Faculty Bibliography

BACKGROUND:Cognitive impairment is common in patients with end-stage renal disease and is associated with poor outcomes on dialysis. We hypothesized that cognitive impairment might be associated with an increased risk of all-cause graft loss (ACGL) in kidney transplant (KT) recipients. METHODS:Using the Modified Mini-Mental State (3MS) examination, we measured global cognitive function at KT hospital admission in a prospective, 2-center cohort of 864 KT candidates (August 2009 to July 2016). We estimated the association between pre-KT cognitive impairment and ACGL using Cox regression, adjusting for recipient, donor, and transplant factors. RESULTS:In living donor KT (LDKT) recipients, the prevalence was 3.3% for mild impairment (60 ≤ 3MS < 80) and 3.3% for severe impairment (3MS < 60). In deceased donor KT (DDKT) recipients, the prevalence was 9.8% for mild impairment and 2.6% for severe impairment. The LDKT recipients with cognitive impairment had substantially higher ACGL risk than unimpaired recipients (5-year ACGL: 45.5% vs 10.6%; P < 0.01; adjusted hazard ratio [aHR] any impairment, 5.40 (95% confidence interval [CI], 1.78-16.34; P < 0.01); aHR severe impairment, 5.57 (95% CI, 1.29-24.00; P = 0.02). Similarly, DDKT recipients with severe impairment had higher ACGL risk than recipients without severe impairment (5-year ACGL, 53.0% vs 24.2%; P = 0.04); aHR severe impairment, 2.92 (95% CI, 1.13-7.50; P = 0.03). CONCLUSIONS:Given the elevated risk of ACGL among KT recipients with cognitive impairment observed in this 2-center cohort, research efforts should explore the mechanisms of graft loss and mortality associated with cognitive impairment and identify potential interventions to improve posttransplant survival.

Livers from older donors (OLDs; age ≥70) are risky and often declined; however, it is likely that some candidates will benefit from OLDs versus waiting for younger ones. To characterize the survival benefit of accepting OLD grafts, we used 2009-2017 SRTR data to identify 24 431 adult liver transplant (LT) candidates who were offered OLD grafts eventually accepted by someone. Outcomes from the time-of-offer were compared between candidates who accepted an OLD graft and matched controls within MELD ± 2 who declined the same offer. Candidates who accepted OLD grafts (n = 1311) were older (60.5 vs. 57.8 years, P < .001), had a higher median MELD score (25 vs. 22, P < .001), and were less likely to have hepatitis C cirrhosis (14.9% vs. 31.2%, P < .001). Five-year cumulative mortality among those who accepted versus declined the same OLD offer was 23.4% versus 41.2% (P < .001). Candidates who accepted OLDs experienced an almost twofold reduction in mortality (aHR:_0.45 0.52_0.59 , P < .001) compared to those who declined the same offer, especially among the highest MELD (35-40) candidates (aHR:_0.10 0.24_0.55 , P = .001). Accepting an OLD offer provided substantial long-term survival benefit compared to waiting for a better organ offer, notably among candidates with MELD 35-40. Providers should consider these benefits as they evaluate OLD graft offers.

In the United States, kidney donation from international (noncitizen/nonresident) living kidney donors (LKDs) is permitted; however, given the heterogeneity of healthcare systems, concerns remain regarding the international LKD practice and recipient outcomes. We studied a US cohort of 102 315 LKD transplants from 2000-2016, including 2088 international LKDs, as reported to the Organ Procurement and Transplantation Network. International LKDs were more tightly clustered among a small number of centers than domestic LKDs (Gini coefficient 0.76 vs 0.58, P < .001). Compared with domestic LKDs, international LKDs were more often young, male, Hispanic or Asian, and biologically related to their recipient (P < .001). Policy-compliant donor follow-up was substantially lower for international LKDs at 6, 12, and 24 months postnephrectomy (2015 cohort: 45%, 33%, 36% vs 76%, 71%, 70% for domestic LKDs, P < .001). Among international LKDs, Hispanic (aOR = _0.23 0.36_0.56 , P < .001) and biologically related (aOR = _0.39 0.59_0.89 , P < .01) donors were more compliant in donor follow-up than white and unrelated donors. Recipients of international living donor kidney transplant (LDKT) had similar graft failure (aHR = _0.78 0.89_1.02 , P = .1) but lower mortality (aHR = _0.53 0.62_0.72 , P < .001) compared with the recipients of domestic LDKT after adjusting for recipient, transplant, and donor factors. International LKDs may provide an alternative opportunity for living donation. However, efforts to improve international LKD follow-up and engagement are warranted.

Recent OPTN proposals to address geographic disparity in liver allocation have involved circular boundaries: the policy selected 12/17 allocated to 150-mile circles in addition to DSAs/regions, and the policy selected 12/18 allocated to 150-mile circles eliminating DSA/region boundaries. However, methods to reduce geographic disparity remain controversial, within the OPTN and the transplant community. To inform ongoing discussions, we studied center-level supply/demand ratios using SRTR data (07/2013-06/2017) for 27 334 transplanted deceased donor livers and 44 652 incident waitlist candidates. Supply was the number of donors from an allocation unit (DSA or circle), allocated proportionally (by waitlist size) to the centers drawing on these donors. We measured geographic disparity as variance in log-transformed supply/demand ratio, comparing allocation based on DSAs, fixed-distance circles (150- or 400-mile radius), and fixed-population (12- or 50-million) circles. The recently proposed 150-mile radius circles (variance = 0.11, P = .9) or 12-million-population circles (variance = 0.08, P = .1) did not reduce the geographic disparity compared to DSA-based allocation (variance = 0.11). However, geographic disparity decreased substantially to 0.02 in both larger fixed-distance (400-mile, P < .001) and larger fixed-population (50-million, P < .001) circles (P = .9 comparing fixed distance and fixed population). For allocation circles to reduce geographic disparities, they must be larger than a 150-mile radius; additionally, fixed-population circles are not superior to fixed-distance circles.

BACKGROUND:HIV+ to HIV+ solid organ transplants in the United States are now legally permitted. Currently, these transplants must adhere to the HIV Organ Policy Equity (HOPE) Act Safeguards and Research Criteria that require the provision of an independent recipient advocate, a novel requirement for solid organ transplant programs. The objective of this study was to understand the experiences of the first advocates serving in this role. METHODS:We conducted semi-structured interviews with 15 HOPE independent recipient advocates (HIRAs) from 12 institutions. RESULTS:All HIRAs had a professional degree and experience in transplantation or infectious diseases. HIRAs' encounters with potential recipients varied in length, modality, and timing. The newness of the role and the lack of guidance were associated with unease among some HIRAs. Some questioned whether their role was redundant to others involved in transplantation and research since some potential recipients experienced informational fatigue. CONCLUSIONS:HOPE independent recipient advocates are ensuring the voluntariness of potential participants' decision to accept an HIV-infected organ. Many suggested additional guidance would be helpful and alleviate unease. Concerns about potential role redundancy raise the question of whether the HIRA requirement may be inadvertently increasing burden for potential recipients. Future work that captures the experiences of potential recipients is warranted.

BACKGROUND:Allocation for pediatric deceased-donor kidney transplantation (pDDKT) in the United States now de-emphasizes HLA matching to improve equality in access to transplantation, but other national systems still consider HLA matching due to concerns about graft survival. We hypothesized that the impact of HLA mismatching has decreased over time due to advances including improved immunosuppression. METHODS:Using Scientific Registry of Transplant Recipient data, we analyzed whether the association between the number of HLA mismatches and outcomes of first-time pDDKTs changed between 2 eras: 1995 to 2004 (N = 2854) and 2005 to 2014 (N = 4643). RESULTS:Between eras, the median number of mismatches increased from 4 to 5 (P < 0.001). Overall graft failure risk was higher among HLA-mismatched versus HLA-matched transplants (adjusted hazard ratio 1.211.431.69 for 3-6 versus 0-2 mismatches; P < 0.001), and this association was similar pre-2005 and post-2005 (Pinteraction = 0.5). Median panel-reactive antibody change at relisting increased from 79 to 85 (P = 0.01), but the association between number of HLA mismatches and panel-reactive antibody change was similar between eras (Pinteraction = 0.6). CONCLUSIONS:Our finding that increased HLA mismatching continues to impact graft survival, with 43% higher risk of graft failure, highlights the tradeoff between transplant access equity and outcomes and calls into question the deemphasis on HLA matching in pDDKT allocation in the United States.

BACKGROUND:Living kidney donors have an increased risk of end-stage renal disease, with hypertension and diabetes as the predominant causes. In this study, we sought to better understand the timeline when these diseases occur, focusing on the early postdonation period. METHODS:We studied 41 260 living kidney donors in the United States between 2008 and 2014 from the Scientific Registry of Transplant Recipients and modeled incidence rates and risk factors for hypertension and diabetes. RESULTS:At 6 months, 1 year, and 2 years postdonation, there were 74, 162, and 310 cases, respectively, of hypertension per 10 000 donors. Donors who were older (per 10 y, adjusted incidence rate ratio [aIRR], 1.40; 95% confidence interval [CI], 1.29-1.51), male (aIRR, 1.31; 95% CI, 1.14-1.50), had higher body mass index (per 5 units, aIRR, 1.29; 95% CI, 1.17-1.43), and were related to their recipient (first-degree relative: aIRR, 1.28; 95% CI, 1.08-1.52; spouse: aIRR, 1.34; 95% CI, 1.08-1.66) were more likely to develop hypertension, whereas donors who were Hispanic/Latino were less likely (aIRR, 0.71; 95% CI, 0.55-0.93). At 6 months, 1 year, and 2 years, there were 2, 6, and 15 cases of diabetes per 10 000 donors. Donors who were older (per 10 y: aIRR, 1.42; 95% CI, 1.11-1.82), had higher body mass index (per 5 units: aIRR, 1.52; 95% CI, 1.04-2.21), and were Hispanic/Latino (aIRR, 2.45; 95% CI, 1.14-5.26) were more likely to develop diabetes. CONCLUSIONS:In this national study, new-onset diabetes was rare, but 3% of donors developed hypertension within 2 years of nephrectomy. These findings reaffirm that disease pathways for kidney failure differ by donor phenotype and estimate the population most at-risk for later kidney failure.

The Organ Procurement and Transplantation Network (OPTN) went up for competitive bid again this year, yet this contract has been held by only 1 entity since its inception. The OPTN's scope has grown steadily, and it now embraces several disparate missions: to operate the computing and coordination infrastructure that maintains waitlists and makes organ offers in priority order, to regulate transplant centers and organ procurement organizations, to follow and protect living donors, and to decide organ allocation policy in concert with the many voices of the transplant community. The contracting process and performance work statement continue to discourage both innovative approaches to the OPTN and competitive bids outside of United Network for Organ Sharing (UNOS), with evaluation criteria that either disqualify or strongly disadvantage new applicants. The performance work statement also emphasizes bureaucratic tasks while obligating the OPTN contractor to the specific committee structure that has impeded decision-making and tended to preserve the status quo in controversial matters. Finally, the UNOS computing infrastructure is antiquated and requires months to years to implement small changes. Restructuring the OPTN contract to separate the information technology requirements from the policy/regulatory responsibilities might allow more nimble and effective specialty contractors to offer their capabilities in service of the national transplant enterprise.

Prior studies have shown that beginning hemodialysis (HD) with a hemodialysis catheter (HC) is associated with worse mortality than with an arteriovenous fistula (AVF) or arteriovenous graft (AVG). We hypothesized that transplant waitlisting would modify the effect of HD access on mortality, given waitlist candidates' more robust health status. Using the US Renal Data System, we studied patients with incident ESRD who initiated HD between 2010 and 2015 with an AVF, AVG, or HC. We used Cox regression including an interaction term for HD access and waitlist status. There were 587,607 patients that initiated HD, of whom 82,379 (14.0%) were waitlisted for transplantation. Only 26,264 (4.5%) were transplanted. Among patients not listed, those with an AVF had a 34% lower mortality compared to HC [adjusted hazard ratio (aHR) 0.66, 95% confidence interval (CI) 0.65-0.67] while those with an AVG had a 21% lower mortality compared to HC (aHR 0.79, 95% CI 0.77-0.81). Transplant waitlisting attenuated the association between hemodialysis access type and mortality (interaction p < 0.001 for both AVF and AVG vs. HC). Among patients on the waitlist, those with an AVF had a 12% lower mortality compared to HC (aHR 0.88, 95% CI 0.84-0.93), while those with an AVG had no difference in mortality (aHR 0.95, 95% CI 0.84-1.08). While all patients benefit from AVF or AVG over HC, the benefit was attenuated in waitlisted patients. Efforts to improve health status and access to healthcare for non-waitlisted ESRD patients might decrease HD-associated mortality and improve rates of AVF and AVG placement.

BACKGROUND:Inflammation is more common among African Americans (AAs), and it is associated with frailty, poor physical performance, and mortality in community-dwelling older adults. Given the elevated inflammation levels among end-stage renal disease (ESRD) patients, inflammation may be associated with adverse health outcomes such as frailty, physical impairment, and poor health-related quality of life (HRQOL), and these associations may differ between AA and non-AA ESRD patients. METHODS:One thousand three ESRD participants were recruited at kidney transplant evaluation (4/2014-5/2017), and inflammatory markers (interleukin-6 [IL-6], tumor necrosis factor-a receptor-1 [TNFR1], C-reactive protein [CRP]) were measured. We quantified the association with frailty (Fried phenotype), physical impairment (Short Physical Performance Battery [SPPB]), and fair/poor HRQOL at evaluation using adjusted modified Poisson regression and tested whether these associations differed by race (AA vs. non-AA). RESULTS:Non-AAs had lower levels of TNFR1 (9.7 ng/ml vs 14.0 ng/ml, p < 0.001) and inflammatory index (6.7 vs 6.8, p < 0.001) compared to AAs, but similar levels of IL-6 (4.5 pg/ml vs 4.3 pg/ml, p > 0.9) and CRP (4.7 μg/ml vs 4.9 μg/ml, p = 0.4). Non-AAs had an increased risk of frailty with elevated IL-6 (RR = 1.58, 95% CI:1.27-1.96, p < 0.001), TNFR1 (RR = 1.60, 95% CI:1.25-2.05, p < 0.001), CRP (RR = 1.41, 95% CI:1.10-1.82, p < 0.01), and inflammatory index (RR = 1.82, 95% CI:1.44-2.31, p < 0.001). The associations between elevated inflammatory markers and frailty were not present among AAs. Similar results were seen with SPPB impairment and poor/fair HRQOL. CONCLUSIONS:Non-AAs with elevated inflammatory markers may need closer follow-up and may benefit from prehabilitation to improve physical function, reduce frailty burden, and improve quality of life prior to transplant.