Diabetic nephropathy, characterized by increasing levels of microalbuminuria, hypertension, and ultimately renal failure, afflicts approximately 35% to 40% of patients with either type I or type II diabetes [1]. Many studies show the benefits of adequate blood pressure control to slow progression of diabetic renal disease and reduce albuminuria in hypertensive patients with either type I or type II diabetes [2-4]. Moreover, early clinical studies show that any pharmacologic agent that controls arterial pressure slows progression of diabetic renal disease [2, 4]. Recent studies, however, show that angiotensin-converting enzyme (ACE) inhibitors may have selective renal effects that are separate from reduction of arterial pressure [2, 5].

Given these renal effects of ACE inhibitors in established diabetic nephropathy, two important questions remain unanswered: Can we predict development of diabetic nephropathy before the onset of hypertension, that is, what are the risk factors? Second, can the use of antihypertensive agents that reduce microalbuminuria without lowering blood pressure (ACE inhibitors) also slow progression of diabetic renal disease? Many studies in normotensive patients with type I diabetes have attempted to answer these questions [6-13]. The study by Ravid and colleagues, in this issue of Annals, is the first large-scale, double-blind, randomized trial that addresses these issues in patients with type II diabetes [14].

For patients with type I diabetes, risk factors for nephropathy include a positive family history for cardiovascular disease or hypertension or both [15, 16], microalbuminuria [2, 17], and elevated plasma prorenin levels that occur before development of microalbuminuria or hypertension [18]. The potential for plasma prorenin levels to serve as a marker for development of diabetic nephropathy is the focus of an ongoing, international research study.

Of these risk factors, well characterized for patients with type I diabetes, only microalbuminuria has been examined in type II diabetic patients [2, 17]. The study by Ravid and colleagues [14] determined the effect of an ACE inhibitor on changes in microalbuminuria and its correlation with progression of renal disease, as assessed by the reciprocal of serum creatinine, in patients with type II diabetes. The results of their study are consistent with four previous long-term, randomized trials that used an ACE inhibitor in normotensive type I diabetic patients [8-11]. These studies showed a reduction in microalbuminuria that correlated with a slowed decline in renal function in the absence of blood pressure reduction or any other acute renal hemodynamic process.

Other long-term studies, which examined the effects of ACE inhibitors on microalbuminuria and preservation of renal function in normotensive patients with type I diabetes, showed similar findings [6, 7, 12, 13]. In all these studies either arterial pressure or glomerular filtration rate was reduced. Therefore, no conclusive statements could be made about the isolated effects of ACE inhibitors on preservation of renal function. These and other studies are reviewed by Kasiske and colleagues [19]. The conclusion of their meta-analysis was that ACE inhibitors, in normotensive patients with diabetes, appeared to have renal effects independent of blood pressure reduction. These observations in type I diabetic patients are consistent with those of Ravid and colleagues [14] in patients with type II diabetes.

The mechanisms in the development of albuminuria in diabetic patients are the focus of intense research. Both increases in intraglomerular pressure and volume as well as altered interactions of various cellular growth factors contribute to microalbuminuria [2]. A key factor in the genesis of microalbuminuria relates to alterations in synthesis of glomerular extracellular matrices, that is, mesangium and glomerular basement membrane [2, 20]. These changes in matrix structure are secondary to a reduced synthesis of various anionic macromolecules called proteoglycans [2, 20]. Reduced synthesis of heparan sulfate proteoglycans results in loss of negative charge on the membrane and, hence, leakage of albumin [20]. This loss of charge selectivity is partially restored by ACE inhibitors and is not directly affected by angiotensin II [2, 21, 22].

Studies in diabetic dogs also show that ACE inhibitors attenuate increases in intraglomerular pressure and volume as well as prevent mesangial matrix expansion, albuminuria, and focal glomerulosclerosis, all hallmarks of diabetic nephropathy [2, 5]. The attenuated histologic progression of nephropathy by ACE inhibitors in diabetic animal models has not been observed with other classes of antihypertensive medications except the nondihydropyridine calcium antagonists (for example, verapamil, diltiazem [2, 5]). It is clear, however, that all the information about the renal hemodynamic and histologic changes of diabetes was derived from animal models that mimic an insulin deficiency state (for example, type I diabetes). Unfortunately, no histologic data are yet available from clinical trials to assess the effects of ACE inhibitors or other antihypertensive medications on progression of diabetic nephropathy.

The report by Ravid and colleagues [14] adds to the sparse literature on the early stages of diabetic renal disease in normotensive patients with type II diabetes. The size and time course of the study (5 years) allow for a useful assessment of how an ACE inhibitor affects the natural history of diabetic nephropathy in the absence of blood pressure changes. Renal function, however, was assessed by the reciprocal of serum creatinine. It is unfortunate that many of these patients did not have a formal assessment of glomerular filtration rate during the study. Thus, although this is the first study in normotensive patients with type II diabetes to show that ACE inhibition preserves renal function in the absence of blood pressure changes, additional long-term studies with more precise measurements of glomerular filtration rate are needed to confirm these observations.

Increasing evidence exists that low-dose ACE inhibitors preserve renal function in normotensive type I diabetic patients with microalbuminuria. Their role for patients with type II diabetes, however, is less clear and requires further investigation. Thus, low-dose ACE inhibitors should not be given indiscriminately. They should be reserved for the normotensive diabetic patient (types I or II) with risk factors for developing diabetic nephropathy.

Studies in normotensive diabetic patients extend the role of ACE inhibitors to preserve renal function, already documented among hypertensive diabetic patients with mild renal insufficiency [2]. Unlike most antihypertensive agents that lower blood pressure and subsequently preserve renal function, ACE inhibitors also improve insulin resistance, reduce albuminuria, and have neutral effects on lipid profiles [2]. Thus, they should be the preferred initial agents for management of hypertension in the diabetic patient.

The Joint National Committees' Report [23] on the detection, evaluation, and treatment of high blood pressure recommends diuretics and ß-blockers as initial preferred therapy for treatment of hypertension unless otherwise contraindicated. A recent long-term, prospective study [3] in type II diabetic patients showed a 38% faster rate of decline in glomerular filtration rate using ß-blockers and diuretics compared with ACE inhibitors, despite similar blood pressure reduction. Care should be taken, therefore, to select an antihypertensive agent that attenuates the rate of decline in glomerular filtration rate and ultimately reduces the need for dialysis.