Risk of microalbuminuria and progression to macroalbuminuria in a cohort with childhood onset type 1 diabetes: prospective observational study

Amin, Rakesh; Widmer, Barry; Prevost, A. Toby; Schwarze, Phillip; Cooper, Jason D.; Edge, Julie; Marcovecchio, Loredana; Neil, Andrew; Dalton, R. Neil; Dunger, David B.

doi:10.1136/bmj.39478.378241.be

Cited by 180 publications

(233 citation statements)

References 23 publications

(24 reference statements)

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“…This might be the result of an interaction between puberty and the individual's genetic predisposition in accelerating the appearance of early signs of complications. Interestingly, this is in line with previous data from the ORPS cohort, where it was found that although the cumulative prevalence of microalbuminuria was unaffected by age at diagnosis, subjects with an early onset of diabetes (i.e., before age 5 years) had a longer "free" interval before the onset of microalbuminuria (40). However, in the current study, the differences in age at diagnosis and duration might also reflect the effect of other environmental factors that we did not explore.…”

Section: Discussionsupporting

confidence: 80%

Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT): Urinary Screening and Baseline Biochemical and Cardiovascular Assessments

Marcovecchio¹,

Woodside

Jones

et al. 2014

Diabetes Care

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OBJECTIVEWe assessed the association between early increases in albumin excretion and cardiovascular (CV) and renal markers in a large cohort of young people with type 1 diabetes. RESEARCH DESIGN AND METHODSAs part of preliminary screening for a multicenter, randomized controlled trial of statins/ACE inhibitors, we measured albumin-creatinine ratio (ACR) in six early morning urine samples from 3,353 adolescents (10-16 years of age) and calculated tertiles based on an established algorithm. From those subjects deemed to be at higher risk (upper ACR tertile), we recruited 400 into the intervention study (trial cohort). From those subjects deemed to be at lower risk (middle-lower ACR tertiles), we recruited 329 to the observation cohort. At baseline, vascular measurements (carotid intima-media thickness, pulse wave velocity [PWV], flow-mediated dilatation, digital pulse amplitude tonometry), renal markers (symmetric dimethylarginine, cystatin C, creatinine), and CV disease markers (lipids and apolipoproteins [Apo] A-1 and B, C-reactive protein, asymmetric dimethylarginine) were assessed. RESULTSAge-and sex-adjusted PWV was higher in the trial than in the observational cohort (5.00 6 0.84 vs. 4.86 6 0.70 m/s; P = 0.021). Similarly, non-HDL cholesterol (2.95 6 0.83 vs. 2.81 6 0.78 mmol/L; P = 0.02) and ApoB-ApoA-1 ratio (0.50 6 0.14 vs. 0.47 6 0.11; P = 0.04) were higher in the trial cohort. Cystatin C and creatinine were decreased (0.88 6 0.13 vs. 0.90 6 0.13 mg/L, P = 0.04; 51.81 6 10.45 vs. 55.35 6 11.05 mmol/L, P < 0.001; respectively) and estimated glomerular filtration rate (137.05 6 23.89 vs. 129.31 6 22.41 mL/min/1.73 m 2 ; P < 0.001) increased in the trial compared with the observational cohort. CONCLUSIONSOur data demonstrate that in adolescents with type 1 diabetes, the group with the highest tertile of albumin excretion showed more evidence of early renal and CV disease than those in the lower tertiles.

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Section: Discussionsupporting

confidence: 80%

Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT): Urinary Screening and Baseline Biochemical and Cardiovascular Assessments

Marcovecchio¹,

Woodside

Jones

et al. 2014

Diabetes Care

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“…It is therefore surprising that this group, with a 69% prevalence of hyperfiltration, had the lowest risk of progressing to nephropathy. It is generally recognised that younger age of diabetes onset also leads to a younger age of progression [34]; however, these older patients were diagnosed years after exposure to pubertal hormonal changes, which are thought to increase hyperfiltration, and perhaps this plays some part in confounding against their overall risk of progression [29]. In other words, the pathophysiology of increased GFR may differ at different ages and these differences may themselves confer variable nephropathy risk.…”

Section: Discussionmentioning

confidence: 99%

Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis

et al. 2009

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Aims/hypothesis Glomerular hyperfiltration is a wellestablished phenomenon occurring early in some patients with type 1 diabetes. However, there is no consistent answer regarding whether hyperfiltration predicts later development of nephropathy. We performed a systematic review and meta-analysis of observational studies that compared the risk of developing diabetic nephropathy in patients with and without glomerular hyperfiltration and also explored the impact of baseline GFR. Methods A systematic review and meta-analysis was carried out. Cohort studies in type 1 diabetic participants were included if they contained data on the development of incipient or overt nephropathy with baseline measurement of GFR and presence or absence of hyperfiltration. Results We included ten cohort studies following 780 patients. After a study median follow-up of 11.2 years, 130 patients had developed nephropathy. Using a random effects model, the pooled odds of progression to a minimum of microalbuminuria in patients with hyperfiltration was 2.71 (95% CI 1.20-6.11) times that of patients with normofiltration. There was moderate heterogeneity (heterogeneity test p=0.05, measure of degree of inconsistency= 48%) and some evidence of funnel plot asymmetry, possibly due to publication bias. The pooled weighted mean difference in baseline GFR was 13.8 ml min −1 1.73 m −2 (95% CI 5.0-22.7) greater in the group progressing to nephropathy than in those not progressing (heterogeneity test p<0.01). Conclusions/interpretation In published studies, individuals with glomerular hyperfiltration were at increased risk of progression to diabetic nephropathy using study level data. Further larger studies are required to explore this relationship and the role of potential confounding variables.

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“…For example, patients with type 1 diabetes carry a 20%-50% risk of developing ESRD requiring dialysis or renal transplantation. [38][39][40] Although effective interventions to slow the progression of diabetes-induced CKD have been described, 41 enhanced therapeutic approaches are urgently needed. Therefore, studies to identify novel therapeutic interventions to prevent diabetic nephropathy or slow its progression are an area of intense investigation and would significantly affect the disease course of diabetes mellitus.…”

mentioning

confidence: 99%

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

Tak¹,

Ridyard²,

Kim

et al. 2014

Journal of the American Society of Nephrology

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Nucleotide phosphohydrolysis by the ecto-59-nucleotidase (CD73) is the main source for extracellular generation of adenosine. Extracellular adenosine subsequently signals through four distinct adenosine A receptors (Adora1, Adora2a, Adora2b, or Adora3). Here, we hypothesized a functional role for CD73-dependent generation and concomitant signaling of extracellular adenosine during diabetic nephropathy. CD73 transcript and protein levels were elevated in the kidneys of diabetic mice. Genetic deletion of CD73 was associated with more severe diabetic nephropathy, whereas treatment with soluble nucleotidase was therapeutic. Transcript levels of renal adenosine receptors showed a selective induction of Adora2b during diabetic nephropathy. In a transgenic reporter mouse, Adora2b expression localized to the vasculature and increased after treatment with streptozotocin. Adora2b 2/2 mice experienced more severe diabetic nephropathy, and studies in mice with tissue-specific deletion of Adora2b in tubular epithelia or vascular endothelia implicated endothelial Adora2b signaling in protection from diabetic nephropathy. Finally, treatment with a selective Adora2b agonist (BAY 60-6583) conveyed potent protection from diabetes-associated kidney disease. Taken together, these findings implicate CD73-dependent production of extracellular adenosine and endothelial Adora2b signaling in kidney protection during diabetic nephropathy.

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Risk of microalbuminuria and progression to macroalbuminuria in a cohort with childhood onset type 1 diabetes: prospective observational study

Cited by 180 publications

References 23 publications

Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT): Urinary Screening and Baseline Biochemical and Cardiovascular Assessments

Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT): Urinary Screening and Baseline Biochemical and Cardiovascular Assessments

Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

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