Article Sex and Glomerular Filtration Rate Trajectories in Children Ste´phanie Bonne´ric,1 Geeta Karadkhele,2 Ce´cile Couchoud,3 Rachel E. Patzer,2,4 Larry A. Greenbaum ,5 and Julien Hogan 1,2 Abstract Background and objectives Differences in CKD progression by sex have been hypothesized to explain disparities in 1Department of access to kidney transplantation in children. This study aims to identify distinct trajectories of eGFR decline and to Pediatric Nephrology, investigate the association of sex with eGFR decline. Robert Debre´ Hospital, Assistance Design, setting, participants, & measurements We used data from the CKD in Children study. Latent class mixed Publique-Hoˆpitaux de models were used to identify eGFR trajectories and patient characteristics were compared between trajectories. Paris (AP-HP), Paris, France; 2Department Progression was studied to two outcomes: ESKD (dialysis or transplantation) and a combined outcome of ESKD or of Surgery, Emory 50% eGFR decline from baseline, using multivariable parametric failure time models. Transplant Center, Emory School of Results Among 888 patients, 613 with nonglomerular and 275 with glomerular diseases, we observed four and two Medicine, Atlanta, Georgia; 3Renal distinct GFR trajectories, respectively. Among patients with nonglomerular diseases, there was a higher Epidemiology and proportion of males in the group with a low baseline GFR. This group had an increased risk of ESKD or 50% GFR Information Network decline, despite a similar absolute decline in GFR. Eight patients with nonglomerular diseases, mostly males with (REIN) Registry, French obstructive uropathies, had a more rapid absolute GFR decline. However, the association between male sex and Biomedicine Agency, rapid absolute GFR decline was NS after adjustment for age, baseline GFR, and proteinuria. Among patients with La Plaine-Saint Denis, France; 4Department glomerular diseases, a subgroup including mostly females with systemic immunologic diseases or crescentic GN of Epidemiology, had a rapid absolute GFR decline. Rollins School of Public Health, Emory Conclusions This study identifies different trajectories of CKD progression in children and found a faster University, Atlanta, fi Georgia; and progression of CKD in females in patients with glomerular diseases, but no signi cant sex difference in patients 5Department of with nonglomerular diseases. The differences in progression seem likely explained by sex differences in the Pediatric Nephrology, underlying primary kidney disease and in baseline GFR rather than by a direct effect of sex on progression. Children’s Healthcare CJASN 15: 320–329, 2020. doi: https://doi.org/10.2215/CJN.08420719 of Atlanta, Emory School of Medicine, Atlanta, Georgia Introduction used to identify patients at high risk of progression Correspondence: CKD affects 15% of the adult population in the United to ESKD and to better prepare these patients for Dr. Julien Hogan, States (1). The prevalence of CKD in children is much dialysis and transplantation. Department of lower. Several European studies estimated this prev- The prevalence and incidence of CKD and ESKD are Surgery, Emory Transplant Center, alence to be between 55 and 95 patients per million higher in men (13,14) and boys (15), compared with Emory University children (2–5), representing around 0.01% of children; women and girls. In adults, male sex is associated School of Medicine, however, surveillance studies in the general popula- with a faster CKD progression, even when comparing 5001 Woodruff tion suggest a much higher prevalence of approxi- Memorial Research patients with the same underlying disease (16). This Building, 101 mately 1% (6,7). CKD is associated with many observation was strengthened by animal studies Woodruff Circle, complications, includingpoorgrowth,metabolic suggesting that estrogens may slow progression (17) Atlanta, GA 30322. bone disease, and anemia (8). Moreover, progression and clinical studies supporting their protective effects Email: Julien.hogan@ emory.edu to ESKD compromises the life expectancy of these against kidney injury (18). fi children, with an age-speci c mortality rate for chil- Among children, females have been reported to dren receiving dialysis that is 30 times higher than in have delayed access to transplantation and lower access healthy children (9). Many studies aimed to identify to preemptive transplant. A recent study from the risk factors for CKD progression and focused on European Renal Association-European Dialysis and modifiable risk factors such as hypertension (10), Transplantation Association (ERA-EDTA) registry sug- proteinuria (10), acidosis (11), and elevated uric acid gested that a faster CKD progression in females than in levels (12), with the ultimate goal to design interven- males might partially explain these disparities (19). tions to slow CKD progression. Fewer studies report- Finally, many studies investigating CKD progression ed on nonmodifiable risk factors. However, both used ESKD, or a combination of rate of GFR decline modifiable and nonmodifiable risk factors can be and ESKD, as the primary outcome. However, these 320 Copyright © 2020 by the American Society of Nephrology www.cjasn.org Vol 15 March, 2020 CJASN 15: 320–329, March, 2020 Sex and GFR Trajectories in Children, Bonneric et al. 321 outcomes may not reflect the true progression rate of CKD provided in the Supplemental Methods and Supplemental because they are highly dependent on the baseline GFR and Tables 1 and 2. Patient characteristics are presented as differences in medical practice on when to initiate KRT (20). medians and interquartile ranges (IQR) for continuous In this study, we used recently developed statistical variables, and counts and percentages for categoric vari- methodologies to investigate the trajectories of GFR decline ables. Chi-squared test or Fisher exact test and ANOVA in children with CKD and whether differences in CKD were used to compare patient characteristics at baseline progression exist between males and females. between sex and eGFR trajectory groups for categoric variables and continuous variables, respectively, and mul- tivariable logistic regression models were used to assess Materials and Methods characteristics independently associated with each trajec- Study Population tory. To compare our results to previous reports on CKD The CKD in Children (CKiD) study design, methods, and progression (28), we studied progression to two commonly baseline characteristics of the cohort have been described used outcomes: ESKD (defined as maintenance dialysis or – previously (21,22). Patients 1 16 years of age with an eGFR transplantation) and a combined outcome of ESKD or 50% – 2 of 30 90 ml/min per 1.73 m were enrolled from 54 eGFR decline from baseline. Multivariable parametric participating centers in the United States, from January failure time models assuming a log-normal distribution 2005 to July 2009. In this longitudinal observational cohort of failure times were used to evaluate the association study, we used the data from the CKiD study publicly between eGFR trajectories and outcomes. This method was available through the National Institute of Diabetes and chosen for comparison purposes with a previously pub- Digestive and Kidney Diseases Central Repository. The lished study on the CKiD data and because it provides a study was approved by the ethics committee of our clinically relevant way to communicate the results in terms institution. of relative time rather than hazard ratios. We also per- formed a sensitivity analysis excluding patients with only Data Collected one eGFR assessment. Statistical analyses were performed Patient Data. Patient data included demographics; clin- using SAS 9.4 for Windows (SAS Institute) and R statistical ical characteristics, including primary CKD diagnosis and software version 3.6.1 (R Foundation for Statistical Com- type of disease (glomerular or nonglomerular); pubertal puting). The “lcmm” R package (29) was used to fitLCMM status, categorized using the Tanner classification based on models and a P value ,0.05 was considered statisti- testicular volume in males and breast development in cally significant. females; and comorbidities at the time of inclusion (di- abetes, hypertension, and history of febrile urinary tract infection [UTI]). We also collected laboratory values at Results baseline, including urine protein/creatinine (Up/c) ratio, A total of 3931 eGFR assessments were available from serum albumin, acidosis, uric acid, serum potassium, 891 patients. We excluded 13 potentially incorrect eGFR phosphate, and anemia defined as a hemoglobin less values that resulted in the exclusion of three patients. A than fifth percentile using age- and sex-specific norms (23). total of 888 patients were included: 549 males (62%) and Measurements of Glomerular Filtration Rate. The eGFR 339 females (38%). They underwent 3941 visits and 3917 was estimated using the modified Schwartz equation based eGFR assessments over a median follow-up of 4.1 (IQR, on centrally measured serum creatinine, cystatin C, and 2.3–7.5) years (Figure 1). The median baseline age was 11 BUN using the updated Schwartz formula (24). (IQR, 8–15) years, and 613 (69%) had a nonglomerular disease. Table 1 presents the demographic and clinical Statistical Analysis characteristics of our study population overall and by sex To identify subgroups of distinct eGFR trajectories over (Supplemental Table 3). Males tended to be younger, had a time, we used latent class linear mixed model