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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.

Key points

  • Albuminuria is common in patients with sickle cell disease (SCD) and predicts the progression of chronic kidney disease (CKD).

  • Haematuria is usually benign in individuals with sickle cell trait and SCD, but might be a presenting symptom of renal medullary carcinoma.

  • The pathophysiology of SCD-related nephropathy is likely driven by hyperfiltration, increased oxidative stress and glomerular hypertension.

  • Genetic modifiers, including APOL1, HMOX1, HBA1 and HBA2 variants, are implicated in the development and/or progression of CKD.

  • Kidney function declines more rapidly in individuals with sickle cell trait and SCD than in the general African American population; baseline CKD and rapid decline in estimated glomerular filtration rate are associated with increased mortality in SCD.

  • Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and hydroxyurea decrease albuminuria in short-term studies; adequately controlled studies are required to evaluate the long-term effects of these agents on progressive kidney disease.

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Fig. 1: Proposed mechanisms and biomarkers of sickle cell nephropathy.
Fig. 2: Approach to screening, evaluation and management of chronic kidney disease in sickle cell disease.

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Acknowledgements

K.I.A. and V.K.D. are supported by FDA grant FD006030 and NIH grant HL159376. S.L.S. is supported by NIH grants HL146788, HL153161 and HL159376.

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All authors researched data for the article, made substantial contributions to discussions of the content, and wrote, reviewed and/or edited the manuscript before submission.

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Correspondence to Kenneth I. Ataga.

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K.I.A. has received research funding from Novartis and Global Blood Therapeutics, served on advisory boards for Novartis, Global Blood Therapeutics, Novo Nordisk, Editas Medicine, Forma Therapeutics and Agios Pharmaceuticals, and as a consultant for Roche. S.L.S. receives research funding support from Novartis, Pfizer and Global Blood Therapeutics, and served on advisory boards for Novartis and Global Blood Therapeutics. V.K.D. has served on advisory boards for Novartis, Bayer and Travere.

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Nature Reviews Nephrology thanks C. Sharpe, S.L. Thein and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Nocturnal enuresis

The persistence of night-time urination in bed two or more times per week for at least 3 months after the age of 5.

Dysmorphic haematuria

The presence of abnormally shaped red blood cells in the urine; suggests glomerular injury.

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Ataga, K.I., Saraf, S.L. & Derebail, V.K. The nephropathy of sickle cell trait and sickle cell disease. Nat Rev Nephrol 18, 361–377 (2022). https://doi.org/10.1038/s41581-022-00540-9

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