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Objective: Irbesartan was renoprotective independently of its blood pressure-lowering effect in the Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA2) study. However, blood pressure was evaluated by trough office blood pressure (OBP), which may underestimate reductions in 24-h ambulatory blood pressure (ABP). In the present study, we evaluated 24-h blood pressure patterns in a subpopulation of the IRMA2 trial.Research Design and Methods: Type 2 diabetic patients (n = 43) with persistent microalbuminuria (as determined by repeated overnight measurements of urinary albumin excretion [UAE]) and hypertension who were included in the IRMA2 study at the Steno Diabetes Center were subjected to 24-h ABP (Takeda, TM2420) measurements before and 2 years after randomization to placebo (n = 15), irbesartan 150 mg daily (Irb150; n = 13), or irbesartan 300 mg daily (Irb300; n = 15).Results: At baseline, the placebo, Irb150, and Irb300 groups were comparable: OBP: 157 +/- 15/89 +/- 7, 156 +/-15/91 +/- 11, and 159 +/- 16/90 +/- 9 mmHg (NS); 24-h ABP: 148 +/- 13/83 +/- 11, 148 +/- 16/82 +/- 7 and 147 +/- 16/81 +/- 10 mmHg (NS); and UAE (geometric mean with 95% CI): 43 (32-57), 46 (30-70), and 59 (42-85) micro g/min (NS), respectively. We found that 2 years after randomization, OBP was significantly reduced in all three groups (by 11/7, 13/8, and 13/8 mmHg in the placebo, Irb150, and Irb300 groups, respectively), but that there were no significant differences among groups. Reductions in 24-h ABP were similar in the three groups (11/10, 5/7, and 7/8 mmHg, respectively; NS), as were reductions in day ABP (11/9, 7/7, and 8/9 mmHg, respectively; NS) and night ABP (4/11, 7/7, and 3/3 mmHg, respectively; NS). The reduction in UAE at the end of the study was 0% (-86 to 42), 38% (-14 to 66), and 73% (59 to 82), respectively (overall, P < 0.01).Conclusion: Irbesartan is renoprotective independently of its beneficial effect in lowering 24-h blood pressure in patients with type 2 diabetes and persistent microalbuminuria. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the cumulative incidence of nephrotic-range albuminuria (NRA), the frequency of remission, and the impact on progression, we analyzed data from a prospective cohort study of type 1 diabetic patients with diabetic nephropathy.Research Design and Methods: All of the albuminuric type 1 diabetic patients (n = 321, 121 women), who had at least yearly measurements of glomerular filtration rate (GFR) with a (51)Cr-EDTA plasma clearance technique and were followed for at least 3 years, were evaluated. NRA, defined as persistent albuminuria >2,500 mg/24 h, occurred in 126 patients (35 women) aged (mean +/- SD) 34 +/- 8 years, with duration of diabetes 22 +/- 8 years and follow-up time from onset of NRA (median [range]) 8.7 (3.0-20.9) years. Remission of NRA was defined as sustained albuminuria <600 mg/24 h for at least 1 year.Results: The cumulative incidence of NRA was 39%. Remission was induced in 28 of 126 (22%) patients; 21 were predominantly treated with ACE inhibitors, 7 with non-ACE inhibitor medications. Remission lasted 3.6 (1.0-18.1) years. More women (37%) than men (16%) obtained remission (P = 0.01). In the remission group compared with the no-remission group, mean arterial blood pressure (mean +/- SEM) was reduced (102 +/- 1 vs. 106 +/- 1 mmHg, P < 0.01), the rate of decline in GFR was diminished (3.8 +/- 0.6 vs. 7.5 +/- 0.5 ml x min(-1) x year(-1), P < 0.001), and serum cholesterol was lower (5.3 +/- 0.2 vs. 6.1 +/- 0.1 mmol/l, P < 0.01) during the whole follow-up period. No difference in glycemic control was found between groups (HbA(1c) 9.2 vs. 9.4%, NS).Conclusions: In contrast to observations made before the use of antihypertensive treatment, our prospective observational study suggests that aggressive antihypertensive treatment with and without ACE inhibitors can induce long-lasting remission in a sizeable fraction of type 1 diabetic patients with NRA. The group of patients obtaining remission is characterized by slow progression of diabetic nephropathy and improved cardiovascular risk profile. [ABSTRACT FROM AUTHOR]

Objective: To evaluate vitamin D as a predictor of all-cause mortality, progression from normoalbuminuria to micro- or macroalbuminuria, and the development of background or proliferative retinopathy in patients with type 1 diabetes., Research Design and Methods: A prospective observational follow-up study in which an inception cohort of type 1 diabetic patients was followed from onset of diabetes diagnosed between 1979 and 1984. Plasma vitamin D [25(OH)D3] levels were determined by high performance liquid chromatography/tandem mass spectrometry in 227 patients before the patients developed microalbuminuria. Values equal to or below the 10% percentile (15.5 nmol/L) were considered severe vitamin D deficiency., Results: Median (range) vitamin D was 44.6 (1.7-161.7) nmol/L. Vitamin D level was not associated with age, sex, urinary albumin excretion rate (UAER), or blood pressure. During follow-up, 44 (18%) patients died. In a Cox proportional hazards model, the hazard ratio for mortality in subjects with severe vitamin D deficiency was 2.7 (1.1-6.7), P = 0.03, after adjustment for UAER, HbA(1c), and conventional cardiovascular risk factors (age, sex, blood pressure, cholesterol, smoking). Of the 220 patients, 81 (37%) developed microalbuminuria and 27 (12%) of these progressed to macroalbuminuria. Furthermore, 192 (87%) patients developed background retinopathy, whereas 34 (15%) progressed to proliferative retinopathy. Severe vitamin D deficiency at baseline did not predict the development of these microvascular complications., Conclusions: In patients with type 1 diabetes, severe vitamin D deficiency independently predicts all-cause mortality but not development of microvascular complications in the eye and kidney. Whether vitamin D substitution in type 1 diabetic patients can improve the prognosis remains to be investigated.

Objective: Urinary liver-type fatty acid-binding protein (u-LFABP) is a marker of tubulointerstitial inflammation and has been shown to be increased in patients with type 1 diabetes and is further increased in patients who progress to micro- and macroalbuminuria. Our aim was to evaluate u-LFABP as a predictor of progression to micro- and macroalbuminuria in type 1 diabetes., Research Design and Methods: From an inception cohort of 277 patients, u-LFABP, adjusted for urinary creatinine (enzyme-linked immunosorbent assay), was measured in 24-h urine samples from 165 normoalbuminuric patients 9.6 +/- 3.5 (mean +/-SD) years after onset of type 1 diabetes. The outcome measured was development of persistent micro- or macroalbuminuria or death., Results: Patients were followed for a median of 18 (range 1-19) years; 39 progressed to microalbuminuria, 8 of those progressed further to macroalbuminuria, and 24 died. In a Cox regression model, baseline log u-LFABP levels predicted the development of microalbuminuria, adjusted for known risk factors (sex, age, A1C, systolic and diastolic blood pressure, albumin excretion rate, serum creatinine, and smoking) (hazard ratio [HR] 2.3 [95% CI 1.1-4.6]) and log u-LFABP predicted mortality (adjusted HR 3.0 [1.3-7.0]). u-LFABP (above versus below the median) predicted the development of macroalbuminuria (adjusted HR 2.6 [1.2-5.4]). As a continuous variable, u-LFABP tended to predict macroalbuminuria (HR 1.9, P = 0.2), but numbers were small., Conclusions: High levels of the tubular inflammation marker u-LFABP predict the initiation and progression to diabetic nephropathy and all-cause mortality, independent of urinary albumin excretion rate and other established risk factors.

Objective: Levels of connective tissue growth factor (CTGF; CCN-2) in plasma are increased in various fibrotic disorders, including diabetic nephropathy. Recently, several articles have reported a strong increase of urinary CTGF excretion (U-CTGF) in patients with diabetic nephropathy. However, these studies addressed too small a number of patients to allow general conclusions to be drawn. Therefore, we evaluated U-CTGF in a large cross-sectional study of patients with type 1 diabetes., Research Design and Methods: Subjects were 318 type 1 diabetic patients and 29 normoglycemic control subjects. U-CTGF was measured by sandwich enzyme-linked immunosorbent assay. Groups were compared by Kruskal-Wallis and Mann-Whitney analysis. The relation between U-CTGF and markers of diabetic nephropathy was determined by regression analysis., Results: U-CTGF in patients with diabetic nephropathy (n = 89, median 155 pmol/24 h [interquartile range 96-258]) was significantly higher than in microalbuminuric (n = 79, 100 [65-78]) and normoalbuminuric (n = 150, 85 [48-127]) patients and control subjects (n = 29, 100 [78-114]). U-CTGF correlated with urinary albumin excretion (UAE) (R = 0.31) and glomerular filtration rate (R = -0.38) in patients with diabetic nephropathy. A standardized increase in U-CTGF was associated with diabetic nephropathy (odds ratio 2.3 [95% CI 1.7-3.1]), which was comparable with the odds ratios for diabetic nephropathy of increased HbA(1c) (2.0 [1.5-2.7]), and blood pressure (2.0 [1.5-2.6])., Conclusions: This is the first large cross-sectional study addressing U-CTGF in human type 1 diabetes. The observed association of U-CTGF with UAE and glomerular filtration rate might reflect a role of CTGF as progression promoter in diabetic nephropathy.

Objective: Diabetes, the leading cause of end-stage renal disease in the U.S., is believed to involve activation of the renin angiotensin system (RAS) as a risk factor for nephropathy. RAS activation occurs in healthy women using oral contraceptives (OCs), but the effects of OC use on the diabetic kidney are unclear., Research Design and Methods: Renal plasma flow (RPF) response to captopril, as an index of RAS activity, was investigated in 92 women (41 nondiabetic OC nonusers, 10 nondiabetic OC users, 29 diabetic OC nonusers, and 12 diabetic OC users). Based on the hemodynamic findings, we examined the impact of OC use on the development of nephropathy as a post hoc analysis in an inception cohort of 114 female patients with newly diagnosed type 1 diabetes followed for a median of 20.7 years (range 1-24)., Results: Nondiabetic OC nonusers showed minimal RPF vasodilator response to captopril (9 +/- 10 ml x min(-1) x 1.73 m(-2), P = 0.6). In comparison, nondiabetic OC users showed a significant increase (69 +/- 35 ml x min(-1) x 1.73 m(-2), P = 0.02) (P = 0.04 vs. nondiabetic OC nonusers). Diabetic OC nonusers demonstrated the anticipated vasodilator response (58 +/- 12 ml x min(-1) x 1.73 m(-2), P < 0.0001). Diabetic OC users showed the largest responses (84 +/- 12 ml x min(-1) x 1.73 m(-2), P = 0.002) (P = 0.04 vs. diabetic OC nonusers). Plasma renin activity did not vary with OC use (P = 0.3). The RPF responses to captopril and angiotensin receptor blocker were highly correlated (r = 0.72, P < 0.001), suggesting clear involvement of the RAS. In the observational study, 18% (6/33 [95% CI 4.3-32.1]) of OC users developed macroalbuminuria compared with 2% (2/81 [0-5.9]) of OC nonusers (P = 0.003, univariate analysis). After adjustment for known risk factors with a Cox regression model, OC use remained a predictor for the development of macroalbuminuria (relative risk 8.90 [95%CI 1.79-44.36], P = 0.008)., Conclusions: The strong association of OC use with angiotensin-dependent control of the renal circulation and the development of macroalbuminuria suggest that OC use may be a risk factor for diabetic nephropathy. Large prospective studies are required to further investigate this relationship.

Objective: Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy., Research Design and Methods: ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 micromol/l [range 52-684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9])., Results: In patients with diabetic nephropathy, mean +/- SD plasma ADMA concentration was elevated 0.46 +/- 0.08 vs. 0.40 +/- 0.08 micromol/l in normoalbuminuric patients (P<0.001). An increase in plasma ADMA of 0.1 micromol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89-4.05) (P<0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (<76 ml.min(-1).1.73 m(-2)) (P<0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P>0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 +/- 0.08 micromol/l compared with 0.46 +/- 0.08 micromol/l in patients without major cardiovascular events (P=0.05)., Conclusions: Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.

Objective: Conflicting evidence of a decline in incidence of microvascular complications in type 1 diabetes during the last decades has been reported. To assess recent trends in the cumulative incidence of diabetic microangiopathy in type 1 diabetes, we analyzed data from long-term prospective observational studies lasting >/=20 years., Research Design and Methods: A total of 600 Caucasian patients with onset of type 1 diabetes between 1965 and 1984 were followed until death or until the year 2000. Patients were divided into four groups based on the year of diabetes onset: group A, 1965-1969 (n = 113); group B, 1970-1974 (n = 130); group C, 1975-1979 (n = 113); and group D, 1979-1984 (n = 244). Group A, B, and C are prevalence cohorts identified in 1984; group D is an inception cohort., Results: In patients followed for >/=20 years, the cumulative incidence (95% CI) of diabetic nephropathy after 20 years of diabetes (urinary albumin excretion >300 mg/24 h) was reduced in patients with more recent diabetes onset (groups A-D): 31.1% (22.5-39.7) vs. 28.4% (19.8-37.0) vs. 18.9% (10.9-26.9) vs. 13.7% (6.2-21.2) (P = 0.015). Similarly, the cumulative incidence of proliferative retinopathy was as follows: 31.2% (22.2-39.8) vs. 30.3% (22.2-38.4) vs. 19.3% (11.2-27.4) vs. 12.5% (5.2-19.8) (P < 0.01). In the latter groups, antihypertensive treatment was started earlier, blood pressure and HbA(1c) were lower, and fewer patients smoked., Conclusions: Our study demonstrates a decrease in the cumulative incidence of diabetic microangiopathy in type 1 diabetes over the past 35 years. Improved glycemic control, lower blood pressure (in part due to early aggressive antihypertensive treatment), and reduced prevalence of smoking rates were associated with the improved prognosis.

Objective: Cigarette smoking contributes to development of diabetic nephropathy. However, long-term studies on the effect of smoking on decline in kidney function in diabetic nephropathy are lacking. We assessed the impact of smoking on progression of diabetic nephropathy in type 1 diabetic patients enrolled in a prospective observational cohort study started in 1983., Research Design and Methods: We identified all albuminuric type 1 diabetic patients (n = 301) followed for at least 3 years, median (range) 7 years (3-14), who underwent at least yearly measurement of glomerular filtration rate (GFR) by the (51)Cr-EDTA plasma clearance technique (n = 8, range 3-24). In total, 192 men and 109 women were included (age [mean +/- SD] 36 +/- 11 years, duration of diabetes 22 +/- 8 years); 271 patients were treated with antihypertensive drugs, predominantly ACE inhibitors in 179 patients. Patients were classified as smokers if they smoked more than one cigarette per day during a portion of or the entire observation period. Blood pressure, albuminuria, HbA(1c), and serum cholesterol were measured every 3-4 months during the study., Results: In all 301 patients, the mean (SE) rate of decline in GFR (deltaGFR) was 4.0 (0.2) mlx min(-1) x year(-1) during the investigation period. No difference in Delta GFR was demonstrated between nonsmokers (n = 94), deltaGFR 4.5 (0.4), ex-smokers (n = 31), deltaGFR 3.1 (0.7), and smokers (n = 176), deltaGFR 3.9 (0.3) ml x min(-1) x year(-1), respectively (NS). Adjustment for other risk factors for progression of diabetic nephropathy did not alter the results: smoking was not associated with deltaGFR, whereas blood pressure, albuminuria, HbA(1c), and serum cholesterol were demonstrated to be independent progression promoters., Conclusions: In our study, smoking was not associated with decline in kidney function in type 1 diabetic patients with diabetic nephropathy.