C3 Glomerulopathy Recurs Early after Kidney Transplantation in Serial Biopsies Performed within the First Two Years Post-Transplantation.

BACKGROUND: C3 glomerulopathy (C3G), which encompasses C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), results from dysregulation of the alternative complement pathway. Data on disease recurrence after kidney transplantation is 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 immune profiling panel was used for transcriptomic analysis. Disease recurrence was the primary outcome. RESULTS: During a median (IQR) follow-up period of 37 (18, 56) months, C3G recurrence occurred in 16 (89%) of patients (11 with C3GN and five with DDD), at a median (IQR) of 33 (13, 141) days post-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 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: The majority of 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, sub-clinical recurrence of C3GN and DDD, which showed significant overlapping features.

Implementation and Feasibility of Clinical Genome Sequencing Embedded Into the Outpatient Nephrology Care for Patients With Proteinuric Kidney Disease.

Introduction: The diagnosis and management of proteinuric kidney diseases such as focal segmental glomerulosclerosis (FSGS) are challenging. Genetics holds the promise to improve clinical decision making for these diseases; however, it is often performed too late to enable timely clinical action and it is not implemented within routine outpatient nephrology visits. Methods: We sought to test the implementation and feasibility of clinical rapid genome sequencing (GS) in guiding decision making in patients with proteinuric kidney disease in real-time and embedded in the outpatient nephrology setting. Results: We enrolled 10 children or young adults with biopsy-proven FSGS (9 cases) or minimal change disease (1 case). The mean age at enrollment was 16.2 years (range 2-30). The workflow did not require referral to external genetics clinics but was conducted entirely during the nephrology standard-of-care appointments. The total turn-around-time from enrollment to return-of-results and clinical decision averaged 21.8 days (12.4 for GS), which is well within a time frame that allows clinically relevant treatment decisions. A monogenic or APOL1-related form of kidney disease was diagnosed in 5 of 10 patients. The genetic findings resulted in a rectified diagnosis in 6 patients. Both positive and negative GS findings determined a change in pharmacological treatment. In 3 patients, the results were instrumental for transplant evaluation, donor selection, and the immunosuppressive treatment. All patients and families received genetic counseling. Conclusion: Clinical GS is feasible and can be implemented in real-time in the outpatient care to help guiding clinical management. Additional studies are needed to confirm the cost-effectiveness and broader utility of clinical GS across the phenotypic and demographic spectrum of kidney diseases.

Access to kidney transplantation among pediatric candidates with prior solid organ transplants in the United States.

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.

Long-Term Care of the Pediatric Kidney Transplant Recipient.

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 the transition to adult-oriented transplant care and long-term outcomes.

Prevalence of Cardiovascular Disease Risk Factors in Childhood Glomerular Diseases.

Background Cardiovascular disease is a major cause of morbidity and mortality in children with chronic kidney disease. We sought to determine the prevalence of cardiovascular risk factors in children with glomerular disease and to describe current practice patterns regarding risk factor identification and management. Methods and Results Seven-hundred sixty-one children aged 0 to 17 years with any of 4 biopsy-confirmed primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy/vasculitis) were enrolled at a median of 16 months from glomerular disease diagnosis in the multicenter prospective Cure Glomerulonephropathy Network study. Prevalence of traditional (hypertension, hypercholesterolemia, and obesity) and novel (proteinuria, prematurity, and passive smoke exposure) cardiovascular risk factors were determined at enrollment and compared across glomerular disease subtypes. Frequency of screening for dyslipidemia and prescribing of lipid-lowering or antihypertensive medications were compared across glomerular disease subtype, steroid exposure, and remission status groups. Compared with the general population, all traditional risk factors were more frequent: among those screened, 21% had hypertension, 51% were overweight or obese, and 71% had dyslipidemia. Children who were not in remission at enrollment were more likely to have hypertension and hypercholesterolemia. Fourteen percent of hypertensive children were not receiving antihypertensives. Only 49% underwent screening for dyslipidemia and only 9% of those with confirmed dyslipidemia received lipid-lowering medications. Conclusions Children with primary glomerular diseases exhibit a high frequency of modifiable cardiovascular risk factors, particularly untreated dyslipidemia. Lipid panels should be routinely measured to better define the burden of dyslipidemia in this population. Current approaches to screening for and treating cardiovascular risk factors are not uniform, highlighting a need for evidence-based, disease-specific guidelines.

The effect of transfer to adult transplant care on kidney function and immunosuppressant drug level variability in pediatric kidney transplant recipients.

Adolescent age at time of transplant has been recognized as a risk factor for renal allograft loss. Increased risk for graft failure may persist from adolescence to young adulthood. Transfer of care is hypothesized as a risk factor for non-adherence and graft loss. We explored whether kidney allograft function declined at an accelerated rate after transfer of care to adult transplant centers and whether coefficient of variation of tacrolimus (CV TAC) trough levels predicted allograft loss. Single-center, retrospective chart review was performed for pediatric kidney transplant recipients who received transplants between 1999 and 2011. Change in eGFR pre- and post-transfer was performed via a linear mixed-effects model. CV TAC was calculated in transplant recipients with TAC data pre- and post-transfer. t test was performed to determine the difference between means of CV TAC in subjects with and without allograft loss following transfer of care. Of the 138 subjects who transferred to adult care, 47 subjects with data pre- and post-transfer demonstrated a decrease in the rate of eGFR decline post-transfer from 8.0 mL/min/1.73 m2 per year to 2.1 mL/min/1.73 m2 per year, an ~80% decrease in eGFR decline post-transfer (P = 0.01). Twenty-four subjects had CV TAC data pre- and post-transfer of care. Pretransfer CV TAC for subjects with allograft loss post-transfer was significantly higher than in subjects without allograft loss (49% vs 26%, P < 0.05). Transfer of care was not independently associated with acceleration in eGFR decline. CV TAC may aid in identifying patients at risk for allograft loss post-transfer.

Outcomes for potential kidney transplant recipients offered public health service increased risk kidneys: A single-center experience.

BACKGROUND: Discard rate of Public Health Service Increased Risk (PHS-IR) organs is high despite the absence of worse kidney transplant outcomes. METHODS: We conducted a retrospective, single-center study of PHS-IR kidney offers made to kidney transplant-only potential recipients from 6/2004 to 5/2015. Overall mortality and transplant outcomes between potential recipients were stratified by response to PHS-IR kidney offers. Cox regression and Kaplan-Meier analyses of mortality and allograft failure were performed. RESULTS: A total of 2423 potential recipients were offered a PHS-IR kidney, with 1502 transplanted, with or without a PHS-IR kidney. Predictors of accepting a PHS-IR kidney included higher Estimated Post Transplant Survival (EPTS) score, prior kidney transplant, and lower educational achievement on multivariable analysis (P = 0.025, P = 0.004, P = 0.023). A positive response to a PHS-IR kidney was associated with lower risk of mortality (3.63% vs 11.6%; aHR 0.467, P = 0.0008). PHS-IR kidney recipients had decreased risk of allograft loss compared to non-PHS-IR recipients (P = 0.007), though mortality outcomes were not significantly different based on PHS-IR status (P = 0.38). No transmission of HIV, HBV, or HCV occurred from PHS-IR kidney donors in this cohort. CONCLUSIONS: Efforts must be made to increase awareness of the beneficial outcomes of PHS-IR organs to maximize appropriate donor allocation.

Application and interpretation of histocompatibility data in pediatric kidney transplantation.

PURPOSE OF REVIEW: Advances in technology to assess immunologic risk in solid organ transplant offer an opportunity to optimize the approach to pediatric deceased donor kidney transplant in the setting of a new allocation system in the United States. RECENT FINDINGS: Degree of human leukocyte antigen (HLA) mismatch, class II HLA mismatch, unacceptable antigens and donor-specific antibody (DSA) detected by solid-phase assays, and epitope matching pretransplant affect pediatric kidney transplant outcomes. Detection of de novo DSAs (dnDSAs) posttransplant has been associated with increased risk of acute rejection and worse allograft function. Development of dnDSA occurs in recipients with greater epitope mismatching. SUMMARY: Improved long-term outcomes may be anticipated in pediatric kidney transplant recipients by incorporating extended HLA mismatch information and updating the clinical approach to donor kidney matching using available technology to identify clinically relevant immunologic risk.

Monitoring nonadherence and acute rejection with variation in blood immunosuppressant levels in pediatric renal transplantation.

BACKGROUND: Acute rejection associated with medication nonadherence is a major cause of allograft loss in pediatric kidney transplant patients. There is currently no reliable method to detect medication nonadherence and prevent allograft rejection. METHODS: In 46 pediatric patients who underwent renal transplantation between 2002 and 2003, the variation of serum drug levels was studied as a potential objective tool to monitor medication nonadherence. Tacrolimus (TAC) and mycophenolic acid (MPA) trough levels were measured from 1 to 12 months posttransplant, and standard deviation (SD) and percent coefficient of variation (CV%) were calculated. Because SD increased as mean trough levels rose, CV% (CV%=SD/mean multiplied by 100%) was used to eliminate this confounding effect. RESULTS: Ten of 46 patients had biopsy-proven rejection. The median TAC CV% was 53.4% in patients with biopsy-proven rejection, which was significantly higher than 30% in those without rejection (P=0.005). Median MPA CV% was 51.9% in patients without rejection and 45.1% in patients with rejection (P=NS). High TAC CV% correlated with increased risk for rejection, whereas MPA CV% did not. CONCLUSION: The TAC CV% seems to be a useful and superior marker, compared with SD alone, for assessing medication nonadherence and the possibility of allograft rejection in pediatric renal transplantation.

Closing the gap between insecticide treated net ownership and use for the prevention of malaria.

BACKGROUND: Malaria is the leading cause of morbidity and mortality in children younger than 5 years old and pregnant women in sub-Saharan Africa. Insecticide-treated nets (ITNs) reduce clinical malaria by more than 50% and all cause mortality in young children by 15% to 30%. However, use of these nets is poor across sub-Saharan Africa, limiting the potential impact of this effective tool in the fight against malaria. OBJECTIVE: We sought to improve the use of ITNs using a community-created and -implemented approach, and measure the change in ITN use over the year after implementation. METHODS: Using a community-based participatory research approach, we created and implemented an intervention to improve ITN use in a rural village. Our intervention involved providing hands-on instructions and assistance in hanging of nets, in-home small group education, and monthly follow-up by trained community members. ITN use was measured for all individuals in a subset of the community (61 households, 759 individuals) at baseline and at 6 months and 1 year after distribution. RESULTS: Rates of individual usage increased significantly from 29% at baseline to 88.7% (p < .001) at 6 months and to 96.6% (p < .001) at 12 months. For children under age 5, usage rates increased from 46% at baseline to 95.7% (p < .001) at 6 months and 95.4% (p < .001) at 12 months. CONCLUSION: Our study demonstrates that rapidly achieving and sustaining almost universal ITN usage rates is possible using a community-based approach. Closing the gap between ITN ownership and use will help communities to realize the full potential of ITNs in the prevention of malaria.