March-April 2015, Volume 12, Issue 2
Sickle Cell Trait: More Bad News for the Kidneys?
Published on: February 12, 2015
Naik RP, Derebail VK, Grams ME, et al. Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. JAMA. 2014;312:2115-2125.
Approximately one in 12 African Americans and 300 million people worldwide have sickle cell trait. Sickle cell trait arose as such a common, balanced polymorphism during human history because it affords protection against severe forms of malaria. Despite this clear beneficial effect, sickle cell trait is also associated with a handful of adverse effects. Its association with exertion-related heat illness and sudden death, although very rare in absolute terms, has garnered the most attention in the press, the legal system, and the pages of The Hematologist.1 The kidney, however, is the organ that is most commonly adversely affected by sickle cell trait. Classic microradioangiographic studies demonstrated that the vasa recta in the renal medulla are disrupted in sickle cell trait, although to a lesser extent than is seen in sickle cell anemia.2 Known renal manifestations of sickle cell trait include microscopic hematuria, renal papillary necrosis with gross hematuria, isosthenuria (a mild urinary concentrating defect), and renal medullary carcinoma (also quite rare in absolute terms). Sickle cell trait has also been associated with earlier progression to end-stage renal disease (ESRD) in people with autosomal dominant polycystic kidney disease.3
In the general population, an important and largely unexplained observation is that African Americans have a higher risk of chronic kidney disease (CKD) and progression to ESRD than European Americans or Asian Americans. Some, but not all, of this risk has recently been attributed to variants of apolipoprotein L-1 encoded by APOL1.4 Might sickle cell trait, given its known adverse renal effects and high frequency in the African American population, additionally explain the racial disparity in the risk of CKD? Dr. Rakhi Naik and colleagues sought to answer this question. The investigators conducted a pooled analysis of more than 15,000 individuals from five population-based African American cohorts. Sickle cell trait status was genetically determined, and different models were adjusted for age, sex, proportion of African genetic ancestry, baseline diabetes, baseline hypertension, and the presence of APOL1 risk variants. Indeed, the investigators found that sickle cell trait was associated with incident and prevalent CKD, decline in the estimated glomerular filtration rate (eGFR), and albuminuria. These associations were independent of APOL1 risk variants. There was no association with ESRD in their analysis, but the number of incident ESRD cases was relatively small.
This study had a number of limitations. The causes of all cases of CKD were not recorded uniformly, direct genotyping of sickle cell trait status was not available for all individuals, potential modifying effects of co-inherited α-thalassemia were not studied,5 and APOL1 status was only available in two of the five pooled cohorts. Nevertheless, this was a rigorous study with many strengths, given that it was a large, prospective, population-based sample of African Americans with detailed genotypic and phenotypic data that evaluated outcomes not studied before in individuals with sickle cell trait.
In summary, Dr. Naik and colleagues present a persuasive analysis that supports an association between sickle cell trait and the occurrence of CKD, decline in eGFR, and albuminuria in the African American population. Notably, the association of CKD with sickle cell trait was independent of APOL1 risk variants. These findings indicate that sickle cell trait is an additional genetic risk factor that can help to explain the racial disparity in the occurrence of CKD. Quantitatively, according to this analysis, sickle cell trait has a population attributable risk for incident CKD of 6 percent. Important research like this accords well with ASH’s recently published research priorities for sickle cell disease, which includes a specific call for an investment in research on sickle cell trait. Sickle cell trait is associated with numerous potential adverse effects, mainly renal; however, it is also important to remember that most individuals with trait will have no related health consequences. An ongoing challenge for hematologists is to communicate with our colleagues in other specialties and with the public about the results of such research on adverse effects of sickle cell trait without generating undue alarm. This can happen by continuing to demand and generate the best epidemiologic and medical evidence, and by always clearly communicating the magnitude of the risk of adverse effects of sickle cell trait. Websites that provide quality information in proper context about sickle cell trait, written primarily for the public include: www.cdc.gov/ncbddd/sicklecell/toolkit.html (from ASH and the Centers for Disease Control and Prevention) and www.sicklecelltrait.org (by Cincinnati Children’s Hospital Medical Center).
Abkowitz JL. Sickle cell trait and sports: is the NCAA a hematologist?. The Hematologist. 2013;10:1-2.
Statius van Eps LW, Pinedo-Veels C, de Vries GH, et al. Nature of concentrating defect in sickle-cell nephropathy: microradioangiographic studies. Lancet. 1970;1:450-452.
Yium J, Gabow P, Johnson A, et al. Autosomal dominant polycystic kidney disease in blacks: clinical course and effects of sickle-cell hemoglobin. J Am Soc Nephrol. 1994;4:1670-1674.
Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329:841-845.
Gupta AK, Kirchner KA, Nicholson R, et al. Effects of alpha-thalassemia and sickle polymerization tendency on the urine-concentrating defect of individuals with sickle cell trait. J Clin Invest. 1991;88:1963-1968.
Conflict of Interests
Dr. Charles T. Quinn indicated no relevant conflicts of interest.
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