Faculty Bibliography

Importance:Living kidney donation is associated with increased long-term risk of end-stage renal disease (ESRD). An early postdonation marker of ESRD risk could improve postdonation risk assessment and counseling for kidney donors and allow early intervention for donors at increased risk. Objective:To determine the association between renal function in the first 6 months postdonation and subsequent risk of ESRD in kidney donors. Design, Setting, and Participants:This secondary analysis of a prospective national cohort uses a population-based registry of all living kidney donors in the United States between October 26, 1999, and January 1, 2018, with follow-up through December 31, 2018. All kidney donors who had donated in the date range and had serum creatinine measured at 6 months (±3 months) postdonation were included. Exposures:Renal function as measured by estimated glomerular filtration rate 6 months after donation (eGFR6). Main Outcomes and Measures:End-stage renal disease, ascertained via linkage to Centers for Medicare & Medicaid Services data. Results:A total of 71 468 living kidney donors were included (of 109 065 total donors over this period). Their median (interquartile range) eGFR6 was 63 (54-74) mL/min/1.73 m2. Cumulative incidence of ESRD at 15 years postdonation ranged from 11.7 donors per 10 000 donors with eGFR6 values greater than 70 mL/min/1.73 m2 to 33.1 donors per 10 000 donors with eGFR6 values of 50 mL/min/1.73 m2 or less. Adjusting for age, race, sex, body mass index, and biological relationship, every 10 mL/min/1.73 m2 reduction in eGFR6 was associated with a 28% increased risk of ESRD (adjusted hazard ratio, 1.28 [95% CI, 1.06-1.54]; P = .009). The association between predonation eGFR and ESRD was not significant and was fully mediated by eGFR6 (adjusted hazard ratio, 1.00 [95% CI, 0.86-1.17]; P = .97). The postdonation eGFR value was a better marker of ESRD than eGFR decline after donation or the ratio of eGFR6 to predonation eGFR, as determined by the Akaike information criterion (in which a lower value indicates a better model fit; eGFR6, 1495.61; predonation eGFR - eGFR6, 1503.58; eGFR6 / predonation eGFR, 1502.30). Conclusions and Relevance:In this study, there was an independent association of eGFR6 with subsequent ESRD risk in living kidney donors, even after adjusting for predonation characteristics. The findings support measurement of early postdonation serum creatinine monitoring in living kidney donors, and the use of these data to help identify donors who might need more careful surveillance and early intervention.

BACKGROUND:Optimizing antithymocyte globulin (ATG) dosage is critical, particularly for high-risk kidney transplant (KT) recipients without cytomegalovirus (CMV) prophylaxis. METHODS:We studied 630 KT recipients with expanded criteria donors or panel reactive antibody ≥50% at Hospital do Rim, Brazil (January 1, 2013 to May 21, 2015) to determine whether a single ATG dose was safe and effective in patients without CMV prophylaxis. Patients received ≥4 doses (1-1.5 mg/kg/per dose) until June 17, 2014, when the induction protocol changed to a single ATG dose (3 mg/kg). We used Cox regression to compare the risk of CMV infection and acute rejection (AR) among KT recipients by ATG dose. RESULTS:Adjusting for clinical and transplant factors, a single ATG dose was associated with a lower risk of CMV infection (adjusted hazard ratio [aHR]: 0.63; 95% confidence interval [CI], 0.42-0.93; P = 0.02) and a similar risk of AR (aHR: 1.16; 95% CI, 0.47-2.83; P = 0.8), compared to multiple doses. We found no differences in death-censored graft loss (5.0% versus 4.8%, aHR: 1.06; 95% CI, 0.51-2.23; P = 0.9) or mortality (4.7% versus 3.4%; aHR: 1.42; 95% CI, 0.62-3.24; P = 0.4) at 1-year post-KT by ATG dose. CONCLUSIONS:In our study of high-risk KT recipients without CMV prophylaxis, a single ATG dose decreased the risk of CMV infection without increasing the risk of AR or compromising graft or patient survival.

Understanding the economic implications of induction and maintenance immunosuppression (ISx) is important in developing personalized kidney transplant (KTx) care. Using data from a novel integrated data set including financial records from the University Health System Consortium, Medicare, and pharmacy claims (2007-2014), we estimated the differences in the impact of induction and maintenance ISx regimens on transplant hospitalization costs and Medicare payments from KTx to 3 years. Use of thymoglobulin (TMG) significantly increased transplant hospitalization costs ($12 006; P = .02), compared with alemtuzumab and basiliximab. TMG resulted in lower Medicare payments in posttransplant years 1 (-$2058; P = .05) and 2 (-$1784; P = .048). Patients on steroid-sparing ISx incurred relatively lower total Medicare spending (-$10 880; P = .01) compared with patients on triple therapy (tacrolimus, antimetabolite, and steroids). MPA/AZA-sparing, mammalian target of rapamycin inhibitors-based, and cyclosporine-based maintenance ISx regimens were associated with significantly higher payments. Alternative ISx regimens were associated with different KTx hospitalization costs and longer-term payments. Future studies of clinical efficacy should also consider cost impacts to define the economic effectiveness of alternative ISx regimens.

The construct of frailty was first developed in gerontology to help identify older adults with increased vulnerability when confronted with a health stressor. This article is a review of studies in which frailty has been applied to pre- and post-kidney transplantation (KT) populations. Although KT is the optimal treatment for end-stage kidney disease (ESKD), KT candidates often must overcome numerous health challenges associated with ESKD before receiving KT. After KT, the impacts of surgery and immunosuppression represent additional health stressors that disproportionately impact individuals with frailty. Frailty metrics could improve the ability to identify KT candidates and recipients at risk for adverse health outcomes and those who could potentially benefit from interventions to improve their frail status. The Physical Frailty Phenotype (PFP) is the most commonly used frailty metric in ESKD research, and KT recipients who are frail at KT (~20% of recipients) are twice as likely to die as nonfrail recipients. In addition to the PFP, many other metrics are currently used to assess pre- and post-KT vulnerability in research and clinical practice, underscoring the need for a disease-specific frailty metric that can be used to monitor KT candidates and recipients. Although frailty is an independent risk factor for post-transplant adverse outcomes, it is not factored into the current transplant program risk-adjustment equations. Future studies are needed to explore pre- and post-KT interventions to improve or prevent frailty.

BACKGROUND:Recipients of kidneys from living donors who subsequently develop end-stage renal disease (ESRD) also have higher graft failure, suggesting the 2 donor kidneys share risk factors that could inform recipient outcomes. Given that donor ESRD is rare, an earlier and more common postdonation outcome could serve as a surrogate to individualize counseling and management for recipients. Hypertension is a frequent event before donor ESRD; thus, early postdonation hypertension might indicate higher risk of graft failure. METHODS:We studied Scientific Registry of Transplant Recipients data to quantify the association between early postdonation hypertension and recipient graft failure using propensity score-weighted Cox proportional hazards regression. We also examined the association between postdonation systolic blood pressure and graft failure. RESULTS:Of 37 901 recipients, 2.4% had a donor who developed hypertension within 2 years postdonation. Controlling for donor and recipient characteristics, recipients whose donors developed hypertension had no higher risk for graft failure (adjusted hazard ratio [aHR] 1.03, 95% confidence interval [CI] 0.85-1.25, P = 0.72). This was consistent among subgroups of recipients at higher risk for adverse outcomes due to hyperfiltration: African American recipients (aHR 1.10, 95% CI 0.70-1.73, P = 0.68) and those with ESRD caused by hypertension (aHR 1.10, 95% CI 0.65-1.85, P = 0.73) or diabetes (aHR 0.80, 95% CI 0.56-1.13, P = 0.20). However, graft failure was associated with postdonation systolic blood pressure (per 10 mm Hg, aHR 1.05, 95% CI 1.03-1.08, P < 0.001). CONCLUSIONS:Although postdonation systolic blood pressure is associated with graft failure, the reported diagnosis of hypertension as determined by the requirement for blood pressure treatment early postdonation did not portend a higher risk of recipient graft failure in the same way as eventual postdonation ESRD.

Prioritization of highly sensitized (HS) candidates under the kidney allocation system (KAS) and growth of large, multicenter kidney-paired donation (KPD) clearinghouses have broadened the transplant modalities available to HS candidates. To quantify temporal trends in utilization of these modalities, we used SRTR data from 2009 to 2017 to study 39 907 adult HS (cPRA ≥ 80%) waitlisted candidates and 19 003 recipients. We used competing risks regression to quantify temporal trends in likelihood of DDKT, KPD, and non-KPD LDKT for HS candidates (Era 1: January 1, 2009-December 31, 2011; Era 2: January 1, 2012-December 3, 2014; Era 3: December 4, 2014-December 31, 2017). Although the likelihood of DDKT and KPD increased over time for all HS candidates (adjusted subhazard ratio [aSHR] Era 3 vs 1 for DDKT: _1.74 1.85_1.97 , P < .001 and for KPD: _1.70 2.20_2.84 , P < .001), the likelihood of non-KPD LDKT decreased (aSHR: _0.69 0.82_0.97 , P = .02). However, these changes affected HS recipients differently based on cPRA. Among recipients, more cPRA 98%-99.9% and 99.9%+ recipients underwent DDKT (96.2% in Era 3% vs 59.1% in Era 1 for cPRA 99.9%+), whereas fewer underwent non-KPD LDKT (1.9% vs 30.9%) or KPD (2.0% vs 10.0%). Although KAS increased DDKT likelihood for the most HS candidates, it also decreased the use of non-KPD LDKT to transplant cPRA 98%+ candidates.

RATIONALE & OBJECTIVE:Intact cognition is generally a prerequisite for navigating through and completing evaluation for kidney transplantation. Despite kidney transplantation being contraindicated for those with severe dementia, screening for more mild forms of cognitive impairment before referral is rare. Candidates may have unrecognized cognitive impairment, which may prolong evaluation, elevate mortality risk, and hinder access to kidney transplantation. We estimated the burden of cognitive impairment and its association with access to kidney transplantation and waitlist mortality. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:3,630 participants (January 2009 to June 2018) with cognitive function measured (by the Modified Mini-Mental State Examination [3MS]) at kidney transplantation evaluation at 1 of 2 transplantation centers. PREDICTORS:Cognitive impairment (3MS score<80). OUTCOMES:Listing, waitlist mortality, and kidney transplantation. ANALYTICAL APPROACH:We estimated the adjusted chance of listing (Cox regression), risk for waitlist mortality (competing-risks regression), and kidney transplantation rate (Poisson regression) by cognitive impairment. Given potential differences in cause of cognitive impairment among those with and without diabetes, we tested whether these associations differed by diabetes status using a Wald test. RESULTS:=0.02). Among candidates without diabetes, those with cognitive impairment were at 2.47 (95% CI, 1.31-4.66) times greater risk for waitlist mortality; cognitive impairment was not associated with this outcome among candidates with diabetes. LIMITATIONS:Single measure of cognitive impairment. CONCLUSIONS:Cognitive impairment is associated with a lower chance of being placed on the waitlist, and among patients without diabetes, with increased mortality on the waitlist. Future studies should investigate whether implementation of screening for cognitive impairment improves these outcomes.

Stakeholders have expressed concerns regarding decreased deceased donor kidney transplant (DDKT) rates for pediatric candidates under the Kidney Allocation System (KAS). To better understand what might be driving this, we studied Scientific Registry of Transplant Recipients kidney offer data for 3642 pediatric (age <18 years) kidney-only transplant candidates between December 31, 2012 to December 3, 2014 (pre-KAS) and December 4, 2014 to January 6, 2017 (post-KAS). We used negative binomial regression and multilevel logistic regression to compare offer and acceptance rates pre- and post-KAS. We stratified by donor age (<18, 18-34, and 35+ years) and KDPI (<35% and ≥35%) to reflect differing allocation prioritization pre-KAS and post-KAS. As might be expected from prioritization changes, post-KAS candidates were less likely to receive offers for donors 18-34 years old with KDPI ≥ 35% (adjusted incidence rate ratio [aIRR]: _0.18 0.21_0.25 , P < .001), and more likely to receive offers for donors 18-34 years old and KDPI < 35% (aIRR: _1.12 1.20_1.29 , P < .001). However, offer acceptance practices also changed post-KAS: kidneys from donors 18-34 years old and KDPI < 35% were 23% less likely to be accepted post-KAS (adjusted odds ratio: _0.61 0.77_0.98 , P = .03). Using kidneys from donors 18-34 years old with KDPI < 35% post-KAS to the same extent they were used pre-KAS might be an effective strategy to mitigate any decrease in DDKT rates for pediatric candidates.

Hypertension guidelines recommend calcium channel blockers (CCBs), thiazide diuretics, and angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) as first-line agents to treat hypertension. Hypertension is common among kidney transplant (KTx) recipients, but data are limited regarding patterns of antihypertensive medication (AHM) use in this population. We examined a novel database that links national registry data for adult KTx recipients (age > 18 years) with AHM fill records from a pharmaceutical claims warehouse (2007-2016) to describe use and correlates of AHM use during months 7-12 post-transplant. For patients filling AHMs, individual agents used included: dihydropyridine (DHP) CCBs, 55.6%; beta-blockers (BBs), 52.8%; diuretics, 30.0%; ACEi/ARBs, 21.1%; non-DHP CCBs, 3.0%; and others, 20.1%. Both BB and ACEi/ARB use were significantly lower in the time period following the 2014 Eighth Joint National Committee (JNC-8) guidelines (2014-2016), compared with an earlier period (2007-2013). The median odds ratios generated from case-factor adjusted models supported variation in use of ACEi/ARBs (1.51) and BBs (1.55) across transplant centers. Contrary to hypertension guidelines for the general population, KTx recipients are prescribed relatively more BBs and fewer ACEi/ARBs. The clinical impact of this AHM prescribing pattern warrants further study.