|ISSN No. 1606-7754 Vol.13 No.1 April 2005|
Update in Diabetic Nephropathy
Enyioma N Obineche1 and Abdu Adem2
Department of Internal Medicine1, Department of Pharmacology2, Faculty of Medicine & Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
Diabetic nephropathy has become the leading cause of end-stage kidney disease worldwide and is associated with an increased cardiovascular risk. The earliest clinical manifestation is microalbuminuria. Tight blood glucose and blood pressure control reduce the risk of microalbuminuria. Once microalbuminuria is present, the rate of progression to end stage kidney disease and cardiovascular disease can be delayed by aggressive management of blood pressure, glucose, and lipids. Inhibition of the renin-angiotensin system is important in reducing intraglomerular pressure but other classes of antihypertensive agents may also be needed to obtain adequate control of systemic blood pressure. Such measures can at least reduce by half the rate of progression of nephropathy and cardiovascular disease.
Key words: Diabetes, nephropathy, microalbuminuria, proteinuria, cardiovascular risk
The classical definition of diabetic nephropathy is a progressive rise in urine albumin excretion, coupled with increasing blood pressure, leading to declining glomerular filtration and eventually end stage kidney failure. Patients generally have diabetic retinopathy. Recently, greater appreciation of the close links between nephropathy and cardiovascular disease have led to the inclusion of premature cardiovascular disease, cardiovascular risk increasing in parallel with albuminuria. Diabetic nephropathy is now the single commonest cause of end-stage kidney failure worldwide and is acknowledged as an independent risk factor for cardiovascular disease. In many countries, including the Middle East the majority of diabetic patients starting kidney replacement therapy now have type 2 rather than type 1 diabetes. This review will therefore discuss nephropathy in both type 1 and type 2 diabetes.
Type 1 Diabetes
The initial rise in protein excretion is small and highly selective, albumin being the main protein excreted in excess. At this stage, specific immunologically based assays detect small increases in urine albumin which are below the detection limit of conventional dipstick tests (Table 1). This so-called microalbuminuria generally appears within 5–15 years’ duration of diabetes. Without specific intervention, over approximately a further 10 years, albumin excretion slowly increases through the microalbuminuric range, until dipstick positive or conventional proteinuria is present. Glomerular filtration generally does not begin to fall until proteinuria is present, when, untreated, there is a progressive decline in glomerular filtration over a further 10 years, until end stage kidney failure is reached.
Earlier literature suggested that the cumulative incidence of microalbuminuria after 30 years of type 1 diabetes was approximately 50% and that 30%-40% of patients would develop proteinuria.1 The incidence of proteinuria peaked at 4%-5% around 15-20 years’ duration, with a smaller peak at 30-35 years’ duration.2 However, more recently, work has shown that the appearance of nephropathy may be delayed.3-5 The cumulative incidence of microalbuminuria and proteinuria in several more recent studies is 35%-40% and 25% respectively after 25-30 years of diabetes. Initially earlier studies suggested that 80% of type 1 diabetic patients with microalbuminuria would progress to proteinuria.6,7 However, more recent studies suggest that around one third of microalbuminuric patients will revert to normal albumin excretion and only one third will progress to proteinuria.8–10 In addition, in one small study, 24.4% of initially normoalbuminuric type 1 diabetic patients with duration of diabetes >30 years developed microalbuminuria or proteinuria in a seven-year follow-up.11 Also in this study, 32% of the initially microalbuminuric patients progressed to proteinuria, in contrast to earlier suggestions that microalbuminuria in long-term duration diabetes was a benign condition.12
Thus, the classical natural history of the development of nephropathy in type 1 diabetes is undoubtedly being modified. Microalbuminuria develops at around 2%-3% a year, with a cumulative incidence over a lifetime of diabetes of approximately 50%. Around one third of individuals with microalbuminuria will progress to proteinuria, at a rate of 2%-3% a year, and almost all proteinuric patients eventually develop end-stage disease. One small study has suggested that microalbuminuria and proteinuria may appear at any duration of diabetes, and patients with diabetes of long duration not protected.
Type 2 diabetes
The cumulative incidence of proteinuria in type 2 diabetic patients is similar to that of type 1 patients. Several studies have demonstrated rates of development of microalbuminuria and proteinuria in type 2 diabetic patients that are approximately comparable to those in type 1 patients.13,14
In non-Caucasians, the cumulative risk of nephropathy is almost certainly higher and the disease may develop more rapidly than in Caucasian people. In Pima Indians (the most intensively studied population) more than 50% develop proteinuria within 20 years of diabetes.15 Longitudinal studies suggest that as in type 1 diabetes, glomerular filtration rate is preserved at the microalbuminuric stage. It is particularly concerning that the incidence of end-stage kidney disease in the Pima Indians continues to rise despite improvements in blood glucose and blood pressure control. In other non-Caucasian populations, cross sectional studies indicate a prevalence of microalbuminuria of 30%–60%16-18 and longitudinal studies suggest a rate of progression from normal albumin excretion to microalbuminuria of around 4%.19
End-stage kidney disease
Worldwide, diabetic nephropathy is now the single commonest cause of entry to kidney replacement therapy (KRT) programmes.20 In 2001, the incidence of end-stage kidney disease caused by diabetes was 148 per million population in the United States, 44.3% of the population beginning KRT having diabetes. However, the proportion of new entrants to KRT with diabetes varies widely geographically, from 54.4% in Brunei to 9.7% in Bulgaria.