Hydration and Kidney Health

The worldwide prevalence of diabetes mellitus is expected to rise to over 550 million by 2030; this continuous increase being driven by aging and obesity [1]. Diabetes has direct human and monetary costs, but the main burden for patients and health care systems comes from vascular complications of diabetes. If diabetes is well recognized as a risk factor for myocardial infarction, stroke, and peripheral artery disease, it has also to be seen as a major provider of end-stage renal disease (ESRD) [2]. High plasma vasopressin concentrations have been consistently reported in experimental models of diabetes and patients with diabetes, either of type 1 or type 2 [3,4,5]. Interestingly, this was described in patients with uncontrolled diabetes, but also in those with a good glycemic control. However, the study of large populations was problematic due to the low stability of vasopressin, a short peptide, and the limited availability of high-quality assays. A few years ago, an assay for copeptin, the stable C-terminal portion of the precursor of vasopressin and as such a good surrogate for the secretion of vasopressin, was made commercially available [6]. Since then, nearly 300 papers based on copeptin measurements were published. Several works not only confirmed the elevation of copeptin in diabetic patients, but also extended this observation. Actually, plasma copeptin was already elevated in patients with metabolic abnormalities such as those preceding type 2 diabetes (metabolic syndrome) [7]. It has been validated as a prognostic marker of diabetes, independent of other classical risk factors like BMI or age. Water intake is a major determinant of vasopressin secretion. In the French D.E.S.I.R. study, a cohort recruited in the population, our group found that the risk of new-onset hyperglycemia during a 9-year follow-up was inversely and independently associated with daily water intake [8]. After adjustment for classical confounders and intake of alcoholic beverages and sweet drinks, participants who reported drinking more than 1 l water per day were 21% less likely to develop hyperglycemia than those with a water intake below 0.5 l/day (p = 0.016). Several lines of evidence support a causal role of vasopressin in these associations. First, in the liver, vasopressin stimulates glycogenolysis and gluconeogenesis through V1a receptor in vitro [9,10,11]. V1b, another G-protein-coupled vasopressin receptor, is expressed in pancreatic Langerhans islets, and perfused pancreas experiments revealed a role of vasopressin in glucagon and insulin secretion [12]. In healthy humans, acute infusion of vasopressin increases plasma glucose, due to an increased glucose production, which is consistent with the expected vasopressin action on the liver [13]. Finally, genetic association studies found a link between vasopressin receptor polymorphisms and metabolic disorders [14].Diabetic nephropathy accounts for up to 45% of incident cases of ESRD in the USA [2]. Prevention and treatment include blood glucose and blood pressure control, and the use of renin-angiotensin system (RAS) blockers is mandatory when diabetic nephropathy is diagnosed. Despite the best recommended care, a residual risk of development and progression of diabetic nephropathy remains. Once the decline of renal function is established, even with optimal treatment, up to 20% of patients with diabetes and proteinuria develop ESRD within only a 3-year follow-up [15]. Many approaches have been tested in response to the huge unmet need of persistent proteinuria and loss of renal function in diabetic patients despite recommended care, but they failed to demonstrate any favorable risk-to-benefit balance, for example dual blockade of RAS, anti-inflammatory and anti-oxidant therapies, just to name a few recent reports of negative results [16,17]. To explore new therapeutic avenues, physicians need to better understand the pathogenesis of the disease; many decades after the studies of Brenner and co-workers, this is still a relevant area of research. The pathogenesis of diabetic nephropathy is multifactorial. Hemodynamic and metabolic factors are involved. The role of hyperglycemia is central, of course, but some factors associated with the progress of the disease are shared with other causes of chronic kidney disease (CKD) involving primarily the glomerulus; such factors include hypertension or dyslipidemia. The natural history of diabetic nephropathy has been recently challenged. Classically, it is the sequence of hyperfiltration, albuminuria of increasing amplitude, and then progressive loss of nephrons and glomerular filtration rate (GFR) down to ESRD. The observation of a non-negligible proportion of patients with CKD despite persistent normal or only slightly elevated levels of albuminuria illustrates the actual heterogeneity of the course of nephropathy associated with diabetes.Hyperfiltration is likely linked to several mechanisms leading to intraglomerular hypertension [18]. Endothelial dysfunction, secondary to hyperglycemia, causes an imbalance between afferent and efferent arterioles, with a net effect of relatively increased efferent arteriole resistance and an increase in glomerular hydrostatic pressure, the main driving force of filtration. Many regulatory systems are involved in renal hemodynamic perturbations related to diabetes, but activation of the intrarenal renin-angiotensin system is considered to be the key event. Moreover, direct toxic effects of glucose on arteriolar endothelium are likely not to be the only determinants of hyperfiltration. The increased amount of glucose filtered, due to the high level of plasma glucose, elevates the reabsorption of glucose in the proximal tubule. This is done through sodium-glucose co-transporters, which are up-regulated and activated in uncontrolled diabetes. Increased proximal reabsorption reduces salt delivery to the macula densa. Via tubuloglomerular feedback, it leads to reduced resistance to blood flow in the afferent arteriole, contributing to increased glomerular pressure. In addition to these vascular and tubular effects, high plasma glucose induces alterations of the cellular homeostasis, relevant for every cell types in the kidney: oxidative stress, activation of the formation of advanced end products and the expression of their receptors, increased flux through the polyol and hexosamine pathways, activation of protein kinase C isoforms, production of pro-inflammatory cytokines, profibrotic growth factors and vascular growth factors, finally leading to an inflammatory response and functional and structural renal injury with increased leak of albumin, an early landmark of diabetic nephropathy.Experimental studies in the late 1990s supported a role for vasopressin in diabetic nephropathy. Brattleboro rats are spontaneously deficient in vasopressin, due to a mutation in the vasopressin gene. When treated with streptozotocin, a chemical that is toxic to the insulin-producing beta cells of the pancreas, they develop diabetes, but do not show similar changes in kidney function as controls; they do not hyperfiltrate as diabetic Long-Evans rats do, and they have a much lower urinary albumin excretion rate during the follow-up [19]. In streptozotocin-treated diabetic Wistar rats, albuminuria increase is blocked by a selective vasopressin V2 receptor antagonist [20]. Albuminuria and other markers of renal damages were correlated to the urine-concentrating activity of the kidney. In humans also (a cohort of type 1 patients with diabetes), intra-individual plasma vasopressin changes were shown to be independently associated with variations in GFR [21]. The effect on kidney function of an acute administration of a V2 agonist was tested by Bardoux et al. [19] in healthy humans. The increased V2 receptor-mediated antidiuretic action lead to a reduced urinary flow rate and increased urinary electrolytes concentrations, but also tripled the urinary albumin excretion rate, an effect not observed in patients who were genetically unable to respond to vasopressin receptor stimulation (diabetes insipidus due to aquaporin-2 gene mutations). These results strongly support a direct V2 receptor-mediated role of vasopressin in the development of renal damage. They are extended by several epidemiological studies, including in the specific context of diabetes. In the large cross-sectional population-based PREVEND study [22], the 24-hour urinary albumin excretion was measured, and prevalence of microalbuminuria (increased albuminuria not reaching the proteinuria stage) was positively associated with plasma copeptin concentrations. In a 15-year follow-up study which was also based on the general population [23], baseline copeptin concentration was independently associated with later onset of microalbuminuria. In elderly patients with diabetes, high baseline plasma copeptin was also associated with higher baseline urinary albumin [24]. Moreover, the association of baseline plasma copeptin with progression of albuminuria and decline of estimated GFR was also observed during the 6.5-year follow-up of this study.Despite this consistent evidence, data were lacking regarding the association of plasma copeptin with the rate of clinically relevant renal events, namely severe decline of GFR or ESRD, and its independency of classical risk factors such as baseline albuminuria and baseline GFR. We examined this association in 3,101 persons with type 2 diabetes and microalbuminuria or macroalbuminuria from the prospective DIABHYCAR study [25], with a 6-year follow-up. We found that plasma copeptin was strongly associated with the rate of these renal events, or with the annual loss of estimated GFR in the whole population, but the association was even stronger in the subset of 729 patients with proteinuria at baseline. The association was independent of relevant covariates such as sex, age, duration of diabetes, blood pressure, and baseline levels of HbA1c, albuminuria, and GFR. There was no interaction with the treatment by renin-angiotensin system blockers. Death was not a competing risk in the association of copeptin levels with renal events. Despite a limited number of occurrences of ESRD (19 patients) during the follow-up, we were able to show that the hazard ratio (adjusted on other prognostic factors) associated with the third tertile (higher values) of baseline copeptin compared to the first tertile was as dramatically elevated as 15.92 (95% CI 3.17-289.23, p = 0.0001). In the multivariate analysis, plasma copeptin and the rate of albuminuria, a well-established renal risk factor, had prognostic values of similar amplitudes. Taken together, these observations raise exciting hypotheses of new therapeutic options in diabetic nephropathy. Plasma copeptin can help target patients with the highest risk of CKD progression, as shown above, but also with a likely high response rate to blockade of vasopressin action. Increasing water intake (or even simply correcting insufficient water intake) may lower vasopressin secretion; such ‘medicinal use of water' has been discussed for kidney diseases other than diabetic nephropathy elsewhere in this issue. Also, vaptans (vasopressin receptor antagonists) could selectively target the V2 receptor-mediated deleterious effects of vasopressin. Pros and cons of both options are debatable [26]. If the increase of water intake or V2 receptor antagonists were shown to carry a benefit, then this could allow individualization of renoprotective therapy and the specific unmet need of patients with diabetes and persistent albuminuria despite renin-angiotensin system blockers. these could be in with high copeptin levels who are likely to the from the of vasopressin studies are to these recognized as the for has therapeutic on many systems including the kidney. in the of kidney has been for several in more recent years large studies have a therapeutic role in CKD a of water in kidney disease has been based on data from in vitro and in This the of regarding in CKD and and the associated with increasing water of and water is an function of the kidney. The between and water excretion can be expressed 24-hour excretion 24-hour = 24-hour also to daily and water the normal kidney can a of from at the end to at the can as a However, when is as in the or increase in to between water and kidney was first in the when the of formation was observed to be higher in with less to compared to those in Increasing water intake after the first the of studies to the of increased water intake in the of secondary a on a increase in than those with 0.5 l that to increased water intake was In a et al. found that 2 l/day reduced to which is lower than the in the group the of which was 1 l/day (p 0.0001). an increase of to l was found to be associated with a much lower rate compared to no p The of water in to has been reported in studies large population-based The cohort years who were up for up to years the cohort years up for up to years studies found that the of was inversely related to the risk of formation in with daily l was reduced to compared to those with daily l similar were in the evidence that increased water intake is associated with reduced of both and kidney increased water intake or CKD progression a of Water intake plasma levels of vasopressin high levels of which have been to deleterious in models of kidney of in renal and albuminuria in both normal and rats of V2 vasopressin and Several mechanisms have been in the effects of on the including of glomerular hyperfiltration, stimulation of and of cell Several recent studies have examined the role of water intake in CKD et al. observed a of lower CKD prevalence in who had higher intake in cross-sectional intake of l/day the highest was associated with a of CKD prevalence compared to l/day et al. found in a prospective cohort up for years that the rate of estimated glomerular filtration rate decline was inversely related to increased 24-hour The ratio of renal as loss was for with l/day compared with the group et al. a cross-sectional of the and and found higher CKD prevalence those with intake of l/day l/day (adjusted ratio Interestingly, it was intake in the of than from other that was associated with lower CKD Taken together, these large population-based studies the association between high intake and of kidney at those with renal function with and These are not a = study by et al. reported a more decline associated with higher However, the of the association was after adjustment for that factors other than water intake may have been for their of this study is that participants had a low GFR at baseline. renal function of the kidney is more for a level of the high in this may well be a than a of more CKD The association between water intake and of renal function is by studies of insufficient water et al. healthy participants in and found that the development of CKD was higher in who in or who in more The ratio of an elevated concentration was for and for who for years at a or production compared to those who in these However, as with studies, 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proteinuria and blood pressure studies have shown that the use of an antagonist or increased which results in of is associated with a in the progression of renal disease in models of kidney injury we have similar evidence in observations in humans have that increased as flow from 1 to 2 and blood is lower in patients who on more filtration rate as by in humans There are recent reports that show a association with and levels in the general population and evidence in and that infusion causes albuminuria et al. that copeptin, a surrogate marker of is associated with renal decline in renal chronic from stress, which is associated with high levels of vasopressin, was to have been the causal factor in a of CKD in This observation has and increased in the of vasopressin to kidney injury as well as its by increased with There is evidence in studies in the role of increased with water in patients with et al. that increased was associated with a renal decline in patients with This study reported 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