Hyperfiltration during early childhood precedes albuminuria in pediatric sickle cell nephropathy

Abstract

Background In patients with diabetes mellitus, hyperfiltration precedes the development of albuminuria. Pediatric sickle cell anemia (SCA) patients have a high prevalence of hyperfiltration and albuminuria during early childhood and adolescence. We tested the hypothesis that hyperfiltration precedes the development of albuminuria in a longitudinal pediatric SCA cohort. Methods We identified 91 participants with HbSS or SB0 thalassemia 5‐21 years of age enrolled in a longitudinal sickle cell nephropathy cohort study who had a cystatin C measured during early childhood (4‐10 years of age). Early hyperfiltration was defined as a mean eGFR >180 mL/min/1.73m2 using cystatin C obtained from 4 to 10 years of age. Persistent albuminuria was defined as an albumin to creatinine ratio > 30 mg/g on two of three untimed urine specimens. Time to event analysis estimated survival curves for participants with and without hyperfiltration using Kaplan‐Meier curves and used logrank test for categorical variables to assess the association with time to development of the first episode persistent albuminuria. Results Persistent albuminuria occurred more often and at an earlier age in participants with early hyperfiltration compared to those without early hyperfiltration (log‐rank, P = .004). Participants who developed albuminuria have a significant increase in their eGFR during childhood (P = .003) as compared to participants who have not yet progressed to albuminuria (P = .26). For every 1 g/dL increase in hemoglobin, the hazard ratio for developing persistent proteinuria decreased by 0.56 (95% CI: 0.3, 1.06, P = .07). Conclusion Hyperfiltration precedes the development of persistent proteinuria in pediatric SCA patients. Intervention strategies should target lowering eGFR during early childhood.

Progression of albuminuria in patients with sickle cell anemia: a multicenter, longitudinal study

“…Only persistent, and not transient, albuminuria has been linked to kidney diseases in children and adults without SCA. [19][20][21] Previous longitudinal studies of sickle nephropathy showed that albuminuria measurements are variable 22,23,25 ; almost one-third of patients with albuminuria had intermittent albuminuria over years in 1 study, whereas only 9% of patients developed PA in another study. 37,38 In our study, albuminuria was common overall; however, PA, and not merely the presence of albuminuria, was associated with a decline in eGFR and development of CKD in adults.…”

“…Recently, Lebensburger et al 25 showed that in children with SCA, PA was associated with hyperfiltration. Although we did not find an association between hyperfiltration and PA, likely because of the broad age range in our study, we found that PA may be a marker of CKD in SCA, because it correlates with a rapid decline in eGFR.…”

“…Microalbuminuria was defined by ACR 30 to 300 mg/g and macroalbuminuria as .300 mg/g. Participants with albuminuria for at least 2 annual measurements (2 years) were considered to have PA. 25 Two methods were used to calculate estimated GFR (eGFR): serum creatinine based (eGFR-Cr), using Schwartz formula in children and CKD Epidemiology Collaboration (CKD-EPI) in adults, and cystatin C method (eGFR-CysC), using Larsson's formula per manufacturer recommendations. [26][27][28] Hyperfiltration was defined by eGFR-CysC $140 mL/min/m 2 .…”

“…The introduction of hydroxyurea or transfusions was not associated with a change in ACR in this small sample (P 5 .14). AST, U/L 51 (25) ALT, U/L 28 (17) ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase; WBC, white blood cell.…”

A Pilot Study Comparing Uric Acid and Biomarkers of Renal Injury and Inflammation in Pediatric Sickle Cell Disease at Vaso-Occlusive Crisis and Steady State

“…Nearly all SCA patients are affected by sickle cell nephropathy (SCN), and 16-18% of mortality is attributed to the manifestations of SCN [1][2][3]. SCN is detectable early in the majority of infants with SCA as glomerular hyperfiltration, an important early mediator of chronic glomerular damage [4][5][6]. This is followed by an increasing prevalence (26-46%) of abnormal albuminuria in the teenage and young adult years [2,7].…”