Katharina Heller

Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study.

ZEUS study was an open‐label, 12‐month, multicenter study in which 300 de novo kidney transplant recipients were randomized to continue receiving cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant. Five‐year follow‐up data were available for 245/269 patients (91.1%) who completed the core 12‐month study (123 everolimus, 109 CsA). At 5 years, adjusted estimated GFR was 66.2 mL/min/1.73 m2 with everolimus versus 60.9 mL/min/1.73 m2 with CsA; the mean difference was 5.3 mL/min/1.73 m2 in favor of everolimus (95% CI 2.4, 8.3; p < 0.001 [intent‐to‐treat population]). In a post hoc analysis of patients remaining on study drug at 5 years (everolimus 77, CsA 86), mean difference was 8.2 mL/min/1.73 m2 (95% CI 4.3, 12.1; p < 0.001) in favor of everolimus. The cumulative incidence of biopsy‐proven acute rejection postrandomization was 13.6% with everolimus versus 7.5% with CsA (p = 0.095), largely accounted for by grade I rejection (16/21 patients and 7/11 patients, respectively). Postrandomization, graft loss, mortality, serious adverse events and neoplasms were similar in both arms. In conclusion, conversion of kidney transplant patients to everolimus at 4.5 months posttransplant is associated with a significant improvement in renal function that is maintained to at least 5 years. The increase in early mild acute rejection did not affect long‐term graft function.

BK viremia and polyomavirus nephropathy in 352 kidney transplants; risk factors and potential role of mTOR inhibition.

BackgroundPolyomavirus BK nephropathy (PyVAN) remains an important cause of early graft dysfunction and graft loss in kidney transplantation.MethodsIn this retrospective, single centre cohort study we studied the incidence and outcome of BK viral infection in 352 patients transplanted in 2008–2011.ResultsDuring follow-up viral replication was detected in 48 patients (13.6%); 22 patients (6.2%) had biopsy proven PyVAN.In multivariate logistic regression analyses risk factors for BK-viremia were lack of enrolment into randomized controlled trials (RCTs), biopsy proven acute rejections, cytomegaly virus (CMV) serostatus of both donor and recipient and previous transplantation.In patients without PyVAN reduction or switch of immunosuppression was associated with rapid viral clearance and stable graft function. In contrast, in most patients with PyVAN graft function deteriorated and 5 patients prematurely lost their allograft. Switch of immunosuppression to a low dose cyclosporine plus mTOR inhibitor based regimen in patients with PyVAN was safe, well tolerated and tended to be associated with a better short-term outcome in terms of graft function compared to reduction of existing immunosuppression alone.ConclusionsWith the lack of licensed anti-polyoma viral drugs reduction or conversion of immunosuppression remains the mainstay of therapy in patients with PyVAN. The combination of low dose cyclosporine plus mTOR inhibition appears to be safe and warrants further investigation.

Effects of Dopamine Donor Pretreatment on Graft Survival after Kidney Transplantation: A Randomized Trial

BACKGROUND AND OBJECTIVES Donor dopamine improves initial graft function after kidney transplantation due to antioxidant properties. We investigated if a 4 µg/kg per minute continuous dopamine infusion administered after brain-death confirmation affects long-term graft survival and examined the exposure-response relationship with treatment duration. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Five-year follow-up of 487 renal transplant patients from 60 European centers who had participated in the randomized, multicenter trial of dopamine donor pretreatment between 2004 and 2007 (ClinicalTrials.gov identifier: NCT00115115). RESULTS Follow-up was complete in 99.2%. Graft survival was 72.6% versus 68.7% (P=0.34), and 83.3% versus 80.4% (P=0.42) after death-censoring in treatment and control arms according to trial assignment. Although infusion times varied substantially in the treatment arm (range 0-32.2 hours), duration of the dopamine infusion and all-cause graft failure exhibited an exposure-response relationship (hazard ratio, 0.96; 95% confidence interval [95% CI], 0.92 to 1.00, per hour). Cumulative frequency curves of graft survival and exposure time of the dopamine infusion indicated a maximum response rate at 7.10 hours (95% CI, 6.99 to 7.21), which almost coincided with the optimum infusion time for improvement of early graft function (7.05 hours; 95% CI, 6.92 to 7.18). Taking infusion time of 7.1 hours as threshold in subsequent graft survival analyses indicated a relevant benefit: Overall, 81.5% versus 68.5%; P=0.03; and 90.3% versus 80.2%; P=0.04 after death-censoring. CONCLUSIONS We failed to show a significant graft survival advantage on intention-to-treat. Dopamine infusion time was very short in a considerable number of donors assigned to treatment. Our finding of a significant, nonlinear exposure-response relationship disclosed a threshold value of the dopamine infusion time that may improve long-term kidney graft survival.

Proteinuria and sirolimus after renal transplantation: a retrospective analysis from a large German multicenter database

The German Sirolimus Study Group has established a database among 10 transplant centers throughout Germany to study the outcomes in 726 renal transplant patients being converted to a sirolimus‐containing therapy between 2000 and 2008 with a total of more than 1500 recorded patient years on therapy. In this study, we present a detailed description of the cohort, of characteristic changes over the observation period, proteinuria and graft survival, and new‐onset proteinuria after conversion. Over the study period, age, graft function at the time of conversion, and the proportion of patients switched to sirolimus because of malignancy increased, whereas the proportion of patients with significant proteinuria at conversion decreased. Already modest proteinuria (151–268 mg/L) at conversion and new‐onset proteinuria (>500 mg/L) after conversion were associated with inferior graft survival. Even mild proteinuria (>71 mg/L) at conversion was associated with new‐onset proteinuria (>500 mg/L) post‐conversion. Serum creatinine and urinary protein excretion at conversion together with age at transplantation had a significant impact on patient and graft survival. This large data set confirms and extends previous observations that proteinuria is an important indicator for graft outcome after conversion to sirolimus. We conclude that patients without any proteinuria have the greatest benefit from conversion to sirolimus.

Depression, Anxiety, Resilience and Coping Pre and Post Kidney Transplantation – Initial Findings from the Psychiatric Impairments in Kidney Transplantation (PI-KT)-Study

Purpose Depression/anxiety, impaired Health-Related Quality of Life (HRQoL) and coping and resilience structures, are associated with increased mortality/poor outcome in chronic kidney disease (CKD) patients before (CKD/pre-KT) and after kidney (CKD-T) transplantation. Less is known about prevalence rates of psychiatric symptoms and impaired HRQoL of non-transplanted compared with transplanted patients. Methods In a cross-sectional study comparing 101 CKD/pre-KT patients with 151 cadaveric-transplanted (CKD-T) patients, we examined prevalence of depression/anxiety (HADS questionnaire) and coping, resilience and HRQoL (SF-12, Resilience-Scale and FKV-questionnaire). Results The prevalence of both depressive and anxiety symptoms was not significantly different between different pre-/and CKD-T patient groups. In CKD-T no significant relations of coping strategies with kidney function were identified. Furthermore, the Resilience Scales for acceptance and competence did not suggest any differences between the CKD/pre-KT and CKD-T subgroup. In the CKD/pre-KT patients, significant correlations were identified between the acceptance subscale and partnership, as well as between the competence subscale and older age/partnership. Conclusions Both the CKD/pre-KT and CKD-T patients exhibited notable impairments in the HRQoL which which showed a comparable pattern of results. KT itself does not appear to be the main risk factor for the development of mental impairments.

Deceased Donor Kidney Transplantation in the Eurotransplant Senior Program (ESP): A Single-Center Experience from 2008 to 2013.

BACKGROUND The aim of this study was to evaluate the outcome after transplantation of deceased allografts in donor/recipient pairs aged ≥65 years enrolled in the Eurotransplant Senior Program (ESP). MATERIAL AND METHODS In this retrospective cohort study we evaluated data from 89 patients transplanted under the ESP protocol from 2008 to 2013. Outcome parameters included graft and patient survival, rate of biopsy-proven acute rejections (BPAR), peri- and post-operative complications, tumor development, development of donor-specific antibodies (DSA), and the prognostic role of preimplantation biopsies. RESULTS One-year patient and allograft survival rates were 92.1% and 84.3%, respectively. During follow-up, 23 (26%) patients died; the major cause of death was sepsis, followed by cardiovascular events and malignancies. BPAR episodes were frequent within the first year (~33%) and overall were less common in patients treated with tacrolimus. Post-transplant malignancies were seen in 15 (17%) patients. During follow-up, 16 (18%) patients developed DSA; patients with delayed graft function (DGF) were more likely to develop DSA (p=0.029). A higher preimplantation biopsy score was associated with DGF but did not predict later graft outcome. CONCLUSIONS The results highlight increased risks in ESP transplant candidates and the importance of careful surveillance of this patient group.

Donor acute kidney injury and short‐term graft outcome in renal transplantation

With increased waiting times for kidney transplantation, marginal organs from expanded criteria donors (ECD) are increasingly offered for allocation. In addition to ECD status, donors may have suffered from acute kidney injury (AKI) prior to organ procurement.

Early conversion from cyclosporine to everolimus following living-donor kidney transplantation: outcomes at 5 years posttransplant in the randomized ZEUS trial

AIMS To assess 5-year efficacy, renal, and safety outcomes following early conversion from cyclosporine to everolimus vs. a standard cyclosporine-based regimen in living-donor kidney transplant (LDKT) recipients. MATERIALS AND METHODS The ZEUS study was a randomized, open-label, 1-year, multicenter study in which 300 de novo kidney transplant recipients continued to receive cyclosporine or converted to everolimus at 4.5 months post-transplant, with annual follow-up visits to 5 years post-transplant. RESULTS Of the 80 LDKT patients who were randomized, 75 completed the 1-year core study and 60 attended the 5-year follow-up visit. At year 5, 15/31 (48.4%) everolimus patients and 20/29 (69.0%) cyclosporine patients remained on the study drug. Mean adjusted estimated glomerular filtration rate (GFR) at year 5 in LDKT recipients was 67.2 vs. 60.8 mL/min/1.73m2 for everolimus vs. cyclosporine (mean difference 6.4 mL/min/1.73m2; p = 0.031). For patients who remained on study drug, the mean difference was 13.2 mL/min/1.73m2 (p = 0.003), but no significant difference was seen in patients who switched from study drug (mean -2.6 mL/min/1.73m2, p = 0.701). Patient and graft survival rates were similar with everolimus and cyclosporine. Biopsy-proven acute rejection occurred in 22.0% vs. 7.5% of LDKT patients randomized to everolimus vs. cyclosporine (p = 0.116). Only 1 LDKT patient discontinued everolimus due to adverse events during years 1 - 5. CONCLUSIONS Early initiation of everolimus with calcineurin-inhibitor (CNI) withdrawal after LDKT improved graft function to 5 years post-transplant compared to standard CNI-based therapy. The renal benefit was concentrated in patients who remained on everolimus. An increase in mild acute rejection was not associated with long-term graft loss.

Efficacy and safety of conversion from cyclosporine to everolimus in living-donor kidney transplant recipients: an analysis from the ZEUS study

Conversion of living‐donor kidney transplant patients from calcineurin inhibitor therapy to an mTOR inhibitor is poorly documented. In the prospective, multicentre ZEUS study, 300 kidney transplant recipients without prior rejection (Banff grade >1) and serum creatinine ≤265 μmol/l were randomized to continue cyclosporine or convert to everolimus at 4.5 months post‐transplant. In a post hoc analysis of 80 living‐donor recipients, adjusted estimated GFR (Nankivell) at month 12 (the primary endpoint) was 74.3 (95% CI [70.7, 77.9]) ml/min/1.73 m2 with everolimus versus 63.8 (95% CI [60.0, 67.7]) ml/min/1.73 m2) with cyclosporine, a difference of 10.5 ml/min/1.73 m2 in favour of everolimus (P < 0.001). From randomization to month 12, adjusted estimated GFR increased by a mean of 9.8 (95% CI [6.2, 13.4]) ml/min/1.73 m2 with everolimus versus −0.7 (95% CI [−4.6, 3.1]) ml/min/1.73 m2) (P < 0.001) with cyclosporine. There were six biopsy‐proven acute rejection episodes in everolimus‐treated patients (five Banff grade I) and one episode in cyclosporine‐treated patients (Banff grade 1). Overall safety profile was similar between groups. Discontinuation due to adverse events occurred in three everolimus patients (7.1%) and five cyclosporine patients (13.2%) between randomization and month 12. Initiation of everolimus with early elimination of calcineurin therapy is associated with a significant renal benefit at 12 months post‐transplant that is observed in both living and deceased‐donor recipients. (clinicaltrials.gov NCT00154310)

Results of Renal Transplantation on Alloplastic Arterial Grafts.

Background: The aim of this retrospective study was to report results of a consecutive series of kidney transplant patients in whom the renal artery was implanted on a prosthetic vascular graft (PVG). Methods: Between January 2011 and December 2014, 208 deceased donor renal transplantations (68 female, 140 male, mean age 52, SD 16 years) were performed. Medical charts and outpatient clinical records of patients who had undergone renal artery implantation on a PVG were reviewed. Extensive literature research added to our 4 patients further 170 published cases during 1989 and 2015 and was compared with regular transplanted patients. Data on patient characteristics, prior vascular procedures, postoperative and long-term outcome were collected. Results: Patients with transplant renal artery anastomosis on a PVG were 4 years older than the control group. Function of the graft was similar in these patients compared to regular renal transplant patients. Resistance indices assessed in our clinic over the entire follow-up period showed also no significant difference between the 2 groups. Thirty-day mortality was 6% (none in our group), which occurred mostly in combination when renal transplantation and PVG replacement was performed simultaneously. Conclusion: Grafting of the renal artery to a PVG is feasible and yields good results, despite the technical difficulties involved.