Understanding Diabetic Nephropathy – Is There a Genetic Susceptibility?

Savage David, Maxwell Peter
European Endocrinology, 2008;4(2):66-9

Abstract

Diabetes is rapidly increasing in prevalence,1 resulting in profound socioeconomic impacts in both developed and developing countries. Furthermore, the parallel increase in the prevalence of complications of diabetes, particularly nephropathy, retinopathy and associated cardiovascular disease, is placing enormous demands on healthcare budgets.2

Citation European Endocrinology, 2008;4(2):66-9
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Improved understanding of the aetiology and pathogenesis of these complications is urgently needed. Effective screening strategies to identify individuals with diabetes most likely to develop complications could improve outcomes by focusing resources on those at highest risk.

What Is Diabetic Nephropathy?
Diabetic nephropathy (DN) is a microvascular complication affecting patients with both type 1 and type 2 diabetes. It has become the leading cause of end-stage renal disease (ESRD) in Europe and the US managed by renal replacement therapy (kidney dialysis and/or renal transplantation).3,4 The clinical phenotype includes persistent proteinuria, a decreasing glomerular filtration rate (GFR) and hypertension.5 A sizeable minority of patients with diabetes eventually develop definite DN.6 The earliest clinical manifestation is microalbuminuria (incipient nephropathy), which may progress to overt proteinuria (dipstick urinalysis positive for proteinuria) followed by the emergence of hypertension, a declining GFR and, later, development of ESRD. Nevertheless, microalbuminura is not an absolutely reliable predictor of progression to DN as some patients remain microalbuminuric while others show regression of albuminuria to normal albumin excretion rates.7 Patients with DN have much higher mortality rates than individuals with diabetes with normal albumin excretion rates. The excess mortality is largely attributed to higher rates of coronary artery disease, stroke and amputation,8 and the five-year survival rate for ESRD patients with diabetes is worse than for most cancers.

DN in type 1 and 2 diabetes differs in a number of ways. For example, compared with type 1 diabetes the rate of progression of renal failure in patients with type 2 diabetes is more variable. In patients with type 2 diabetes, microalbuminuria progression to advanced renal disease is less frequent and increases in blood pressure generally occur before onset of microalbuminuria.9 Older patients with type 2 diabetes may also have concurrent hypertensive renal vascular disease, and unlike patients with type 1 diabetes the age at diabetes onset is more difficult to establish. Therefore, phenotypic definition of DN is simpler in patients with type 1 diabetes, which is one reason why efforts to discover genetic variants associated with risk of DN might be more successful in these patients.

Pathophysiological features of DN include glomerular capillary hypertension, glomerular hyperfiltration, mesangial matrix expansion and glomerulosclerosis. Prolonged hyperglycaemia leads to chronic metabolic and haemodynamic changes that modify the activity of various intracellular signalling pathways and transcription factors.10 There is the subsequent induction of cytokines, chemokines and growth factors, particularly transforming growth factor beta (TGFβ). These effects promote structural abnormalities in the kidney such as glomerular basement membrane thickening, podocyte injury and mesangial matrix expansion with the later development of irreversible glomerular sclerosis and tubulointerstitial fibrosis associated with declining GFR. The clinical management of DN includes optimal glycaemic control, treatment of dyslipidaemia and aggressive lowering of blood pressure ideally with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1 receptor (ARB) blockers.11–14

Table 1: Key Risk Factors for Diabetic Nephropathy

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