The Natural History of Glomerular Hyperfiltration in Sickle Cell Disease

Introduction: Glomerular hyperfiltration, an early manifestation of kidney disease in individuals with sickle cell disease (SCD), refers to a supraphysiologic elevation in the glomerular filtration rate (GFR) and is evident in early childhood. The contribution of hyperfiltration in childhood to the development of chronic kidney disease in early adulthood is not well defined. Our goal was to define the prevalence of glomerular hyperfiltration in sickle cell disease (SCD), assess its association with development of persistent albuminuria (PA) and evaluate the change in estimated glomerular filtration rate (eGFR) over time.

Methods: Individuals with SCD enrolled in the Sickle Cell Clinical Research and Intervention Program (SCCRIP), a longitudinal, lifetime cohort study of individuals with sickle cell disease that tracks organ function throughout the lifespan (Clinicaltrials.gov #NCT02098863) were examined. Those with data from birth through adulthood were evaluated. Hyperfiltration was defined by an eGFR >135 ml/min/1.73 m² using the bedside Schwartz 2009 equation (<18 years) and CKD-EPI-2021 equation (≥18 years). Hyperfiltration was stratified based on disease genotype (HbSS/HbSβ⁰thalassemia and HbSC/HbSβ⁺ thalassemia) and age groups (1-5, 6-10, 11-17, 18-20, 21-30 and 31-40 years). The maximum eGFR values were used for each individual, if there were multiple values. Chi-square and Fisher exact test was used to compare hyperfiltration outcomes between the strata. We assessed the effect of sex, genotype, hemoglobin, treatment duration with hydroxyurea, hyperfiltration, and APOL1 G1/G2 risk-variants on the development of PA utilizing a Cox regression model. PA was assessed after age 10 and was defined as an albumin-creatinine ratio (ACR) ≥30mg/g in ≥2 out of 3 consecutive time points. Hyperfiltration for PA analysis was defined as ever having an eGFR >180 ml/min/1.73m² before the event time. To assess the change in eGFR over time in individuals with HbSS/HbSβ⁰, a mixed model approach incorporating linear, quadratic and cubic polynomials for age (age terms), was employed. The models were adjusted for baseline age, treatment status, and sex. We augmented the model by adding hyperfiltration status at first eGFR and then explored this impact on the trajectory of eGFR change over time by incorporating interaction terms of hyperfiltration status with age terms. P<0.05 was considered significant.

Results: We examined 350 patients (HbSS/HbSβ⁰ - 237; HbSC/HbSβ⁺ - 113). There were no differences in the mean ages (23.4 3.4 years vs. 23.73.5 years, p=0.52) or sex (female - 117 [49.4%] vs. 61 [53.9%], p=0.42) by genotype. Participants with HbSS/HbSβ⁰ had a higher prevalence of hyperfiltration in all age groups up to 31-40 years when compared to HbSC/HbSβ⁺ (57.3% vs. 10.2%, p<0.01): 1-5 years (68.7% vs. 13.5%), 6-10 years (66.9% vs. 17.9%), 11-17 years (62.9% vs. 14%), 18-20 years (62.4% vs. 10.8%), 21-30 years (54.0% vs. 5.1%). In univariate analysis, the hazard ratio (HR, with standard error [SE]) for PA was higher in individuals with HbSS/HbSβ⁰ (HR: 5.3 0.371, p<0.001), hyperfiltration (HR: 2.8 0.238, p<0.001), APOL1 status (HR: 3.1 0.4, p=0.0023), and lower hemoglobin at age of PA confirmation (HR 1.24 SE 0.053, p<0.001). In multivariable analysis, PA was associated with hyperfiltration (HR 2.55 p=0.001) following adjustment for sex, genotype, and hydroxyurea treatment duration, but not after adjusting for APOL1 status. Evaluating change over time, eGFR increased and peaked by age 10 years, with subsequent decline (p<0.0001 for all age terms). Adding hyperfiltration status at first eGFR, a significant increase in eGFR in hyperfiltration group was found (estimate=12.9 , p<0.0001). The hyperfiltration group showed a greater initial eGFR increase followed by a greater eGFR decline (p<0.01, except cubic age term).

Conclusion: Hyperfiltration is highly prevalent in SCD and is associated with development of PA, although this does not appear to be independent of APOL1 status. In patients with HbSS/HbSβ⁰, there is a significant association between eGFR and age, with hyperfiltration status impacting the trajectory of eGFR. More studies are required to determine whether hyperfiltration is independently associated with PA.

Rai:Global Blood Therapeutics: Consultancy. Lebensburger:Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Ataga:Novartis: Honoraria; GSK: Consultancy, Honoraria; Hillhurst Biopharmaceuticals: Consultancy, Honoraria; Forma Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Research Funding; Sanofi: Consultancy; Vertex: Membership on an entity's Board of Directors or advisory committees; Vitalant: Membership on an entity's Board of Directors or advisory committees.