Sickle cell disease: renal manifestations and mechanisms

Abstract

Sickle cell disease (SCD) substantially alters renal structure and function, and causes various renal syndromes and diseases. Such diverse renal outcomes reflect the uniquely complex vascular pathobiology of SCD and the propensity of red blood cells to sickle in the renal medulla because of its hypoxic, acidotic, and hyperosmolar conditions. Renal complications and involvement in sickle cell nephropathy (SCN) include altered haemodynamics, hypertrophy, assorted glomerulopathies, chronic kidney disease, acute kidney injury, impaired urinary concentrating ability, distal nephron dysfunction, haematuria, and increased risks of urinary tract infections and renal medullary carcinoma. SCN largely reflects an underlying vasculopathy characterized by cortical hyperperfusion, medullary hypoperfusion, and an increased, stress-induced vasoconstrictive response. Renal involvement is usually more severe in homozygous disease (sickle cell anaemia, HbSS) than in compound heterozygous types of SCD (for example HbSC and HbSβ(+)-thalassaemia), and is typically mild, albeit prevalent, in the heterozygous state (sickle cell trait, HbAS). Renal involvement contributes substantially to the diminished life expectancy of patients with SCD, accounting for 16-18% of mortality. As improved clinical care promotes survival into adulthood, SCN imposes a growing burden on both individual health and health system costs. This Review addresses the renal manifestations of SCD and focuses on their underlying mechanisms.

Figure 1

The pathobiology of sickle cell disease. The formation of deoxyHbS leads to RBC sickling and vascular stasis. Stasis induces vascular occlusion, which either leads to infarction or resolves and causes ischaemia–reperfusion and its accompanying processes. Recurrent cycles of ischaemia–reperfusion in microcirculatory beds amplify organ injury (the `big bang' effect) because they induce inflammation and endothelial dysfunction, both regionally and systemically. Endothelial dysfunction promotes adhesion of RBCs and WBCs to the endothelium. This adhesion is critical because it impedes the transit of RBCs through the microcirculation, thereby promoting RBC sickling and vascular stasis. This vascular stasis explains why RBC sickling occurs in the microcirculation, despite the fact that the time required for sickling usually exceeds RBC transit through the microcirculation. Additional pathobiological pathways include haemolysis and increased free plasma haemoglobin. Plasma haemoglobin scavenges NO from the endothelium. Autoxidation and degradation of HbS lead to the release of free haem, which is toxic to the endothelium via its pro-oxidant and proinflammatory properties. Abbreviations: deoxyHbS, deoxygenated HbS; HbS, sickle haemoglobin; NO, nitric oxide; pO₂, partial pressure of oxygen; RBC, red blood cell; WBC, white blood cell.

Figure 2

Salient pathogenetic processes in the development of sickle cell nephropathy. Sickle cell nephropathy largely reflects an underlying functional vasculopathy. This vasculopathy leads to a perfusion paradox, wherein medullary hypoperfusion occurs in conjunction with kidney and/or cortical hyperperfusion. The renal vasculopathy also leads to aberrant renal vascular responses to stress that occur systemically or in distant organs and tissues. This response is characterized by enhanced renal vasoconstriction and resultant vasoocclusion. Recurrent cycles of ischaemia and ischaemia–reperfusion injury thus occur, thereby leading to subclinical and clinical acute kidney injury. These processes summate in the initiation and progression of sickle cell nephropathy.