Renal Functional Decline in Sickle Cell Disease and Trait

Kidney diseases are broadly categorized by the renal compartment targeted by the disease process and by the rate and reversibility of renal functional decline. Sickle cell disease (SCD) fundamentally challenges such categorization because all renal compartments may be indiscriminately affected by SCD in early life, and SCD may lead to AKI or CKD.¹ SCD results from the inheritance of two mutant hemoglobin genes, either one or both being the sickle β-globin gene; SCD afflicts some 100,000 individuals in the United States and predisposes to multiorgan disease.¹ In contrast, sickle cell trait (SCT) reflects the inheritance of one allele of the sickle hemoglobin gene and essentially targets the renal medulla; SCT is much more prevalent (present in 2.5 million individuals in the United States) and lacks the multiorgan morbidity and increased mortality exhibited by SCD.² SCD and SCT also diverge in the risk for ESKD: renal involvement in SCD can, indubitably, culminate in ESKD, but whether this outcome occurs in SCT is controversial.^3–5

In this issue of JASN, Olaniran et al.⁶ advance the current understanding of kidney disease caused by SCT and SCD by providing the only study to date evaluating the decline in eGFR and the attendant risk factors in black Americans with SCD, SCT, and a normal hemoglobin phenotype. The data demonstrate that, compared with the reference group, the rate of decline in eGFR in patients with SCT was significantly higher and markedly more so in SCD. These findings are significant for several reasons. First, SCD exhibits what was previously termed the perfusion paradox wherein hypoperfusion is endemic in the medulla (and other microcirculatory beds), whereas hyperperfusion occurs in the whole kidney and cortex (and in the systemic circulation and other macrocirculatory beds).⁷ SCD thus imposes on the kidney numerous processes—glomerular hyperfiltration, heightened glomerular growth, hemodynamically mediated glomerulosclerosis, tubular hypermetabolism, and oxidant stress, among others—not evinced by SCT, the latter exhibiting essentially medullary hypoperfusion.^1,7 The abundance of these pathobiologic cortical changes in SCD may accelerate progressive CKD, thereby underlying the faster eGFR decline in SCD. Second, that eGFR declined at a faster rate in SCT compared with the reference group indicates that CKD in SCT is not a static process, but rather a progressive one; and, as for any form of progressive CKD and with sufficient time, SCT carries the risk for ESKD. These findings may thus be interpreted as consistent with studies that conclude that the risk for ESKD is increased in patients with SCT.^3,5 Third, blacks compared with whites are at an increased risk for CKD and exhibit higher rates of eGFR decline.⁸ The studies of Olaniran et al.⁶ point to SCT as an accompanying condition that may predispose to both outcomes in black patients.

For SCT and SCD, a faster eGFR decline associated with men, diabetes, and a baseline eGFR ≥90 ml/min per 1.73 m²; the former two factors are established as risks for renal functional decline, whereas the latter is observed in other settings (diabetic CKD).⁶ Additional associations in this study merit comment. In SCD, the rate of decline of eGFR was associated with hospital admissions for sickle crisis. Such episodes are generally attended by systemic inflammation and hemolysis and may be associated with AKI,¹ whereas chronic hemoglobinuria is implicated in CKD in SCD.⁹ Consequently, recurrent hemolysis during repeated crises may promote not only AKI, but also the AKI-CKD transition and CKD. It is notable that eGFR decline was associated with lower hemoglobin in SCD, the latter possibly reflecting more severe hemolysis. Extrarenal processes, such as inflammation and hemolysis, as abundantly manifested in SCD, but not in SCT, may thus contribute as well to the observed faster decline in eGFR in SCD.

An unexpected and perplexing finding by Olaniran et al.⁶ is that, in SCT, a higher rate of eGFR decline was associated with lower levels of hemoglobin S (HbS). The authors provide plausible speculations on the basis of the recognized mitigating effect of higher levels of hemoglobin F and concomitant presence of α-thalassemia on manifestations of SCD. We offer another speculation. Sickling of red blood cells (RBCs) and hemolysis in the sickle milieu instigate countervailing systems, including those that are vasodilatory, antiadhesive, and antithrombotic such as heme oxygenase-1 and prostanoids.^1,7,10 We speculate that, in SCT, RBCs containing higher HbS levels traversing the inimical hypoxic, acidotic, hyperosmotic, low-flow medullary microcirculation attain the needed threshold for HbS and attendant RBC sickling to elicit such counterregulatory systems, whereas RBCs containing lower HbS levels do not. The elicitation of these countervailing systems by RBCs containing higher HbS content mitigates RBC sludging, RBC rupture, and the resulting medullary disarray, whereas the lack of recruitment of these countervailing systems by RBCs with lower HbS levels leaves entirely unopposed the adverse effects of these sickle RBCs, albeit with lesser HbS content. In this regard, whether urinary concentration ability associates with HbS levels in SCT would be of interest.

The finding that SCT per se accelerates the decline in eGFR in black subjects adds to mounting evidence that SCT may not be a benign condition because SCT predisposes to venous thromboembolic disease, rhabdomyolysis, and renal medullary carcinoma.¹¹ Current understanding of renal involvement by SCT is limited and generally holds that such involvement is largely restricted to the renal medulla. The study by Olaniran et al.⁶ not only underscores the need to re-examine such assumptions and to characterize renal involvement in SCT in depth, but also is relevant to the management of CKD. CKD in black patients involves the interplay of genetic determinants (APOL1 variants), diseases such as diabetes and hypertension, a propensity toward cardiovascular diseases and low cardiorespiratory fitness, and the adverse effects of marked disparities in health care.⁸ This study by Olaniran et al.⁶ highlights the need for cognizance of the potential contribution of SCD and SCT to progressive CKD in black patients; vigilance in avoiding dehydration and other stressors that promote RBC sickling; and diligence in mitigating and/or avoiding those potentially tractable nongenetic conditions that may drive the progression of CKD.

Disclosures

None.

Funding

Dr. Nath is supported by National Institutes of Health grant R01 DK47060, and Dr. Vercellotti is supported by National Institutes of Health grant R01 HL114567.