Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:This review provides a comprehensive examination of the current inequities and ethical challenges in kidney transplantation and highlights some of the most urgent issues related to organ allocation and emerging technologies. RECENT FINDINGS/RESULTS:Several recent news and media reports have significantly undermined public trust in the organ transplantation and allocation process. This review discusses some of these controversies and proposes strategies to restore confidence in the system. With advancements in gene editing, xenotransplantation is becoming a tangible reality, bringing forth new ethical challenges explored in this paper. Likewise, as artificial intelligence continues to permeate medicine and moves closer to integration within transplantation, proactive preparation and ethical foresight are essential. SUMMARY/CONCLUSIONS:In conclusion, we aim to draw attention to pressing ethical dilemmas in kidney transplantation and suggest actionable steps to restore trust.

PURPOSE OF REVIEW/OBJECTIVE:The 2023 CONVINCE trial demonstrated improved survival with high-dose hemodiafiltration (HDF), prompting discussions about widespread adoption. However, this clinical advancement occurs amid growing awareness of healthcare's environmental impact, particularly dialysis treatments that consume extensive water and energy resources. This review examines the environmental implications of HDF adoption, synthesizing recent evidence on resource consumption and emerging sustainability solutions in the context of the climate crisis facing nephrology. RECENT FINDINGS/RESULTS:Life cycle assessments indicate HDF has a carbon footprint 30-40% higher than conventional hemodialysis, consuming an additional 10 300 L of water per patient annually. However, recent technological innovations show promise: expanded hemodialysis (HDx) using medium cut-off membranes reduces water usage by >20% and energy consumption by >30% compared to HDF while potentially achieving similar clinical outcomes. Water conservation technologies, including reverse osmosis, reject water reuse and reduced dialysate flow protocols, can decrease environmental impact by 30-50% without any difference in patient outcomes. SUMMARY/CONCLUSIONS:The adoption of HDF represents a critical test case for sustainable healthcare innovation. While the potential benefits should not be ignored, technology is not static and, if confirmed, additional sustainability work and comprehensive policy frameworks integrating environmental impact assessments into technology evaluation are urgently needed. The nephrology community must balance clinical excellence with planetary stewardship through technological innovation, resource optimization, and evidence-based environmental guidelines that benefit, not compromise, patient care.

BACKGROUND:People on hemodialysis (HD) often report lower quality of life (QoL) compared to people not on HD. People with kidney disease have a high prevalence of health-related social needs (HRSN). The association of HRSN and QoL in people on HD remains understudied. Though some groups of patients treated with HD tend to have lower QoL, there exists minimal research investigating the mechanism by which this occurs. METHODS:We surveyed people receiving HD at five urban dialysis units using the Kidney Disease Quality of Life (KDQOL) and the Accountable Health Communities Health-Related Social Needs Screening Tool (AHC-HRSN) to assess their housing, food, transportation, utilities, and perceived safety. We calculated physical and mental component scores as well as sub scores measuring burden, symptoms, and effect of kidney disease. We analyzed scores using Python packages. We used the Shapiro-Wilk test to assess normality. For analysis we used the Wilcoxon Rank Sum test and univariate, multivariate, and LASSO regressions. RESULTS:A total of 324 patients participated in the study. HRSN was common with 56% of participants reporting at least one HRSN. Food insecurity (35%) and housing instability (24%) was most common. All QoL sub scores were significantly lower in patients who had at least one HRSN. In regression models, housing and transportation insecurity most frequently emerged as significant variables associated with lower QoL sub scores even after adjusting for patient demographics. Burden scores showed the largest effect sizes (housing instability β=-17.90, P<0.001, transportation problems β=-14.03, P=0.001). CONCLUSION/CONCLUSIONS:HRSN is significantly associated with lower QoL scores, with largest effect sizes seen with housing instability and transportation problems. Increased screening and intervention for HRSN may improve QoL among people on HD.

BACKGROUND/UNASSIGNED:Kidney transplant recipients are at risk for adverse health outcomes. Digital health tools such as wearable accelerometers and continuous glucose monitors (CGMs) can provide detailed, noninvasive tracking of health behaviors and measures, such as physical activity, sleep, and glucose levels, that may offer insights into future health concerns, such as posttransplant diabetes mellitus, cognitive health, and transplant rejection. However, there is limited evidence on the feasibility and acceptability of these devices in kidney transplant candidates older than 50 y. METHODS/UNASSIGNED:This observational cross-sectional pilot study aimed to examine the feasibility of 2 digital health tools: an accelerometer and a continuous glucose monitor. Participants were eligible for the study if they were living donor kidney transplant candidates, aged 50 y or older, had no known cognitive impairments, and could provide informed consent. Participants were asked to wear a CGM and an accelerometer for up to 14 d before their kidney transplant surgery. Device feasibility was quantified by (1) the total time the devices were worn, and (2) the validated System Usability Scale survey administered after the devices were returned. RESULTS/UNASSIGNED:20 participants enrolled in the study (mean age 64 ± 9 y, 25% women, 40% with type 2 diabetes). The median number of days of accelerometer and CGM wear were 7 (interquartile range, 6-10) d and 7 (interquartile range, 7-10) d, respectively. Ninety percent of participants reported a favorable opinion of both devices. Participants wore the CGM 100% of the time and the accelerometer 90% of the time, indicating high adherence. CONCLUSIONS/UNASSIGNED:The use of digital devices was acceptable among kidney transplant candidates aged older than 50 y, paving the way for larger studies to identify early digital biomarkers of health outcomes in this high-risk population.

RATIONALE & OBJECTIVE/OBJECTIVE:Adults receiving maintenance hemodialysis (HD) frequently report pain, yet detailed descriptions of pain in this population are lacking. This study examines pain locations, characteristics, and associations with other symptoms in adults receiving HD. STUDY DESIGN/METHODS:Cross-sectional analysis. SETTING & PARTICIPANTS/METHODS:Adults with moderate to severe chronic pain receiving maintenance HD enrolled in the multicenter HOPE Consortium Trial from 2021 to 2023. EXPOSURES/METHODS:Sociodemographic, pain treatment, dialysis, medical comorbidity, and psychological and behavioral characteristics. Other patient-reported symptoms. OUTCOME/RESULTS:Pain interference and severity as assessed by the Brief Pain Inventory (BPI) Interference and Severity subscales (range 0-10). ANALYTICAL APPROACH/METHODS:Multivariable regression with LASSO to examine associations between participant characteristics and pain interference/severity, and Spearman's correlation to examine relationships between other symptoms and pain interference/severity at baseline. RESULTS:Among 643 participants, the median (IQR) BPI interference was 6.6 (5.1-7.9) and severity was 6.0 (4.5-7.5). 84% of participants reported pain >1 year and 75% had daily pain. 89% and 66% of participants endorsed musculoskeletal and neuropathic pain, respectively. Of 32 body regions, the median (IQR) number of painful regions was 8 (4-14). C ommon regions in females were lower back (72%), knees (64%), legs (60%), and upper back (59%). A similar pattern existed for males. In LASSO analyses, cardiovascular disease and depression were associated with significantly higher pain interference whereas White race (ref: Black race) and non-Hispanic ethnicity were associated with significantly lower pain interference. Similar findings were noted for pain severity. Pain catastrophizing and symptoms of fatigue, depression, and anxiety were moderately correlated with pain interference (r>0.4). LIMITATIONS/CONCLUSIONS:Neither relationship directionality nor causality can be inferred. CONCLUSIONS:Among adults treated with HD who have chronic pain, pain locations were numerous and diverse, with substantial musculoskeletal and neuropathic characteristics. Factors associated with pain interference were predominantly sociodemographic and psychological rather than those related to comorbid diseases and dialysis.

BACKGROUND:Urinary stone disease with a clear genetic cause, monogenic stone disease (MSD), is increasingly recognized as a significant proportion of the total population. When MSD is suspected, genetic testing provides a firm diagnosis that can alter management and treatment. Here we present testing results from a large cohort with suspected MSD. METHODS:Subjects with features suggestive of MSD (early onset, family history, frequent stones, nephrocalcinosis [NC], and/or CKD) were recruited by the Rare Kidney Stone Consortium and genotyped for up to 160 known or candidate MSD genes via a targeted massively parallel sequencing (tMPS) panel. We compared clinical and biochemical features between genetically resolved MSD and unresolved individuals. RESULTS:Of 426 families (657 patients) enrolled, 145 (34%) were resolved with identified disease associated variants in 22 known MSD genes. Ninety-nine families were biallelic, 37 monoallelic, and 2 digenic. An additional 21 of the 231 screened family members were resolved. Genes identified in 10 or more families were: AGXT, HOGA1, SLC34A3, CYP24A1, SLC3A1, and CLCN5. Compared to the unresolved group, MSD probands had a lower baseline and last visit estimated glomerular filtration rate (eGFR), earlier age of stone presentation, and more stone events and procedures/year of life. The resolve rate was higher in those less than 16 years, and NC was seen earlier in the MSD group. Overall, NC was a risk factor for lower eGFR. Among the specific disorders, primary hyperoxaluria patients had the earliest age of stone and NC diagnosis, and as expected, the highest urinary oxalate level. CONCLUSIONS:Our study emphasizes the value of selecting patients enriched for factors associated with MSD, and comprehensive genetic testing to achieve a high yield of genetic diagnoses. Significant clinical and biochemical characteristics of MSD patients were defined. A definitive MSD diagnosis facilitates individualized management and strategies to delay disease progression in probands and affected family members.

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution^1-3. Despite gene-editing, the immune reactions following xenotransplantation can still cause transplant failure⁴. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host's blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked by S100A6⁵, SPP1⁶ (Osteopontin), and COLEC11⁷, at POD21-POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

We sought to understand the potential impacts of a rapidly evolving donor pool on the annual recalibration of the kidney donor profile index (KDPI). Using OPTN data, we examined the kidney donor risk index (KDRI) among deceased kidney donors recovered 2011-2024. We mimicked the OPTN's annual re-mapping process to measure the KDRI-to-KDPI calibration drift and used Cox regression to translate this drift into all-cause graft failure rate differences. The 50th/75th/95th KDRI percentile among recovered donors rose from 1.19/1.47/2.0 in 2011 to 1.40/1.77/2.36 in 2024. For donors with the same KDRI, the KDPI assigned in 2024 was as much as 13 points lower than the KDPI assigned in 2012. Holding other factors constant, the KDRI-KDPI calibration shift equated to 7 years of increased age (65 vs. 58) for KDPI 86% donors. Five-year graft failure risk was 9% higher (RR: _1.0871.093_1.097) for a kidney assigned a KDPI of 86% in 2024 versus 2012. Organ recovery practices have changed. The relationship between KDPI and organ quality has become a moving target, complicating shared decision-making and altering the meaning of allocation policy thresholds. Alternative solutions to annually remapping KDPI, such as establishing a fixed reference cohort or migrating away from KDPI, could be considered.