Faculty Bibliography

Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using in vitro human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes (CXCL11, CCL4, MS4A7, MS4A6A, and FCGR3A) indicative of endothelial activation, IFNgamma response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval [95% CI], 38% to 74% versus 19%; 95% CI, 8% to 35%; P=0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; P=0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition.

New regulations require living kidney donor (LKD) follow-up for 2 years, but donor retention remains poor. Electronic communication (eg, text messaging and e-mail) might improve donor retention. To explore the possible impact of electronic communication, we recruited LKDs to participate in an exploratory study of communication via telephone, e-mail, or text messaging postdonation; communication through this study was purely optional and did not replace standard follow-up. Of 69 LKDs recruited, 3% requested telephone call, 52% e-mail, and 45% text messaging. Telephone response rate was 0%; these LKDs were subsequently excluded from analysis. Overall response rates with e-mail or text messaging at 1 week, 1 month, 6 months, 1 year, and 2 years were 94%, 87%, 81%, 72%, and 72%. Lower response rates were seen in African Americans, even after adjusting for age, sex, and contact method (incidence rate ratio (IRR) nonresponse _2.07 5.81_16.36 , P = .001). Text messaging had higher response rates than e-mail (IRR nonresponse _0.11 0.28_0.71 , P = .007). Rates of nonresponse were similar by sex (IRR 0.68, P = .4) and age (IRR 1.00, P > .9). In summary, LKDs strongly preferred electronic messaging over telephone and were highly responsive 2 years postdonation, even in this nonrequired, nonincentivized exploratory research study. These electronic communication tools can be automated and may improve regulatory compliance and postdonation care.

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.

To assess factors that influence the choice of induction regimen in contemporary kidney transplantation, we examined center-identified, national transplant registry data for 166 776 US recipients (2005-2014). Bilevel hierarchical models were constructed, wherein use of each regimen was compared pairwise with use of interleukin-2 receptor blocking antibodies (IL2rAb). Overall, 82% of patients received induction, including thymoglobulin (TMG, 46%), IL2rAb (22%), alemtuzumab (ALEM, 13%), and other agents (1%). However, proportions of patients receiving induction varied widely across centers (0-100%). Recipients of living donor transplants and self-pay patients were less likely to receive induction treatment. Clinical factors associated with use of TMG or ALEM (vs. IL2rAb) included age, black race, sensitization, retransplant status, nonstandard deceased donor, and delayed graft function. However, these characteristics explained only 10-33% of observed variation. Based on intraclass correlation analysis, "center effect" explained most of the variation in TMG (58%), ALEM (66%), other (51%), and no induction (58%) use. Median odds ratios generated from case-factor adjusted models (7.66-11.19) also supported large differences in the likelihood of induction choices between centers. The wide variation in induction therapy choice across US transplant centers is not dominantly explained by differences in patient or donor characteristics; rather, it reflects center choice and practice.

BACKGROUND:HIV-infected (HIV+) donor organs can be transplanted into HIV+ recipients under the HIV Organ Policy Equity (HOPE) Act. Quantifying HIV+ donor referrals received by organ procurement organizations (OPOs) is critical for HOPE Act implementation. METHODS:We surveyed the 58 USA OPOs regarding HIV+ referral records and newly discovered HIV+ donors. Using data from OPOs that provided exact records and CDC HIV prevalence data, we projected a national estimate of HIV+ referrals. RESULTS:Fifty-five (95%) OPOs reported HIV+ referrals ranging from 0 to 276 and newly discovered HIV+ cases ranging from 0 to 10 annually. Six OPOs in areas of high HIV prevalence reported more than 100 HIV+ donor referrals. Twenty-seven (47%) OPOs provided exact HIV+ referral records and 28 (51%) OPOs provided exact records of discovered HIV+ cases, totaling 1450 HIV+ referrals and 39 discovered HIV+ donors in the prior year. These OPOs represented 67% and 59% of prevalent HIV cases in the USA; thus, we estimated 2164 HIV+ referrals and 66 discovered HIV+ cases nationally per year. CONCLUSIONS:OPOs reported a high volume of HIV+ referrals annually, of which a subset will be medically eligible for donation. Particularly in areas of high HIV prevalence, OPOs require ongoing support to implement the HOPE Act.

BACKGROUND:The Fried frailty phenotype, a measure of physiologic reserve defined by 5 components (exhaustion, unintentional weight loss, low physical activity, slow walking speed, and poor grip strength), is associated with poor outcomes among ESRD patients. However, these 5 components may not fully capture physiologic reserve in this population. We aimed to ascertain opinions of ESRD clinicians and patients about the usefulness of the Fried frailty phenotype and interventions to improve frailty in ESRD patients, and to identify novel components to further characterize frailty in ESRD. METHODS:Clinicians who treat adults with ESRD completed a 2-round Delphi study (n = 41 and n = 36, respectively; response rate = 87%). ESRD patients completed a survey at transplant evaluation (n = 460; response rate = 81%). We compared clinician and patient opinions on the constituent components of frailty. RESULTS:Clinicians were more likely than patients to say that ESRD makes patients frail (97.6% vs. 60.2%). There was consensus among clinicians that exhaustion, low physical activity, slow walking speed, and poor grip strength characterize frailty in ESRD patients; however, 29% of clinicians thought weight loss was not relevant. Patients were less likely than clinicians to say that the 5 Fried frailty components were relevant. Clinicians identified 10 new ESRD-specific potential components including falls (64%), physical decline (61%), and cognitive impairment (39%). Clinicians (83%) and patients (80%) agreed that intradialytic foot-peddlers might make ESRD patients less frail. CONCLUSIONS:There was consensus among clinicians and moderate consensus among patients that frailty is more common in ESRD. Weight loss was not seen as relevant, but new components were identified. These findings are first steps in refining the frailty phenotype and identifying interventions to improve physiologic reserve specific to ESRD patients.

Importance:Over the past 2 decades, there has been increased attention and effort to reduce disparities in live donor kidney transplantation (LDKT) for black, Hispanic, and Asian patients with end-stage kidney disease. The goal of this study was to investigate whether these efforts have been successful. Objective:To estimate changes over time in racial/ethnic disparities in LDKT in the United States, accounting for differences in death and deceased donor kidney transplantation. Design, Setting, and Participants:A secondary analysis of a prospectively maintained cohort study conducted in the United States of 453 162 adult first-time kidney transplantation candidates included in the Scientific Registry of Transplant Recipients between January 1, 1995, and December 31, 2014, with follow-up through December 31, 2016. Exposures:Race/ethnicity. Main Outcomes and Measures:The primary study outcome was time to LDKT. Multivariable Cox proportional hazards and competing risk models were constructed to assess changes in racial/ethnic disparities in LDKT among adults on the deceased donor kidney transplantation waiting list and interaction terms were used to test the statistical significance of temporal changes in racial/ethnic differences in receipt of LDKT. The adjusted subhazard ratios are estimates derived from the multivariable competing risk models. Data were categorized into 5-year increments (1995-1999, 2000-2004, 2005-2009, 2010-2014) to allow for an adequate sample size in each analytical cell. Results:Among 453 162 adult kidney transplantation candidates (mean [SD] age, 50.9 [13.1] years; 39% were women; 48% were white; 30%, black; 16%, Hispanic; and 6%, Asian), 59 516 (13.1%) received LDKT. Overall, there were 39 509 LDKTs among white patients, 8926 among black patients, 8357 among Hispanic patients, and 2724 among Asian patients. In 1995, the cumulative incidence of LDKT at 2 years after appearing on the waiting list was 7.0% among white patients, 3.4% among black patients, 6.8% among Hispanic patients, and 5.1% among Asian patients. In 2014, the cumulative incidence of LDKT was 11.4% among white patients, 2.9% among black patients, 5.9% among Hispanic patients, and 5.6% among Asian patients. From 1995-1999 to 2010-2014, racial/ethnic disparities in the receipt of LDKT increased (P < .001 for all statistical interaction terms in adjusted models comparing white patients vs black, Hispanic, and Asian patients). In 1995-1999, compared with receipt of LDKT among white patients, the adjusted subhazard ratio was 0.45 (95% CI, 0.42-0.48) among black patients, 0.83 (95% CI, 0.77-0.88) among Hispanic patients, and 0.56 (95% CI, 0.50-0.63) among Asian patients. In 2010-2014, compared with receipt of LDKT among white patients, the adjusted subhazard ratio was 0.27 (95% CI, 0.26-0.28) among black patients, 0.52 (95% CI, 0.50-0.54) among Hispanic patients, and 0.42 (95% CI, 0.39-0.45) among Asian patients. Conclusions and Relevance:Among adult first-time kidney transplantation candidates in the United States who were added to the deceased donor kidney transplantation waiting list between 1995 and 2014, disparities in the receipt of live donor kidney transplantation increased from 1995-1999 to 2010-2014. These findings suggest that national strategies for addressing disparities in receipt of live donor kidney transplantation should be revisited.

We examined a novel database wherein national US transplant registry identifiers were linked to records from a large pharmaceutical claims warehouse (2008-2015) to characterize antidepressant use before and after kidney transplantation, and associations [adjusted hazard ratio (aHR) 95% CI] with death and graft failure. Among 72 054 recipients, 12.6% filled antidepressant medications in the year before transplant, and use was more common among women and patients who were white, unemployed, and had limited functional status. Pre-transplant antidepressant use was associated with 39% higher 1-year mortality (aHR 1.39, 95% CI 1.18-1.64) and 15% higher all-cause graft loss risk (aHR 1.15, 95% CI 1.02-1.30). More than 50% of patients who filled antidepressants pre-transplant continued fill post-transplant. Antidepressant use in the first year after transplant was associated with twofold higher risk of death (aHR 1.94, 95% CI 1.60-2.35), 38% higher risk of death-censored graft failure, and 61% higher risk of all-cause graft failure in the subsequent year. Pre-listing antidepressant use was also associated with increased mortality, but transplantation conferred a survival benefit regardless of prelisting antidepressant use status. While associations may in part reflect underlying behaviors or comorbidities, kidney transplant candidates and recipients treated with antidepressant medications should be monitored and supported to reduce the risk of adverse outcomes.

Introduction:Cognitive decline is common and increases mortality risk in hemodialysis patients. Intradialytic interventions like cognitive training (CT) and exercise training (ET) may preserve cognitive function. Methods:values were generated from linear regression. Results: = 0.16) for ET. Conclusion:Preliminary findings of our pilot study suggested that cognitive decline in psychomotor speed and executive function is possibly prevented by intradialytic CT and ET. These preliminary pilot findings should be replicated.

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.