Clinical and metabolomic risk factors associated with rapid renal function decline in sickle cell disease

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.

Rapid decline in estimated glomerular filtration rate is common in adults with sickle cell disease and associated with increased mortality

“…As expected, the prevalence is higher in patients with HbSS/HbSb 0 thalassaemia than in those with HbSC/HbSb + thalassaemia, probably due to their more severe disease phenotype. These results are similar to recently published data of 193 subjects with 5-year follow-up data in whom rapid eGFR decline of ≥3 ml/min/ year over 5 years was observed in approximately 37% of patients (Xu et al, 2018). In addition, consistent with reports in patients with type 1 diabetes (Young et al, 2016), we find that rapid decline in kidney function is associated with CKD progression in patients with SCD.…”

“…Glomerular filtration rate progressively declines with age, with an annual rate of decline of kidney function of 1·27 ± 1·97 ml/min/1·73 m 2 reported in African‐American adults (Young et al , ). Multiple previous studies suggest that kidney function progressively declines in SCD (Gosmanova et al , ; Asnani et al , ; van Tuijn et al , ; Xu et al , ; Derebail et al , ). In a 25‐year prospective longitudinal demographic and clinical cohort study, 31 out of 725 patients with HbSS (4·2%) and 5 out of 209 patients with HbSC disease (2·4%) developed chronic renal failure (Powars et al , ).…”

“…adults (Young et al, 2016). Multiple previous studies suggest that kidney function progressively declines in SCD (Gosmanova et al, 2014;Asnani et al, 2016;van Tuijn et al, 2017;Xu et al, 2018;Derebail et al, 2019). In a 25-year prospective longitudinal demographic and clinical cohort study, 31 out of 725 patients with HbSS (4Á2%) and 5 out of 209 patients with HbSC disease (2Á4%) developed chronic renal failure (Powars et al, 1991).…”

“…Albuminuria is the most frequently assessed marker of kidney damage in clinical practice and occurs in up to 68% of adult patients with SCD (Ataga et al , ). Although the natural history of CKD in patients with SCD remains inadequately defined, multiple studies suggest that kidney function declines at a more rapid rate in SCD than in healthy individuals (Asnani et al , ; Xu et al , ; Derebail et al , ). We and others have reported on the prevalence of CKD as well as the rate of decline in estimated glomerular filtration rate (eGFR) in adults with SCD (Asnani et al , ; Xu et al , ; Derebail et al , ).…”

“…Although the natural history of CKD in patients with SCD remains inadequately defined, multiple studies suggest that kidney function declines at a more rapid rate in SCD than in healthy individuals (Asnani et al , ; Xu et al , ; Derebail et al , ). We and others have reported on the prevalence of CKD as well as the rate of decline in estimated glomerular filtration rate (eGFR) in adults with SCD (Asnani et al , ; Xu et al , ; Derebail et al , ). In our earlier publication, the baseline prevalence of CKD in this patient cohort was 19·9%, with an annual rate of decline in eGFR among individuals with HbSS and HbSβ 0 thalassaemia of 2·05 ml/min/1·73 m 2 per year (Derebail et al , ).…”