYP3A5*1/*3 were determined by a TaqMan PCR method. Cyclosporine dose requirements, blood pressure and graft survival were analyzed in relation to the presence or absence of the CYP3A5*1 allele in recipients and donor kidneys. The CYP3A5*1 allele was found in 15.5% of the recipients and in 11.8% of the donor kidneys. The recipient CYP3A5*1 allele had no effect on cyclosporine dose and blood concentrations at trough with and without dose-adjustment. Blood pressure, number of antihypertensive compounds used for treatment and graft survival evaluated by Kaplan-Meier curves and Cox regression analysis were also not affected by the CYP3A5*1 allele either in recipients or donor kidneys. Cyclosporine dose requirements, blood pressure and long-term renal graft survival are not influenced by the CYP3A5*1 allele in Caucasian patients.

Fungal infections

Fungal infections

Lung transplantation for cystic fibrosis

BackgroundLung transplantation is a robust therapeutic option to treat patients with cystic fibrosis. Patients and methodsSince 1996, 109 patients with cystic fibrosis were accepted onto our waiting list with 58 bilateral sequential lung transplants performed in 56 patients and two patients retransplanted for obliterative bronchiolitis syndrome. ResultsPreoperative mean FEV1 was 0.64 L/s, mean PaO2 with supplemental oxygen was 56 mm Hg, and the mean 6-minute walking test was 320 m. Transplantation was performed through a “clam shell incision” in the first 29 patients and via bilateral anterolateral thoracotomies without sternal division in the remaining patients. Cardiopulmonary bypass was required in 14 patients. In 21 patients the donor lungs had to be trimmed by wedge resections with mechanical staplers and bovine pericardium buttressing to fit the recipient chest size. Eleven patients were extubated in the operating room immediately after the procedure. Hospital mortality of 13.8% was related to infection (n = 5), primary graft failure (n = 2), and myocardial infarction (n = 1). Acute rejection episodes occurred 1.6 times per patient/year; lower respiratory tract infections occurred 1.4 times per patient in the first year after transplantation. The mean FEV1 increased to 82% at 1 year after operation. The 5-year survival rate was 61%. A cyclosporine-based immunosuppressive regimen was initially employed in all patients; 24 were subsequently switched to tacrolimus because of central nervous system toxicity, cyclosporine-related myopathy, or renal failure, obliterative bronchiolitis syndrome, gingival hyperplasia, or hypertrichosis. Ten patients were subsequently switched to sirolimus. Freedom from bronchiolitis obliterans at 5 years was 60%. ConclusionsOur results confirm that bilateral sequential lung transplantation is a robust therapeutic option for patients with cystic fibrosis.

Cyclosporine monitoring in stable, long-term, pediatric kidney transplant recipients: the value of C2 determination

Although a generalized consensus has been reached for therapeutic drug monitoring of cyclosporine microemulsion in adult transplant patients, clear guidelines are recently not available for the pediatric population. In this retrospective analysis of pharmacokinetic data obtained from stable, long-term, pediatric kidney transplant recipients, we sought to define a possible approach to manage cyclosporine therapy in a pediatric setting. The 2-hour postdose cyclosporine blood concentration, C2, rather than trough levels, was the best single time point predictor of the area under the concentration curve. We concluded that therapeutic drug monitoring of cyclosporine-based immunosuppressive regimens should be tailored based on C2 determinations for pediatric kidney transplant recipients.