Stegall, Mark D

Background Despite substantial evidence demonstrating clear benefit, rates of preemptive kidney transplantation (PreKTx) remain low in the United States. Our goal was to identify barriers to PreKTx. Methods Using a telephone-administered questionnaire including questions about barriers, timing of referral, timing of education, we retrospectively studied first living donor kidney transplant recipients (2006-2010) at Mayo Clinic, Rochester, MN. Of 235 patients, 145 (62%) responded to the questionnaire (74 PreKTx and 71 non-PreKTx). We compared categorical data with Fisher exact test and median times with Wilcoxon rank sum test. Results Polycystic kidney disease (PCKD), longer median time between diagnosis and transplant, and time between education about transplant and transplant correlated with PreKTx (P < 0.01). The presence of at least 1 patient-identified barrier (lack of referral, financial barriers, medical barriers, no identified living donor and donor evaluation delays) was associated with non-PreKTx (0.034) though no single barrier predominated. Age, education level, insurance status and source of referral (primary care, nephrology, and nonphysician referral) were not associated with the rate of PreKTx. Univariate logistic regression identified white race, PCKD, and increased time from diagnosis as factors favoring PreKTx; PCKD and increased time remained significant factors after multivariate analysis. Conclusions Even among a patient population that is primarily white, educated, and has a spouse or first-degree relative donor, PreKTx rates remain concerningly low. Increased time between diagnosis or education and transplant are predictors of PreKTx. Greater emphasis on transplant education earlier in the stages of chronic kidney disease and community outreach from transplant centers may help to increase the rate of PreKTx.

AbstractBackground and objectivesThe risk of de novo donor‐specific antibody (dnDSA) development following BK viremia (BKV) or nephropathy (BKN) after kidney transplant remains unclear. We aimed to evaluate the relationships among dnDSA, BKV (BK blood PCR > 15 000 copies), BKN, antibody‐mediated rejection (AMR), and allograft loss.Patients and methodsWe performed a retrospective cohort study of 904 solitary kidney transplant recipients transplanted between 10/2007 and 5/2014. Cox proportional hazards regression with time‐dependent covariates were used to assess the relationships among BKN, isolated BKV, dnDSA, and the subsequent risk of AMR and allograft loss.ResultsIn multivariate analysis, we observed that BKN, but not BKV was a risk factor for dnDSA (HR, 3.18, P = .008). Of the patients with BK nephropathy, 14.0% (6/43) developed dnDSA, which occurred within 14 months of BK diagnosis. DnDSA in this setting remains a risk factor for subsequent AMR (HR 4.75, P = .0001) and allograft loss (HR 2.63, P = .018).ConclusionsBKN is an independent risk factor for development of dnDSA. Improved understanding of the characteristics of patients with BKN who are at highest risk for development of dnDSA would be valuable to customize immunosuppression reduction in this population.

AbstractThe aim of this study was to investigate correlations between early subclinical findings (10‐ and 90‐day histology and gene expression data) and late outcomes (transplant glomerulopathy and graft loss) in positive crossmatch kidney transplants (+XMKTx). We compared 34 +XMKTx (19 receiving eculizumab and 15 receiving standard of care without eculizumab) to 13 −XMKTx (between August 2001 and August 2011). At 10 days, light microscopy identified subclinical inflammation in only 18% of +XMKTx, while intragraft gene expression identified inflammation in 79% (gene sets for activated macrophages, dendritic cells, NK cells or T cells). Inflammation persisted at 90 days and was associated with the development of transplant glomerulopathy by 2 years and graft loss. In contrast, endothelial cell (EC) changes present at 90 days by either electron microscopy or gene expression were not associated with transplant glomerulopathy or graft loss in this cohort. Eculizumab treatment did not appear to alter inflammation or EC changes. Therefore, intragraft inflammation might be an appropriate surrogate marker of progression and also a target of therapy to prevent chronic antibody‐mediated rejection.

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.

AbstractThe majority of kidney transplant recipients die from cardiovascular events. Physical activity may be a modifiable risk factor for cardiovascular disease following transplant. The goal of our study was to examine adherence to a physical activity intervention following kidney transplant and its impact on metabolic parameters. All patients who received a kidney transplant at our center between 12/2010 and 12/2011 received usual care (n = 162), while patients transplanted between 12/2011 and 1/2013 received a 90‐day pedometer‐based physical activity intervention (n = 145). Metabolic parameters were assessed at four and 12 months post‐transplant. Baseline demographics and clinical management were similar between cohorts. Adherence to the prescription was 36.5%. Patients in the physical activity cohort had lower systolic and diastolic blood pressure four months post‐transplant compared to the usual care cohort (122 ± 18 vs. 126 ± 16 mmHg, p = 0.049 and 73 ± 10 vs. 77 ± 9, p = 0.004) and less impaired fasting glucose (20.7% vs. 30.9%, p = 0.04). Twelve‐month outcomes were not different between cohorts. Over one‐third of our cohort adhered to a pedometer‐based physical activity intervention following kidney transplant, and the intervention was associated with improved metabolic parameters. Further study of post‐transplant exercise interventions and methods to optimize long‐term adherence are needed.

AbstractRenal retransplantation after a failed prior kidney and pancreas transplant is being increasingly performed. In these complex cases, both iliac fossae have been used for prior transplants, and the placement of the new allograft can be problematic. We describe our experience with an alternative technique for renal retransplantation (RRTx) in the setting of severe bilateral aortoiliac atherosclerosis or scarring and fibrosis on the iliac vessels. Nephrectomy of the failed allograft is performed, and the renal vessels of the failed allograft (RVFA) are preserved. The new kidney is implanted on RVFA at the same operative time. This technique was attempted and successfully accomplished in a total of six patients (mean operative time = 240 ± 63 min). One postoperative complication occurred: poor arterial inflow to the allograft, being corrected reoperatively. Hospitalizations ranged from five to eight d. Five of the six patients were alive with a functioning allograft at last follow‐up (a single graft failure occurred 21 months postoperatively in the setting of post‐transplant lymphoproliferative disease that also led to patient death). Renal vessels of the failed allograft seem to be suitable alternative vascular conduits for renal retransplantation after prior kidney and pancreas transplants.

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.