Objective To evaluate baseline predictors for the development of persistent microalbuminuria and macroalbuminuria prospectively in patients with type 1 diabetes.

Our long-term prospective study of type 2 diabetic patients with nephropathy has revealed several modifiable risk factors of enhanced progression in kidney disease and increased mortality.

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 Ն20 years. RESULTS -In patients followed for Ն20 years, the cumulative incidence (95% CI) of diabetic nephropathy after 20 years of diabetes (urinary albumin excretion Ͼ300 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 ϭ 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 Ͻ 0.01). In the latter groups, antihypertensive treatment was started earlier, blood pressure and HbA 1c were lower, and fewer patients smoked. RESEARCH DESIGN AND METHODSCONCLUSIONS -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.

The prognosis of diabetic nephropathy has improved during the past decades, predominantly because of effective antihypertensive treatment. Genuine normotensive patients have a slow progression of nephropathy. Several modifiable variables have been identified as progression promoters.

Diabetic nephropathy (DN) is a progressive kidney disease, a well-known complication of long-standing diabetes. DN is the most frequent reason for dialysis in many Western countries. Early detection may enable development of specific drugs and early initiation of therapy, thereby postponing/preventing the need for renal replacement therapy. We evaluated urinary proteome analysis as a tool for prediction of DN. Capillary electrophoresis–coupled mass spectrometry was used to profile the low–molecular weight proteome in urine. We examined urine samples from a longitudinal cohort of type 1 and 2 diabetic patients (n = 35) using a previously generated chronic kidney disease (CKD) biomarker classifier to assess peptides of collected urines for signs of DN. The application of this classifier to samples of normoalbuminuric subjects up to 5 years prior to development of macroalbuminuria enabled early detection of subsequent progression to macroalbuminuria (area under the curve [AUC] 0.93) compared with urinary albumin routinely used to determine the diagnosis (AUC 0.67). Statistical analysis of each urinary CKD biomarker depicted its regulation with respect to diagnosis of DN over time. Collagen fragments were prominent biomarkers 3–5 years before onset of macroalbuminuria. Before albumin excretion starts to increase, there is a decrease in collagen fragments. Urinary proteomics enables noninvasive assessment of DN risk at an early stage via determination of specific collagen fragments.

BackgroundDespite no international consensus on the diagnostic criteria for sarcopenia, low lean mass, muscle strength, and physical function are important risk factors for disability, frailty, and mortality in older individuals, as well as in a wide range of patients with muscle loss. Here, we provide a population‐based reference material of total and regional lean body mass, muscle strength/power parameters, and physical function in a healthy cohort of Danish men and women across the lifespan.MethodsVolunteers aged 20–93 years from the Copenhagen City Heart Study were invited to establish a Danish reference material (Copenhagen Sarcopenia Study) on lean mass characteristics [appendicular lean mass (ALM), iDXA, GE Lunar], muscle function [handgrip strength (HGS), Jamar dynamometer and leg extension power (LEP), Nottingham Power Rig], and physical function [30 s sit‐to‐stand test (STS), 10‐m maximal and habitual gait speed (GS)].ResultsA total of 1305 participants [729 women (age: 56.4 ± 18.9 years, height: 1.66 ± 0.01 m, body mass index: 24.6 ± 4.3 kg/m2 and 576 men, age: 57.0 ± 17.5 years, height: 1.80 ± 0.07 m, body mass index: 26.0 ± 3.9 kg/m2] completed all measurements and were included in the present analysis. Lean mass characteristics (TLM, ALM, and ALM/h2) decreased with increasing age in both men and women (P < 0.001). Men demonstrated larger absolute and relative total ALM and higher HGS and LEP compared with women at all age intervals (P < 0.001). HGS and LEP decreased progressively with age in both men and women (P < 0.01); 30 s STS performance, habitual GS, and maximal GS decreased at an accellerated rate of decline with increasing age in both men and women (P < 0.001). Habitual GS was reduced in men and women aged ≥70 years, while maximal GS was reduced from the age of ≥60 years compared with young adults (P < 0.001). Regardless of sex, 30 s STS was reduced from the age of ≥50 years compared with the young reference group (P < 0.001)ConclusionsWhile the power‐based measurements (LEP and 30 s STS) started to decline already at age +50 years, less power‐based parameters (GS and HGS) and lean mass characteristics (TLM, ALM, and ALM/h2) remained unaltered until after the age of +70 years. Notably, the cut‐off thresholds derived in the present study differed from earlier reference data, which underlines the importance of obtaining updated and local reference materials.

OBJECTIVEExperimental 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 METHODSThis 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.RESULTSDuring 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.CONCLUSIONSUric acid level soon after onset of type 1 diabetes is independently associated with risk for later development of diabetic nephropathy.

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. RESULTS -In patients with diabetic nephropathy, mean Ϯ SD plasma ADMA concentration was elevated 0.46 Ϯ 0.08 vs. 0.40 Ϯ 0.08 mol/l in normoalbuminuric patients (P Ͻ 0.001). An increase in plasma ADMA of 0.1 mol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89 -4.05) (P Ͻ 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 (Ͻ76 ml ⅐ min -1 ⅐ 1.73 m -2 ) (P Ͻ 0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P Ͼ 0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 Ϯ 0.08 mol/l compared with 0.46 Ϯ 0.08 mol/l in patients without major cardiovascular events (P ϭ 0.05). RESEARCH DESIGN AND METHODSCONCLUSIONS -Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy. Diabetes Care 27:765-769, 2004N itric oxide is synthesized by the vascular endothelium from the amino acid L-arginine by constitutive and inducible nitric oxide synthases and plays an important role as vasodilator and in the maintenance of vascular homeostasis (1). The endogenous L-arginine metabolite, asymmetric dimethylarginine (ADMA), inhibits cellular L-arginine uptake and nitric oxide synthase activity competitively. In contrast, its stereoisomer symmetrical dimethylarginine (SDMA) is produced in equivalent amounts but has no inhibitory effect on nitric oxide synthase (2).Accumulation of ADMA has first been shown in chronic renal failure (3) and has subsequently been confirmed by other studies of advanced nondiabetic kidney disease (4,5). The idea was simple: as the kidneys fail, ADMA excretion diminishes and its concentration in plasma increases to levels sufficient to block nitric oxide generation and thereby cause cardiovascular, neurological, and other unwanted effects (3). Later reports of ADMA as a potential mediator of cardiovascular morbidity and mortality in patients with chronic renal impairment have supported this concept (6,7). However, the recent finding of a marked increase in ADMA in nondiabetic kidney disease, when glomerular filtration rate is still within the normal range (8), suggests that other mechanisms may be involved.Although a proportion of ADMA is excreted in the urine, its major catabolism is via the enzyme dimethylarginine dimethylaminohydrolase (4), shown ...