Determinants of progression from microalbuminuria to proteinuria in patients who have type 1 diabetes and are treated with angiotensin-converting enzyme inhibitors.

The aims of this study were to assess the frequency and determinants of (1) treatment with angiotensin-converting enzyme inhibitors (ACE-I) and (2) progression to proteinuria in the presence of ACE-I treatment in patients with type 1 diabetes and microalbuminuria. A clinic-based cohort study of patients with type 1 diabetes was begun in 1991. The patients who were included in this study (n = 373) are the cohort members who received a diagnosis of microalbuminuria during a 2-yr baseline observation and were followed for 10 yr with frequent assessments of urinary albumin excretion and biennial examinations. Progression to proteinuria occurred when the median urinary albumin excretion during a 2-yr interval exceeded 299 mug/min. During the decade-long study, the proportion of patients who had a history of microalbuminuria and were treated with ACE-I rose from 17 to 67%. Patients who started this treatment had (on average) higher BP, higher urinary albumin excretion, and longer diabetes duration than those who did not. Microalbuminuria often progressed to proteinuria (6.3/100 person-years) in those who were treated. Poor glycemic control and elevated serum cholesterol were the major determinants/predictors of this progression. Although treatment with ACE-I increased during the past decade, it was not completely effective, because microalbuminuria progressed to proteinuria in many treated patients. Poor glycemic control and elevated serum cholesterol were the major determinants/predictors for progression while on ACE-I treatment. The mechanisms that are responsible for the frequent failure of ACE-I to prevent progression of microalbuminuria to proteinuria in a clinical setting are not clear.

Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes.

This study aimed to establish the time of initiation and the determinants of renal function decline in type 1 diabetes. Until now, such decline has been assumed to be a late-occurring event associated with proteinuria. A total of 267 patients with normoalbuminuria and 301 patients with microalbuminuria were followed for 8 to 12 yr. Linear trends (slopes) in GFR were estimated by serial measurement of serum cystatin C. Cases of early renal function decline were defined by loss in cystatin C GFR that exceeded -3.3%/yr, a threshold that corresponds to the 2.5th percentile of the distribution of GFR slopes in an independent nondiabetic normotensive population. Cases of early renal function decline occurred in 9% (mean slope -4.4; range -5.9 to -3.3%/yr) of the normoalbuminuria group and 31% (mean slope -7.1; range -23.8 to -3.3%/yr) of the microalbuminuria group (P < 0.001). Risk for early renal function decline depended on whether microalbuminuria regressed, remained stable, or progressed, rising from 16 to 32 and 68%, respectively (P < 0.001). In multivariate analysis, risk for decline was higher after age 35 yr or when glycosylated hemoglobin exceeded 9% but did not vary with diabetes duration, smoking, BP, or angiotensin-converting enzyme inhibitor treatment. Contrary to the existing paradigm of diabetic nephropathy, progressive renal function decline in type 1 diabetes is an early event that occurs in a large proportion of patients with microalbuminuria. Together with testing for microalbuminuria, clinical protocols using cystatin C to diagnose early renal function decline and track response to therapeutic interventions should be developed.

Regression of microalbuminuria in type 1 diabetes.

BACKGROUND: In the present study, we aimed to determine the frequency of a significant reduction in urinary albumin excretion and factors affecting such reduction in patients with type 1 diabetes and microalbuminuria. METHODS: The study included 386 patients with persistent microalbuminuria, indicated by repeated measurements of urinary albumin excretion (estimated on the basis of albumin-to-creatinine ratios) in the range of 30 to 299 microg per minute during an initial two-year evaluation period. Subsequent measurements during the next six years were grouped into two-year periods, averaged, and analyzed for regression of microalbuminuria, which was defined as a 50 percent reduction in urinary albumin excretion from one two-year period to the next. RESULTS: Regression of microalbuminuria was frequent, with a six-year cumulative incidence of 58 percent (95 percent confidence interval, 52 to 64 percent). The use of angiotensin-converting-enzyme inhibitors was not associated with the regression of microalbuminuria. However, microalbuminuria of short duration, salutary levels of glycosylated hemoglobin (less than 8 percent), low systolic blood pressure (less than 115 mm Hg), and low levels of both cholesterol and triglycerides (less than 198 mg per deciliter [5.12 mmol per liter] and 145 mg per deciliter [1.64 mmol per liter], respectively) were independently associated with the regression of microalbuminuria. Patients with salutary levels of all modifiable factors had a hazard ratio for regression of 3.0 (95 percent confidence interval, 1.5 to 6.0), as compared with patients with no salutary levels of any modifiable factor. CONCLUSIONS: Frequent regression of microalbuminuria in patients with type 1 diabetes indicates that elevated urinary albumin excretion does not imply inexorably progressive nephropathy. Identification of the multiple determinants of the regression of microalbuminuria has implications for current theories about the mechanisms of early diabetic nephropathy.