Vasopressin, cardiorenal disease and hydration. The vasopressin system in relation to the risk of cardiorenal disease and how vasopressin levels are affected by salt and water interventions in humans.

Aim: The aims of the first three studies were to investigate copeptin, a surrogate marker of vasopressin, in relation to salt sensitivity, coronary artery disease (CAD) as well as cardiovascular (CV) mortality and chronic kidney disease (CKD). In the fourth sudy, the aim was to investigate levels of copeptin and glucometabolic parameters in relation to increased water intake in humans. Methods: In the first study, 39 healthy swedish individuals received meals containing 50 mmol NaCl and additionally capsules containing either 100 mmol NaCl or corresponding placebo capsules, in random order, during 4 weeks. Plasma copeptin was then compared do low respectively high dietary salt intake as well as the change in systolic blood pressure (salt sensitivity). In the second study, individuals recruited in The Malmö Preventive Project (MPP) (n=5386) were followed during a mean of 6.5 years and analyzed for incident CAD and CV mortality and related to levels of plasma copeptin. In the third study individuals recruited in The Malmö Diet and Cancer Cardiovascular Study (MDC-CS) (n=3186) were followed during 16.6 ± 1.5 years. Levels of plasma copeptin were then related to incident CKD, calculated by the MDRD formula, and yearly decline in eGFR. In the fourth study, 39 healthy individuals underwent, in random order, one week of high water intake (3L/d on top of habitual intake) and one week of normal (habitual) fluid intake (control) as well as an acute water load test. Levels of copeptin and glucometabolic parameters were then analyzed and compared during low respectively high water intake. Results: Copeptin increased after a high compared to low dietary salt consumption in all subjects, 3,59 ± 2,28 versus 3,12 ± 1,95 ( = 0,02) but salt sensitivity i.e. blood pressure increase due to salt intake, was inversely correlated with salt-induced changes of copeptin, a finding only observed in females (r = -0.58; P=0.017). Copeptin was also inversely correlated with urinary volume, at both low ( = −0,42; = 0,001) and high ( = −0,60; < 0,001) salt consumption, as well as with the change in body weight ( = −0,53; < 0,001). Among subjects free from CAD at baseline, the multivariate adjusted HR (95% confidence interval (CI)) per 1 SD increment of log-transformed copeptin for risk of CAD development was 1.20 (1.08 to 1.33) (p=0.001). Each SD increment of copeptin independently predicted CV mortality (1.36 (1.21 to 1.53); p<0.001). The results were significant both in diabetics (p=0.004)) and nondiabetics (p=0.02). Copeptin was independently associated with significantly greater annual decline of eGFR (ml/min/1.73 m2) and each SD increment of copeptin independently predicted incident CKD with the MDRD formula calcutated as eGFR <60 (OR 1.19, 95% CI 1.04–1.36; p = 0.010). After acute intake of 1L of water, plasma copeptin was significantly reduced within 30 min with an average reduction of 39 % (95% CI 34-45) (p<0.001). One week of increased water intake led to a 15 % reduction (95CI 5-25) (p=0.003) in fasting copeptin and a subgroup responting well do hydration (low-drinkers) showed a significant water-induced reduction in fasting glucagon concentration. No significant water-induced difference was observed in glucose or insulin. Conclusions: As suppression of copeptin on high versus low salt intake was associated with systolic salt sensitivity in women, our data suggest that high fluid intake and fluid retention may contribute to salt sensitivity. Copeptin predicts development of CAD and cardiovascular mortality both in diabetics and in nondiabetics and predicts decline in eGFR as well as greater risk of new-onset CKD. Finally, both acute and chronic water intake potently reduced plasma copeptin concentration in habitually low-water drinkers motivating long-term trials to assess the effects of water and on glucometabolic traits primarily in this sub-population.