“Benign” nephrosclerosis results in small kidneys with finely granular surface and thinned cortex in late stages. Malignant (accelerated) nephrosclerosis grossly shows petechial hemorrhage of the subcapsular surface, with mottling and occasional areas of infarct. Microscopically, in “benign” arterionephrosclerosis there is vascular wall medial thickening with frequent afferent arteriolar hyaline deposits and varying degree of intimal fibrosis. The hyalinization is due to endothelial injury and increased pressure, leading to an insudate of plasma macromolecules. There are associated focal glomerular ischemic changes with variable thickening and wrinkling of the basement membrane and/or global sclerosis, tubular atrophy, and interstitial fibrosis (Fig. 10.1). Global sclerosis more commonly is of the obsolescent type, with fibrous material obliterating Bowman’s space. Solidified glomeruli, where the tuft is globally sclerosed without collagen in Bowman’s space, has been called “decompensated” arterionephrosclerosis. Secondary focal segmental glomerulosclerosis (FSGS) may also occur, often with associated glomerular basement membrane (GBM) corrugation and filling of Bowman’s space with fibrous material [4–10]. These morphologic features hint that the segmental sclerotic process is secondary to hypertension-associated injury, rather than idiopathic FSGS. The lesions associated with accelerated hypertension consist of mucoid change of the arterioles, often with red blood cell (RBC) fragments within the wall. In malignant hypertension, arterioles show fibrinoid necrosis, and interlobular arteries have a concentric onion-skin pattern of intimal proliferation and fibrosis, overlapping with the appearance of scleroderma and chronic thrombotic microangiopathy (Fig. 10.2) (see below). There is proportional tubulointerstitial fibrosis in arterionephrosclerosis.

Immunofluorescence may show trapping of IgM and C3 in glomeruli, but there are no immune complex-type deposits. In malignant hypertension, fibrin/fibrinogen staining may be present in necrosed arterioles/arteries and injured glomeruli.

Electron microscopy confirms the corrugated, wrinkled GBM and ischemic changes with increased lamina rara interna but without immune deposits. Hyaline may be present in sclerosed segments. Some foot process effacement of podocytes may also be present, but it is usually not extensive.

Although none of the above lesions are pathognomonic, the constellation of these changes in the absence of other lesions of primary glomerular disease is indicative of arterionephrosclerosis.

Hypertension has been presumed to cause end-organ damage in the kidney, and hypertension undoubtedly accelerates progressive scarring of renal parenchyma, but the relationship of hypertension and arterionephrosclerosis is not simple and linear [11]. In a large series of renal biopsies in patients with essential hypertension, arterionephrosclerosis was present in the vast majority, and the severity of arteriolar sclerosis correlated significantly with level of diastolic blood pressure [9]. However, in several large autopsy series of patients with presumed benign hypertension, significant renal lesions were rare [4, 5]. Further, the level of blood pressure does not directly predict degree of end-organ damage: African-Americans have higher risk for more severe end-organ damage at any level of blood pressure [2]. The African American Study of Kidney Disease (AASK) trial showed that African-Americans with presumed arterionephrosclerosis indeed did not have other lesions, by renal biopsy, but the global sclerosis was severe and did not correlate with vascular sclerosis [12]. It is possible that underlying microvascular disease causes the hypertension and the renal disease in susceptible patients. In a large study of patients without clinically evident kidney disease at baseline, even relatively modest elevation in blood pressure was an independent risk factor for development of end-stage kidney disease [13]. Underlying causes in addition to direct hemodynamic injury could include possible genetic and structural components, such as decreased nephron number and consequently fewer, but enlarged glomeruli [14]. Whether hypertension can cause kidney scarring, or a primary microvascular renal injury causes the hypertension, which in turn accelerates the sclerosis, has not been proven. Apolipoprotein L1 allele variants are tightly linked to excess arterionephrosclerosis, focal segmental glomerulosclerosis, and HIV-associated nephropathy, but not diabetic nephropathy in African-Americans [15]. The ApoL1 allele variant confers protection against some trypanosomes, which could have a survival advantage and thus, by natural selection, have led to its high prevalence in African-Americans. The mechanisms of increased risk of kidney disease are unknown [16].