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Sickle cell trait may increase risk for renal disease in blacks

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November 13, 2014

Black individuals who carried sickle cell trait demonstrated increased risk for chronic kidney disease and were more likely to experience declines in estimated glomerular filtration rate, according to study results.

They also were more likely to experience albuminuria, results showed.

Rakhi P. Naik, MD, a hematologist at Johns Hopkins University, and colleagues evaluated data from 15,975 adults enrolled on one of five prospective studies: the Atherosclerosis Risk in Communities Study; Jackson Heart Study; Coronary Artery Risk Development in Young Adults; Multi-Ethnic Study of Atherosclerosis; and the Women’s Health Initiative.

All patients were self-identified African Americans and had genotyping data available for rs334 encoding the sickle cell trait mutation.

Overall, 1,248 of the participants carried sickle cell trait, the prevalence of which ranged from 6.4% to 9.3% in the five study cohorts.

Researchers identified chronic kidney disease — defined as an estimated glomerular filtration rate (eGFR) ˂60 mL/min/1.73 m2 — in 2,233 of the study participants. A greater proportion of patients who carried sickle cell trait had chronic kidney disease (19.2% vs. 13.5%). Results of a meta-analysis indicated sickle cell trait carriers were at increased risk for chronic kidney disease (OR=1.57; 95% CI, 1.34-1.84).

The association between sickle cell trait carriage and chronic kidney disease persisted regardless of baseline hypertension (P=.09) or diabetes (P=.6), researchers wrote.

Researchers determined incident chronic kidney disease was more common in sickle cell trait carriers (20.7% vs. 13.7%), and results of a meta-analysis indicated sickle cell trait carriers were at increased risk for incident chronic kidney disease (OR=1.79; 95% CI, 1.45-2.2).

A greater proportion of sickle cell trait carriers experienced decline in eGFR (22.6% vs. 19%), defined as a yearly decrease of ˃3 mL/min/1.73 m2. Sickle cell trait carriers also were more likely to experience albuminuria (31.8% vs. 19.6%), which researchers measured based on a spot urinary albumin:creatinine ratio of ˃30 mg/g or by an albumin excretion rate ˃30 mg over 24 hours.

Multivariate analyses indicated sickle cell trait carriers were at increased risk for a decline in eGFR (OR=1.32; 95% CI, 1.07-1.61) and albuminuria (OR=1.86; 95% CI, 1.49-2.31).

Additional genetic analyses indicated APOL1 risk variants did not impact the associations between sickle cell trait and chronic kidney disease (P=.17) or albuminuria (P=.18).

“These associations … may offer an additional genetic explanation for the increased risk of chronic kidney disease observed among African Americans compared with other racial groups,” Naik said. “Our study also highlights the need for further research into the renal complications of sickle cell trait. Because screening for sickle cell trait is already being widely performed, accurate characterization of disease associations with sickle cell trait is critical to inform policy and treatment recommendations.”

Disclosure: The researchers report grant funding and personal fees from, as well as advisory board roles with, Amarin, AstraZeneca, Catabasis, Emmaus Life Sciences, GlycoMimetics, LabCorp, Merck, Novartis, Regeneron and Roche.

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Alexis A. Thompson

Alexis A. Thompson

The estimated 3 million to 4 million Americans and 300 million people worldwide who have sickle cell trait (SCT) are generally healthy and have normal lifespans. Chronic kidney disease and progression to end-stage renal disease disproportionately affect African Americans, and previous studies examining associations of kidney impairment with SCT have been conflicting. The framework agenda for SCT proposed by the NIH’s NHLBI consensus workshop identified the need for more research into the rare renal manifestations associated with SCT. Similarly, the ASH sickle cell disease and sickle cell trait research priorities call for greater investment in research to improve our mechanistic understanding of as well as the population-level impact of sickle cell trait on the relative risk for kidney disease. 

Naik and colleagues have aligned multiple well-established population-based cohorts to examine associations of renal impairment — such as chronic kidney disease, albuminuria, hypertension and end-stage renal disease — with coinheritance of SCT in African Americans. Their findings strongly suggest relationships between the subtle, generally subclinical renal impairment in SCT with the development and progression of renal injury in chronic kidney disease, which appears to be independent of APOL1, a known genetic risk variant associated with chronic kidney disease in African Americans. Compared with non-carriers, individuals with SCT also were more likely to have albuminuria and lower estimated glomerular filtration rates, but the association of SCT to end-stage renal disease could not be established in their study. 

The principal reason for identifying individuals with SCT has been to provide them with information about their reproductive risk of having offspring with sickle cell disease, an autosomal recessive disorder. This interesting paper underscores the need for more research and may point to additional potential health benefits to knowing one’s genetic status.

Alexis A. Thompson, MD, MPH
Ann & Robert H. Lurie Children’s Hospital of Chicago
Feinberg School of Medicine, Northwestern University
ASH Councillor

Disclosure: Thompson reports no relevant financial disclosures.