The nephropathy of sickle cell trait and sickle cell disease

Abstract

Sickle cell syndromes, including sickle cell disease (SCD) and sickle cell trait, are associated with multiple kidney abnormalities. Young patients with SCD have elevated effective renal plasma flow and glomerular filtration rates, which decrease to normal ranges in young adulthood and subnormal levels with advancing age. The pathophysiology of SCD-related nephropathy is multifactorial - oxidative stress, hyperfiltration and glomerular hypertension are all contributing factors. Albuminuria, which is an early clinical manifestation of glomerular damage, is common in individuals with SCD. Kidney function declines more rapidly in individuals with SCD than in those with sickle cell trait or in healthy individuals. Multiple genetic modifiers, including APOL1, HMOX1, HBA1 and HBA2 variants are also implicated in the development and progression of SCD-related nephropathy. Chronic kidney disease and rapid decline in estimated glomerular filtration rate are associated with increased mortality in adults with SCD. Renin-angiotensin-aldosterone system inhibitors are the standard of care treatment for albuminuria in SCD, despite a lack of controlled studies demonstrating their long-term efficacy. Multiple studies of novel therapeutic agents are ongoing, and patients with SCD and kidney failure should be evaluated for kidney transplantation. Given the high prevalence and severe consequences of kidney disease, additional studies are needed to elucidate the pathophysiology, natural history and treatment of SCD-related nephropathy.

Figure 1:. Proposed mechanisms and biomarkers of sickle cell nephropathy.

Sickle cell disease is complicated by multiple functional and structural abnormalities that occur along the nephron — clinical complications include hyposthenuria, haematuria, albuminuria and progressive estimated glomerular filtration rate (eGFR) decline. Medullary ischaemia drives localized prostaglandin release and results in marked vasodilation, increasing effective renal blood flow and GFR. In the glomerulus, the pathogenesis of albuminuria seems to be multifactorial — ischaemia-reperfusion injury, haemolysis, oxidative stress, hyperfiltration and glomerular hypertension have all been implicated. ANP, atrial natriuretic peptide; CCL2, CC-chemokine ligand 2; ET1: endothelin 1; KIM1: kidney injury molecule 1; NAG, N-acetyl-β-d-glucosaminidase; NH₄⁺: ammonium ion; NO, nitric oxide; sVEGFR1, soluble vascular endothelial receptor 1; RBC, red blood cell; ROS, reactive oxygen species.

Figure 2:. Approach to screening, evaluation and management of CKD in SCD.

From age 10, patients should be screened for albuminuria at least annually. Repeat evaluation using first-morning void or random urine sample should be obtained to confirm albuminuria, if the initial test is positive. Earlier screening might be considered in the presence of high-risk factors, including glomerular hyperfiltration at an early age, a strong family history of kidney disease or the known presence of APOL1 risk-variants. Renin–angiotensin–aldosterone system (RAAS) blocking agents should be considered in patients with persistent albuminuria or urinary albumin-to-creatinine ratio (UACR) ≥ 100 mg/g. Kidney function (GFR) and serum potassium should be monitored after starting RAAS inhibition. *Although APOL1 testing is available clinically, current data do not support routine screening for APOL1 risk variants.