R.M. Langer

Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation

There is increasing interest in tacrolimus‐minimization regimens. ASSET was an open‐label, randomized, 12‐month study of everolimus plus tacrolimus in de‐novo renal‐transplant recipients. Everolimus trough targets were 3–8 ng/ml throughout the study. Tacrolimus trough targets were 4–7 ng/ml during the first 3 months and 1.5–3 ng/ml (n = 107) or 4–7 ng/ml (n = 117) from Month 4. All patients received basiliximab induction and corticosteroids. The primary objective was to demonstrate superior estimated glomerular filtration rate (eGFR; MDRD‐4) at Month 12 in the tacrolimus 1.5–3 ng/ml versus the 4–7 ng/ml group. Secondary endpoints included incidence of biopsy‐proven acute rejection (BPAR; Months 4–12) and serious adverse events (SAEs; Months 0–12). Statistical significance was not achieved for the primary endpoint (mean eGFR: 57.1 vs. 51.7 ml/min/1.73 m2), potentially due to overlapping of achieved tacrolimus exposure levels (Month 12 mean ± SD, tacrolimus 1.5–3 ng/ml: 3.4 ± 1.4; tacrolimus 4–7 ng/ml: 5.5 ± 2.0 ng/ml). BPAR (months 4–12) and SAE rates were comparable between groups (2.7% vs. 1.1% and 58.7% vs. 51.3%; respectively). Everolimus‐facilitated tacrolimus minimization, to levels lower than previously investigated, achieved good renal function, low BPAR and graft‐loss rates, and an acceptable safety profile in renal transplantation over 12 months although statistically superior renal function of the 1.5–3 ng/ml tacrolimus group was not achieved. (ClinicalTrials.gov: NCT00369161) is registered at http://www.clinicaltrials.gov.

De novo hemolytic uremic syndrome after kidney transplantation in patients treated with cyclosporine-sirolimus combination.

Objective. We sought to examine factors that predisposed 1.5% (10/672) of renal transplant recipients treated with a cyclosporine (CsA)/sirolimus (SRL)/steroid immunosuppressive regimen to develop hemolytic uremic syndrome (HUS). Methods. Two cohorts of recipients were treated for 1–212 months (mean: 25.0±26.4, median: 18.1) with concentration-control CsA regimens based upon either area under the concentration-time curve (AUC; n=412 patients) or trough measurements (C0; n=260 patients). Results. The only demographic feature more common to affected patients was an original glomerulopathic disease in 7 patients, 4 of whom had displayed IgA glomerulonephritis. All 10 affected patients showed a clinical picture of hemolysis with schistocytes, thrombocytopenia (nadir: 35,000±19,600 platelets/mm3), as well as elevated serum levels of lactate dehydrogenase (1697±1427 IU) and creatinine (Scr; 2.05±1.52 mg/dL prediagnosis to 5.13±2.43 mg/dL at diagnosis). Seven patients experienced adverse events concomitant with the bout of HUS, namely, acute rejection episodes prior to (n=2) or during (n=3), and 2 patients, infections (Herpes simplex and pancolitis). The mean values of daily steroid dose and the immunosuppressive drug C0 values were above the putative therapeutic targets: namely, CsA C0=294.9±153.2 ng/ml versus 150±50 ng/ml and SRL C0=20.1±14.0 ng/ml versus 10±5 ng/ml, respectively. The therapeutic approach included discontinuation of CsA in 9/10, which was transient in 6/9; discontinuation of SRL in all 10, which was transient in 3, OKT3 for concurrent rejection in 3, and plasmapheresis in 5 patients. At 24 weeks postdiagnosis 9/10 patients have well-functioning kidneys with a mean Scr value of 1.6±0.59 mg/dL. One patient who underwent transplant nephrectomy subsequently succumbed due to a cluster of refractory thrombocytopenia, Aspergillus infection, and multiorgan failure. Conclusion. This initial experience suggests that a time-limited and reversible de novo HUS syndrome may be less frequent and milder among renal transplant recipients treated with SRL-based immunosuppression.

Steroid Pretreatment of Organ Donors to Prevent Postischemic Renal Allograft Failure A Randomized, Controlled Trial

BACKGROUND Posttransplantation acute renal failure (ARF) occurs in roughly 25% of recipients of organs from deceased donors. Inflammation in the donor organ is associated with risk for ARF. OBJECTIVE To determine whether administering corticosteroids to deceased organ donors reduces the incidence and duration of ARF in organ recipients more than placebo. DESIGN Parallel, blocked randomized trial, performed between February 2006 and November 2008, with computer-generated randomization and centralized allocation. Investigators were masked to group assignment. (Controlled-trials.com registration number: ISRCTN78828338) SETTING: 3 renal transplantation centers in Austria and Hungary. PATIENTS 306 deceased heart-beating donors and 455 renal transplant recipients. INTERVENTIONS Organ donors were administered an intravenous infusion of either 1000 mg of methylprednisolone (136 donors) or placebo (0.9% saline) (133 donors) at least 3 hours before organ harvesting. MEASUREMENTS Incidence of ARF, defined as more than 1 dialysis session in the first week after transplantation, was the primary end point. Secondary and other end points included duration of ARF and trajectories of serum creatinine level. The suppression of immune response and inflammation by the intervention was assessed in the donor organ on a genome-wide basis. RESULTS 52 of 238 recipients (22%) of kidneys from steroid-treated donors and 54 of 217 recipients (25%) of kidneys from placebo-treated donors had ARF (difference, 3 percentage points [95% CI, -11 to 5 percentage points]). One graft was lost on day 1 in each group, and 1 recipient in the placebo group died of cardiac arrest on day 2. The median duration of ARF was 5 days (interquartile range, 2 days) in the steroid group and 4 days (interquartile range, 2 days) in the placebo group (P = 0.31). The groups had similar trajectories of serum creatinine level in the first week (P = 0.72). Genomic analysis showed suppressed inflammation and immune response in kidney biopsies from deceased donors who received corticosteroids. LIMITATION Donors and recipients were mainly white, and all were from 3 transplantation centers in central Europe, which may limit generalizability. CONCLUSION Systemic suppression of inflammation in deceased donors by corticosteroids did not reduce the incidence or duration of posttransplantation ARF in allograft recipients. PRIMARY FUNDING SOURCE Austrian Science Fund and Austrian Academy of Science.

Islet transplantation: lessons learned since the Edmonton breakthrough.

This work sought to summarize the main issues of the last decade in the field of clinical islet transplantation. Ten years ago in Edmonton, a new protocol initiated for islet transplantation brought a breakthrough to the field. The earlier, rather poor results were in a sharp contrast to the first published results of 100% insulin freedom at 1 year. However, later it became clear that the promising initial results decline with time; at around 5 years, only about 10% of the patients maintain freedom from external insulin. Despite that fact, a milestone was set and intensive research started worldwide. New hopes were raised for patients. Modifications of the original protocol have been implemented to improve clinical results; however, islet transplantation remains an experimental procedure to date.

Sirolimus does not increase the risk for postoperative thromboembolic events among renal transplant recipients.

Background. Deep venous thrombosis (DVT) tends to occur in greater frequency among cyclosporine (CsA)-treated renal-transplant recipients. Because administration of sirolimus may increase the whole-blood concentrations of CsA, we sought to assess the impact of the combination regimen on the incidence, predisposing factors, and consequences of postoperative DVT, transplant renal-vein or artery thrombosis, and pulmonary embolus. Methods. We retrospectively evaluated two cohorts of renal transplant recipients: CsA/prednisone (Pred)±azathioprine (n=136, group A) or sirolimus+CsA+Pred (n=354, group B) using Fisher’s exact t and chi-square tests, as well as Kaplan-Meier analyses, odds ratios, and multiple logistic regression methods. Results. The 7 of 136 (5.1%) incidence of thrombotic events in group A was similar to the 20 of 354 (5.6%) incidence in group B (P =0.513; NS) and occurred no more frequently ipsilateral to the transplant. Although the occurrence of an acute-rejection episode was not associated with the DVT diagnosis, all affected patients displayed elevated serum creatinine (Scr) values, which remained slightly higher than baseline following recovery (group A 1.63±1.22–1.95±0.93 mg/dL; group B 1.70±1.11–2.01±0.88 mg/dL). Renal biopsies failed to show evidence of intrarenal coagulopathy. No patient lost a graft as a complication of DVT, nor did these events produce other lasting adverse effects. Patients in the sirolimus group showed a strong correlation between the occurrence of DVT and the previous existence of an ipsilateral or contralateral lymphocele. Conclusion. Addition of sirolimus to a CsA+Pred regimen does not increase the incidence of postoperative thrombotic events among renal transplant recipients.

Randomized Trial of Micafungin for the Prevention of Invasive Fungal Infection in High-Risk Liver Transplant Recipients

In this randomized clinical trial comparing micafungin 100 mg with standard-care antifungal prophylaxis (fluconazole, liposomal amphotericin B, or caspofungin) in high-risk liver transplant patients, micafungin 100 mg was noninferior and had a better kidney safety profile.

Molecular pathogenesis of post-transplant acute kidney injury: Assessment of whole-genome mRNA and miRNA profiles

Acute kidney injury (AKI) affects roughly 25% of all recipients of deceased donor organs. The prevention of post-transplant AKI is still an unmet clinical need. We prospectively collected zero-hour, indication as well as protocol kidney biopsies from 166 allografts between 2011 and 2013. In this cohort eight cases with AKI and ten matched allografts without pathology serving as control group were identified with a follow-up biopsy within the first twelve days after engraftment. For this set the zero-hour and follow-up biopsies were subjected to genome wide microRNA and mRNA profiling and analysis, followed by validation in independent expression profiles of 42 AKI and 21 protocol biopsies for strictly controlling the false discovery rate. Follow-up biopsies of AKI allografts compared to time-matched protocol biopsies, further baseline adjustment for zero-hour biopsy expression level and validation in independent datasets, revealed a molecular AKI signature holding 20 mRNAs and two miRNAs (miR-182-5p and miR-21-3p). Next to several established biomarkers such as lipocalin-2 also novel candidates of interest were identified in the signature. In further experimental evaluation the elevated transcript expression level of the secretory leukocyte peptidase inhibitor (SLPI) in AKI allografts was confirmed in plasma and urine on the protein level (p<0.001 and p = 0.003, respectively). miR-182-5p was identified as a molecular regulator of post-transplant AKI, strongly correlated with global gene expression changes during AKI. In summary, we identified an AKI-specific molecular signature providing the ground for novel biomarkers and target candidates such as SLPI and miR-182-5p in addressing AKI.

Molecular biomarker candidates of acute kidney injury in zero‐hour renal transplant needle biopsies

The aim of this study was to assess gene expression levels of four biomarker candidates [lipocalin 2 (LCN2), the kidney injury molecule 1 (HAVCR1), netrin 1, and the cysteine‐rich, angiogenic inducer, 61] in the tubulointerstitial and the glomerular compartment of zero‐hour kidney biopsies in order to predict developing delayed graft function (DGF). Thirty‐four needle kidney biopsy samples of deceased donors were manually microdissected. Relative gene expression levels were determined by real‐time RT‐PCR. For the validation of the biomarker candidates, we calculated a mixed model comparing kidneys with DGF, primary function and control samples from the healthy parts of tumor nephrectomies. Significant biomarker candidates were analyzed together with donor age in multivariable regression models to determine the prognostic value. Expression levels of LCN2 and HAVCR1 in the tubulointerstitium were significantly upregulated in the DGF group (LCN2: fold change = 3.78, P = 0.031 and HAVCR1: fold change = 3.44, P = 0.010). Odds ratios of both genes could not reach significance in the multivariable model together with donor age. The area under the curve of the receiver operating characteristic ranges between 0.75 and 0.83. LCN2 and HAVCR1 gene expression levels in zero‐hour biopsies show potential to act as early biomarkers for DGF.

The effect of steroid pretreatment of deceased organ donors on liver allograft function: A blinded randomized placebo-controlled trial

Background & Aims Brain death-associated inflammatory response contributes to increased risk of impaired early liver allograft function, which might be counterbalanced by steroid pretreatment of the organ donor. The aim of this randomized controlled trial was to elucidate whether steroid pretreatment of liver donors improves early liver allograft function, prevents rejection and prolongs survival. Methods A placebo-controlled blinded randomized clinical trial was performed in three different centers in Austria and Hungary between 2006 and 2008. Ninety deceased organ donors received either 1000 mg of methylprednisolone or placebo 6 h before recovery of organs. The primary end point was the concentration slope of transaminases within the first week. The secondary end point included survival and biopsy-confirmed acute rejection (BCAR) within 3 years after transplantation. Results Of the 90 randomized donors, 83 recipients were eligible for study. The trajectories of ALT and AST were not different between treatments (p = 0.40 and p = 0.13, respectively). Eight subjects died in the steroid and 13 in the placebo group within 3 years after engraftment (RR = 0.63 95% CI [0.29, 1.36], p = 0.31). Eleven recipients experienced biopsy-confirmed rejection (BCAR) in the steroid and 11 in the placebo group (RR = 1.02 95% CI [0.50, 2.10], p = 1.00). No effect modification could be identified in the predefined strata of donor age, sex, cold ischemic time, and cause of donor death. Conclusions Steroid pretreatment of organ donors did not improve outcomes after liver transplantation.

Renal cell carcinoma of the native kidney: a frequent tumor after kidney transplantation with favorable prognosis in case of early diagnosis.

INTRODUCTION The frequency of malignant tumors as a cause of death is increasing among kidney transplant patients. The aim of our study was to characterize kidney tumors occurring in the native kidneys of renal transplanted patients, and to determine their impact on recipient survival. METHODS We retrospectively analyzed the 43/3003 (1.43%) renal cell carcinomas (RCC) in the native kidneys of patients transplanted between 1973 and 2010. RESULTS During this period we diagnosed 293 posttransplant tumors, 14.6% of which were RCC. The male/female ratio was 2.1:1. The mean age of recipients at the time of tumor detection was 52.4 ± 12.1 years. The mean time from transplantation to diagnosis was 72.4 ± 61.6 months. RCC occurred on both sides in similar numbers. Tumors were multifocal in 8 cases. According to TNM staging, RCC was stage I in 38 cases. The histologic type was clear cell (n=27), papillary (n=13), chromophobe (n=2) or sarcomatoid (n=1). Radical nephrectomy was performed in 41 cases. Immunosuppressive management was converted to proliferation signal inhibitors in 27 patients (sirolimus n=19 or everolimus n=8). Fifteeen patients died at a mean survival time of 38.9 ± 62.4 months with 28 patients still alive at a mean follow-up 43.8 ± 35.6 months. Cumulative survival according to the Kaplan-Meier method was 79.2% at 1 year, 66.1% at 5 years, and 59.0% at 10 years. The patient survival rate was better among papillary than clear cell RCC (P=.038). CONCLUSION RCC was the second most frequent tumor among kidney transplanted patients at our center. The diagnosis established at an early stage in the majority of cases, leading to favorable patient survivals. A regular yearly abdominal ultrasound screening is suggested for early tumor diagnosis.