Long-term Renal Outcomes of Patients With Type 1 Diabetes Mellitus and Microalbuminuria An Analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Cohort

Kidney Research Institute and Division of Nephrology, University of Washington, Campus Box 359606, 325 Ninth Ave, Seattle, WA 98104, USA.
Archives of internal medicine (Impact Factor: 17.33). 03/2011; 171(5):412-20. DOI: 10.1001/archinternmed.2011.16
Source: PubMed


Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes mellitus. Long-term outcomes after the development of microalbuminuria are variable.
We quantified the incidence of and risk factors for long-term renal outcomes after the development of microalbuminuria in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. The DCCT randomly assigned 1441 persons with type 1 diabetes to intensive or conventional diabetes therapy, and participants were subsequently followed up during the observational EDIC study. During the DCCT/EDIC study, 325 participants developed incident persistent microalbuminuria (albumin excretion rate, ≥30 mg/24 h at 2 consecutive study visits). We assessed their subsequent renal outcomes, including progression to macroalbuminuria (albumin excretion rate, ≥300 mg/24 h at 2 consecutive visits), impaired glomerular filtration rate (estimated glomerular filtration rate, <60 mL/min/1.73 m(2) at 2 consecutive study visits), end-stage renal disease, and regression to normoalbuminuria (albumin excretion rate, <30 mg/24 h at 2 consecutive visits).
The median follow-up period after persistent microalbuminuria diagnosis was 13 years (maximum, 23 years). Ten-year cumulative incidences of progression to macroalbuminuria, impaired glomerular filtration rate, end-stage renal disease, and regression to normoalbuminuria were 28%, 15%, 4%, and 40%, respectively. Albuminuria outcomes were more favorable with intensive diabetes therapy, lower glycated hemoglobin level, absence of retinopathy, female sex, lower blood pressure, and lower concentrations of low-density lipoprotein cholesterol and triglycerides. Lower glycated hemoglobin level, absence of retinopathy, and lower blood pressure were also associated with decreased risk of impaired glomerular filtration rate.
After the development of persistent microalbuminuria, progression and regression of kidney disease each commonly occur. Intensive glycemic control, lower blood pressure, and a more favorable lipid profile are associated with improved outcomes.

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Available from: Wanjie Sun, Nov 06, 2014
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    • "High glucose exposition and hypertension play important roles in the development of kidney damage in both T1DM and in T2DM patients. However, a genetic component is also present (since family history of kidney disease is a strong predictor of renal functional decline).17,18 Previously, we described a familial clustering of increased urinary albumin excretion (AER+), in T2DM families, with no association with hypertension.19 "
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    ABSTRACT: Diabetes mellitus is the major cause of end stage renal disease (ESRD). We cannot predict which patient will be affected. ESRD patients suffer an extremely high mortality rate, due to a very high incidence of cardiovascular disease. Several randomized, prospective studies have been conducted to quantify the impact of strict glycemic control on morbidity and mortality, and have consistently demonstrated an association between strict glycemic control and a reduction in ESRD. Within the past 20 years, despite the implementation of treatments that were presumed to be renoprotective, diabetes mellitus has continued to rank as the leading cause of ESRD, which clearly indicates that we are still far from understanding the mechanisms involved in the initiation of ESRD. Progressive albuminuria has been considered as the sine qua non of diabetic nephropathy, but we know now that progression to diabetic nephropathy may well happen in the absence of initial microalbuminuria. The search for new biomarkers of early kidney damage has received increasing interest, since early identification of the pathways leading to kidney damage may allow us to adopt measures to prevent the development of ESRD. Most of these biomarkers are deeply influenced by environment, genetics, sex differences, and so on, making it extremely difficult to identify the ideal biomarker to target. At present, there are no new drugs that come close to providing the solutions we desire for our patients (ie, reducing complications). Even when used in combination with standard care, renal complications are, at best, only modestly reduced, at the considerable expense of additional pill burden and exposure to serious off-target effects. In this review, some of the hypothesized mechanisms of this heterogeneous disease will be considered, with particular attention to the tubule-interstitial compartment.
    Full-text · Article · Mar 2014 · International Journal of Nephrology and Renovascular Disease
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    • "Wada et al. [5] reported that diabetic patients who have albuminuria/overt proteinuria and a low glomerular filtration rate are at risk of developing cardiovascular events as well as renal events. De Boer et al. [6] suggested that intensive glycemic control, blood pressure reduction and diet are associated with an improved outcome. However, patients with diabetes and proteinuria were enrolled in these studies and were assumed to have DN without biopsy for histological confirmation. "
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    ABSTRACT: A new classification of diabetic nephropathy was reported by Tervaert et al., but the association between pathological findings and the clinical outcomes remains unclear. Among 310 patients with diabetes mellitus who underwent renal biopsy from March 1985 to January 2010 and were confirmed to have diabetic nephropathy according to the Tervaert's classification, 205 patients were enrolled in this study. Cox proportional hazard regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for death-censored renal death. Each regression analysis employed two levels of multivariate adjustment. After adjustment for age, gender, estimated glomerular filtration rate, type of diabetes, urinary protein excretion, systolic blood pressure, body mass index, HbA1c, diabetic retinopathy and red blood cells in urinary sediment at the time of renal biopsy, compared with glomerular class IIA, the HRs for death-censored renal death of glomerular classes I, IIB, III and IV were 0.23 (95% CI: 0.04-1.34), 2.15 (0.91-5.09), 4.35 (1.86-10.18) and 3.41 (1.38-8.45), respectively. Also, compared with an interstitial fibrosis and tubular atrophy score 1 group, HRs for score 0 group, score 2 group and score 3 group were 0.07 (0.008-0.57), 2.07 (0.92-4.67) and 4.95 (2.04-11.97), respectively. The progression of glomerular, tubulointerstitial and vascular lesions was associated with higher HRs for renal death. These results suggest the clinical utility of Tervaert's pathological classification.
    Full-text · Article · Oct 2013 · Nephrology Dialysis Transplantation
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    • "Previous cross-sectional and longitudinal studies in the DCCT/EDIC have shown that total cholesterol, triglyceride, and ApoB levels (Jenkins et al., 2003a; de Boer et al., 2011; Jaffa et al., 2008; Molitch et al., 2010), and low HDL-C (Molitch et al., 2010), predict nephropathy; our cross-sectional study provides evidence on the lipoprotein subclasses that may be involved. Also, our observed associations between elevated cholesterol-rich-(Lp-B and ApoB) and triglyceriderich (Lp-B:C and ApoC-III) subclasses and individual apolipoproteins, and presence of nephropathy, remained significant following adjustments of several factors known to influence lipid metabolism. "
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    ABSTRACT: Aims: Dyslipoproteinemia has been associated with nephropathy in diabetes, with stronger correlations in men than in women. We aimed to characterize and compare plasma lipoprotein profiles associated with normal and increased albuminuria in men and women using apolipoprotein-defined lipoprotein subclasses and simple apolipoprotein measures. Methods: This is a cross-sectional study in a subset (154 women and 282 men) of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, using samples obtained in 1997-9. Immunochemical methods were used to quantify plasma apolipoprotein-based lipoprotein subclasses and individual apolipoprotein levels. Results: In adjusted analyses, elevated Lipoprotein-B (Lp-B) was significantly associated with macroalbuminuria in men [odds ratios (OR) and 95% confidence interval (CI): 2.13 (1.15-3.97)] and women [3.01 (1.11-8.12)], while association with Lp-B:C was observed only in men [1.84 (1.19-2.86)]. For individual apolipoproteins the following significant associations with macroalbuminuria were observed in men only: Apolipoprotein B (ApoB) [1.97 (1.20-3.25)], Apo-AII [0.52 (0.29-0.93)], ApoC-III [1.95 (1.16-3.30)], "ApoC-III in VLDL" (heparin-manganese precipitate) [1.88 (1.16-3.04)], and "ApoCIII in HDL" (heparin-manganese supernatant) [2.03 (1.27-3.26)], all P<0.05). Conclusions: Atherogenic apolipoprotein-based profiles are associated with nephropathy in Type 1 diabetic men and to a lesser extent in women. The difference could result from the greater prevalence and severity of dyslipoproteinemia, and from the greater prevalence of renal dysfunction, in men vs women.
    Full-text · Article · Jul 2013 · Journal of Diabetes and its Complications
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