Faculty Bibliography

BACKGROUND:While genetic testing is now more accessible in pediatric nephrology, little is known about the views of pediatric nephrologists regarding genetic testing in clinical settings. METHODS:An online 41-item survey was developed and distributed via professional listservs to self-identified U.S. licensed pediatric nephrologists from January 22 to May 4, 2021. RESULTS:Pediatric nephrologists had a high referral rate to genetic counseling and agreed on the significant impact of genetic testing on diagnosis, treatment, prognosis, counseling, and kidney transplant planning. Challenges for the utilization of genetic testing among pediatric nephrologists include the need to (1) learn how to counsel patients on the risks and benefits of genetic testing, (2) choose appropriate testing, (3) interpret genetic results, and (4) return those results to patients and families. CONCLUSION/CONCLUSIONS:There exists an opportunity to expand genetic testing education for pediatric nephrologists to assist incorporation of genetic testing into clinical practice.

Transmitted donor-derived glomerular diseases in the allograft kidney are rare, especially when encountered in an allograft from a living donor. To date, only individual reports of donor-derived membranous nephropathy (MN) have been described. In this report, we present a case of MN discovered in a postreperfusion biopsy of a living-donor allograft. A follow-up biopsy 3 weeks later demonstrated persistent deposits. Thirteen months posttransplant, the recipient showed mildly worsening proteinuria but stable kidney function. To further our understanding of this exceedingly rare complication, we share our experience with 7 additional in-house cases together with 6 cases described in the literature to date. A minority of the donors were living. Most donors did not exhibit significant proteinuria illustrating how predonation screening could potentially miss donor-derived MN. Reactivity for phospholipase A2 receptor and thrombospondin type 1 domain containing 7A were negative in all stained cases. On follow-up, recipients variably exhibited slow resolution of the immune deposits, variable degrees of proteinuria (mainly subnephrotic), and no significant impairment of kidney function. Donor-derived MN is rare, phospholipase A2 receptor-negative, and can still be encountered in living donors despite rigorous screening. This report provides a brief examination of the pathology, clinical, and laboratory features of such patients involved.

BACKGROUND:C3 glomerulopathy (C3G), which encompasses C3GN and dense deposit disease (DDD), results from dysregulation of the alternative complement pathway. Data on disease recurrence after kidney transplantation are limited, and details on histologic features of recurrent C3G are scarce. We aimed to evaluate C3G recurrence in the allograft, with a focus on histologic presentation and progression. METHODS:We retrospectively analyzed 18 patients with native kidney failure attributed to C3G (12 C3GN and six DDD), who received a kidney transplant from January 2016 to January 2023. Demographic, genetic, clinical, and histologic data were studied. The NanoString 770 genes PanCancer Immune Profiling Panel was used for transcriptomic analysis. Disease recurrence was the primary outcome. RESULTS:During a median (interquartile range) follow-up period of 37 (18–56) months, C3G recurrence occurred in 16 (89%) patients (11 with C3GN and five with DDD) at a median (interquartile range) of 33 (13–141) days after transplantation. Over a third (38%) of recurrent cases were detected in protocol biopsies, and only 31% of patients presented with >300 mg/g of proteinuria. Recurrence in index biopsies was mainly established through a combination of immunofluorescence and electron microscopy findings, while it showed only subtle histologic alterations and no characteristic transcriptomic signals. Over time, histologic chronicity indices increased, but all the allografts were functioning at the end of follow-up. Patients with recurrence of C3GN and DDD showed overlapping immunofluorescence and electron microscopy findings and had similar recurrence rate and time to recurrence. CONCLUSIONS:Most of the patients with native kidney failure attributed to C3G developed disease recurrence very early after kidney transplantation, usually with minimal proteinuria, mild histologic alterations, and favorable short-term allograft survival. Immunofluorescence and electron microscopy played a crucial role in detecting early, subclinical recurrence of C3GN and DDD, which showed significant overlapping features.

BACKGROUND:Acute kidney injury (AKI) is a common complication of pediatric heart transplant, with a subset of patients developing severe AKI requiring dialysis (AKI-D). We aimed to identify the epidemiology, risk factors, and outcomes of postoperative AKI-D in pediatric heart transplant recipients. METHODS:We retrospectively identified all pediatric first-time, single-organ heart transplants at our institution from 2014 to 2022. Postoperative AKI was defined as AKI within 2 weeks of transplant. Unadjusted and adjusted logistic regression were used to identify characteristics associated with AKI-D, and unadjusted time-to-event analyses were used to determine the association between AKI-D and survival free of kidney failure. RESULTS:Among 177 patients included, 116 (66%) developed postoperative AKI of any stage, including 13 (7%) who developed AKI-D with median time from transplant to dialysis initiation of 6 days (IQR 3-13). In adjusted models, increased cardiopulmonary bypass time (OR 1.19, 95% CI 1.04-1.37, per 15 min increase in bypass time) and higher weight at transplant were associated with higher odds of AKI-D, whereas patient demographics and pretransplant kidney function were not associated with AKI-D. AKI-D was associated with greater mortality during initial hospitalization (46% vs. 1%, p < 0.001) and a lower rate of survival free of kidney failure. CONCLUSIONS:The incidence of AKI-D after pediatric heart transplant was 7%, with extended cardiopulmonary bypass time associated with postoperative AKI-D even in adjusted models. Further research is needed to improve the prediction and management of AKI-D in this population.

PURPOSE:The success of genomic medicine hinges on the implementation of genetic knowledge in clinical settings. In novel subspecialties, it requires that clinicians refer patients to genetic evaluation or testing, however referral is likely to be affected by genetic knowledge. METHODS:An online survey was administered to self-identified nephrologists working in the United States. Nephrologists' demographic characteristics, genetic education, confidence in clinical genetics, genetic knowledge, and referral rates of patients to genetic evaluation were collected. RESULTS:In total, 201 nephrologists completed the survey. All reported treating patients with genetic forms of kidney disease, and 37% had referred <5 patients to genetic evaluation. A third had limited basic genetic knowledge. Most nephrologists (85%) reported concerns regarding future health insurance eligibility as a barrier to referral to genetic testing. Most adult nephrologists reported insufficient genetic education during residency (65%) and fellowship training (52%). Lower rating of genetic education and lower knowledge in recognizing signs of genetic kidney diseases were significantly associated with lower number of patients referred to the genetic evaluation (P < .001). Most nephrologists reported that improving their genetic knowledge is important for them (>55%). CONCLUSIONS:There is a need to enhance nephrologists' genetic education to increase genetic testing use in nephrology.

BACKGROUND:Chronic active antibody-mediated rejection (CAAMR) constitutes a dominant form of late allograft failure. Several treatment strategies directed at CAAMR have been attempted but proven ineffective at delaying kidney function decline or reducing donor-specific antibodies (DSA). We describe our single-center experience using tocilizumab in patients with CAAMR. METHODS:This is a retrospective analysis using electronic medical records. 38 kidney transplant recipients at Columbia University Irving Medical Center who had been prescribed tocilizumab and followed for at least 3 months between August 2013 through December 2019 were included. RESULTS:(SE = .8, p = .002) per month for up to 6 months following Tocilizumab initiation). Allograft biopsies showed significant improvement in interstitial inflammation scores (score 1(0,1) to 0 (0,1), p = .03) while other histologic scores remained stable. There was no significant change in proteinuria or DSA titers post-treatment with tocilizumab. CONCLUSIONS:Treatment of CAAMR with tocilizumab was associated with a decrease in the rate of eGFR decline and a reduction in interstitial inflammation scores in patients with CAAMR.

BACKGROUND:Pediatric kidney transplant candidates require timely access to transplant to optimize growth and neurodevelopmental outcomes. We studied access to transplant for pediatric candidates with prior organ transplants. METHODS:We used US registry data to identify pediatric kidney transplant candidates added to the waiting list 2015-2019 and used competing risk regression to study the association between prior transplant status and probability of receiving a kidney transplant, treating wait-list removal and death as competing events. RESULTS:Of 4962 pediatric kidney transplant candidates included, 89% had no prior transplant and 11% had received a prior organ transplant (kidney 87%, liver 5%, heart 5%). Prior transplant recipients were older at listing (median 15 vs. 12 years) and more likely to have PRA≥98% (22% vs. 0.3%) (both p < .001). There was no significant difference in the proportion of candidates from each group who were preemptively wait-listed. Unadjusted competing risk regression showed a lower risk of kidney transplant after wait-listing among candidates with prior organ transplant (HR 0.52, 95%CI 0.47-0.59, p < .001). This association remained significant after adjusting for candidate characteristics (HR 0.73, 95%CI 0.63-0.83, p < .001). Among deceased donor kidney recipients, median KDPI was similar between groups, but recipients with prior transplants were more likely to receive kidneys from donors with hypertension (4% vs. 1%, p = .01) and donors after cardiac death (11% vs. 4%, p < .001). CONCLUSIONS:Pediatric kidney transplant candidates with prior organ transplants have reduced access to transplant after wait-listing. Allocation system changes are needed to improve timely access to transplant for this vulnerable group.

Pediatric kidney transplant recipients are distinguished from adult recipients by the need for many decades of graft function, the potential effect of CKD on neurodevelopment, and the changing immune environment of a developing human. The entire life of an individual who receives a transplant as a child is colored by their status as a transplant recipient. Not only must these young recipients negotiate all of the usual challenges of emerging adulthood (transition from school to work, romantic relationships, achieving independence from parents), but they must learn to manage a life-threatening medical condition independently. Regardless of the age at transplantation, graft failure rates are higher during adolescence and young adulthood than at any other age. All pediatric transplant recipients must pass through this high-risk period. Factors contributing to the high graft failure rates in this period include poor adherence to treatment, potentially exacerbated by the transfer of care from pediatric- to adult-oriented care providers, and perhaps an increased potency of the immune response. We describe the characteristics of pediatric kidney transplant recipients, particularly those factors that may influence their care throughout their lives. We also discuss the risks associated with the transition from pediatric- to adult-oriented care and provide some suggestions to optimize transition to adult-oriented transplant care and long-term outcomes.