In the past year six sets of recommendations on the prevention of diabetic nephropathy, with special reference to microalbuminuria, have been published [1][2][3][4][5][6]. The background to this activity was the large and increasing number of diabetic patients in whom end-stage renal failure (ESRD) develops and who therefore require dialysis or renal transplantation. Throughout the world about half a million patients are registered as being on renal replacementtherapy, and diabetic nephropathy is the cause in nearly one-fifth of them [7]. These data are extrapolated from countries which have registeries but in many areas, especially in the densely populated countries of the Far East, accurate information on numbers of patients with ESRDis not yet available. Moreover, the half-million figure probably underestimates the number of diabetic patients with ESRD because selection criteria for renal replacementtherapies vary from country to country. Both insulin dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients contribute to the increase in ESRD. Prevention of diabetic renal disease, or at least the postponement or slowing down of the disease process, has emerged as a key issue. Our strategy is to develop programmes for all patients with diabetes, focused on early detection of renal diseasefollowed by intervention.Increased urinary albumin excretion also predicts early mortality in NIDDM [8,9], and the same relation is observed in the general population too [10][11][12][13], possibly associated with the metabolic syndrome, of which raised blood pressure (BP) is an important component. The association with vascular disease is important [10,12,13]. Microalbuminuria is common in poorly treated individuals with essential hypertension [14]. It is not yet known if screening for microalbuminuria and subsequent treatment will improve outcome in hypertensive non-diabetic patients or in the general population. In diabetes, however, the evidence is strong.

Forty-four non-insulin-dependent diabetics (NIDD), all with urine negative to Albustix, were studied in 1966/67. By the end of 1980, 17 had died, all but two from cardiovascular causes. All causes of mortality and time to death were significantly related in univariate analyses to age and to the overnight urinary albumin excretion rate (AER), but not to systolic and diastolic blood pressure levels or to duration of diabetes when the latter was corrected for age. Age and duration were highly correlated with each other. In multivariate analyses age and AER were independent predictors of both mortality and time to death, with AER having the greater degree of significance. Thus subclinically elevated albumin excretion rates ('microalbuminuria') indicate a substantially increased mortality risk in non-insulin-dependent diabetes.

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There is an individual susceptibility to diabetic nephropathy, and oxidative stress is believed to play an important role in the pathogenesis of diabetic complications. Active oxygen species induce antioxidant enzyme expression in tissues, an effect considered to be a defensive mechanism. To test whether altered intracellular antioxidant enzyme production might explain the predisposition to diabetic nephropathy, we studied the effect of long-term (12 weeks) exposure to normal (5 mmol/l) or high (22 mmol/l) glucose concentrations on fibroblast antioxidant enzyme gene expression and protein activity in type 1 diabetic patients with and without nephropathy, nondiabetic nephropathic patients, and nondiabetic control subjects. Under conditions of normal glucose concentration in the culture media, CuZnSuperoxide-dismutase, MnSuperoxide-dismutase, catalase, and glutathione-peroxidase activity and mRNA expression were not different among the four groups. Under high-glucose conditions, CuZnSuperoxide-dismutase mRNA and activity increased similarly in all groups (P < 0.001 vs. basal), whereas MnSuperoxide-dismutase did not change. In contrast, catalase mRNA and activity as well as glutathione-peroxidase mRNA and activity increased in fibroblasts from type 1 diabetic patients without nephropathy (P < 0.001), in fibroblasts from nondiabetic nephropathic patients (P < 0.001), and in fibroblasts from nondiabetic control subjects (P < 0.001), but not in fibroblasts from type 1 diabetic patients with nephropathy. Exposure to high glucose concentrations significantly increased lipid peroxidation in cells, higher levels being found in cells from diabetic patients with nephropathy (P < 0.001). These data, while confirming that exposure to high glucose concentrations induces an antioxidant defense in skin fibroblasts from normal subjects, demonstrate a failure of this defensive mechanism in cells from type 1 diabetic patients with nephropathy, whereas skin fibroblasts from diabetic patients without complications or from nondiabetic nephropathic patients have an intact antioxidant response to glucose-induced oxidative stress.

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