The Combined Roles of Race/Ethnicity and Substance Use in Predicting Likelihood of Kidney Transplantation.

BACKGROUND: Racial/ethnic minorities face known disparities in likelihood of kidney transplantation. These disparities may be exacerbated when coupled with ongoing substance use, a factor also reducing likelihood of transplantation. We examined whether race/ethnicity in combination with ongoing substance use predicted incidence of transplantation. METHODS: Patients were enrolled between March 2010 and October 2012 at the time of transplant evaluation. Substance use data were retrieved from transplant evaluations. Following descriptive analyses, the primary multivariable analyses evaluated whether, relative to the referent group (White patients with no substance use), racial/ethnic minority patients using any substances at the time of evaluation were less likely to receive transplants by the end of study follow-up (August 2020). RESULTS: Among 1152 patients, 69% were non-Hispanic White, 23% non-Hispanic Black, and 8% Other racial/ethnic minorities. White, Black, and Other patients differed in percentages of current tobacco smoking (15%, 26%, and 18%, respectively; P = 0.002) and illicit substance use (3%, 8%, and 9%; P < 0.001) but not heavy alcohol consumption (2%, 4%, and 1%; P = 0.346). Black and Other minority patients using substances were each less likely to receive transplants than the referent group (hazard ratios ≤0.45, P ≤ 0.021). Neither White patients using substances nor racial/ethnic minority nonusers differed from the referent group in transplant rates. Additional analyses indicated that these effects reflected differences in waitlisting rates; once waitlisted, study groups did not differ in transplant rates. CONCLUSIONS: The combination of minority race/ethnicity and substance use may lead to unique disparities in likelihood of transplantation. To facilitate equity, strategies should be considered to remove any barriers to referral for and receipt of substance use care in racial/ethnic minorities.

Impact of Subclinical and Clinical Kidney Allograft Rejection Within 1 Year Posttransplantation Among Compatible Transplant With Steroid Withdrawal Protocol.

Early acute kidney rejection remains an important clinical issue. METHODS: The current study included 552 recipients who had 1-2 surveillance or indication biopsy within the 1 y posttransplant. We evaluated the impact of type of allograft inflammation on allograft outcome. They were divided into 5 groups: no inflammation (NI: 95), subclinical inflammation (SCI: 244), subclinical T cell-mediated rejection (TCMR) (SC-TCMR: 110), clinical TCMR (C-TCMR: 83), and antibody-mediated rejection (AMR: 20). Estimated glomerular filtration rate (eGFR) over time using linear mixed model, cumulative chronic allograft scores/interstitial fibrosis and tubular atrophy (IFTA) ≥2 at 12 mo, and survival estimates were compared between groups. RESULTS: The common types of rejections were C-TCMR (15%), SC-TCMR (19.9%), and AMR (3.6%) of patients. Eighteen of 20 patients with AMR had mixed rejection with TCMR. Key findings were as follows: (i) posttransplant renal function: eGFR was lower for patients with C-TCMR and AMR (P < 0.0001) compared with NI, SCI, and SC-TCMR groups. There was an increase in delta-creatinine from 3 to 12 mo and cumulative allograft chronicity scores at 12 mo (P < 0.001) according to the type of allograft inflammation. (ii) Allograft histology: the odds of IFTA ≥2 was higher for SC-TCMR (3.7 [1.3-10.4]; P = 0.04) but was not significant for C-TCMR (3.1 [1.0-9.4]; P = 0.26), and AMR (2.5 [0.5-12.8]; P = 0.84) compared with NI group, and (iii) graft loss: C-TCMR accounted for the largest number of graft losses and impending graft losses on long-term follow-up. Graft loss among patient with AMR was numerically higher but was not statistically significant. CONCLUSIONS: The type of kidney allograft inflammation predicted posttransplant eGFR, cumulative chronic allograft score/IFTA ≥2 at 12 mo, and graft loss.

KDOQI US Commentary on the 2020 KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation.

Evaluation of patients for kidney transplant candidacy is a comprehensive process that involves a detailed assessment of medical and surgical issues, psychosocial factors, and patients' physical and cognitive abilities with an aim of balancing the benefits of transplantation and potential risks of surgery and long-term immunosuppression. There is considerable variability among transplant centers in their approach to evaluation and decision-making regarding transplant candidacy. The 2020 KDIGO (Kidney Disease: Improving Guidelines Outcome) clinical practice guideline on the evaluation and management of candidates for kidney transplantation provides practice recommendations that can serve as a useful reference guide to transplant professionals. The guideline, covering a broad range of topics, was developed by an international group of experts from transplant and nephrology through a review of literature published until May 2019. A work group of US transplant nephrologists convened by NKF-KDOQI (National Kidney Foundation-Kidney Disease Quality Initiative) chose key topics for this commentary with a goal of presenting a broad discussion to the US transplant community. Each section of this article has a summary of the key KDIGO guideline recommendations, followed by a brief commentary on the recommendations, their clinical utility, and potential implementation challenges. The KDOQI work group agrees broadly with the KDIGO recommendations but also recognizes and highlights the decision-making challenges that arise from lack of high-quality evidence and the need to balance equity with utility of organ transplantation.

Evaluation of Renal Anionic Secretion Following Living-donor and Deceased-donor Renal Transplantation: A Clinical Pharmacokinetic Study of Cefoxitin Microdosing.

Renal transplantation is the treatment of choice for patients with end-stage renal disease. Because kidneys are the primary excretory organs for various drugs/drug metabolites, changes in renal graft function would significantly alter the clearance and exposure of renally secreted drugs. Renal allografts from living and deceased donors normally undergo numerous insults, including injuries associated with prolonged cold ischemic time, reperfusion, and nephrotoxicity due to calcineurin inhibitors. These physiologic and pharmacologic stresses can alter the expression and functional capacity of renal organic anionic transporters (OATs). METHODS: The objectives of this study were to assess the longitudinal changes in renal anionic secretion in kidney transplant patients, to study the effect of prolonged cold ischemic time on OAT secretion in kidney transplant patients (living- versus deceased-donor recipients), and to compare OAT secretory capacity of renal transplant recipients with healthy volunteers. Cefoxitin was used as a probe drug to assess OAT secretion. Cefoxitin pharmacokinetics was studied in 15 de novo renal transplant recipients following intravenous administration of 200 mg cefoxitin within 14 d and beyond 90 d posttransplantation. RESULTS: No longitudinal changes in real OAT secretion in early posttransplant period were observed, and there were no differences in renal OAT secretion between living- and deceased-donor renal transplant recipients. Overall, cefoxitin exposure was 2.6-fold higher and half-life increased by 2.2-fold in renal transplant recipients when compared with historical healthy controls. CONCLUSIONS: These results suggest that OAT system is functioning well, but renal transplant recipients would need significantly lower dosage of drugs that are primarily secreted via the OAT system compared with normal subjects.

Octreotide Delaying the Progression of Recurrent IgA Nephropathy After Kidney Transplantation.

IgA Nephropathy (IgAN) is a common cause of end-stage kidney disease worldwide. Unfortunately, the exact pathogenesis of IgAN remains uncertain without any targeted therapy. While kidney transplantation remains the gold standard treatment for those with end-stage kidney disease from IgAN, recurrence occurs frequently and may lead to early kidney transplant loss. Research has suggested that insulin-like growth factor-1 may play a role in mesangial cell proliferation in IgAN and Somatostatin may inhibit insulin-like growth factor-1. In this single case study, we report the use of octreotide, a somatostatin analogue, as a potential novel therapy for early recurrent IgAN post kidney transplant.

Epidemiology of end-stage renal failure among twins and diagnosis, management, and current outcomes of kidney transplantation between identical twins.

The aim of the study is to provide a comprehensive overview of identical twin kidney transplantation in the modern era. We provide epidemiologic trends in the US twin population from 1959 to 2000, current methods to identify zygosity, outcomes for identical twin transplants, and a comprehensive management strategy for identical twin kidney transplantation. By 2019, we project that 433 010 dizygotic and monozygotic twins will be alive and at risk for developing ESRF. Monozygosity between a donor-recipient pair can be confirmed by concordance in sex, blood type, and HLA antigen match with precision testing using 13/17 Short Tandem Repeat sequencing to a likelihood of nearly 100%. Among identical twin transplants from 2001 to 2017, excellent patient and kidney graft survival rates were noted. Approximately 50% of kidney transplant recipients of identical twins transplant did not receive maintenance immunosuppression, and no differences in graft survival were noted among patients with and without immunosuppression at 6 and 12 months (P = .8 and .7). Patients with glomerulonephritis as the cause of ESRF had lower graft survival (P = .06) suggesting that recurrent glomerulonephritis as a likely cause of graft loss among these recipients.

High Calcineurin Inhibitor Intrapatient Variability Is Associated With Renal Allograft Inflammation, Chronicity, and Graft Loss.

BACKGROUND: High calcineurin inhibitor (CNI) intrapatient variability (IPV) has been associated with poor kidney allograft outcomes. However, the relationship between early allograft histological changes, their progression, and CNI-IPV is less well studied. Hence, we evaluated effect of CNI-IPV defined by the degree of fluctuation of CNI levels in all kidney transplant patients over 2 to 12 months posttransplant on early allograft inflammation, subsequent chronicity, and later clinical outcomes. METHODS: Two hundred eighty-six patients transplanted from January 2013 to November 2014 were enrolled with protocol and indication biopsies. The mean CNI-IPV was 28.5% and a quarter of our cohort had IPV of 35% or greater (high CNI IPV). Baseline demographic differences were similar between high and low CNI IPV groups. RESULTS: High CNI-IPV was associated with a higher incidence of acute rejection (AR) within 1 year (52% vs 31% P < 0.001), more persistent/recurrent AR by 1 year (18.2% vs 6.2%, P = 0.002), higher-grade AR (≥Banff 1B, 27.5% vs 7.3%, P < 0.001), and worse interstitial fibrosis/tubular atrophy (P = 0.005). High CNI-IPV was associated with increased graft loss (GL) and impending graft loss (iGL, defined as eGFR<30 ml/min and >30% decline in eGFR from baseline), regardless of donor-specific antibody, delayed graft function, rejection, or race. In a multivariate Cox Proportional Hazards Model, high CNI-IPV was independently associated with GL + iGL (hazard ratio, 3.1; 95% confidence interval, 1.6-5.9, P < 0.001). CONCLUSIONS: High CNI-IPV within 1 year posttransplant is associated with higher incidence of AR, severe AR, allograft chronicity, GL, and iGL. This represents a subset of patients who are at risk for poor kidney transplant outcomes and potentially a modifiable risk factor for late allograft loss.

The Impact of Early Clinical and Subclinical T Cell-mediated Rejection After Kidney Transplantation.

BACKGROUND: We investigated the effect of clinical and subclinical T cell-mediated rejection (C-TCMR and SC-TCMR) on allograft histology, function, and progression. METHODS: Adult kidney recipients with 2 protocol biopsies were divided into No-TCMR on biopsies (n = 104), SC-TCMR (n = 56), and C-TCMR (n = 32) in at least 1 biopsy. Chronicity (ci + ct + cg + cv) scores, renal function, and the burden of renal disease measured by area under the curve (serum creatinine, mg mo/dL) were compared. RESULTS: Baseline characteristics were similar except for mean donor age and Kidney Donor Profile index scores. Patients with C-TCMR had higher mean serum creatinine, lower mean estimated glomerular filtration rate, and higher area under the curve with 95% confidence interval (75.2 [67.7-82.7]) as opposed to patients with SC-TCMR and No-TCMR (58.3 [53.6-62.9], 65.1 [58.8-71.5]), P = 0.0004. Chronicity scores were higher at 3 months in C-TCMR (2.30 ± 1.58) compared with SC-TCMR (2.02 ± 1.42) and No-TCMR (1.31 ± 1.18), P = 0.0001 and also at 12 months. At last follow-up, 18.8% patients with C-TCMR had ≥50% decline in estimated glomerular filtration rate from 3 months compared with 7% and 1% among No-TCMR and SC-TCMR groups (P = 0.038). Multivariate analyses revealed higher odds of Δ-creatinine ≥ 0.5 mg/dL from 3 months to last follow-up for C-TCMR (3.39 [95% confidence interval, 1.25-9.20]) versus No-TCMR (P = 0.016). CONCLUSIONS: Kidney transplant recipients with C-/SC-TCMR have heightened early allograft chronicity and worse renal function compared with those with No-TCMR. Progressive renal dysfunction was noted among patients with C-TCMR as opposed to SC-TCMR and No-TCMR.

Outcomes of Adult Intestinal Transplant Recipients Requiring Dialysis and Renal Transplantation.

BACKGROUND: Data on dialysis and renal transplantation (RT) after intestinal transplantation (IT) are sparse. Whether changes in immunosuppression and surgical techniques have modified these outcomes is unknown. METHODS: Two hundred eighty-eight adult intestinal transplants performed between 1990 and 2014 at the University of Pittsburgh were analyzed for incidence, risk factors and outcomes after dialysis and RT. Cohort was divided into 3 eras based on immunosuppression and surgical technique (1990-1994, 1995-2001, and 2001-2014). Receiving RT, or dialysis for 90 days or longer was considered as end-stage renal disease (ESRD). RESULTS: During a median follow-up of 5.7 years, 71 (24.7%) patients required dialysis, 38 (13.2%) required long-term dialysis and 17 (6%) received RT after IT. One-, 3-, and 5-year ESRD risk was 2%, 7%, and 14%, respectively. No significant era-based differences were noted. Higher baseline creatinine (hazard ratio [HR], 3.40 per unit increase, P < 0.01) and use of liver containing grafts (HR, 2.01; P = 0.04) had an increased ESRD risk. Median patient survival after dialysis initiation was 6 months, with a 3-year survival of 21%. Any dialysis (HR, 12.74; 95% CI 8.46-19.20; P < 0.01) and ESRD (HR, 9.53; 95% CI, 5.87-15.49; P < 0.01) had higher mortality after adjusting for covariates. For renal after IT, 1- and 3-year kidney and patient survivals were 70% and 49%, respectively. All graft losses were from death with a functioning graft, primarily related to infectious complications (55%). CONCLUSIONS: In intestinal transplant recipients, renal failure requiring dialysis or RT is high and is associated with increased mortality. Additionally, the outcomes for kidney after IT are suboptimal due to death with a functioning graft.

Anti-CD20 Blocker Rituximab in Kidney Transplantation.

Rituximab is a chimeric anti-CD20 monoclonal protein used in various clinical scenarios in kidney transplant recipients. However, its evidence-based use there remains limited due to lack of controlled studies, limited sample size, short follow-up and poorly defined endpoints. Rituximab is indicated for CD20+ posttransplant lymphoproliferative disorder. It may be beneficial for treating recurrent membranous nephropathy and recurrent allograft antineutrophilic cytoplasmic antibody vasculitis and possibly for recurrent focal segmental glomerulosclerosis. Rituximab, in combination with IVIg/plasmapheresis, appears to decrease antibody level and increase the odds of transplantation in sensitized recipients. The role of Rituximab in ABOi transplant remains unclear, as similar outcomes are achieved without its use. Rituximab is not efficacious in antibody-mediated rejection/chronic antibody-mediated rejection. Strict randomized control trials are necessary to elucidate its true role in these settings.

Kidney Transplant Outcomes After Primary, Repeat and Kidney After Nonrenal Solid Organ Transplantation: A Single-Center Experience.

BACKGROUND: Improvements in renal allograft outcomes have permitted kidney transplantation after prior kidney allograft failure as well as after nonrenal solid organ transplantation. This study compares renal allograft outcomes in the 3 groups, that is, primary, repeat, and kidney after nonrenal solid organ transplantation, where transplant group was coded as a time-dependent variable. METHODS: We retrospectively reviewed registry data for kidney transplant recipients at University of Pittsburgh Medical Center from January 2000 to December 2011. We compared overall graft survival between the 3 groups using Cox regression modeling. We calculated 1-, 3-, and 5-year graft survival and half-lives for each group where feasible. RESULTS: The study cohort (N = 2014) consisted of group A (primary kidney transplant, n = 1578, with 7923.2 years of follow-up time), group B (repeat kidney transplant, n = 314, with 1566.7 years of follow-up time) and group C (kidney post-nonrenal solid organ transplant, n = 176, with 844.8 years of follow-up time). Of the 1578 patients in the primary kidney transplant group, 74 later received a repeat transplant and thus also have follow-up counted in the repeat kidney transplant group. The median follow-up was 56, 53, and 55 months, respectively. The 5-year actuarial and death-censored graft survival was 68.69%, 68.79%, and 66.48% and 65.53%, 67.68%, and 62.92%, respectively (P = 0.70). There was no difference in overall graft survival in the Cox-adjusted analysis (group B: odds ratio, 1.02; 95% confidence interval, 0.84-1.26; P = 0.79; group C: odds ratio, 0.96; 95% confidence interval, 0.75-1.23; P = 0.76). CONCLUSIONS: The adjusted kidney graft survivals in the 3 groups were similar.

Subclinical Rejection in Renal Transplantation: Reappraised.

Short-term outcomes in renal transplantation have improved significantly in the past few years. However, the improvement in long-term outcomes has been modest. The reasons for graft failure beyond the first year of transplantation have been attributed to several different factors. We believe that subclinical rejection (SCR) may be 1 of the factors that contribute to graft loss in the long run. We also believe that there are data to suggest that SCR leads to progressive fibrosis and loss of graft function. This has been demonstrated even in patients who have mild degrees of subclinical inflammation. This review outlines the major studies that have been published on this important topic. It also outlines potential risk factors for the development of SCR. The current approach and diagnostic methods are discussed as well as their pros and cons. Newer noninvasive methods of diagnosis as well as molecular diagnostics and their merits and shortcomings are also discussed in some depth. Thus, the proposed state of the art review on SCR will create a renewed interest at all levels including transplant clinicians, transplant researchers, pharmaceutical industries as well as regulatory organizations.

Kidney Transplant Survival: Transforming Early Post-Transplant Opportunities to Long-Term Success.

Substantial strides have been made in improving the short-term success after kidney transplantation. Although there has been some progress, there has not been a robust improvement with respect to long-term outcomes. However, there remain many potentially modifiable transplant-specific risks to long-term patient and graft survival. In this chapter, we detail the current state of five important short-term transplant-specific clinical events. The early post-transplant events that negatively impact long-term survival discussed in this chapter are: acute T cell mediated rejection, acute antibody mediated rejection, delayed graft function, post-transplant viral infections, and recurrent and de novo diseases after transplantation. This chapter focuses on unmet needs and outlines important goals, specific to each of the topics, that hold promise for achieving better long-term graft survival in kidney transplant patients. Consistent across all five areas are: the need for better standardization and improvement in diagnosis and testing, identification of relevant clinical surrogate markers in the design of new studies, newer immunosuppressive agents, anti-viral agents and targeted therapy for certain diseases, and innovative newer clinical trials. A multifaceted approach will further enhance long-term kidney transplant survival.