爱肾分享 | Sickle Cell Nephropathy

AJKDAtlas of Renal Pathology: Sickle Cell Nephropathy

Mark A. Lusco, MD,1 Agnes B. Fogo, MD,1Behzad Najafian, MD,2 and Charles E. Alpers, MD2

Clinicaland Pathologic Features

Sickle cell disease is an autosomalrecessive disease that occurs most commonly in individuals of African ancestry,with an incidence of 1 in 500 African Americans. Kidney disease has varyingmanifestations, with microalbuminuria in childhood, progressing to overtproteinuria in 20%-25% and nephrotic syndrome in about 5%, and progressive GFRloss after age 20 years in 5%-8% of all sickle cell patients. Patients oftenshow hyposthenuria and hematuria as well. Some patients develop papillarynecrosis and acute kidney injury due to sickle cell crisis. Patients witheither homozygous sickle cell disease or sickle cell thalassemia can developany of these manifestations related to sickling. Sickle cell trait has beenreported to cause sickle cell nephropathy only in rare cases.

Light microscopy: Cortical infarcts canoccur in sickle cell crisis due to occlusion of arteries. With chronic injury,glomerulomegaly and global and secondary segmental glomerulosclerosis arepresent, often in a perihilar location, with glomerular basement membranecontour duplication and corrugation. Collapsing lesions may be present relatedto vascular compromise resulting in ischemia. There is prominent hemosiderindeposition, seen as reddish granules in tubular epithelial cells and stainingpositive on Prussian blue iron stain, with focal deposition in glomerularepithelial cells. Sickled red blood cells are present, most often in medullaryperitubular areas and more rarely in glomeruli. Interstitial fibrosis andtubular atrophy are present to a varying extent.

Immunofluorescence microscopy: NonspecificIgM and C3 staining in scarred glomeruli.

Electron microscopy: Sickle-shaped redblood cells in glomerular and peritubular capillaries with polymerizedhemoglobin. Glomerular basement membranes show corrugation and expansion oflamina rara interna and cellular interposition without immune deposits, withsubtotal foot process effacement in glomeruli without sclerosis.

Etiology/Pathogenesis

Sickle cell disease is due to a single-basemutation that results in a single amino acid substitution (valine forglutamate) in hemoglobin, and causes hemoglobin polymerization and sicklingunder low oxygen tension, particularly with volume depletion and exercise.Sickling triggers sickle cell crisis due to occlusion of vessels. The vasarecta are most susceptible due to relative hypoxia, low pH, and hypertonicityin the medulla. Secondary segmental sclerosis with gradual development ofproteinuria and CKD is postulated to be due to chronic hypoxia, endothelialinjury related to iron/heme and sickling of red blood cells, nitric oxideimbalance, and altered hemodynamics, related to marked glomerularhypertrophy/hypertension and hyperfiltration.

DifferentialDiagnosis

Primary focal segmental glomerulosclerosis presentswith nephrotic syndrome without hemosiderin deposition, and shows extensivefoot process effacement even in nonsclerotic glomeruli. Chronic thromboticmicroangiopathy has glomerular basement membrane double contours, however, itlacks congestion and sickled cells within peritubular and glomerularcapillaries. Hemolysis results in pigmented granular casts that show positivityon Prussian blue iron stain, but an absence of sickled cells withincapillaries.

KeyDiagnostic Features

-Sickled cells in peritubular andglomerular capillaries

-Hemosiderin deposits in tubularepithelium, rarely in glomerular cells

-Ischemic glomerular changes includingcorrugation and double contours of glomerular basement membranes

Figure1. Sickle cell nephropathy with glomerularcapillary occlusion and extensive peritubular capillary congestion by sickledcells during a sickle cell crisis (hematoxylin and eosin stain). Reproducedwith permission from AJKD 37(5):e34-e35.1.

Figure2. Sickle cell nephropathy with red blood cellcongestion in a glomerular capillary loop during a sickle cell crisis(hematoxylin and eosin stain). Reproduced with permission from AJKD37(5):e34-e35.1.

Figure3. Sickle cell nephropathy with marked sickling invasa recta during an acute sickle cell crisis (hematoxylin and eosin stain).Reproduced with permission from AJKD 37(5):e34-e35.1.

Figure4. Sickle cell nephropathy with iron deposits inglomerular visceral epithelial cells and tubular epithelial cells (bottom leftcorner; Prussian blue iron stain). Reproduced with permission from AJKD37(5):e34-e35.1.

Figure5. Sickle cell nephropathy with hemosiderin intubular epithelial cells (A; hematoxylin and eosin stain) that shows positivityby iron stain (B; Prussian blue iron stain). Continued Atlas of Renal PathologyII e2 Am J Kidney Dis. 2016;68(1):e1-e3

Figure6. Sickle cell nephropathy with red blood cellcongestion and sickled cells in glomerular capillary loops (electronmicroscopy). - Am J Kidney Dis. 2016;68(1):e1-e3 e3 Atlas of Renal Pathology II