Sickle cell disease and diabetes mellitus Free

In this issue of Blood, Sun et al address a critical question regarding the link between diabetes and the progression of glomerular filtration rate in patients with sickle cell disease (SCD).¹ Notably, diabetes predicted a sevenfold increased risk of chronic kidney disease (CKD) progression, even after adjusting for high-risk APOL1 genotype. The independent effects of diabetes and APOL1 high-risk status on CKD progression suggest distinct mechanisms of kidney damage in SCD.

The incidence of diabetes is likely to increase in patients with SCD and be comparable to that observed in African Americans due to several factors.² Among these factors are changes in patient phenotype, with weight gain favored by treatments that improve general health (such as hydroxyurea) and often unbalanced diets in patients from disadvantaged backgrounds.

The study by Sun et al highlights the necessity for screening, vigilant monitoring, and management of diabetes in patients with SCD. It is crucial to inquire about the patient’s family history of diabetes and to perform regular glucose tests for both diagnosis and follow-up, particularly in subjects with micro- or macroalbuminuria. It is imperative to acknowledge that although the hemoglobin A1c (HbA_1c) level is quantifiable in hemoglobin S, this assay underestimates glycemia due to the short lifespan of red blood cells. Additionally, the current method fails to detect hemoglobin F (HbF) glycation, which represents a significant limitation in patients with elevated HbF. Therefore, in case of diagnostic uncertainty, an oral glucose tolerance test should be considered. For patients with diabetes, follow-up procedures should include repeated glycemic measurements, either through subcutaneous sensors or frequent capillaries blood tests to ensure strict diabetes control. Monitoring fructosamine levels is also important, although it is less precise than HbA_1c and only reflects glycemic control over the preceding 3 weeks.

The coexistence of diabetes and SCD also reinforces the interest in nephroprotective treatments such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and possibly sodium-glucose cotransporter 2 inhibitors. Nonetheless, it is imperative to exercise caution in regard to the potential risk of dehydration that accompanies hypernatriuresis. Regarding oral antidiabetics, it should be noted that metformin has been studied for its purported capacity to increase HbF and its antioxidant stress effects via nuclear factor erythroid-2 related factor-2.^3,4 

In summary, the present study provides compelling evidence for the significant impact of diabetes on CKD progression in SCD, independent of APOL1 status. It underscores the need for heightened awareness, early detection, and aggressive management of diabetes in patients with SCD to preserve kidney function and improve overall outcomes. The findings should prompt a reevaluation of current screening and management practices for diabetes in SCD clinics and encourage further research into targeted therapies for this high-risk population.

Conflict-of-interest disclosure: P.B. declares no competing financial interests.