Impact of transplant nephrectomy on peak PRA levels and outcome after kidney re-transplantation.

AIM: To determine the impact of transplant nephrectomy on peak panel reactive antibody (PRA) levels, patient and graft survival in kidney re-transplants. METHODS: From 1969 to 2006, a total of 609 kidney re-transplantations were performed at the University of Freiburg and the Campus Benjamin Franklin of the University of Berlin. Patients with PRA levels above (5%) before first kidney transplantation were excluded from further analysis (n = 304). Patients with graft nephrectomy (n = 245, NE+) were retrospectively compared to 60 kidney re-transplants without prior graft nephrectomy (NE-). RESULTS: Peak PRA levels between the first and the second transplantation were higher in patients undergoing graft nephrectomy (P = 0.098), whereas the last PRA levels before the second kidney transplantation did not differ between the groups. Age adjusted survival for the second kidney graft, censored for death with functioning graft, were comparable in both groups. Waiting time between first and second transplantation did not influence the graft survival significantly in the group that underwent nephrectomy. In contrast, patients without nephrectomy experienced better graft survival rates when re-transplantation was performed within one year after graft loss (P = 0.033). Age adjusted patient survival rates at 1 and 5 years were 94.1% and 86.3% vs 83.1% and 75.4% group NE+ and NE-, respectively (P < 0.01). CONCLUSION: Transplant nephrectomy leads to a temporary increase in PRA levels that normalize before kidney re-transplantation. In patients without nephrectomy of a non-viable kidney graft timing of re-transplantation significantly influences graft survival after a second transplantation. Most importantly, transplant nephrectomy is associated with a significantly longer patient survival.

The impact of FTY720 (fingolimod) on vasodilatory function and arterial elasticity in renal transplant patients.

BACKGROUND: FTY720 has recently demonstrated a similar efficacy in prevention of acute graft rejection compared with mycophenolate mofetil (MMF) in a large phase III trial of de novo renal transplant recipients. Creatinine clearance, however, was significantly lower in FTY720-treated patients. In the present study, we examined the impact of FTY720 on vascular function in a subgroup of patients of this trial. METHODS: Eighteen patients (12 FTY720, 6 MMF) agreed to be enrolled for an analysis of vascular function. Vascular measurements were performed 1.5 years post-transplant and were repeated 3 months after conversion of the patients from FTY720 to MMF. Arterial stiffness was assessed as augmentation index (AI(75)); endothelium-dependent and -independent vasodilation were measured sonographically as flow-mediated dilation (FMD) and as vasodilation after application of glyceroltrinitrate (GTN). RESULTS: Conversion from 2.5 mg FTY720 to MMF led to a significant improvement of FMD (5.40 +/- 1.84 vs 7.77 +/- 3.36%, P 0.02). AI(75) and GTN tended to be higher after conversion without reaching significance (83 +/- 20.43 vs 78.69 +/- 15.39%, P 0.06; 13.76 +/- 4.52 vs 17.39 +/- 3.76%, P 0.07). In the MMF group, AI(75), FMD and GTN did not significantly change during the observation period. CONCLUSION: The present study constitutes the first analysis of the impact of FTY720 on vascular function in humans and reveals an improvement of arterial vasodilatory function after discontinuation of FTY720 in de novo renal transplant recipients on cyclosporine.

Time-dependent effects of cadaveric renal transplantation on arterial compliance in patients with end-stage renal disease.

BACKGROUND: Cardiovascular complications are the leading cause of mortality in patients undergoing hemodialysis. Increased arterial stiffness is a strong and independent predictor of cardiovascular risk in these patients. In the present study, we investigated the time-dependent effects of cadaveric renal transplantation on arterial elasticity in end-stage renal disease patients. METHODS: Thirty-six patients underwent successful cadaveric kidney transplantation. Pulse-wave analysis of the radial artery was performed prior to transplantation (day 0) and at six defined intervals after transplantation (day 1 to 90). Compliance of large conduit arteries (C1) and of small resistance arteries (C2) was assessed using a modified Windkessel model of the circulation. RESULTS: Both large artery and small artery compliance were transiently improved within the first four weeks posttransplant reaching a maximum of 122 +/- 42% (C1) and 147 +/- 93% (C2) between day 19 and 23. After the first month, however, elasticity gradually deteriorated to reach baseline values three months after transplantation again. CONCLUSION: The benefits of cadaveric renal transplantation on oscillatory and capacitive artery compliance are only transient. It may be speculated that the subacute and long-term vasoactive effects of calcineurin inhibitors counteract the metabolic benefits of increased renal function on the vasculature.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Cyclosporine dose requirements, blood pressure and long-term renal graft survival are not influenced by the CYP3A5*1 allele in Caucasian patients.

Effects of parathyroidectomy on renal allograft survival.

BACKGROUND: Hyperparathyroidism is a common problem secondary to renal insufficiency and is often not entirely resolved after renal transplantation (TX). METHODS: In this retrospective analysis, the effects of parathyroidectomy (PTX) on allograft function were evaluated and the risk factors involved in allograft deterioration in patients after PTX will be discussed. RESULTS: The rise in creatinine was steeper 1 year after PTX compared to 2 years before PTX in the majority (13 of 22) of patients. Compared to a cohort without PTX, graft survival was significantly decreased by 60% in 6 years (p < 0.0001). After multivariate adjustment, risk factors attributed to graft function included baseline creatinine (p = 0.02), baseline systolic blood pressure (p = 0.04) and time between TX and PTX, but not PTX itself. The peri-PTX drop in serum calcium was significantly more accentuated in patients exhibiting a worsening of graft function after PTX (p = 0.04). CONCLUSIONS: In patients requiring PTX, graft function is in danger of worsening. Since many factors contribute to this negative correlation and no association with parathyroid hormone (PTH) levels before PTX has been observed, we do not recommend prophylactic PTX on the basis of PTH levels only. However, appropriate management of peri-PTX risk factors is highly important. If the clinical situation, e.g. progressive renal osteodystrophy, requires removal of parathyroid glands, the procedure should be performed, if possible, in the presence of stable graft function.

Immunosuppression for long-term maintenance of renal allograft function.

The incidence and severity of acute rejection episodes was markedly reduced by the introduction of new immunosuppressive drug regimens for renal transplantation, resulting in improved graft survival at 1 year. However, only modest improvement has been shown in long-term graft function rates. This overview evaluates the efficacy of currently used immunosuppressive drugs and drug combinations for long-term maintenance therapy. Prospective controlled trials rarely extend beyond 5 years; therefore, registry data and retrospective reports have also been employed. From currently available data it may be concluded that the initial beneficial effect of ciclosporin (cyclosporin) is lost 10 years after transplantation. Tacrolimus is an alternative to ciclosporin with a different profile of adverse effects and a higher efficacy in acute rejection treatment. For long-term maintenance, projected half-lives of kidney graft function are in favour of tacrolimus. Mycophenolate mofetil (MMF) has been shown to significantly reduce the incidence of early rejections. However, the improved long-term graft survival reported in retrospective studies has still to be confirmed in controlled trials. There is no convincing evidence for superiority of triple therapy including prednisone (or prednisolone), calcineurin inhibitors and azathioprine/MMF over dual therapy without azathioprine/MMF with respect to long-term outcome. Withdrawal of corticosteroids or calcineurin inhibitors clearly reduces adverse drug effects but carries the risk of acute rejection episodes. Avoidance of corticosteroids by using new immunosuppressive drug combinations may be an option to minimise toxic adverse effects in the future. At present, it seems unjustified to convert renal transplant recipients with stable graft function and tolerable adverse effects from one drug to another solely in expectation of future benefits. Acute early or late rejection episodes and intolerable adverse effects are good reasons for conversions between calcineurin inhibitors or cytotoxic agents. Chronic allograft nephropathy with slowly deteriorating graft function remains an unresolved problem.

Late-onset cytomegalovirus reactivation in critically ill renal transplant patients.

BACKGROUND: Cytomegalovirus (CMV) reactivation occurs frequently in the first months after renal transplantation. However, reports concerning long-term kidney transplant recipients are rare and have always pertained to symptomatic CMV disease. METHODS: We report four cases of late-onset asymptomatic CMV reactivation in critically ill renal transplant patients who suffered from severe bacterial infections and in whom CMV antigenemia was observed. RESULTS AND CONCLUSION: CMV reactivation in these patients might indicate an additional disturbance in the patients' immune defenses at the time of critical illness, possibly even necessitating a temporary reduction in immunosuppressive therapy. Prospective, controlled trials are needed to define the role of CMV antigenemia in critically ill patients, including the role of antiviral therapy for asymptomatic reactivations.

Five-year results of renal transplantation on immunosuppressive triple therapy with mycophenolate mofetil.

Mycophenolate mofetil (MMF) combined with cyclosporine and prednisolone significantly lowers acute rejection frequency in the early post-renal transplantation phase. To date only registry data with very high transplant numbers have shown that MMF significantly influences long-term outcome. A comparative retrospective analysis of the 5-yr results with MMF in a single transplant center was thus undertaken vs. other standard immunosuppressive regimens. The results of 1579 renal transplantations were grouped by treatment modality, subjected to Kaplan-Meier analysis, and compared using the log rank test. Both the total population and subgroups showed a non-significant trend towards better graft survival with MMF, evident at 2 yr and persisting for 5 yr. Extrapolation indicates that on combination therapy with MMF vs. azathioprine, approximately 10% more patients will be alive at 10 yr with a functional graft.

Matrix analysis for the dissection of interactions of G-protein beta3 subunit C825T genotype, allograft function, and posttransplant hypertension in kidney transplantation.

BACKGROUND: Complex relationships between genes and environment and the resulting biological impact have been dissected predominantly by conventional association studies. A major limitation of such studies results from the fact that only bidirectional investigations of genes and clinical end-points are commonly performed. The authors, therefore, applied matrix analyses to account for interactions between genetic and environmental factors influencing kidney allograft function. METHODS: By using matrices of correlation coefficients we tested the genetic effect of a variant within the gene encoding the beta3-subunit of heterotrimeric G-proteins (Gbeta3-C825T polymorphism) on posttransplant hypertension and kidney allograft function. This strategy allowed the authors to account for the influence of additional well-established genetic, clinical, and environmental confounders. The authors studied 281 consecutive white kidney recipients recruited between 1988 and 1993. Correlation coefficients of indices of relative change (percent) of systolic blood pressure (BP) and creatinine clearance (CrCl) were used in correlation coefficient matrices to elucidate interactions of parametrical biological parameters with environmental and genetic risk factors. RESULTS: A significant relationship was found between decreasing CrCl and increasing systolic BP in only those recipients who carried the Gbeta3-825TT genotype and did not lose graft during the first 3 years (R2 = 0.25; P = 0.021). CONCLUSIONS: In transplant recipients who did not lose their graft during the first 3 years after transplantation, the Gbeta3-TT genotype contributed to accelerated loss of allograft function by exaggeration of posttransplant hypertension. This relationship could only be elucidated by means of matrix analyses that allow the detection of complex relations between clinical, genetic, and environmental factors.

Duration of donor brain death and its influence on kidney graft function.

Short- and long-term rates of success after cadaveric kidney transplantation are significantly inferior to those from living related or unrelated donors. The major difference between cadaveric and living donation is brain death. In the present study we analyzed the influence of duration of brain death on short- and long-term graft function after cadaveric kidney transplantation. The interval between declaration of donor brain death and the beginning of the cold ischemia time before graft explantation was defined as duration of brain death (DBD). The influence of DBD on incidence of primary graft function and on duration of delayed kidney graft function as well as on kidney graft survival was analyzed in 1106 patients transplanted in one center and confirmed in a validation study of a second series of 752 kidney graft recipients from another transplant center. Kidney grafts harvested from donors with longer DBD (>470 min) exhibited a significantly higher incidence of primary graft function and a significantly better graft survival rate in comparison to kidneys from donors with a shorter DBD (<470 min). The tendency of these results could be confirmed in an independent validation study; however, the differences were not statistically significant. Although the dramatic hemodynamic and immunological changes in brain-dead donors may impair the quality of a potential kidney transplant, a longer duration of donor brain death did not deteriorate early and long-term kidney graft function.