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. To determine whether administering corticosteroids to deceased organ donors reduces the incidence and duration of ARF in organ recipients more than placebo. 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) 3 renal transplantation centers in Austria and Hungary. 306 deceased heart-beating donors and 455 renal transplant recipients. 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. 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. 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. Donors and recipients were mainly white, and all were from 3 transplantation centers in central Europe, which may limit generalizability. Systemic suppression of inflammation in deceased donors by corticosteroids did not reduce the incidence or duration of posttransplantation ARF in allograft recipients. Austrian Science Fund and Austrian Academy of Science.

Background. Anaemia is a common complication in dialysis patients. In most cases, it is treated with erythropoietin-stimulating agents (ESA). It is not entirely clear whether the variability of haemoglobin caused by changing ESA response is associated with increased mortality. Therefore, we conducted a retrospective cohort study to evaluate ESA responsiveness and haemoglobin variability in association with mortality. Methods. We used the Austrian dialysis and transplant registry, and identified 932 patients who were on maintenance haemodialysis in the years 2005–08 with recorded weekly ESA doses and haemoglobin concentrations. ESA response was defined as a positive regression slope over the observation period. Cox regression analysis with spline functions and purposeful variable selection algorithms were used. Results. Adjusted Cox regression analysis showed an increased mortality risk in subjects with wide ranges of haemoglobin variability (from 12 g/dL) (HR = 2.38, 95% CI 1.20–4.71, P = 0.013). Furthermore, patients that never reached haemoglobin levels >10 g/dL despite ESA therapy exhibited the highest risk of mortality (HR = 6.37, 95% CI 2.15–18.82, P < 0.001). ESA hypo-responsiveness was associated with increased risk of mortality in the low as well as high haemoglobin ranges [HR = 2.06, 95% CI 1.49–2.86 at haemoglobin of 9.5 g/dL and HR = 1.64, 95% CI 0.68–3.92 at 13.5 g/dL both vs. 11 g/dL (reference)]. ESA dose equivalents >16 000 units per week were associated with increased mortality in ESA responders (HR = 1.30, 95% CI 1.02–1.64). However, in hypo-responders, mortality is not associated with ESA dose (HR = 1.02, 95% CI 0.87–1.20) [both at weekly ESA dose of 20 000 units vs. 16 000 (reference)]. Conclusions. These findings suggest that the risk of mortality of haemodialysis patients requiring ESA therapy is lowest if the haemoglobin concentration is stably maintained in the range between 10 and 12 g/dL with weekly ESA dose equivalents <16 000 units.

Introduction: Epirubicin is a common adjuvant treatment for breast cancer. It is mainly eliminated after glucuronidation through uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7). The present study aimed to describe the impact of theUGT2B7^His268Tyrpolymorphism on invasive disease-free survival in breast cancer patients after epirubicin treatment.Methods: This is a pharmacogenetic study based on samples collected from 745 breast cancer patients of the AustrianTumor of breast tissue:Incidence,Genetics, andEnvironmentalRisk factors (TIGER) cohort who did not present metastases at baseline. This cohort included 205 women with epirubicin-based combination chemotherapy, 113 patients having received chemotherapy without epirubicin and 427 patients having received no chemotherapy at all. Of the epirubicin-treated subgroup, 120 were subsequently treated with tamoxifen. For all womenUGT2B7^His268Tyrwas genotyped. Invasive disease-free survival was assessed using Kaplan-Meier and Cox's proportional hazard regression analysis.Results: Among the 205 epirubicin-treated patients, carriers of twoUGT2B7^268Tyralleles had a mean invasive disease-free survival of 8.6 (95% confidence interval (CI) 7.9 to 9.3) years as compared to 7.5 (95% CI 6.9 to 8.0) years in carriers of at least oneUGT2B7^268Hisallele (adjusted hazard ratio (HR) = 2.64 (95% CI 1.22 to 5.71);P= 0.014). In addition, the impact of theUGT2B7^His268Tyrpolymorphism became even more pronounced in patients subsequently treated with tamoxifen (adjusted HR = 5.22 (95% CI 1.67 to 26.04);P= 0.015) whereas no such difference in invasive disease-free survival was observed in patients not receiving epirubicin.Conclusions: Breast cancer patients carrying theUGT2B7^268Tyr/Tyrgenotype may benefit most from adjuvant epirubicin-based chemotherapy. These results warrant confirmation in further studies.

Background and objectives: The median kidney transplant half-life is 10–15 years. Because of the scarcity of donor organs and immunologic sensitization of candidates for retransplantation, there is a need for quantitative information on if and when a second transplantation is no longer associated with a lower risk of mortality compared with waitlisted patients treated by dialysis. Therefore, we investigated the association of time on waiting list with patient survival in patients who received a second transplantation versus remaining on the waiting list. Design, setting, participants, & measurements: In this retrospective study using target trial emulation, we analyzed data of 2346 patients from the Austrian Dialysis and Transplant Registry and Eurotransplant with a failed first graft, aged over 18 years, and waitlisted for a second kidney transplantation in Austria during the years 1980–2019. The differences in restricted mean survival time and hazard ratios for all-cause mortality comparing the treatment strategies “retransplant” versus “remain waitlisted with maintenance dialysis” are reported for different waiting times after first graft loss. Results: Second kidney transplantation showed a longer restricted mean survival time at 10 years of follow-up compared with remaining on the waiting list (5.8 life months gained; 95% confidence interval, 0.9 to 11.1). This survival difference was diminished in patients with longer waiting time after loss of the first allograft; restricted mean survival time differences at 10 years were 8.0 (95% confidence interval, 1.9 to 14.0) and 0.1 life months gained (95% confidence interval, −14.3 to 15.2) for patients with waiting time for retransplantation of <1 and 8 years, respectively. Conclusions: Second kidney transplant is associated with patient survival compared with remaining waitlisted and treatment by dialysis, but the survival difference diminishes with longer waiting time.

Antibody-mediated rejection (ABMR) is a leading cause of graft failure. Emerging evidence suggests a significant contribution of natural killer (NK) cells to microvascular inflammation (MVI). We investigated the influence of genetically determined NK cell functionality on ABMR development and activity. The study included 86 kidney transplant recipients subjected to systematic biopsies triggered by donor-specific antibody detection. We performed killer immunoglobulin-like receptor typing to predict missing self and genotyped polymorphisms determining NK cell functionality (FCGR3A^V/F158 [rs396991], KLRC2^wt/del, KLRK1^HNK/LNK [rs1049174], rs9916629-C/T). Forty-four patients had ABMR with considerable MVI and elevated NK cell transcripts. Missing self was not related to MVI. Only KLRC2^wt/wt showed an association (MVI score: 2 [median; interquartile range: 0-3] versus 0 [0-1] in KLRC2^wt/del recipients; p=0.001) and remained significant in a proportional odds multivariable model (odds ratio [OR]: 7.84, 95% confidence interval [CI]: 2.37-30.47, p=0.001). A sum score incorporating all polymorphisms and missing self did not outperform a score including only KLRC2 and FCGR3A variants, which were predictive in univariable analysis. NK cell genetics did not affect graft functional decline and survival. In conclusion, a functional KLRC2 polymorphism emerged as an independent determinant of ABMR activity, without a considerable contribution of missing self and other NK cell gene polymorphisms.