Page 25 - 2019_06-Haematologica-web

Sickle cell trait is not completely harmless
studies showing that hydration and progressive exercise training may reverse various hematologic abnormalities observed during exertion in SCT, such as increased blood viscosity, red blood cell rigidity, oxidative stress, endothe- lial activation, and red blood cell sickling.12-17
Nonetheless, soldiers with SCT appear to be at higher risk of developing exertional rhabdomyolysis;12 the risk is modest (hazard ratio, 1.54; 95% CI: 1.12-2.12), under conditions of extreme exertion, as also supported by a recent systematic review.2
Renal manifestations of sickle cell trait
The renal medulla with its unique hyperosmolar and acidotic environment, together with the low oxygen ten- sion and low-flow state in medullary vasa recta, create optimal conditions for HbS polymerization,3 leading to a reduced number of vasa recta and loss of its normal vas- cular architecture.18 Hyposthenuria (a defect in concen- trating urine) results, and in turn may predispose individ- uals to dehydration, postulated to be a contributory fac- tor to the exertional rhabdomyolysis associated with SCT.
Among the renal manifestations associated with SCT, the most common are hematuria and proteinuria. In one large-scale study, hematuria was found to be twice as common in hospitalized African-American patients with HbAS than in those with normal hemoglobin.19 Urographic evaluation in a separate case series revealed that ~50% of hematuria cases in individuals with SCT were related to renal papillary necrosis.1,20 A much rarer cause of hematuria is renal medullary carcinoma, an aggressive malignancy found almost exclusively in young black patients with SCT.21 The tumor is hypothesized to arise from the distal collecting duct epithelium as a result of abnormal proliferation stimulated by chronic ischemia.22 The prognosis of patients with renal medullary carcinoma is poor, with a typical median sur- vival of <1 year, and response to traditional chemothera- py is limited.23 It has been proposed that individuals with SCT presenting with new-onset hematuria should under- go urological evaluation.24
The chronic microvascular damage in the renal medulla also predisposes individuals with SCT to proteinuria and
chronic kidney disease.2 A large study combining data from several African-American population-based prospective cohorts showed that the presence of SCT imparts a 1.86-fold higher odds of albuminuria (95% CI: 1.49-2.31).25 SCT is also a recognized risk factor for chron- ic kidney disease, for which a 1.5- to 2-fold increased risk is attributed to SCT.25,26 It is important to note that several co-morbid conditions such as type 2 diabetes and hyper- tension, as well as co-inherited genetic risk factors could influence the risk of chronic kidney disease, which is a potential explanation for the lack of association of SCT and chronic kidney disease in smaller cohort studies involving different ethnic groups.27,28 Additionally, SCT may increase the risk of proteinuria and retinopathy in individuals with diabetes.2,29,30
A common genetic risk modifier of renal disease in the African-American population is APOL1; inheritance of the G1 and G2 risk alleles is believed to account for much of the excess risk of chronic kidney disease and end-stage renal disease in individuals of African ancestry overall.31 APOL1 risk alleles have also been associated with pro- teinuria in patients with SCD,32,33 but so far, no genetic interactions between SCT and APOL1 risk alleles have been observed.25,26,34 The evidence for SCT itself being a risk factor for the development of end-stage renal disease remains inconclusive.
Another well-known genetic modifier of disease sever- ity in SCD is α-thalassemia trait, co-inherited in ~35% of individuals of African descent. Co-inherited α-tha- lassemia reduces intracellular HbS concentration, a key determinant of polymerization kinetics. The protective effect of α-thalassemia on anemia and chronic kidney dis- ease in individuals with SCT has been demonstrated in a cohort from the Jackson Heart Study.35
Other complications related to sickle cell trait
Despite numerous reported associations with SCT, few complications are supported by strong evidence (Figure 1). One final strong association is that of venous thromboem- bolic disease and pulmonary embolism in particular.2 In a study of 65,154 hospitalized African-Americans, HbS carri- ers had a slightly higher relative risk of pulmonary embolism, but the study was limited by the lack of radio-
Figure 1. The strength of association of sickle cell trait with various complications reported in the literature.
haematologica | 2019; 104(6)
1107