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Background: In vitro and animal experiments have shown inhibiting effects of angiotensin receptor blockers (ARBs) on the formation of advanced glycation end products (AGEs), which are known to be involved in the development of cardiovascular complications in diabetes. However, sufficient human data to confirm such beneficial effects of ARBs on AGEs are lacking. Therefore, we investigated the effects of irbesartan treatment on plasma levels of the AGEs N(ε)(1-carboxymethyl)lysine (CML) and N(ε)(1-carboxyethyl)lysine (CEL) in hypertensive patients with type 2 diabetes and microalbuminuria., Methods: We analysed data from a multicentre, double-blind, parallel, randomized controlled trial in patients with type 2 diabetes and microalbuminuria, the primary goal of which was to examine the renoprotective effects of irbesartan treatment (150 or 300 mg daily). Secondary end points included plasma CML and CEL in the treatment arm receiving 300 mg irbesartan (n = 139) and in the placebo group (n = 125). Effects of treatment at 1- and 2-year follow-up were analysed by means of generalized estimating equations according to an intention-to-treat principle., Results: Levels of CML and CEL did not differ between groups at baseline. No significant changes were observed in CML and CEL over time in either group and there was no effect of treatment on CML and CEL at any time-point. Mean differences for the irbesartan versus placebo group over time were -0.96 μmol/mol lysine (95% confidence interval: -3.43 to 1.51) for CML and -0.10 μmol/mol lysine (-0.76 to 0.56) for CEL., Conclusions: Long-term irbesartan treatment does not influence plasma levels of the AGE CML and CEL in patients with type 2 diabetes and microalbuminuria.

Objective: Derangements of the GH-IGF-I axis have been associated with microalbuminuria (MA) in type 1 diabetes. The aim of this study was to investigate whether an IGF-I gene promoter polymorphism influenced the development of persistent MA in type 1 diabetes., Design: A prospective follow-up study of a cohort of 277 patients with newly diagnosed type 1 diabetes consecutively enrolled between September 1979 and August 1984., Methods: Urinary albumin excretion rate over 24 h was measured in each patient at least once a year. Persistent MA was defined as a urinary albumin excretion rate between 30 and 300 mg/24 h., Results: During a median follow-up of 18.0 years (range 1.0-21.5), 79 of 277 patients developed persistent MA. IGF-I gene genotype was available for 216 subjects; in 73% of the subjects, the wild-type genotype of this IGF-I gene polymorphism was present, while 27% had the variant type. At baseline, there were no differences in IGF-I levels and HbA(1c) values between subjects with the wild type and subjects with variant type. By Kaplan-Meier analysis, subjects with the variant type of this polymorphism had during follow-up a higher risk of development of MA compared subjects with the wild type (P = 0.03)., Conclusions: Subjects with the variant type of an IGF-I gene polymorphism had a significantly increased risk of developing MA. This risk was not mediated through changes in circulating IGF-I levels. Our study suggests that in type 1 diabetes, this IGF-I gene polymorphism is a risk factor of MA.

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, AIC, 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. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Experimental and clinical studies have suggested that uric acid may contribute to the development of hypertension and kidney disease. Whether uric acid has a causal role in the development of diabetic nephropathy is not known. The objective of the present study is to evaluate uric acid as a predictor of persistent micro- and macroalbuminuria. RESEARCH DESIGN AND METHODS--This prospective observational follow-up study consisted of an inception cohort of 277 patients followed from onset of type 1 diabetes. Of these, 270 patients had blood samples taken at baseline. In seven cases, uric acid could not be determined; therefore, 263 patients (156 men) were available for analysis. Uric acid was measured 3 years after onset of diabetes and before any patient developed microalbuminuria. RESULTS--During a median follow-up of 18.1 years (range 1.0-21.8), 23 of 263 patients developed persistent macroalbuminuria (urinary albumin excretion rate >300 mg/24 h in at least two of three consecutive samples). In patients with uric acid levels in the highest quartile (>249 µmol/l), the cumulative incidence of persistent macroalbumnuria was 22.3% (95% CI 10.3-34.3) compared with 9.5% (3.8-15.2) in patients with uric acid in the three lower quartiles (log-rank test, P = 0.006). In a Cox proportional hazards model with sex and age as fixed covariates, uric acid was associated with subsequent development of persistent macroalbuminuria (hazard ratio 2.37 [95% CI 1.04-5.37] per 100 µmol/l increase in uric acid level; P = 0.04). Adjustment for confounders did not change the estimate significantly. CONCLUSIONS--Uric acid level soon after onset of type 1 diabetes is independently associated with risk for later development of diabetic nephropathy. Diabetes 58:1668-1671, 2009 [ABSTRACT FROM AUTHOR]

Inflammation and complement activation via the mannose-binding lectin (MBL) pathway have been suggested to play a role in the pathogenesis of diabetic microvascular complications. The association between the complement-activating protein MBL and the development of persistent microalbuminuria was evaluated in an inception cohort of 286 newly diagnosed type 1 diabetic patients consecutively admitted to the Steno Diabetes Center between 1 September 1979 and 31 August 1984. Serum MBL was measured with an immunofluorometric assay in 270 of the patients (159 men) after 3 years of diabetes duration. During the median (range) follow-up period of 18.0 (1.0-21.8) years, 75 patients subsequently progressed to persistent micro- or macroalbuminuria (urinary albumin excretion rate >30 mg/24 h). In patients with MBL levels above the median (1,597 microg/l), the cumulative incidence of persistent micro- or macroalbuminuria was 41% (CI 31-50) as compared with 26% (CI 17-34) in patients with MBL levels below the median (log-rank test, P = 0.003). In a Cox proportional hazard model with sex and age as fixed covariates, MBL was independently associated with later development of persistent micro- or macroalbuminuria (hazard ratio 1.21 [CI 1.02-1.42] per 1,000 microg/l increase in MBL; P = 0.03) after adjusting for possible confounders. In our study, high levels of MBL early in the course of type 1 diabetes was significantly associated with later development of persistent micro- or macroalbuminuria, suggesting that complement activation initiated by MBL may be involved in the pathogenesis of diabetic microvascular complications. [ABSTRACT FROM AUTHOR]

Improved survival in patients obtaining remission of nephrotic range albuminuria in diabetic nephropathy. Background. The level of albuminuria is related to progression of diabetic nephropathy, and patients with nephrotic range albuminuria have advanced renal structural changes and the fastest decline in glomerular filtration rate (GFR). We have previously demonstrated that the rate of decline in GFR is diminished in patients obtaining remission of nephrotic range albuminuria, but information is scarce concerning the impact of remission of nephrotic range albuminuria on the long-term prognosis. Methods. At the Steno Diabetes Center, we performed a prospective cohort study of all type 1 diabetic patients with nephrotic range albuminuria ( N= 125), who had annual measurement of GFR [51chromium-ethylenediaminetetraacetic acid (51Cr-EDTA) plasma clearance] carried out for at least 3 years. Patients were followed from onset of nephrotic range albuminuria until death or the end of year 2003. Nephrotic range albuminuria was defined as persistent albuminuria above 2.5 g/24 hours, remission of nephrotic range albuminuria was defined as sustained albuminuria <0.6 g/24 hours for at least 1 year. Results. Nephrotic range albuminuria occurred in 90 men and 35 women, age [mean (SD)] 34 (8) years, duration of diabetes 22 (8) years, and follow-up time from onset of nephrotic range albuminuria [median (range)] 12.4 (3.0 to 24.9) years. Remission was induced in 32 patients (26%), 25 predominantly treated with angiotensin-converting enzyme (ACE) inhibitors, seven with non-ACE inhibitors. The remission lasted 5.5 (1.0 to 22.4) years. At the end of follow-up, 25% in the remission group and 74% in the no remission group had reached the composite end point of end-stage renal disease (ESRD) (dialysis, transplantation) or death. A Cox proportional hazard regression analysis with gender and age as fixed covariates and remission as time-dependent covariate revealed that obtaining remission was associated with a lower risk of dialysis, transplantation, or death, relative risk (95% CI) 0.28 (0.13 to 0.59), P= 0.001, whereas older age at onset of nephrotic range albuminuria (per 10-year increase) was associated with higher risk of reaching the end point, 1.42 (1.08 to 1.87), P= 0.01. Conclusion. Our prospective study suggests that remission of nephrotic range albuminuria in type 1 diabetic patients, induced by aggressive antihypertensive treatment with and without ACE inhibitors, is associated with a slower progression in diabetic nephropathy and a substantially improved survival. [ABSTRACT FROM AUTHOR]

Remission and regression in the nephropathy of type 1 diabetes when blood pressure is controlled aggressively. Background. Diabetic nephropathy is a chronic, progressive kidney disease with a mean rate of decline of in glomerular filtration rate (GFR) of 10 to 12 mL/min/year (natural history). The introduction of aggressive antihypertensive treatment has improved the renal prognosis during the last decades. To examine whether remission and regression of diabetic nephropathy are possible in type 1 diabetic patients, we analyzed data from a prospective observational cohort study that was started in 1983. Methods. We measured GFR with a 51Cr-EDTA plasma clearance technique every year for seven years (range 3 to 14 years) in 301 consecutive type 1 diabetic patients with diabetic nephropathy. Diabetic nephropathy was diagnosed clinically if the following criteria were fulfilled: persistent albuminuria> 200 μg/min, presence of diabetic retinopathy, and no evidence of other kidney or renal tract disease. Blood pressure, albuminuria, glycosylated hemoglobin A1c, and serum cholesterol were measured every three to four months during the study. In total, 271 patients received antihypertensive treatment, 179 patients predominantly with angiotensin-converting enzyme inhibitors. Remission was defined as albuminuria <200 μg/min sustained for at least one year and a decrease of at least 30% from preremission levels (surrogate endpoint), and regression as a rate of decline in GFR (ΔGFR) equal to the natural aging process: ≤1 mL/min/year during the entire observation period (principal end point). Results. The total number of patients who obtained remission was 92 (31%), with a duration of remission of [median (range)] 3.4 (1.0 to 14.1) years, and regression 67 (22%). The patients were stratified in quintiles by the average value of office mean arterial blood pressure (mean ± SE): 93 ± 0.5, 99 ± 0.2, 103 ± 0.1, 107 ± 0.2, and 113 ± 0.4 mm Hg. The prevalence of patients obtaining remission/regression was 58/42, 33/32, 25/11, 20/20, and 17/7% in each quintile, respectively. Spontaneous remission and regression occurred in 10 and 14 patients from the persistent normotensive group (N = 30), none of whom had ever received antihypertensive treatment. In all 301 consecutive patients, the (mean ± SE) ΔGFR was 4.0 ± 0.2 mL/min/year during the investigation period. Conclusions. Our study suggests that aggressive antihypertensive treatment in type 1 diabetic patients can induce remission and regression in a sizable fraction of patients with diabetic nephropathy. Lower arterial blood pressure, reduced albuminuria, and better glycemic control were predictors of regression of diabetic nephropathy. [ABSTRACT FROM AUTHOR]