The Relevance Of The Problem

Nephropathy is a major cause of illness and death of patients with type 2 diabetes mellitus (DM), the excess being confined to proteinuric patients due to complications of end-stage renal disease (ESRD) and particularly due to cardiovascular events [1]. Diabetic nephropathy is the single most common cause of ESRD in the United States and more than one third of all patients enrolled in the Medicare ESRD program are actually diabetics [2]. It derives that costs of renal replacement therapy for diabetics alone is a major public health issue, approaching almost epidemic proportions for type 2 DM in Western countries [3;4].

The continuous increase in the number of diabetics needing renal replacement therapy (twice the annual rate of ESRD from other conditions [2;3] depends on one hand from a growing number of patients suffering diabetes (in particular type 2), as well as from the constant improvement in health care facilities that allows more and more patients to live long enough to progress to ESRD. Once on renal replacement therapy, however, mortality among diabetic patients is 1.5 to 2.5 times higher than in non-diabetics [4] so that less than 20% of diabetics survive for 5 years on dialysis [3;4]. This disturbing epidemiology underscores the urgent need to identify potentially treatable risk factors in order to delay or

Mogensen CE (ed.) THE KIDNEY AND HYPERTENSION IN DIABETES MELLITUS. Copyright© 2004 by Martin Dunitz, a member of the Taylor & Francis Group, plc. All rights reserved.

even completely halt the progression of diabetic nephropathy towards ESRD and need of replacement therapy.

Traditionally, the natural history of nephropathy in type 2 DM has been more difficult to characterize than in type 1 DM. This is particularly true for Caucasians in whom the onset of type 2 DM is difficult to detect and occurs at an advanced age. The confounding factors include an effect of aging per se to lower the glomerular filtration rate (GFR) [5] and a high frequency of coexistent renal disease unrelated to DM beyond the age of 50 years [6-8]. Furthermore, premature cardiovascular death, occurring in the majority of these patients before they reach ESRD [9] limits the full expression of the natural history of the renal disease.

Yet, the outcome in terms of ESRD, cardiovascular events and death is becoming predictable from the constellation of risk factors. The pivotal role of albuminuria has been further elaborated. In addition, the classical cardiovascular risk factors hypertension, dyslipidemia, obesity and smoking all seem to be involved in progression of renal disease.

ALBUMINURIA Microalbuminuria

In addition to the increased risk of progression to nephropathy, microalbuminuria also predicts cardiovascular disease. Actually, the "Steno hypothesis" has postulated that microalbuminuria points to a widespread disturbance of the endothelial cell function in diabetic and perhaps in non-diabetic patients [10]. Thus, endothelial cell barrier dysfunction in the macrocirculation may allow the transudation of plasma proteins (including lipoproteins) into the vessel wall to promote the atherogenetic process and predispose to cardiovascular events.

The presence of microalbuminuria as a predictor of progression to macroalbuminuria has been recognized since several years and applies to both type 1 and type 2 DM [11]. In 1984 Mogensen found that over 9 years the risk of progression to macroalbuminuria was only 22% in type 2 DM [9] as compared with 80% in type 1 DM patients with microalbuminuria. However, later studies in non-European series found that the predictive value of microalbuminuria is comparable in type 1 and type 2 DM. Indeed, Nelson and coworkers found that over four year the cumulative incidence of macroalbuminuria was 37% in microalbuminuric Pima Indians [12]. This is in agreement with the five-year incidence of 42% reported by Ravid et al [13] in young Jewish patients with type 2 DM and microalbuminuria at baseline. Probably, the younger age of patients in both these series as compared to that in the Mogensen study (approximately 20 years difference) allowed a larger proportion of diabetics to live enough to progress to overt nephropathy [14].

Whether the onset of microalbuminuria predicts a progressive fall in GFR is less clear. Although the Nelson's study found that in microalbuminuric Pima Indians the GFR was stable over time [12], a progressive decline in renal function, reflected by an increase in serum creatinine concentration, was reported in the Ravid's series [13].

Apart from predicting overt nephropathy, microalbuminuria also predicts cardiovascular mortality in type 2 DM [9;15]. The competing risk of cardiac death and progression to renal failure may explain, at least in part, the Mogensen's findings of a lower predictive value of microalbuminuria for the development of overt nephropathy in type 2 DM as compared with type 1 DM [9]. Indeed, in one series, over 10 years only 3% of microalbuminuric type 2 diabetic patients died from uremia, while 58% died from cardiac causes [16]. Higher urinary albumin excretion rates were found in type 2 diabetic patients with coronary heart disease both at the time the diagnosis of diabetes was made and later on. Meanwhile, in the general population too, the association between microalbuminuria and cardiovascular risk [17] and mortality [18] has been recognized.

Macroalbuminuria

In established nephropathy due to type 1 DM [19] and in non-diabetic nephropathies [20], the severity of macroalbuminuria (or proteinuria) is the strongest known predictor of progressive renal function loss. Moreover, in non-diabetic renal disease, during treatment with renin-angiotensin system (RAS) blockade (i.e. ACE inhibition or angiotensin receptor blockade, ARB), the improved renal outcome is strongly related to the effect on proteinuria [20]. Similarly, ACE inhibitors slow progression of type 1 diabetic nephropathy [19] together with usually considerable reduction of proteinuria in these patients [21]. These findings are all consistent with the view that proteins, once leaked through the glomerular barrier, are tubulotoxic and that proteinuria thus is a true mediator of disease progression [22].

In contrast, the role of proteinuria in type 2 DM has been less well-studied -until recently. Notably, type 2 diabetic patients usually are resistant to antihypertensive therapy, often requiring several drugs to control blood pressure. This therapy-resistance also applies to the antihypertensive and antiproteinuric effect of ACE inhibitors and ARBs: these effects are considerably smaller in type 2 DM than usually observed in non-diabetics or type 1 DM and this has previously prevented the possibility to study the role of proteinuria and proteinuria reduction in nephropathy due to type 2 DM.

However, two recent large double-blind, randomized trials, the Irbesartan in Diabetic Nephropathy Trial (IDNT)[23] and the Reduction of Endpoints in TYPE 2 with the Angiotensin II Antagonist Losartan (RENAAL) trial [24] have demonstrated that ARB, compared with non-RAS blocking agents, reduced the number of renal endpoints (e.g. doubling of serum creatinine and progression to ESRD) in type 2 diabetic patients with nephropathy. These studies provided an excellent opportunity to study risk factors in a time-dependent fashion, because both were prospective studies including over 1500 patients.

The issue whether proteinuria is an independent risk marker for renal -and also cardiovascular- endpoints, has specifically been addressed in the RENAAL-dataset (RENAAL study group, unpublished data). First, the predictive value of a series of putative risk factors, including blood pressure, cholesterol, HbA1C, hemoglobin, serum creatinine and proteinuria was evaluated at baseline. This analysis demonstrated that proteinuria not only is an independent risk factor, but, moreover, proteinuria is the strongest of all putative risk factors tested -both for renal as well as cardiovascular endpoints.

Together with previous findings in Caucasian [25] and Asian [26] proteinuric type 2 diabetic patients, this proves that baseline proteinuria has important predictive value, not only in non-diabetic and type 1 diabetic nephropathy, but also in type 2 DM. Moreover, in type 2 diabetic nephropathy, baseline proteinuria is to be considered also a cardiovascular risk factor.

Second, to study which changes induced by therapy predicted the renal and cardiovascular outcome, several parameters (including blood pressure, proteinuria, body weight and GFR), measured six months after randomisation, were tested in a multivariate model. This showed that suppression of proteinuria by losartan was the strongest predictor of long-term protection from renal and cardiovascular events. If proteinuria reduction was considered as the percentage change from baseline, again more benefit was achieved with a higher antiproteinuric response. Patients with more than 30% reduction of proteinuria, i.e. the average reduction observed in studies with type 1 DM and non-diabetic renal patients, had a considerably lower risk to reach renal or cardiovascular endpoints than patients with less effective proteinuria reduction -even after correction for other cardiovascular risk factors.

On the same line, a similar analysis, performed in the IDNT data-set [27], found that baseline proteinuria predicts cardiovascular and renal endpoints. Again, also the residual proteinuria and percentage change of proteinuria (measured twelve months after randomisation), were strong predictors of outcome and it was estimated that approximately 35-40% of the renoprotective effect of ARB is accounted for by the antiproteinuric effect.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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