Rulan Savita Parekh

Background: Health administrative datasets have the potential to provide valuable insights into pediatric solid organ transplantation; however, validation is necessary to ensure their accuracy. This study aimed to assess the validity of administrative data by comparing it to direct transplant records from a major pediatric transplant center in Ontario, Canada (1991–2011). Methods: Using linked administrative healthcare databases, we conducted a retrospective analysis to evaluate the validity of physician billing claims and hospital diagnostic and procedural codes in identifying pediatric solid organ transplants. Sensitivity and positive predictive value (PPV) were calculated for various algorithms. Results: During the study period, a total of 347 kidney, 250 liver, 200 heart, and 28 lung transplants were performed. The best algorithm for identifying these transplants utilized hospital procedural codes from the Canadian Institute for Health Information Discharge Abstract Database. Compared to transplant center records, these codes demonstrated a sensitivity of 91% (95% CI: 89–93) and PPV of 93% (95% CI: 91–95) when including all organ types, and performed similarly well when evaluating individual organ types. Conclusion: This study is the first to validate administrative data for identifying pediatric solid organ transplant recipients, demonstrating the reliability of procedural codes for population‐level health research in this domain.

More than 50% of patients with kidney failure undergoing maintenance hemodialysis die within 5 years, a fate unexplained by traditional risk factors. To identify biological risk factors, we analyze 6287 circulating proteins and mortality in 893 participants undergoing hemodialysis in the Chronic Renal Insufficiency Cohort (CRIC) and Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) studies. Proteins are measured shortly after (incident period) and one year after (prevalent period) dialysis initiation. In CRIC prevalent period, Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1), R-spondin 4, tetranectin and 24 other proteins attain Bonferroni significance (p < 7 × 10^-6). At false discovery rate<0.05, 184 proteins are significant in CRIC; 123/184 remain significant after adjustment for covariates including those linked to inflammation. Pathways related to insulin-like growth factor are prominent. In the pooled CRIC + PACE cohort, prevalent time period, AUC(95%CI) for a 3-protein model of 5-year mortality is 0.826 (0.742, 0.896), compared to 0.629 (0.528, 0.722) for a Cohort Clinical model (p < 0.001). Adding the 3 proteins (SVEP1, R-spondin 4 and tetranectin) to the Cohort Clinical model significantly improves the AUC (p < 0.001). These biomarkers should be validated in future studies and their roles as potential disease mediators elucidated.

Key Points: Serum glycerol-3-phosphate (G3P) levels were significantly associated with higher fibroblast growth factor 23 levels in ESKD. Pathway and mediation analyses identified the pentose phosphate pathway as the top mediator of the relationship between serum G3P and fibroblast growth factor 23. The role of G3P in ESKD provides new insights into potential therapeutic targets for CKD-mineral and bone disorder. Background: Fibroblast growth factor 23 (FGF23) is a key regulator of mineral metabolism that is independently associated with mortality in patients with ESKD. Glycerol-3-phosphate (G3P), a byproduct of glycolysis that can be derived from injured kidneys, stimulates FGF23 production. We aimed to determine if serum G3P is associated with FGF23 levels in patients with ESKD and identify potential molecular pathways that mediate their relationship. Methods: We conducted a cross-sectional study of 99 nondiabetic patients with ESKD on hemodialysis. We used linear regression to examine the association between G3P terciles and log-transformed C-terminal FGF23 levels, adjusting for demographics, coronary artery disease, serum calcium, phosphorus, and parathyroid hormone. Mann–Whitney U tests compared 247 serum metabolite levels between the first and third FGF23 terciles; significant metabolites ( P < 0.01) were selected for pathway enrichment analyses. Top pathway scores were used in mediation analyses. Results: The median age of participants was 54 years (interquartile range [IQR], 44–63), 38% were women, 71% self-identified as Black, and 27% had coronary artery disease. The median FGF23 level was 777 (interquartile range, 222–1310) RU/ml. In adjusted analyses, compared with participants with the lowest G3P tercile, those with the highest G3P tercile had a 95% higher FGF23 level (95% Confidence Interval, 6% to 260%; P = 0.04). Of the 27 metabolites significantly associated with FGF23 levels, pathway enrichment analysis identified the pentose phosphate pathway as the top hit (impact score=0.33, false discovery rate-adjusted P value = 0.01). The pentose phosphate pathway mediated the relationship between G3P and FGF23, resulting in a 62% change in the β coefficient. Conclusions: In nondiabetic patients with ESKD on hemodialysis, serum G3P positively correlated with serum C-terminal FGF23, and this relationship was mediated by the pentose phosphate pathway. Exploring the pentose phosphate pathway could yield critical mechanistic insights into the regulation of FGF23, enhancing our understanding of its broader biologic functions.

Key Points: Three quarters of children with steroid-resistant nephrotic syndrome respond to other immunosuppression and have good kidney outcomes. Children classified as frequently relapsing by International Pediatric Nephrology Association versus Kidney Disease Improving Global Outcomes criteria have similar relapse rates and risk of CKD. These findings support defining treatment resistance by response to any immunosuppression and implementing the International Pediatric Nephrology Association criteria for frequent relapses. Background: In childhood nephrotic syndrome, definitions of immunosuppression response, frequently relapsing nephrotic syndrome (FRNS), and long-term remission are conflicting and based on limited evidence. Our goal was to define treatment response, FRNS, and long-term remission on the basis of associated disease outcomes. Methods: We included children (6 months–18 years) diagnosed with nephrotic syndrome between 1993 and 2023 in combined Canadian cohorts. We evaluated different definitions of ( 1 ) immunosuppressive treatment response, ( 2 ) FRNS, including Kidney Disease Improving Global Outcomes (KDIGO) 2021 and International Pediatric Nephrology Association (IPNA) 2023 criteria, and ( 3 ) long-term remission. Outcomes were time to CKD, relapse count throughout follow-up, and time to relapse, analyzed by Cox proportional hazards and negative binomial regression. Results: We included 1114 children with nephrotic syndrome (median age at diagnosis, 3.8 years; 63% male; median follow-up, 4.7 years). Among them, 1054 (95%) were steroid sensitive, 60 (5%) were steroid resistant (steroid-resistant nephrotic syndrome [SRNS]), and 73% with SRNS achieved complete remission with steroid-sparing immunosuppression. No child with treatment-responsive SRNS developed CKD. Within 1 year of diagnosis, 281 steroid-sensitive children (27%) were classified with FRNS by KDIGO and 383 (36%) by IPNA criteria. Children with FRNS by IPNA criteria (versus KDIGO) had a similar number of relapses (adjusted rate ratio, 0.95; 95% confidence interval, 0.81 to 1.12) and CKD risk (2% each) but less often received steroid-sparing immunosuppression (hazard ratio, 0.42; 95% confidence interval, 0.32 to 0.56). Ninety-eight percent of relapses occur within 3 years of the initial diagnosis or the last relapse event. Conclusions: Children with SRNS who achieve remission have a similar CKD risk to steroid-sensitive children. Children with FRNS by IPNA 2023 and KDIGO 2021 criteria experience similar rates of relapse and CKD. This supports defining treatment resistance by response to any immunosuppressive medication, implementation of the IPNA FRNS criteria, and use of 3-year relapse-free survival as a surrogate for long-term remission.

Background Children with nephrotic syndrome are at risk of obesity and growth impairment from repeated steroid treatment. However, incidence and risk factors for obesity and short stature remain uncertain, which is a barrier to preventative care. Our aim was to determine risk, timing, and predictors of obesity and short stature among children with nephrotic syndrome. Methods We evaluated obesity and longitudinal growth among children (1–18 years) enrolled in Insight into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics. We included children with nephrotic syndrome diagnosed between 1996–2019 from the Greater Toronto Area, Canada, excluding congenital or secondary nephrotic syndrome. Primary outcomes were obesity (body mass index Z-score ≥ + 2) and short stature (height Z-score ≤ -2). We evaluated prevalence of obesity and short stature at enrolment (< 1-year from diagnosis) and incidence during follow-up. Cox proportional hazards models determined the association between nephrotic syndrome classification and new-onset obesity and short stature. Results We included 531 children with nephrotic syndrome (30% frequently relapsing by 1-year). At enrolment, obesity prevalence was 23.5%, 51.8% were overweight, and 4.9% had short stature. Cumulative incidence of new-onset obesity and short stature over median 4.1-year follow-up was 17.7% and 3.3% respectively. Children with frequently relapsing or steroid dependent nephrotic syndrome within 1-year of diagnosis were at increased risk of new-onset short stature (unadjusted hazard ratio 3.99, 95%CI 1.26–12.62) but not obesity (adjusted hazard ratio 1.56, 95%CI 0.95–2.56). Children with ≥ 7 and ≥ 15 total relapses were more likely to develop obesity and short stature, respectively. Conclusions Obesity is common among children with nephrotic syndrome early after diagnosis. Although short stature was uncommon overall, children with frequently relapsing or steroid dependent disease are at increased risk of developing short stature. Effective relapse prevention may reduce steroid toxicity and the risk of developing obesity or short stature. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information