Bentall, Andrew

AbstractKidney paired donation (KPD) and the new kidney allocation system (KAS) in the United States have led to improved transplantation rates for highly sensitized candidates. We aimed to assess the potential need for other approaches to improve the transplantation rate of highly sensitized candidates such as desensitization. Using the UNOS STAR file, we analyzed transplant rates in a prevalent active waiting‐list cohort as of June 1, 2016, followed for 1 year. The overall transplantation rate was 18.9% (11 129/58769). However, only 9.7% (213/2204) of candidates with a calculated panel reactive antibody ≥99.9% received a transplant, and highly sensitized candidates were less likely to receive a living donor transplant. Among candidates with a CPRA ≥ 99.5% (ie. 100%), only 2.5% of transplants were from living donors (13 total, 7 from KPD). Nearly 4 years after KAS (6/30/2018), 1791 actively wait‐listed candidates had a CPRA of ≥99.9% and 34.6% (620/1791) of these had ≥5 years of waiting time. Thus, despite KPD and KAS, many sensitized candidates have not been transplanted even with prolonged waiting time. We conclude that candidates with a CPRA ≥ 99.9% and sensitized candidates with an incompatible living donor and prolonged waiting time may benefit from desensitization to improve their ability to receive a transplant.

Background. Active antibody-mediated rejection (AMR) that occurs during the amnestic response within the first month posttransplant is a rare but devastating cause of early allograft loss after kidney transplant. Prior reports of eculizumab treatment for AMR have been in heterogeneous patient groups needing salvage therapy or presenting at varied time points. We investigated the role of eculizumab as primary therapy for active AMR early posttransplant. Methods. We performed a retrospective observational study of a consecutive cohort of solitary kidney transplant recipients who were transplanted between January 1, 2014, and January 31, 2018, and had AMR within the first 30 days posttransplant and treated with eculizumab ± plasmapheresis. Results. Fifteen patients had early active AMR at a median (interquartile range [IQR]) of 10 (7–11) days posttransplant and were treated with eculizumab ± plasmapheresis. Thirteen cases were biopsy proven, and 2 cases were presumed on the basis of donor-specific antibody trends and allograft function. Within 1 week of treatment, the median estimated glomerular filtration rate increased from 21 to 34 mL/min (P = 0.001); and persistent active AMR was only found in 16.7% (2/12) of biopsied patients within 4–6 months. No graft losses occurred, and at last follow-up (median [IQR] of 13 [12–19] mo), the median IQR estimated glomerular filtration rate increased to 52 (46–60) mL/min. Conclusions. Prompt eculizumab treatment as primary therapy is safe and effective for early active AMR after kidney transplant or abrupt increases in donor-specific antibodies when biopsy cannot be performed for diagnosis confirmation.

The ability to predict outcomes for individual patients would be a significant advance for not only counseling, but also identifying those for whom interventions may be needed. The goals of this study were to validate an existing risk prediction score that incorporates easily obtainable clinical factors and determine if histologic findings at 1-year surveillance biopsy and/or serum donor–specific alloantibody status could improve predictability of graft loss by 5 years. We retrospectively studied 1465 adults who received a solitary kidney transplant between January of 1999 and December of 2008 and had sufficiently detailed 5-year follow-up data for modeling. In this cohort, the Birmingham risk model (incorporating recipient factors at 1 year, including age, sex, ethnicity, renal function, proteinuria, and prior acute rejection) predicted death–censored and overall graft survival (c statistics =0.84 and 0.78, respectively). The presence of glomerulitis or chronic interstitial fibrosis (g and ci scores by Banff, respectively) on 1-year biopsy specimens independently correlated with graft loss by 5 years. Adding these variables to the model for death–censored graft loss increased predictability (c statistic =0.90), improved calibration (ability to stratify risk from high to low), and reclassified risk of failure in 29% of patients. Adding the presence of donor-specific alloantibody at 1 year did not improve predictability or reclassification but did improve calibration marginally. We conclude that, at 1 year after kidney transplant, a risk model of graft survival that incorporates clinical factors and histologic findings at surveillance biopsy is highly predictive of individual risk and well calibrated.

AbstractBackgroundBortezomib, a proteasome inhibitor used to treat multiple myeloma, has been administered (± plasma exchange ± intravenous immunoglobulin [IVIg]) in attempts to reduce antibodies against human leukocyte antigens (HLA) in sensitized patients undergoing organ transplantation. To our knowledge, bortezomib has not been investigated for its effect on natural anti‐pig antibodies. If bortezomib could reduce the production of anti‐pig antibodies, this would likely be beneficial to the outcome of pig organ grafts in primates.MethodsNine patients received bortezomib either to reduce anti‐HLA antibody levels before organ allotransplantation or to treat antibody‐mediated rejection. Patients at the Mayo Clinic (Group 1; n = 4) received bortezomib alone, whereas at the UPMC (Group 2; n = 5), this was combined with plasmaphereses ± IVIg in some cases. Anti‐pig IgM and IgG levels against wild‐type (WT) and α1,3‐galactosyltransferase gene knockout (GTKO) pig aortic endothelial cells (flow cytometry—relative mean fluorescence intensity) and anti‐Gal IgM and IgG (ELISA–OD480 nm) were measured pre‐ and post‐bortezomib therapy.ResultsMean anti‐pig IgM levels were 11.2 (WT) and 1.9 (GTKO) pre‐bortezomib treatment and 9.4 (WT: P = 0.02) and 1.7 (GTKO: P = 0.33) post‐bortezomib treatment, respectively. Mean anti‐pig IgG levels were 4.3 (WT) and 1.5 (GTKO) pre‐bortezomib treatment and 3.6 (WT: P = 0.21) and 1.4 (GTKO: P = 0.20) post‐bortezomib treatment, respectively. Mean anti‐Gal IgM and IgG levels were 0.7 and 1.1, respectively, pre‐treatment, and 0.6 (P = 0.03) and 1.1 (NS), respectively, post‐treatment. When the data were analyzed in Groups 1 and 2 separately, there were no significant differences between the pre‐ and post‐bortezomib levels of anti‐pig, anti‐non‐Gal, or anti‐Gal IgM or IgG.ConclusionsFrom this limited study, we conclude that bortezomib might reduce anti‐Gal IgM levels in primates, but, in this respect alone, is unlikely to have any significant effect on the outcome of GTKO pig organ transplantation.