Abstract

Sickle cell disease (SCD) nephropathy and lower estimated glomerular filtration rate (eGFR) are risk factors for early mortality. Furthermore, rate of eGFR decline predicts progression to end-stage renal disease in many clinical settings. However, factors predicting renal function decline in SCD are poorly documented. Using clinical, laboratory, genetic, and metabolomic data, we evaluated predictors of renal function decline in a longitudinal cohort of 288 adults (mean age 33.0 years). In 193 subjects with 5-year follow-up data, mean rate of eGFR decline was 2.35 mL/min/1.73 m /year, nearly twice that of African American adults overall. Hyperfiltration was prevalent at baseline (61.1%), and 36.8% of subjects experienced rapid eGFR decline (≥3 mL/min/1.73 m /year). Severe Hb genotype; proteinuria; higher platelet and reticulocyte counts, and systolic BP; and lower Hb level and BMI were associated with rapid decline. A risk scoring system was created using these 7 variables and was highly predictive of rapid eGFR decline, with odds of rapid decline increasing 1.635-fold for every point increment (P < 0.0001). Rapid eGFR decline was also associated with higher organ system severity score and peak creatinine. Additionally, two metabolites (asymmetric dimethylarginine and quinolinic acid) were associated with rapid decline. Further investigation into longitudinal SCD nephropathy (SCDN) trajectory, early markers of SCDN, and tools for risk stratification should inform interventional studies targeted to slowing GFR decline and improving SCD outcomes.

MeSH

Hematology, Kidney Failure, Chronic, Anemia, Sickle Cell, Risk Factors, Cells, Metabolomics

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• Curative vs targeted therapy for SCD: does it make more sense to address the root cause than target downstream events? Blood Adv, 2021
• Longitudinal study of glomerular hyperfiltration in adults with sickle cell anemia: a multicenter pooled analysis. Blood Adv, 2022
• The nephropathy of sickle cell trait and sickle cell disease. Nat Rev Nephrol, 2022
• Using machine learning to predict rapid decline of kidney function in sickle cell anemia. EJHaem, 2021
• Neutrophil gelatinase-associated lipocalin is elevated in children with acute kidney injury and sickle cell anemia, and predicts mortality. Kidney Int, 2022
• Sex differences in the trajectory of glomerular filtration rate in pediatric and murine sickle cell anemia. Blood Adv, 2020
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• Nontargeted Plasma Proteomic Analysis of Renal Disease and Pulmonary Hypertension in Patients with Sickle Cell Disease. J Proteome Res, 2024
• Rapid decline in estimated glomerular filtration rate is common in adults with sickle cell disease and associated with increased mortality. Br J Haematol, 2020
• All-Cause Mortality and Incidence of Major Adverse Cardiac Events in Sickle Cell Nephropathy: A Comparative Study. Cureus, 2021
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• Potential causal role of l-glutamine in sickle cell disease painful crises: A Mendelian randomization analysis. Blood Cells Mol Dis, 2021