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6. Diabetic Nephropathy

G. Kovacs

Published 2009 in EJIFCC

ABSTRACT

Diabetic nephropathy is the most common cause of end-stage renal disease requiring dialysis in the US (1). The incidence of diabetic nephropathy in this country has increased substantially over the past few years. Advanced diabetic nephropathy is also the leading cause of glomerulosclerosis and end-stage renal disease worldwide (2, 3). Between 20% and 40% of patients with diabetes ultimately develop nephropathy, although the reason why not all patients with diabetes develop this complication is unknown. The natural history of diabetic nephropathy differs according to the type of diabetes and whether microalbuminuria (defined as > 30 mg but 300 mg albumin excreted daily), whereas only 20-40% of those with type 2 diabetes over a period of 15 years will progress. As Nielsen et al. (4) demonstrated more than a decade ago, a clear, early predictor of disease progression is increasing systolic blood pressure, even within the prehypertensive range. Among patients who have type 1 diabetes with nephropathy and hypertension, 50% will go on to develop end-stage renal disease within a decade (5). Mortality among dialysis patients with diabetes is 22% higher in the first year following the initiation of dialysis and 15% higher at 5 years than that among dialysis patients without diabetes (6). Diabetic nephropathy has several distinct phases of development. Functional changes occur in the nephron at the level of the glomerulus, including glomerular hyperfiltration and hyperperfusion, before the onset of any measurable clinical changes. Subsequently, thickening of the glomerular basement membrane, glomerular hypertrophy, and mesangial expansion take place. Seminal studies by Mauer and colleagues (3) and Steinke and colleagues (7) demonstrated that individuals with type 1 diabetes and microalbuminuria in whom these histological alterations were detected were destined to progress to overt nephropathy. Microalbuminuria, however, has a variable course; its progression to macroalbuminuria (> 300 mg per day) is unpredictable and does not always lead to development of nephropathy (7). Moreover, the rate of kidney function decline after the development of nephropathy is highly variable between patients and is influenced by additional factors, including blood pressure and glycemic control. Multiple mechanisms contribute to the development and outcomes of diabetic nephropathy, such as an interaction between hyperglycemia-induced metabolic and hemodynamic changes and genetic predisposition, which sets the stage for kidney injury (8). Hemodynamic factors are the activation of various vasoactive systems, such as the renin-angiotensin-aldosterone and endothelin systems. In response, secretion of profibrotic cytokines, such as transforming growth factor β1 (TGF-β1), is increased and further hemodynamic changes occur, such as increased systemic and intraglomerular pressure. Metabolic pathway involvement, among other features, leads to nonenzymatic glycosylation, increased protein kinase C (PKC) activity, and abnormal polyol metabolism. Findings from various studies support an association between increased secretion of inflammatory molecules, such as cytokines, growth factors and metalloproteinases, and development of diabetic nephropathy (9). Oxidative stress also seems to play a central part (11). Studies that have used inhibitors of the pathways involved in genesis of diabetic nephropathy have shed light on the pathogenesis of this condition but have not led to expansion of the therapeutic armamentarium to halt the disease process (10). This Review is intended for a clinical audience and we discuss pathological changes to the glomeruli during the development of diabetic nephropathy. Although many factors have been implicated in the pathogenesis of diabetic nephropathy, we have focused on the particular factors outlined above.

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