Silas P. Norman

Access and Outcomes Among Minority Transplant Patients, 1999–2008, with a Focus on Determinants of Kidney Graft Survival

Coincident with an increasing national interest in equitable health care, a number of studies have described disparities in access to solid organ transplantation for minority patients. In contrast, relatively little is known about differences in posttransplant outcomes between patients of specific racial and ethnic populations. In this paper, we review trends in access to solid organ transplantation and posttransplant outcomes by organ type, race and ethnicity. In addition, we present an analysis of categories of factors that contribute to the racial/ethnic variation seen in kidney transplant outcomes. Disparities in minority access to transplantation among wait‐listed candidates are improving, but persist for those awaiting kidney, simultaneous kidney and pancreas and intestine transplantation. In general, graft and patient survival among recipients of solid organ transplants is highest for Asians and Hispanic/Latinos, intermediate for whites and lowest for African Americans. Although much of the difference in outcomes between racial/ethnic groups can be accounted for by adjusting for patient characteristics, important observed differences remain. Age and duration of pretransplant dialysis exposure emerge as the most important determinants of survival in an investigation of the relative impact of center‐related versus patient‐related variables on kidney graft outcomes.

Graft and Patient Survival in Kidney Transplant Recipients Selected for de novo Steroid-Free Maintenance Immunosuppression

Steroid‐free regimen is increasingly employed in kidney transplant recipients across transplant centers. However, concern remains because of the unknown impact of such an approach on long‐term graft and patient survival. We studied the outcomes of steroid‐free immunosuppression in a population‐based U.S. cohort of kidney transplant recipients. All adult solitary kidney transplant recipients engrafted between January 1, 2000 and December 31, 2006 were stratified according to whether they were selected for a steroid‐free or steroid‐containing regimen at discharge. Multivariate Cox regression models were used to estimate graft and patient survival. The impact of the practice pattern on steroid use at individual transplant centers was analyzed. Among 95 755 kidney transplant recipients, 17.2% were steroid‐free at discharge (n = 16 491). Selection for a steroid‐free regimen was associated with reduced risks for graft failure and death at 1 year (HR 0.78, 95% CI 0.72–0.85, and HR 0.73, 95% CI 0.65–0.82, respectively, p < 0.0001) and 4 years (HR 0.83, 95% CI 0.78–0.87, and HR 0.76, 95% CI 0.71–0.83, respectively, p < 0.0001). This association was mostly observed at individual centers where less than 65% of recipients were discharged on the steroid‐containing regimen. De novo steroid‐free immunosuppression as currently practiced in the United States appears to carry no increased risk of adverse clinical outcomes in the intermediate term.

Comparative Risk of Impaired Glucose Metabolism Associated with Cyclosporine Versus Tacrolimus in the Late Posttransplant Period

New onset diabetes after transplantation (NODAT) and impaired fasting glucose (IFG) are common in kidney transplant recipients (KTRs). Calcinuerin inhibitor (CNI) therapy is a causal risk factor. NODAT is associated with increased mortality and diminished graft survival. We studied the incidence of NODAT and IFG in KTRs before and after a medically indicated switch of CNI therapy from cyclosporine (CsA) to tacrolimus (Tac). The study population consisted of 704 nondiabetic KTRs. Of them, 171 underwent conversion from CsA to Tac (group I) and 533 remained on the CsA since transplantation (Group II). Time‐dependent Cox regression and generalized estimating equations were used to account for sequential CNI exposure. NODAT and IFG occurred in 15.2% and 22.1% of group I subjects and 15.6% and 25.8% of group II subjects, respectively (p = 0.90 for NODAT and p = 0.38 for IFG). Accounting for equal follow‐up time since conversion from CsA to Tac, the adjusted 5‐year NODAT‐free survival was 87.4% and 91.4% in group I and group II, respectively (p = 0.90). In conclusion, conversion to Tac, compared to continuous exposure to CsA, carries quantitatively similar risk of impaired glucose metabolism in KTRs in the late posttransplant period.

Early pancreas graft failure is associated with inferior late clinical outcomes after simultaneous kidney-pancreas transplantation

Background. Early pancreas graft failure after simultaneous pancreas and kidney (SPK) transplantation is common. We studied the impact of early pancreas graft failure on long-term kidney and patient survival. Methods. We included all primary SPK transplants performed in the United States between January 1, 2000, and December 31, 2007, who had maintained kidney graft function at 90 days posttransplantation. Kaplan-Meier and Cox multivariate analyses were performed. The causes of death between the two cohorts were compared. Results. A total of 6282 SPK recipients were included in the analyses. Of those, 470 had lost pancreas graft within the first 90 days largely related to pancreas graft thrombosis. Early pancreas graft failure was associated with lower subsequent kidney graft and patient survival (log-rank, P=0.02 and P<0.001, respectively). Multivariate regression analyses demonstrated a 70% higher risk of kidney graft failure after 3 years (adjusted hazard ratio 1.69; 95% CI 1.08, 2.66; P=0.022) and more than doubled the risk for death (adjusted hazard ratio 2.18; 95% CI 1.67, 2.85; P<0.001) among SPK recipients with early pancreas graft failure. The causes of death were similar between the two cohorts. Conclusion. Early pancreas graft failure in SPK transplant recipients is associated with an increased risk for subsequent kidney failure and death. Optimization of therapeutic interventions after early pancreas graft failure is needed.

Transition from donor candidates to live kidney donors: the impact of race and undiagnosed medical disease states

Norman SP, Song PXK, Hu Y, Ojo AO. Transition from donor candidates to live kidney donors: the impact of race and undiagnosed medical disease states. 
Clin Transplant 2011: 25: 136–145.

Pre-Kidney Transplant Lower Extremity Impairment and Post-Kidney Transplant Mortality

Prediction models for post‐kidney transplantation mortality have had limited success (C‐statistics ≤0.70). Adding objective measures of potentially modifiable factors may improve prediction and, consequently, kidney transplant (KT) survival through intervention. The Short Physical Performance Battery (SPPB) is an easily administered objective test of lower extremity function consisting of three parts (balance, walking speed, chair stands), each with scores of 0–4, for a composite score of 0–12, with higher scores indicating better function. SPPB performance and frailty (Fried frailty phenotype) were assessed at admission for KT in a prospective cohort of 719 KT recipients at Johns Hopkins Hospital (8/2009 to 6/2016) and University of Michigan (2/2013 to 12/2016). The independent associations between SPPB impairment (SPPB composite score ≤10) and composite score with post‐KT mortality were tested using adjusted competing risks models treating graft failure as a competing risk. The 5‐year posttransplantation mortality for impaired recipients was 20.6% compared to 4.5% for unimpaired recipients (p < 0.001). Impaired recipients had a 2.30‐fold (adjusted hazard ratio [aHR] 2.30, 95% confidence interval [CI] 1.12–4.74, p = 0.02) increased risk of postkidney transplantation mortality compared to unimpaired recipients. Each one‐point decrease in SPPB score was independently associated with a 1.19‐fold (95% CI 1.09–1.30, p < 0.001) higher risk of post‐KT mortality. SPPB‐derived lower extremity function is a potentially highly useful and modifiable objective measure for pre‐KT risk prediction.

A pilot study of gene expression-based categorization of pancreas transplant biopsies.

Gene expression profiling has emerged as a powerful strategy to define transcriptional mechanism activated in organ transplantation. We performed a pilot feasibility study of mRNA-based pancreas transplant biopsy stratification. The mRNAs expression of 32 genes, observed in renal transplant dysfunction, and 10 pancreas-specific genes were evaluated in 26 pancreas transplant biopsy specimens by quantitative real-time polymerase chain reaction using TaqMan Low Density Array technology. Unsupervised 2D hierarchical clustering segregated the biopsies in two main cluster branches, A and B. Six of seven patients (85.7%) in cluster A and 6 of 19 (31.6%) in cluster B retained functioning pancreas allograft. CD20/MS4A1 mRNA and protein, in addition to CD 3 protein, were detected in four specimens in cluster B. Three of those four pancreas transplants were subsequently lost. Our study demonstrates the potential association of gene expression with clinical outcome of pancreas transplants and justifies further studies in an independent cohort.

Inactivity on the kidney transplant wait-list is associated with inferior pre- and post-transplant outcomes

The majority of kidney transplant (KT) candidates spend some time on the transplant wait‐list (WL) prior to kidney transplantation. We examined the impact of WL inactivity on clinical outcomes.

Temporal trends, center-level variation, and the impact of prevalent state obesity rates on acceptance of obese living kidney donors

The impact of pre‐donation obesity on long‐term outcomes of living kidney donors remains controversial. Published guidelines offer varying recommendations regarding BMI (kg/m2) thresholds for donor acceptance. We examined temporal and center‐level variation in BMI of accepted donors across US transplant centers. Using national transplant registry data, we performed multivariate hierarchical logistic regression modeling using pairwise comparisons (overweight, BMI: 25‐29.9; mildly obese, BMI: 30‐34.9; very obese, BMI: ≥35; versus normal BMI: 18.5‐24.9). Metrics of heterogeneity, including median odds ratio (MOR), were calculated. Among 90 013 living kidney donors, 2001‐2016, proportions who were very obese decreased and proportions who were mildly obese or overweight increased. Significant center‐level heterogeneity was noted in BMI of accepted donors; the MOR varied from 1.10 for overweight to 1.93 for very obese donors. At centers located in the 10 states with the highest general population obesity rates, adjusted odds of very obese donor status were 185% higher (reference: normal BMI) than in states with the lowest obesity rates. Although there is a declining trend in acceptance of very obese living kidney donors, variation across centers is significant. Furthermore, local population obesity rates may affect the decision to accept obese individuals as donors.

Frailty and Postkidney Transplant Health-Related Quality of Life

Background Health-related quality of life (HRQOL) reflects a patient’s disease burden, treatment effectiveness, and health status and is summarized by physical, mental, and kidney disease-specific scales among end-stage renal disease patients. Although on average HRQOL improves postkidney transplant (KT), the degree of change depends on the ability of the patient to withstand the stressor of dialysis versus the ability to tolerate the intense physiologic changes of KT. Frail KT recipients may be extra vulnerable to either of these stressors, thus affecting change in HRQOL after KT. Methods We ascertained frailty, as well as physical, mental, and kidney disease-specific HRQOL in a multicenter prospective cohort of 443 KT recipients (May 2014 to May 2017) using Kidney Disease Quality of Life Instrument Short Form. We quantified the short-term (3 months) rate of post-KT HRQOL change by frailty status using adjusted mixed-effects linear regression models. Results Mean HRQOL scores at KT were 43.3 (SD, 9.6) for physical, 52.8 (SD, 8.9) for mental, and 72.6 (SD, 12.8) for kidney disease-specific HRQOL; frail recipients had worse physical (P < 0.001) and kidney disease-specific HRQOL (P = 0.001), but similar mental HRQOL (P = 0.43). Frail recipients experienced significantly greater rates of improvement in physical HRQOL (frail, 1.35 points/month; 95% confidence interval [CI], 0.65-2.05; nonfrail, 0.34 points/month; 95% CI, −0.17-0.85; P = 0.02) and kidney disease-specific HRQOL (frail, 3.75 points/month; 95% CI, 2.89-4.60; nonfrail, 2.41 points/month; 95% CI, 1.78-3.04; P = 0.01), but no difference in mental HRQOL (frail, 0.54 points/month; 95% CI, −0.17-1.25; nonfrail, 0.46 points/month; 95% CI, −0.06-0.98; P = 0.85) post-KT. Conclusions Despite decreased physiologic reserve, frail recipients experience improvement in post-KT physical and kidney disease-specific HRQOL better than nonfrail recipients.