Previous studies by our group have shown that albumin is metabolized in rodents during renal passage and excreted in the urine as a mixture of intact protein and albumin-derived fragments. The aim of this study was to examine whether albumin is metabolized during renal passage in nondiabetic volunteers and in type 1 diabetic patients with varying levels of albuminuria. Nine nondiabetic normoalbuminuric volunteers and 11 type 1 diabetic patients with albumin excretion rates varying from normoalbuminuria to macroalbuminuria were studied. Each subject received an intravenous injection of tritium-labeled albumin ([ 3 H]-albumin). Urine was collected at 4 h and 24 h after injection and analyzed by size exclusion chromatography. The amount of intact and fragmented albumin was quantified, and each fraction was analyzed by radioimmunoassay (RIA) for albumin. [ 3 H]-albumin in nondiabetic volunteers was metabolized during renal passage to small peptide fragments not detectable by conventional RIA (only 0.05-3.8% of the total urinary radioactivity was associated with intact albumin). The process responsible for albumin fragmentation was similar in diabetic patients with normoalbuminuria (intact albumin represented 0.01-4.0% of total urinary radioactivity). However, there was a reduction in the fragmentation ratio (fragmented:intact) in diabetic patients with micro-or macroalbuminuria (intact albumin represented 2.7-55.5%, P = 0.048). This change in the fragmentation ratio was directly related to the degree of albuminuria. These results have important implications for understanding the mechanisms underlying albuminuria in nondiabetic volunteers and type 1 diabetic patients. In nondiabetic volunteers, the renal processing of albumin involves a relatively rapid and comprehensive degradation of albumin to small fragments (range 1-15 kDa). The degradation process is inhibited in diabetic nephropathy in proportion to the level of albuminuria detected by RIA. Diabetes 49:1579-1584, 2000 M icroalbuminuria, as measured by radioimmunoassay (RIA), is generally equated with the development of diabetic nephropathy in type 1 diabetes (1,2). The change in albumin excretion rate (AER) has traditionally been explained as being due to changes in the glomerular permselectivity barrier and intraglomerular pressure (3,4) with the assumption that albumin remains intact during filtration and renal passage. However, recent studies by our group using tritium-labeled albumin ([ 3 H]-albumin) in a rodent model have demonstrated that albumin excretion could be significantly influenced by the metabolism of albumin to small peptide fragments during its renal passage (5-9). The fragmentation is extensive, with 90-95% of the urinary albumin representing a complex fragment population of >30 different fragments with molecular weights in the range of 1-15 kDa. These albumin-derived fragments are not detected by standard immunochemical assays (6,8). A small number of studies have previously identified albumin fragments in human urine, although the source of...

OBJECTIVE -Diabetic subjects have a high prevalence of hypertension, increased total body exchangeable sodium levels, and an impaired ability to excrete a sodium load. This study assessed the effect of dietary sodium restriction on the efficacy of losartan in hypertensive subjects with type 2 diabetes and albumin excretion rates of 10 -200 g/min.RESEARCH DESIGN AND METHODS -In this study, 20 subjects were randomized to losartan 50 mg/day (n ϭ 10) or placebo (n ϭ 10). Drug therapy was given in two 4-week phases separated by a washout period. In the last 2 weeks of each phase, patients were assigned to low-or regular-sodium diets, in random order. In each phase, 24-h ambulatory blood pressure, urinary albumin-to-creatinine ratio (ACR), and renal hemodynamics were measured.RESULTS -Achieved urinary sodium on a low-sodium diet was 85 Ϯ 14 and 80 Ϯ 22 mmol/day in the losartan and placebo groups, respectively. In the losartan group, the additional blood pressureϪlowering effects of a low-sodium diet compared with a regularsodium diet for 24-h systolic, diastolic, and mean arterial blood pressures were 9.7 mmHg (95% confidence interval [CI], 2.2Ϫ17.2; P ϭ 0.002), 5.5 mmHg (2.6Ϫ8.4; P ϭ 0.002), and 7.3 mmHg (3.3Ϫ11.3; P ϭ 0.003), respectively. In the losartan group, the ACR decreased significantly on a low-sodium diet versus on a regular-sodium diet (Ϫ29% [CI Ϫ50.0 to Ϫ8.5%] vs. ϩ14% [Ϫ19.4 to 47.9%], respectively; P ϭ 0.02). There was a strong correlation between fall in blood pressure and percent reduction in the ACR (r ϭ 0.7, P ϭ 0.02). In the placebo group, there were no significant changes in blood pressure or ACR between regularand low-sodium diets. There were no significant changes in renal hemodynamics in either group.CONCLUSIONS -These data demonstrated that a low-sodium diet potentiates the antihypertensive and antiproteinuric effects of losartan in type 2 diabetes. The blood pressure reduction resulting from the addition of a low-sodium diet to losartan was of similar magnitude to that predicted from the addition of a second antihypertensive agent. Diabetes Care 25:663-671, 2002H igh blood pressure is an important modifiable risk factor in preventing diabetic micro-and macrovascular complications. Subjects with diabetes have a high prevalence of hypertension and often require multiple antihypertensive agents to achieve blood pressure targets (1).The role of ACE inhibitors in the prevention and treatment of diabetic nephropathy is well established in patients with type 2 (2) and type 1 diabetes (3). More recently, blockade of the reninangiotensin system (RAS) with angiotensin (ANG)-II receptor antagonists has been shown to attenuate the rate of progression of renal dysfunction in patients with type 2 diabetes (4,5).In nondiabetic subjects with renal disease, the antiproteinuric effects of ACE inhibitors strongly depend on dietary sodium intake (6). Furthermore, the antihypertensive effects of ANG-II receptor antagonists have shown dependence on the baseline activation of the RAS in nondiabetic patients (7). In...

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