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Background. It is unclear whether the choice of maintenance immunosuppression modulates the negative effect of advanced donor age on outcome after renal transplantation. Methods. All 1829 patients who received their first transplant between 1990 and 2003 at the Vienna Medical Centre and had a functioning graft after 90 days were studied. At this time point, 1587 received calcineurin inhibitors (CNI+), 242 did not (CNI−). Actual and functional graft survival was analyzed in subgroups based on donor age ( 64 years) and immunosuppressive therapy. Results. The median follow-up time was 7 years. In total, we observed 312 deaths and 275 graft losses. After adjusting for several variables considered as potential confounders, actual graft survival was better in CNI+ patients compared with CNI− patients only if donor age was less than 36 years (adjusted hazard ratio 0.25, 95% confidence interval 0.17-0.38) or 36 to 49 years (0.43, 95% confidence interval 0.29-0.62). Similar results were obtained for functional graft survival. Patient survival was significantly better in CNI+ subjects irrespective of donor age (0.41, 95% confidence interval 0.30-0.57). Discussion. Use of CNI 90 days after transplantation is associated with improved patient survival even after adjustment for confounders, but its beneficial association with actual and functional graft survival is lost or at least reduced if kidneys from donors older than 50 years are used.

Background. Donor factors such as age profoundly influence long-term graft function after cadaveric renal transplantation, but the molecular signature of these aspects in the allograft remains unknown. Methods. We analyzed the genome-wide gene expression signature of donor kidney biopsies of different ages obtained before transplantation. Subsequent analysis compared expression profiles from allografts with excellent function versus impaired function at 1 yr after engraftment. Differential expression profiles were analyzed on the level of molecular function and biologic role, as well as by analysis of co-regulation through transcription factors, regulatory networks, and protein-protein interaction data utilizing extended bioinformatics. Results. The 15 subjects with excellent transplant function defined as calculated GFR≥45 mL/min/1.73 m 2 at 1 yr exhibited a distinctly different gene expression profile than the matched 16 subjects with impaired function defined as calculated GFR

Background. Postischemic acute renal transplant failure occurs in approximately one fourth of all dead donor transplantations. Uncertainty exists regarding the putative association between the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) and kidney transplant graft survival in patients with delayed allograft function. Methods. We conducted an open cohort study of all 436 patients who experienced an acute renal transplant failure out of all 2,031 subjects who received their first kidney transplant at the Medical University of Vienna between 1990 and 2003. Actual and functional graft survival was compared between users and nonusers of ACEI/ARB using exposure propensity score models and time-dependent Cox regression models. Results. Ten-year actual graft survival averaged 44% in the ACEI/ARB group, but only 32% in patients without ACEI/ARB (P=0.002). The hazard ratio of actual graft failure was 0.58 (95% confidence interval: 0.35-0.80, P=0.002) for ACEI/ARB users compared with nonconsumers. Seventy-one percent of subjects with ACEI/ARB had a functional graft at 10 years versus 64% of ACEI/ARB nonusers (P=0.027). The hazard ratio of functional graft loss was 0.48 (95% confidence interval: 0.24-0.91, P=0.025). Conclusions. Use of ACEI/ARB in patients experiencing delayed allograft function was associated with longer actual and functional transplant survival.

BACKGROUND The increasing use of tacrolimus as a primary immunosuppressant is paralleled by a growing number of pregnancies occurring in mothers receiving tacrolimus systemically. METHODS In this retrospective analysis during 1992-1998; data sources were case reports from clinical studies, spontaneous reports from health care professionals, routine surveys by transplant registries, and the published literature. RESULTS One hundred pregnancies in 84 mothers were recorded. Mean maternal age was 28 years. All except one mother (autoimmune disease) were solid organ transplant recipients (66% liver and 27% kid- ci ney). Mean time from transplantation to conception was 26 months. The mean daily dose of tacrolimus (range 11.7-12.8 mg/day) and the mean tacrolimus whole blood level (range 8.5-11.5 ng/ml) remained fairly constant from preconception through the third trimester. The most frequent maternal complications were graft rejection followed by preeclampsia, renal impairment, and infection. All cases of rejection were successfully treated with corticosteroids and did not result in graft loss. Of 100 pregnancies, 71 progressed to delivery (68 live births, 2 neonatal deaths, and 1 stillbirth), 24 were terminated (12 spontaneous and 12 induced), 2 pregnancies were ongoing, and 3 were lost to follow-up. Mean gestation period was 35 weeks with 59% deliveries being premature (

Introduction The efficacy of tight glycemic control for the prevention of death and renal failure in the general diabetic population is well established. However, in diabetic renal-allograft recipients, the effect of different treatment strategies on outcomes is undetermined. Methods We conducted a cohort study of 798 diabetic, renal-allograft recipients transplanted at the Medical University of Vienna between 1990 and 2004. We studied the influence of glucose parameters and diabetes treatment on mortality and graft loss. Marginal-structural models and multivariable Cox regression analysis were used to control for confounding. Results Maximal glucose levels but not HbA1c were independently associated with mortality. Being in the highest quartile of maximal glucose increased the adjusted risk of death by a factor of 2.2 (P value for trend 0.009). Furthermore, in patients receiving insulin, the risk of death was increased 1.7-fold (95% confidence interval 0.9-3.1) compared with diet and 2.0-fold (95% confidence interval 1.1-3.7) compared with oral medication. Maximal glucose, HbA1c, or diabetes treatment did not influence death-censored functional graft survival. Discussion In conclusion, maximal glucose levels and insulin treatment were independently associated with higher rates of mortality in our cohort of diabetic, renal-allograft recipients. However, graft survival was unaffected.

Mycophenolate mofetil has replaced azathioprine in many transplant centers, but data on hard outcomes such as graft and patient survival are lacking.We analyzed graft and patient survival of the 1219 first renal allograft recipients at the Medical University of Vienna who were treated with azathioprine or mycophenolate mofetil over the past decade. Cox's proportional hazards models were used to compute crude and confounder-adjusted hazard ratio estimates of azathioprine versus mycophenolate mofetil. Model building was performed by applying the purposeful selection algorithm, confounding by indication was addressed by propensity scores and marginal structural models.Five years after transplantation, 12% of mycophenolate mofetil users experienced functional graft loss whereas 26% of the azathioprine users had lost their graft (P0.001). The hazard ratio for functional graft loss was 2.15 (95% confidence interval 1.16-4.02, P=0.016) in azathioprine versus mycophenolate mofetil patients. Actual graft loss at five years had occurred in 25% of the mycophenolate mofetil patients and 49% of the azathioprine users (P0.001); hazard ratio 2.04 (95% confidence interval 1.22-3.39, P=0.006). Patient survival was not different in any of the analyses.The data from our observational study suggest that mycophenolate mofetil use was associated with a lower risk of graft loss than azathioprine-based immunosuppression.

BACKGROUND Several studies investigated the association of histologic scores of donor kidney biopsies obtained before engraftment with posttransplant outcomes. Discrimination and goodness of fit of these scores, however, is low. METHODS Thus, we sought to identify and elucidate the performance of molecular rather than histologic markers for this purpose using whole genome gene expression microarray experiments. RESULTS We identified 80 unique differentially regulated genes in 82 samples, showing no histologic damage versus those with histologic damage, based on the Chronic Allograft Damage Index (CADI) and acute tubular injury. Main biological categories enriched with up-regulated genes in damaged tissue were "immunity and defense," "cell communication," or "apoptosis." Interestingly, genes involved in cell structure, cell adhesion, and protein trafficking were specific for tubular atrophy. Histology (CADI score) explained only 14% of the variability of 1 year creatinine (adjusted R2 for panel-reactive antibodies, biopsy confirmed acute rejection, and sum of human leukocyte antigen mismatches) whereas a combination of three biomarkers without clinical covariables explained 28%. The three molecular markers are the NLR family, pyrin domain containing 2 (NLRP2), immunoglobulin J polypeptide, and the regulator of G-protein signaling 5. CONCLUSION In summary, we identified biomarkers in transplant kidney biopsies, which are predictive for medium-term allograft function.

The increasing use of tacrolimus as a primary immunosuppressant is paralleled by a growing number of pregnancies occurring in mothers receiving tacrolimus systemically.In this retrospective analysis during 1992-1998; data sources were case reports from clinical studies, spontaneous reports from health care professionals, routine surveys by transplant registries, and the published literature.One hundred pregnancies in 84 mothers were recorded. Mean maternal age was 28 years. All except one mother (autoimmune disease) were solid organ transplant recipients (66% liver and 27% kid- ci ney). Mean time from transplantation to conception was 26 months. The mean daily dose of tacrolimus (range 11.7-12.8 mg/day) and the mean tacrolimus whole blood level (range 8.5-11.5 ng/ml) remained fairly constant from preconception through the third trimester. The most frequent maternal complications were graft rejection followed by preeclampsia, renal impairment, and infection. All cases of rejection were successfully treated with corticosteroids and did not result in graft loss. Of 100 pregnancies, 71 progressed to delivery (68 live births, 2 neonatal deaths, and 1 stillbirth), 24 were terminated (12 spontaneous and 12 induced), 2 pregnancies were ongoing, and 3 were lost to follow-up. Mean gestation period was 35 weeks with 59% deliveries being premature (37 weeks). The birth weight (mean 2573 g) was appropriate for gestational age in 90% of cases. Most common complications in the neonate were hypoxia, hyperkalemia, and renal dysfunction. These were transient in nature. Four neonates presented with malformations, without any consistent pattern of affected organs.Pregnancy in tacrolimus-treated transplant recipients resulted in a favourable outcome. Complications of the mother and neonate were similar to those previously described with other immunosuppressants.