Natural Course of Albuminuria in Pediatric and Murine Sickle Cell Disease
Authors: Ho Michael , Baker Kayla , Lebensburger Jeffrey , Kasztan Malgorzata 
Published: May 2023

Sickle cell disease (SCD), an inherited blood disorder, is associated with prevalent chronic kidney disease (CKD), evidenced by persistent albuminuria. It is critical to understand the natural history of albuminuria and albumin to creatinine (ACR) ratio variance to optimally identify, diagnose and treat SCD pediatrics prior to CKD. Thus, we investigated natural course of albuminuria in pediatrics and murine SCD, and identify ACR level predictive of persistent albuminuria.Basic science study: As hyperfiltration occurs at 12 weeks of age in male and 20 weeks of age in female humanized sickle cell (HbSS) mice, we performed metabolic cage studies in 1-week intervals for 4 weeks before (4 weeks old mice, n=21) and after hyperfiltration phase (males: 16 weeks (n=10), females: 20 weeks old (n=8)), and measured albuminuria using GenWay Biotech ELISA kit. Clinical study: We performed a retrospective study of the UAB Pediatric Sickle Cell Kidney Cohort. We identified all participants with HbSS and HbSB0 thalassemia ≥ 5 years of age with ACR measurements performed at a steady-state outpatient clinic visit. We identified the date and age of participants with at least 1 ACR level ≥100mg/g to compare outcomes for albuminuria and to determine the natural course of ACR after an ACR measurement >100mg/g.We observed a significant difference in the trajectory of albuminuria over time prior and post hyperfiltration (p=0.02) in HbSS mice. Young HbSS mice presented with downward trend over time, with average values of albuminuria 47.6±27.2 (week 1), 32.6±20.3 (week 2), 32.0±24.3 (week 3), 31.3±16.1mg/24h (week 4), respectively. After hyperfiltration, older HbSS mice had an upward trend in albuminuria over time (week 1: 49.7±23.6, week 2: 74.5±66.9, week 3: 55.9±82.2, week 4: 73.0±86.4 mg/24h, respectively). Finally, prior to hyperfiltration the average albuminuria over a time of 4 weeks was 35.9±7.8 mg/24h (±21.7%), while following hyperfiltration it was 63.3±12.4 mg/24h (±19.6%). These findings mirror human data in which pediatric patients present with similar degree of natural variability in ACR. We identified 62 patients (17%) with persistent albuminuria, 46 (13%) with intermittent albuminuria, and 247 (70%) with not yet having albuminuria. Out of 107 patients with at least 1 abnormal ACR, 45 had 1 measurement >100mg/g, and 43 of these participants were categorized with persistent albuminuria (50x higher odds ratio than patients with ACR<100mg/g). Assessment of natural history of albuminuria after an initial ACR >100mg/g showed significant variability. Regarding 1-year clinical trial design, the change in ACR showed a decline from 175 to 131 mg/g, accounting for 23% decline in albuminuria without any intervention.The natural course of albuminuria is an important characteristic of renal phenotype in SCD and should be considered while designing and assessing effectiveness of novel therapeutic approaches in preclinical and clinical studies targeting SCD nephropathy. Funded by NIH R25 DK 112731 and NHLBI–R00HL144817 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.