Genetic variants of interferon-response factor 5 are associated with the incidence of chronic kidney disease: the D.E.S.I.R. study.

Inflammation has been associated with renal diseases. The Interferon Regulatory Factor (IRF)-5 is a key transcription factor in the pro-inflammatory polarization of M1-like macrophages. GWAS have reported that the IRF5 locus is associated with autoimmune diseases and with the estimated glomerular filtration rate (eGFR). We study whether allelic variations in IRF5 are associated with the incidence of chronic kidney disease (CKD) in a general population. We genotyped eleven IRF5 SNPs in the French D.E.S.I.R. cohort from the general population (n = 4820). Associations of SNPs with baseline renal parameters were assessed. Data were analyzed for three endpoints during a 9-year follow-up, incidence of:at least stage 3 CKD, the KDIGO criterion "certain drop in eGFR", and incidence of micro/macro albuminuria. In the cross-sectional analysis, rs10954213 and rs10954214 were associated with eGFR and rs1874328 with urinary albumin/creatinine ratio (ACR). Rs3807306, rs11761199, rs78658945, rs1874328, rs10954213 and rs11770589 were associated with the incidence of stage 3 CKD in multi-adjusted models. Rs4731532, rs3807306, and rs11761199 were associated with the incidence of CKD defined by the KDIGO. Rs4731532, rs3807306, rs11761199 and rs79288514 were associated with the incidence of micro/macro albuminuria. Our results support the hypothesis of the importance of IRF5 mediated macrophage polarization in the etiology of CKD.

Plasma total adiponectin and changes in renal function in a cohort from the community: the prospective Data from an Epidemiological Study on the Insulin Resistance Syndrome study.

BACKGROUND: High adiponectin levels are associated with diabetic nephropathy. Nevertheless, it is not known whether plasma adiponectin is associated with renal function decline in the general population. We evaluated whether adiponectin concentrations were associated with changes in renal function in a community cohort, the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. METHODS: Plasma adiponectin concentrations were measured in a random sample of 3284 people from the DESIR study, a 9-year prospective cohort from the general population. Data were analysed for three endpoints during follow-up: incidence of Stage 3 chronic kidney disease (CKD); the Kidney Disease: Improving Global Outcomes (KDIGO) criterion 'certain drop in eGFR' and rapid kidney function decline [estimated glomerular filtration rate (eGFR) slope steeper than -3 mL/min/1.73 m2/year]. RESULTS: After exclusion of participants with an eGFR <60 mL/min/1.73 m2 at baseline and those with type 2 diabetes or impaired fasting glycaemia at any time during follow-up (remaining n = 2174), there was a 113% higher risk for a rapid decline in kidney function in participants with adiponectin above the third tertile (T3) versus below the first tertile (T1) (Ptrend = 0.004) and a 53% higher risk for kidney function decline as defined by the KDIGO criterion (Ptrend = 0.04). In a cross-sectional analysis, adiponectin was positively associated with urinary albumin:creatinine ratio at baseline (P = 0.009). CONCLUSIONS: In a healthy cohort from the general population, higher levels of plasma adiponectin were associated with decreased renal function at baseline and at follow-up. This result is similar to what is observed in people with diabetic nephropathy, in contrast with animal models of nephropathy.

Plasma Copeptin and Risk of Lower-Extremity Amputation in Type 1 and Type 2 Diabetes.

OBJECTIVE: Diabetes is the leading cause of nontraumatic lower-extremity amputations (LEAs). Identification of patients with foot ulcers at risk for amputation remains clinically challenging. Plasma copeptin, a surrogate marker of vasopressin, is associated with the risk of cardiovascular and renal complications in diabetes. RESEARCH DESIGN AND METHODS: We assessed the association between baseline plasma copeptin and risk of LEA during follow-up in four cohorts of people with type 1 (GENESIS, n = 503, and GENEDIAB, n = 207) or type 2 diabetes (DIABHYCAR, n = 3,101, and SURDIAGENE, n = 1,452) with a median duration of follow-up between 5 and 10 years. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay. RESULTS: In the pooled cohorts with type 1 diabetes (n = 710), the cumulative incidence of LEA during follow-up by increasing tertiles (tertile 1 [TER1], TER2, and TER3) of baseline plasma copeptin was 3.9% (TER1), 3.3% (TER2), and 10.0% (TER3) (P = 0.002). Cox regression analyses confirmed the association of copeptin with LEA: hazard ratio (HR) for 1 SD increment of log[copeptin] was 1.89 (95% CI 1.28-2.82), P = 0.002. In the pooled cohorts of type 2 diabetes (n = 4,553), the cumulative incidence of LEA was 1.1% (TER1), 2.9% (TER2), and 3.6% (TER3) (P < 0.0001). In Cox regression analyses, baseline plasma copeptin was significantly associated with LEA: HR for 1 SD increment of log[copeptin] was 1.42 (1.15-1.74), P = 0.001. Similar results were observed in the cohort with type 2 diabetes for lower-limb revascularization (HR 1.20 [95% CI 1.03-1.39], P = 0.02). CONCLUSIONS: Baseline plasma copeptin is associated with cumulative incidence of LEA in cohorts of people with both type 1 and type 2 diabetes and may help to identify patients at risk for LEA.

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

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.

Plasma copeptin and chronic kidney disease risk in 3 European cohorts from the general population.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS: We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion "certain drop in eGFR"; rapid kidney function decline (eGFR slope steeper than -3 ml/min/1.73 m2/yr); and incidence of microalbuminuria. RESULTS: The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008). CONCLUSIONS: High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action. FUNDING: INSERM and Danone Research Centre for Specialized Nutrition.

Vasopressin and Diabetic Kidney Disease.

BACKGROUND: Diabetic nephropathy has become the most common cause of chronic kidney disease (CKD). Despite the progress accomplished in therapy, the prevalence of renal disorders remains high. Some modifiable factors driving the increase in incidence of CKD, in diabetes and other settings, might have been overlooked. Consistent evidence supports a role for vasopressin, hydration state, and urine concentration in kidney health. SUMMARY: Plasma vasopressin is elevated in diabetes, even if metabolic control is good. Several epidemiological studies have pointed to a positive association between markers of vasopressin secretion (24-h fluid intake, urine volume, plasma copeptin concentration) and renal function decline in both the community and populations at high risk of CKD, namely, diabetic patients. Research involving animal models also supports a critical causal role of the V2 receptor antidiuretic effects of vasopressin in the early signs of kidney disease associated with type 1 or type 2 diabetes. Key Messages: Data supporting the detrimental effects of chronic vasopressin action on the kidney is consistent in animal models and human observational studies. Since vasopressin secretion can be modulated by water intake, and its actions by selective receptor antagonists, the vasopressin-hydration system could be a potential therapeutic target for the prevention and treatment of diabetic nephropathy. Intervention studies are needed to examine the relevance of lifestyle or pharmacological interventions.

Antagonism of vasopressin V2 receptor improves albuminuria at the early stage of diabetic nephropathy in a mouse model of type 2 diabetes.

AIMS: Vasopressin is increased in diabetes and was shown to contribute to development of diabetic nephropathy through V2 receptor (V2R) activation in an experimental model of type 1 diabetes. The role of V2R in type 2 diabetes remains undocumented. This study addresses the issue in a mouse model of type 2 diabetes. METHODS: Male obese diabetic db/db mice were treated for 12weeks with a selective V2R antagonist (SR121463) and compared to non-treated db/db and non-diabetic db/m mice. All animals were previously uninephrectomized. RESULTS: The V2R antagonist did not alter glycemia or glycosuria in db/db mice. It induced a two-fold increase in urine output and a 52% decrease in urine osmolality compared to non-treated db/db mice. After four weeks of treatment urinary albumin to creatinine ratio was 50% lower in treated mice compared to non-treated mice, and remained significantly lower until end of experiment. Glomerular filtration rate increased significantly over time in non-treated db/db mice but remained stable in treated mice. CONCLUSIONS: This study shows that vasopressin contributes to albuminuria and glomerular hyperfiltration via V2R in a mouse model of type 2 diabetes. It documents causality behind the association of vasopressin with renal disease observed in diabetic patients.

Plasma Copeptin, Kidney Outcomes, Ischemic Heart Disease, and All-Cause Mortality in People With Long-standing Type 1 Diabetes.

OBJECTIVE: Plasma copeptin, a surrogate for vasopressin, has been associated with a decline in renal function and albuminuria in population-based studies as well as with progression of diabetic nephropathy in people with type 2 diabetes. We assessed the risk of kidney and coronary events and all-cause mortality associated with plasma copeptin in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: Plasma copeptin was measured in baseline samples of the GENEDIAB (n = 398; 56% male; mean ± SD age 45 ± 12 years and diabetes duration 28 ± 10 years) and GENESIS (n = 588; 52% male; age 42 ± 11 years; diabetes duration 27 ± 9 years) cohorts. Follow-up data were available for 218 GENEDIAB and 518 GENESIS participants. Median duration of follow-up was 10.2 and 5.0 years, respectively. RESULTS: Upper sex-specific tertiles of copeptin were associated with a higher incidence of end-stage renal disease (ESRD) during follow-up (hazard ratio [HR] for third vs. first tertile 26.5 [95% CI 8.0-163.3; P < 0.0001]; analysis in pooled cohorts adjusted for age, sex, duration of diabetes, and cohort membership). The highest tertile of copeptin was also associated with incidence of myocardial infarction or coronary revascularization (HR 2.2 [95% CI 1.2-4.0]; P = 0.01) and all-cause mortality (HR 3.3 [95% CI 1.8-6.5]; P < 0.0001) during follow-up. CONCLUSIONS: Plasma copeptin is a predictor for the risk of ESRD, coronary heart disease, and all-cause mortality in people with type 1 diabetes. Results are consistent with data from experimental and epidemiological studies, suggesting that high circulating levels of vasopressin are deleterious to renal function.

Plasma Copeptin, AVP Gene Variants, and Incidence of Type 2 Diabetes in a Cohort From the Community.

CONTEXT: Experimental data support a role for vasopressin in metabolic disorders. OBJECTIVE: We investigated associations of plasma copeptin, a surrogate of vasopressin, and of allelic variations in the arginine vasopressin-neurophysin II gene with insulin secretion, insulin sensitivity, and the risk for impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM). DESIGN, SETTING, AND PARTICIPANTS: We studied 5110 unrelated French men and women from a prospective cohort of the general population (Data from Epidemiological Study on the Insulin Resistance Syndrome cohort, 9-y follow-up). Six single nucleotide polymorphisms were genotyped. MAIN OUTCOME MEASURE: Incidence of IFG or T2DM during follow-up. RESULTS: The incidence of hyperglycemia (IFG/T2DM) during follow-up by quartiles of baseline plasma copeptin was 11.0% (Q1), 14.5% (Q2), 17.0% (Q3), and 23.5% (Q4), log-rank test P = .003. Participants in the upper quartile of plasma copeptin had significantly lower insulin sensitivity (homeostasis model assessment index) at baseline and during follow-up, as compared with other participants. Cox proportional hazards regression analyses showed significant associations of the CC genotype of rs6084264, the TT genotype of rs2282018, the C-allele of rs2770381, and the CC genotype of rs1410713 with the incidence of hyperglycemia. The genotypes associated with an increased risk of hyperglycemia were also associated with increased plasma copeptin in men but not in women. CONCLUSIONS: High plasma copeptin was associated with reduced insulin sensitivity and an increased risk for IFG/T2DM diabetes in this community-based cohort. Moreover, in men, allelic associations support a causal role for vasopressin in these disorders.

Plasma Copeptin and Decline in Renal Function in a Cohort from the Community: The Prospective D.E.S.I.R. Study.

BACKGROUND/AIMS: In recent days, chronic kidney disease (CKD) is becoming an increasing public health problem. Identification of factors contributing to its progression is crucial for designing preventive interventions. Previous studies suggested that chronically high vasopressin is deleterious to the renal function. We evaluated plasma copeptin, a surrogate of vasopressin, as a predictor for renal function decline in a community cohort. METHODS: Plasma copeptin was measured at baseline in 1,234 participants from the D.E.S.I.R. study, a prospective cohort from the French general population. All participants were followed for 9 years. Progression towards CKD during follow-up was defined as an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2 on at least one follow-up visit. We have also considered the criterion 'Certain Drop in eGFR' proposed by the Kidney Disease Improving Global Outcomes (KDIGO) group. RESULTS: Progression towards CKD was observed in 86 (7.0%) participants. Factors like age, female gender, plasma copeptin and use of angiotensin converting enzyme inhibitor or angiotensin 2 receptor blocker at baseline were positively associated, and eGFR inversely associated with CKD progression during follow-up. The hazard ratio per unit of log10-transformed plasma copeptin was 1.65 (95% CI 1.06-2.54) and p=0.02. Copeptin was similarly associated with CKD and this was observed when we considered the KDIGO criterion: OR 3.03 (95% CI 1.21-7.57), p=0.02. CONCLUSION: The plasma copeptin level was independently and positively associated with progression towards CKD in a community-based cohort. Our results add to the available evidence for a deleterious effect of high vasopressin on renal health not only in selected groups of patients with CKD but also in the general population.