Pathology of Human Diabetic Nephropathy

Diabetic nephropathy (DN) develops in a subset of diabetic patients, on average about 15 years after onset of metabolic abnormalities. The earliest lesions consist of thickened glomerular basement membranes (GBM), mild mesangial expansion, and arteriolar accumulation of hyaline. Mesangiolysis and exuberant mesangial repair then develop, ultimately resulting in marked increase in mesangial matrix. Established nephropathy is characterized by mesangial expansion which may be nodular, so-called Kimmelstiel-Wilson nodules, hyaline in both afferent and efferent arterioles, and markedly thickened GBM by electron microscopy. Podocyte loss may be a crucial contributor to this progressive sclerosis. There is a distinct predilection of segmental sclerosis to occur at the glomerulotubular junction in type 1 diabetic patients, which can lead to disruption of outflow from the glomerulus, resulting in so-called a tubular glomeruli. A recent classification of DN may be useful for categorizing stages of development of the diabetic lesions. Diabetic injury also affects the tubulointerstitium. Tubular basement membranes thicken in parallel to GBM. Early interstitial inflammation with predominantly mononuclear cells is followed by later increased interstitial fibrosis and tubular atrophy. Lesions in type 1 and type 2 diabetic patients share many similarities, with more severe vascular disease and heterogeneous lesions, perhaps reflecting older age and comorbid conditions such as hypertension, in the latter. Diabetic patients typically undergo diagnostic renal biopsies only when the clinical course is not typical for DN, and not surprisingly, a range of other lesions may then be present in addition to DN. DN also recurs or occurs de novo in the transplant, developing more quickly than in the native kidney. Efforts to develop rodent animal models that more completely capture these key features of human DN will allow advances to be made in understanding pathogenesis and targeting novel treatment.