Plasma copeptin, kidney disease, and risk for cardiovascular morbidity and mortality in two cohorts of type 2 diabetes

Abstract Background Cardiovascular disease and kidney damage are tightly associated in people with type 2 diabetes. Experimental evidence supports a causal role for vasopressin (or antidiuretic hormone) in the development of diabetic kidney disease (DKD). Plasma copeptin, the COOH-terminal portion of pre-provasopressin and a surrogate marker of vasopressin, was shown to be positively associated with the development and progression of DKD. Here we assessed the association of plasma copeptin with the risk of cardiovascular events during follow-up in two prospective cohorts of type 2 diabetic patients, and we examined if this association could be mediated by deleterious effects of vasopressin on the kidney. Methods We studied 3098 and 1407 type 2 diabetic patients from the French cohorts DIABHYCAR and SURDIAGENE, respectively. We considered the incidence during follow-up (median: 5 years) of a combined end point composed of myocardial infarction, coronary revascularization, hospitalization for congestive heart failure, or cardiovascular death. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay. Results The cumulative incidence of cardiovascular events during follow-up by sex-specific tertiles of baseline plasma copeptin was 15.6% (T1), 18.7% (T2) and 21.7% (T3) in DIABHYCAR (p = 0.002), and 27.7% (T1), 34.1% (T2) and 47.6% (T3) in SURDIAGENE (p < 0.0001). Cox proportional hazards survival regression analyses confirmed the association of copeptin with cardiovascular events in both cohorts: hazard ratio with 95% confidence interval for T3 vs. T1 was 1.29 (1.04–1.59), p = 0.02 (DIABHYCAR), and 1.58 (1.23–2.04), p = 0.0004 (SURDIAGENE), adjusted for sex, age, BMI, duration of diabetes, systolic blood pressure, arterial hypertension, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, estimated glomerular filtration rate (eGFR), urinary albumin concentration (UAC), active tobacco smoking, and previous history of myocardial infarction at baseline. No interaction was observed between plasma copeptin and eGFR (p = 0.40) or UAC (p = 0.61) categories on the risk of cardiovascular events in analyses of pooled cohorts. Conclusions Plasma copeptin was positively associated with major cardiovascular events in people with type 2 diabetes. This association cannot be solely accounted for by the association of copeptin with kidney-related traits

Association of Circulating Biomarkers (Adrenomedullin, TNFR1, and NT-proBNP) With Renal Function Decline in Patients With Type 2 Diabetes: A French Prospective Cohort

International audienceOBJECTIVE We explored the prognostic value of three circulating candidate biomarkers—midregional-proadrenomedullin (MR-proADM), soluble tumor necrosis factor receptor 1 (sTNFR1), and N-terminal prohormone brain natriuretic peptide (NT-proBNP)—for change in renal function in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS Outcomes were defined as renal function loss (RFL), ≥40% decline of estimated glomerular filtration rate (eGFR) from baseline, and rapid renal function decline (RRFD), absolute annual eGFR slope <–5 mL/min/year. We used a proportional hazard model for RFL and a logistic model for RRFD. Adjustments were performed for established risk factors (age, sex, diabetes duration, HbA1c, blood pressure, baseline eGFR, and urinary albumin-to-creatinine ratio [uACR]). C-statistics were used to assess the incremental predictive value of the biomarkers to these risk factors.RESULTS Among 1,135 participants (mean eGFR 76 mL/min, median uACR 2.6 mg/mmol, and median GFR slope −1.6 mL/min/year), RFL occurred in 397, RRFD developed in 233, and 292 died during follow-up. Each biomarker predicted RFL and RRFD. When combined, MR-proADM, sTNFR1, and NT-proBNP predicted RFL independently from the established risk factors (adjusted hazard ratio 1.59 [95% CI 1.34–1.89], P < 0.0001; 1.33 [1.14–1.55], P = 0.0003; and 1.22 [1.07–1.40], P = 0.004, respectively) and RRFD (adjusted odds ratio 1.56 [95% CI 1.7–2.09], P = 0.003; 1.72 [1.33–2.22], P < 0.0001; and 1.28 [1.03–1.59], P = 0.02, respectively). The combination of the three biomarkers yielded the highest discrimination (difference in C-statistic = 0.054, P < 0.0001; 0.067, P < 0.0001 for RFL; and 0.027, P < 0.0001 for RRFD).CONCLUSIONS In addition to established risk factors, MR-proADM, sTNFR1, and NT-proBNP improve risk prediction of loss of renal function in patients with type 2 diabetes

Baroreflex sensitivity assessed with the sequence method is associated with ventricular arrhythmias in patients implanted with a defibrillator for the primary prevention of sudden cardiac death

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MOESM1 of Plasma copeptin, kidney disease, and risk for cardiovascular morbidity and mortality in two cohorts of type 2 diabetes

Additional file 1: Figure S1. Plasma copeptin by KDIGO eGFR categories and by UAC categories at baseline. Table S1. Clinical characteristics at baseline by tertiles of plasma copeptin. Table S2. Risk of individual cardiovascular outcomes during follow-up by tertiles of plasma copeptin at baseline—DIABHYCAR and SURDIAGENE pooled data. Table S3. Rapid kidney function decline during follow-up by tertiles of plasma copeptin at baseline. Table S4. SURGENE cohort—Kidney outcome during the follow-up by tertiles of plasma copeptin at baseline. Table S5. Cardiovascular events during follow-up by tertiles of plasma copeptin at baseline—DIABHYCAR and SURDIAGENE pooled data. Additional information. Centers and staff involved in SURDIAGENE recruitment and adjudication

Plasma Adrenomedullin and Allelic Variation in the ADM Gene and Kidney Disease in People With Type 2 Diabetes

International audienceProduction of adrenomedullin (ADM), a vasodilator peptide, increases in response to ischemia and hypoxia in the vascular wall and the kidney. This may be an adaptive response providing protection against organ damage. We investigated the hypothesis that ADM has a nephroprotective effect in two prospective cohorts of patients with type 2 diabetes recruited in France. The highest tertile of plasma MR-proADM (a surrogate for ADM) concentration at baseline was associated with the risk of renal outcomes (doubling of plasma creatinine concentration and/or progression to end-stage renal disease) during follow-up in both cohorts. Four SNPs in the ADM gene region were associated with plasma MR-proADM concentration at baseline and with eGFR during follow-up in both cohorts. The alleles associated with lower eGFR were also associated with lower plasma MR-proADM level. In conclusion, plasma MR-proADM concentration was associated with renal outcome in patients with type 2 diabetes. Our data suggest that the ADM gene modulates the genetic susceptibility to nephropathy progression. Results are consistent with the hypothesis of a reactive rise of ADM in diabetic nephropathy, blunted in risk alleles carriers, and with a nephroprotective effect of ADM. A possible therapeutic effect of ADM receptor agonists in diabetic renal disease would be worth investigating

MOESM1 of Plasma copeptin, kidney disease, and risk for cardiovascular morbidity and mortality in two cohorts of type 2 diabetes

Additional file 1: Figure S1. Plasma copeptin by KDIGO eGFR categories and by UAC categories at baseline. Table S1. Clinical characteristics at baseline by tertiles of plasma copeptin. Table S2. Risk of individual cardiovascular outcomes during follow-up by tertiles of plasma copeptin at baseline—DIABHYCAR and SURDIAGENE pooled data. Table S3. Rapid kidney function decline during follow-up by tertiles of plasma copeptin at baseline. Table S4. SURGENE cohort—Kidney outcome during the follow-up by tertiles of plasma copeptin at baseline. Table S5. Cardiovascular events during follow-up by tertiles of plasma copeptin at baseline—DIABHYCAR and SURDIAGENE pooled data. Additional information. Centers and staff involved in SURDIAGENE recruitment and adjudication