Does Renal Function Deteriorate in Individuals With Sickle Cell Trait and Sickle Cell Disease? Now We Know

The carrier frequency of the sickle gene in African Americans is 8 to 9 percent¹  but can be as high as 20 to 40 percent in some African countries such as Nigeria.²  This relatively high carrier rate has deemed it imperative that we continue to probe its impact on all-cause mortality and morbidity related to end organ function in aging populations and those with chronic illnesses such as hypertension and diabetes, both in the United States and globally.^3,4  Furthermore, as the population with sickle cell disease (SCD) increasingly survives into adulthood in the United States, chronic kidney disease (CKD) is evolving as a significant contributor to morbidity and mortality.⁵ 

To define the trajectory and the rate of decline of estimated glomerular filtration rate (eGFR) in patients with both sickle cell trait (SCT) and SCD compared to the general noncarrier (AA) status among black patients, a group of investigators examined changes in eGFR over a minimum of three time points in 21,800 patients from the Research Patient Data Registry housed in Partners HealthCare (Boston, MA) throughout a 13 1/2 year period. Among the 10,210 patients eligible for analysis after excluding for missing genotype data and conflicts in coding, the researchers identified 1,251 with SCT, 210 with SCD, and 8,729 who had neither carrier status nor disease as the reference or control group.

In this study, Dr. Kabir Olaniran and colleagues simultaneously evaluated and compared the decline in eGFR among patients with both SCT and SCD, and for the first time, could elucidate “a dose response relationship” between sickle hemoglobin S (HbS) quantitation and eGFR. In comparing the SCT group to controls, they found that SCT was associated with a faster rate of eGFR decline (particularly in male patients) and with associated hyperfiltration at baseline. Their findings suggested that black Americans with SCT lose nearly half an eGFR unit (mL/min/1.73 m² ) more of kidney function every year compared to black Americans with AA status. The findings in SCD of accelerated eGFR were both intuitive and confirmatory.^5,10 

Other elucidated factors associated with eGFR decline in SCT and SCD were hypertension, diabetes, cardiovascular disease, angiotensin converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), aspirin, statins, and higher leucocyte counts. The study as a retrospective cohort study was not designed to tease out the various confounding variables but elicits the question of selection bias. From the indications for hemoglobin electrophoresis in the cohort, they suggest these patients may be “sicker” than the average black population. The patients were already seeking care and requiring frequent blood analysis, and thus may disproportionately be on aspirin, ACEis, or ARBs. The authors also admit another limitation of their study as the absence of APOL1 status data — a known predictor of CKD in the general population. The potential effects of coinheritance of both SCT and the APOL1 genotype would be important to ascertain, as Dr. Rakhi Naik and colleagues reported recently that the degree of risk of end-stage renal disease was similar in SCT and in those with APOL1-high risk genotype.⁶ 

Counterintuitively, in SCT, the authors found an inverse correlation between HbS quantitation and eGFR decline; with a lower HbS being associated with a faster eGFR decline implying that higher hemoglobin A quantitation (of > 70%) strongly associated with a faster eGFR decline in the presence of HbS. Their study also suggested that elevated hemoglobin A2 and hemoglobin F may be renoprotective in SCT.