The saying “drink at least 8 glasses of water per day to be healthy” has had little supporting evidence. The purpose of this article was to briefly introduce the role of hydration in health in order to explore in more detail recent observational studies of hyperhydration in chronic kidney disease (CKD) in man. The Modification of Diet in Renal Disease study initially noted a negative association between increasing urine output and progression of CKD that was absent when corrected for baseline variables. Recently, data from 2 different cross-sectional populations found those with the highest fluid intake had a significantly lower risk of CKD. In a longitudinal, community-based cohort study adjusted for baseline variables, decline in kidney function was significantly slower in those with higher versus lower baseline urine volume. These new and contradictoryresults underline the need for a randomized controlled study to test the hypothesis that increased fluid intake will slow renal decline.
William F. Clark, MD, FRCPC, FACP, FASN, FCAHS, is a professor of medicine at Western University; Victoria Hospital–London Health Sciences Centre, Ontario, Canada.
Shih-Han Susan Huang, MD, FRCPC, is a lecturer at Western University; Victoria Hospital–London Health Sciences Centre, Ontario, Canada.
Amit X. Garg, MD, FRCPC, FACP, PhD, is a professor of medicine at Western University; Victoria Hospital–London Health Sciences Centre, Ontario, Canada.
Andrew House, MD, MSc, FRCPC, FASN, is an associate professor of medicine at Western University; London Health Sciences Centre, University Hospital, Ontario, Canada.
Louise M. Moist, MSc, MD, FRCPC, is a professor of medicine at Western University, Victoria Hospital–London Health Sciences Centre, Ontario, Canada.
Matthew Weir, MD, MSc, FRCPC, is an assistant professor of medicine at Western University; London Health Sciences Centre, University Hospital, Ontario, Canada.
Jessica M. Sontrop, PhD, is an assistant professor at Department of Epidemiology & Biostatistics, Western University, London; and Victoria Hospital–London Health Sciences Centre, Ontario, Canada.
Source of support: Canadian Institutes of Health Research, Kidney Foundation of Canada, Ontario Ministry of Health, Danone Industries, Western University Canada.
The authors have no conflicts of interest to disclose.
Correspondence: William F. Clark, MD, FRCPC, FACP, FASN, FCAHS, Victoria Hospital–London Health Sciences Centre, 800 Commissioners Rd E, A2-343, London, ON, Canada N6A 5W9 (email@example.com).
The message “to drink at least 8 glasses of water a day to be healthy” is an almost universal exhortation, but is now receiving more critical analytic assessment in the scientific literature. A thorough review by Valtin1 in 2002 concluded “despite the ubiquitous admonition to drink at least 8 8-oz glasses of water per day, rigorous proof for this counsel appears to be lacking.” Wenzel et al2 in 2006 describe it as a “widespread belief despite a lack of evidence to support it.” Vreeman and Carroll3 in the British Medical Journal in 2007 rating medical myths place the universal exhortation “to drink 8 glasses of water a day to be healthy” as the no. 1 medical myth, and Lette and Dwyer4 in the Lancet in 2008 label it “the fluid craze propagated by the popular press.” Negoianu and Goldfarb5 in the Journal of the American Society of Nephrology in 2008 strike a more balanced note indicating “Although we wish we could demolish all of the urban myths found on the Internet regarding the benefits of supplemental water ingestion, we concede there is also no clear evidence of a lack of benefit.”5 However, as scientists turn their attention to studying this issue, there is now a small but growing body of evidence that increasing fluid intake may have health benefits. Two randomized controlled trials (RCTs) have demonstrated that increased water intake can promote weight loss in overweight adults.6,7 Observational data show a protective effect of increased water intake on hyperglycemia and cardiovascular mortality.8,9 With respect to kidney health, high fluid intake has proven to be the most effective therapeutic measure to prevent kidney stone formation.10,11 More recently, researchers studying the chronic kidney disease (CKD) epidemic in Central America have identified chronic dehydration resulting from heat stress as the likely causal factor.12,13
Vasopressin in Chronic Kidney Disease
It is increasingly recognized that vasopressin, which is suppressed by increased fluid intake, contributes to CKD progression through its effects on renal hemodynamics and blood pressure.14 Plasma vasopressin levels are increased in animal models and also in patients with diabetic and nondiabetic CKD.14 Several studies of 5/6 nephrectomized rats (the universal model of progressive renal impairment) showed that suppression of vasopressin by increased water intake reduced blood pressure, proteinuria, renal hypertrophy, glomerulosclerosis, and tubular interstitial fibrosis. Through a similar mechanism, high fluid intake preserved the renal function of rats with polycystic kidney disease. A recent RCT of a vasopressin antagonist in patients with polycystic kidney disease showed a similar benefit. Although these findings are provocative, we still require adequate evidence from studies of humans that vasopressin inhibition by increased hydration can protect the kidney.
OBSERVATIONAL STUDIES OF HYDRATION AND KIDNEY HEALTH
To date, 4 observational studies have directly examined the relationship between hydration and kidney function in man.15–18
Renal Decline and Urine Volume in Patients With Chronic Kidney Disease
In an observational study, Hebert et al15 studied 581 patients with CKD, of whom 442 had polycystic kidney disease. Participants had a baseline glomerular filtration rate (GFR) of 25 to 55 mL/min, and advice about fluid intake was left to the discretion of the individual physician. The key outcome measure was a change in annualized GFR slope in relation to mean 24-hour urine volume. In this population, higher urine volume was associated with faster GFR decline; however, this association was eliminated when corrected for blood pressure and diuretic use by participants. This change may be explained by greater diuretic use among those with higher urine volumes. As well, as kidney function decreases, the kidneys are less able to concentrate urine, and because this was observational data, temporality is bidirectional: it is possible that higher urine volume with low osmolality was the result, not the cause, of faster renal decline. To avoid selection bias, it is important to adjust for follow-up variables. Medications such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers used in patients who are progressing can initially decrease kidney function because of hemodynamic changes. Also, diuretics will increase urine volume that can be associated with a worsening in renal function due to volume contraction.
Chronic Kidney Disease Is Lower in Adults With Higher Fluid Intake: A Cross-sectional Study
More recently, a study by Strippoli et al16 analyzed data from 2 cross-sectional populations in which fluid intake was assessed by a validated nutrition and food-frequency questionnaire. Participants with the highest quintile of fluid intake (>3.2 L/d) had a significantly lower risk of having CKD (estimated GFR [eGFR] <60 mL/min per 1.73 m2; odds ratio [OR], 0.5; 95% confidence interval [CI], 0.32–0.77; P for trend of .003). These findings were consistent across both study periods, and the authors concluded the higher fluid intake appeared to protect against CKD. They did emphasize the need for verification from longitudinal observational studies as well as a well-constructed RCT to establish the benefits of hydration. The higher intakes of fluid appear to protect against CKD but because of the cross-sectional nature of their study they could easily also have concluded that people with CKD drink less fluid or healthier people drink more fluid, and all we are noting is selection bias rather than a causal relationship.
Chronic Kidney Disease was Associated With Low Intake of Plain Water in a Cross-sectional Analysis of the 2005–2006 National Health and Nutrition Examination Survey
We recently conducted a cross-sectional analysis of 3427 adults in the National Health and Nutrition Examination Survey 2005–20006 database with an eGFR of 30 mL/min per 1.73 m2 or greater who were not taking diuretics or lithium.17 Thirteen percent had CKD, and it was higher among those with the lowest (<2 L/d) versus the highest water intake (>4.3 L/d) (adjusted OR, 2.52; 95% CI, 0.91–6.96). When stratified by intake of plain water and other beverages, CKD was associated inversely with intake of plain water: adjusted OR, 2.36 (95% CI, 1.10–5.06). This study adjusted for 10 baseline variables and provides additional evidence suggesting a potentially protective effect of higher water intake, particularly plain water on kidney function.
Renal Decline Is Slower in Healthy Adults With Higher Urine Volume: A Prospective Cohort Study
In a longitudinal, community-based cohort study by Clark et al,18 2141 participants free of CKD at baseline provided 24-hour urine samples and had their kidney function measured annually for 6 years. Decline in kidney function was significantly slower in those with higher versus lower baseline urine volume. The age- and sex-adjusted average annual decline in eGFR was 0.6 mL/min per 1.73 m2 per year slower for those with urine volume greater than 3 L/d compared with those with smaller urine volumes. For each increasing category of 24-hour urine volume (<1, 1–1.9, 2–2.9, and >3 L/d), percentage annual eGFR decline was progressively slower (1.3%, 1.0%, 0.8%, and 0.5%, respectively; P = .02). As well, after adjusting for age, sex, baseline eGFR, medication used for hypertension (including diuretics), proteinuria, diabetes, and cardiovascular disease, those with the largest urine volumes (>3 L/d) were least likely to demonstrate mild to moderate renal decline (OR, 0.66; 95% CI, 0.46–0.94) or rapid renal decline (OR, 0.46; 95% CI, 0.23–0.92) (Figure). Although this is a fully adjusted observational study and conclusions regarding causality must be cautious, these findings represent important initial evidence that higher fluid intake may in fact benefit the kidney.
Strengths and Weaknesses of the Human Observational Studies
The initial human observational study by Hebert et al15 appears to suffer from a selection bias relating to medications with the inverse association noted for urine output and kidney function, losing significance when participants are controlled for medication use. The next 2 observational studies also may suffer from selection bias, although the more comprehensive baseline adjustments and exclusion of subjects taking diuretics and lithium in the National Health and Nutrition Examination Survey study do reduce but in no way exclude the possibility of a major unknown selection bias that predisposed participants with CKD to drink less fluid.16,17 The longitudinal observational study in a large population over a 7-year period with adjustment for a wide range of baseline variables does address some of the baseline imbalances that may threaten any observational study.18 In fact, the inverse dose-response relationship between urine output and annual loss of kidney function does suggest a possible causal relationship. However, this is still an observational study, and the lack of randomization precludes proof of a causal relationship between implied fluid intake (urine output) and annual loss of kidney function. Only a well-constructed RCT can overcome selection bias.
Three observational studies suggest increased fluid intake may slow progression of kidney loss (2 of the studies were adjusted for baseline variables). The Modification of Diet in Renal Disease observational study (unadjusted) shows the opposing correlation with a more rapid loss of kidney function associated with increasing urine volume (association lost after adjustment of baseline variables). We concluded that the question has reached clinical equipoise and may be resolved by an RCT.
On the basis of the foregoing review, we hypothesize that increased fluid intake of 1 to 1.5 L will slow renal decline. We have designed an RCT to test whether increased fluid intake slows renal decline in patients with CKD (eGFR 30–60 mL/min per 1.73 m2) and microalbuminuria (albumin-to-creatinine ratio >2.8 mg/mmol [if female], >2.0 mg/mmol [if male]) or trace proteinuria.
All participants will receive coaching on how to follow a healthy lifestyle for CKD; however, participants randomized to the hydration-intervention group will be asked to drink 1.0 to 1.5 L of water per day, depending on age and sex in addition to usual fluid intake (total fluid intake based on usual daily intake of 1–2 L of fluid/day would be eight to twelve 8-oz glasses of water per day in the hyperhydration group) for 1 year. We will estimate the change in eGFR, measured every 3 months for 12 months, and compare the rate of renal decline between the intervention and control groups. We have registered our impending RCT in ClinicalTrials.gov, which can be accessed online. We wish to reiterate that this review and subsequent RCT do not support rapid or aggressive fluid loading because of the attendant serious risk of hyponatremia.
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