Pathophysiology of sickle cell nephropathy (SCN)
Increased blood viscosity and red blood cell sickling promoted by the renal medullary milieu of low oxygen tension, low pH, and high osmolality lead to vasoocclusion and hypoperfusion in the medullary microcirculatory beds, and result in local ischemia and infarction. Severe medullary hypoperfusion can lead to papillary necrosis, sloughing, and obstructive uropathy.
In contrast to medullary hypoperfusion, glomerular ischemia appears to promote compensatory increase in kidney blood flow and the glomerular filtration rate (GFR). Glomerular hyperfiltration is mediated by glomerular hypertrophy and increased activity of vasodilatory factors including prostaglandins, kallikrein, carbon monoxide, and possibly nitric oxide (NO).
Proximal tubular secretory and absorptive hyperfunctioning are characteristic of SCD. Tubular hyperfunctioning is thought to reflect glomerulotubular balance in the face of glomerular hyperfiltration, and is evidenced by increased proximal tubular secretion of uric acid and creatinine and increased tubular reabsorption of low-molecular-weight protein (β2-microglobulins) and phosphate. Hypersecretion of creatinine causes an overestimation of the true GFR when using serum creatinine-based estimated GFR equations.
Chronic hemolysis and hemoglobinuria involving HbS can induce oxidant-mediated tubular injury, proliferation of mesangial cells, and upregulation of proinflammatory and profibrogenic responses to promote glomerulosclerosis and tubulointerstitial fibrosis.
Progressive kidney failure occurs due to:
- • Increased glomerular growth
- • Heme-induced injury to mesangial cells with chronic hemolysis
- • Repetitive vascular congestion and vasoocclusion-induced endothelial injury
- • Capillary rarefaction (reduced capillary density)
- • Ischemia-reperfusion-induced proinflammatory and profibrogenic responses
Contributing factors to kidney vascular congestion and dysfunction include:
- • Endothelin-1: increases kidney vascular congestion, inflammation, and vasoconstriction induced by hypoxia
- • Thrombospondin: induces shedding of microparticles from red blood cells that can lead to oxidant-mediated endothelial injury, red blood cell adhesion to the endothelium, and worsening of kidney vasoocclusive disease
- • Adenosine: promotes red blood cell sickling by increasing levels of 2,3-diphosphoglycerate in red blood cells.
