Fliud therapy in chronic kidney disease: how much to drink?

Jai Prakash*, Vivek C Ganiger**

*Professor and Head, **Senior Resident in Nephrology

Department of Nephrology, Banaras Hindu University, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005


Patients with chronic kidney failure commonly are advised to maintain a generous fluid intake.The reason that physicians tend to recommend such an increased fluid intake is difficult to understand . A scientific basis does not exist. In light of the above, the purpose of this article is to place in modern perspective the widely held but incorrect notion that high fluid intake is a good thing in those with CKD.

The higher the serum creatinine, the higher the prescribed fluid intake, the upper limit in our experience being approximately 4 L/d. Indeed, two recent authoritative publications recommended "increased" fluid intake in the management of CKD1,2. The reason that physicians-in almost all cases, non-nephrologists- tend to recommend such an increased fluid intake is difficult to understand. An increased fluid intake is not supported from modern evidenced-based medicine. In the early years of renal physiology, it was shown that urinary urea clearance was sharply increased as urine flow rates increased from 1 to 2 ml/min3. Lower blood urea nitrogen from chronic high fluid intake seems to be the basis for the historic recommendation to maintain urine volumes up to 4 L in chronic kidney insufficiency. Recent studies on vasopressin have rekindled interest in the possibility that increased water intake may ameliorate the progressive decline in GFR that occurs regularly with aging and at a more rapid pace in those with chronic, progressive renal diseases4. Arginine vasopressin(AVP), a crucial peptide hormone that regulates water homeostasis, is recently suggested to contribute to CKD progression . In the rat model, increasing water intake, which decreases AVP, slowed the decline in GFR and reduced histological damage and protein excretion. Conversely, fluid restriction (which results in sustained high levels of AVP) accelerated CKD progression in the same animal model, an effect duplicated by AVP infusion56


Figure 1Possible mechanisms by which vasopressin may adversely affect the progression of established renal diseases.NaCl, sodium chloride; TALH, thick ascending limb of Henle's loop.


Vasopressin and mechanism of CKD progression (Figure 1):

The experimental study has shown that arginine vasopressin (AVP) may lead to accelerated decline in GFR in patients with CKD56The proposed mechanisms of deleterious effects of AVP on chronic kidney disease includes7;(1) AVP induces glomerular hyperfiltration and hypertension via V2 receptor-mediated, enhanced urea recycling and/or tubular sodium reabsorption 89, as well as partial Vla receptor­ mediated vasoconstriction 10•11• (2) AVP stimulates renin synthesis by the activation of V2 receptorlO, which is the first step in a well-characterized cascade of events leading to scar formation in the kidney12• (3). AVP exerts a direct effect on mesangial cell contraction and proliferation 13• Although the benefits of vasopressin receptor blockade have been well demonstrated in animal models 14, similar findings in humans are yet to be demonstrated 15


Role Of Fluid In Chronic Kidney Disease (CKD):

Epidemiologic evidence also suggests that the balance of water intake and output may have implications for the development of CKD. Insufficient water intake, particularly in settings of arduous physical labor and/or high ambient temperature, may be associated with CKD prevalence. Perazaet al16,17 postulated that chronic volume depletion may cause subclinical acute kidney injury, with repeated insults eventually predisposing to CKD. While these findings provide tantalizing hints that the suppression of AVP by sustained increases of water intake might be beneficial in CKD, a contrarian view has emerged. Hebert et al. performed a retrospective analysis of 581 CKD patients with estimated GFR 25-55ml/min in the Modification of Diet in Renal Disease cohort18. The authors reported that individuals in the highest quartile of urine volume (>2.851/day) showed an estimated GFR decline of 5.5ml/min/year, while individuals in the lowest quartile (<21/day) had an average declines that were significantly lower (3.5ml/min/year) 18Multivariate analysis of the MDRD showed that the association of greater decline in GFR with higher urine volume was independent of baseline GFR, blood pressure, body surface area, race, proteinuria, protein intake, levels of high density lipoprotein, serum sodium and 24h sodium, potassium and use of diuretics, ACE inhibitors, beta blockers or calcium channel blockers. The association of greater urine volume with more rapid CKD progression was particularly strong in patients with polycystic kidney disease (PKD). Recently, Tsai and colleagues tested the hypothesis that fluid overload (defined as an abnormally large difference between the measured and the expected volumes of extracellular water) is a risk factor for progression of chronic kidney disease (CKD) 19Data from this study is consistent with findings of MDRD study, that increased fluid is harmful to kidney function 18.

Hypothesis to explain faster decline in GFR with high urine volume:

Thus, the patients with the highest fluid intake were "pushing fluids."It was concluded that in CKD, there was no evidence of benefit of a high fluid intake. Indeed, although a cause­

Fliud therapy in CKD 9

very predictably. However, it should be noted that age­ related changes in thirst sensation increase the susceptibility for dehydration in the elderly22, particularly in the female elderly23An expanded plasma volume raises renal perfusion, which increases urine production, facilitating enhanced excretion of creatinine and urea. This assumption isvalid only in the case of prerenal kidney failure caused by dehydration. Overuse of diuretics, fluid loss as a result of diarrhea or high fever, and inadequate hydration are examples of prerenal AKI. The decrease in kidney function is functional and fully reversible after administration of fluids. In euvolemic patients, high fluid intake may lead to volume expansion and arterial hypertension, especially when accompanied by high salt intake.

The daily solute load that needs to be excreted by the kidney averages 800 mOsmol (Table 1). The working range of a healthy kidney is from 50 (maximal diluted urine) to 1200 (maximal concentrated urine) mOsmol/kg. Therefore, the healthy kidney needs a urine output of 670 mlto excrete 800 mOsmol of waste. A kidney with a 50% reduction in the concentrating ability will require a daily urine output of 1340 ml.Accordingly, the person with the healthy kidney in our example would require a daily fluid intake of only 470 ml to maintain fluid balance24'25The patient who has CKD and a maximal concentrating capacity of 600 mOsmol/kg would need only 1140 ml of free fluid drinking.There are a few clinical entities that need an increased fluid intake26Patients who need an increased fluid intake can be separated into three categories: ( 1) Those who need high fluid intake to prevent disease such as nephrolithiasis; (2) those who need a high fluid intake to compensate for a underlying disease, such as renal or central diabetes insipidus or salt-wasting nephropathy; and (3) those who have conditions such as polydipsia or salt gluttony , where the underlying disease should be treated.


Table 1 :Relationship Between Solute And Water Intake In Those With Normal Or Impaired Kidney Concentrating Ability

and-effect relationship between high fluid intake and faster GFR decline could not be established, by these association studies, high fluid intake was shown to be an independent risk factor. A hypothesis that could explain how high urine volume might cause faster kidney disease progression is

Urine concentrating capacity Normal

Urine osmolality (mOsmol/kg) 1200

Solute excretion (mOsmol) 800

Water needed = urine volume (ml) 670 Water balance





that high urine volume increases intratubular volume and

pressure, and these stretch forces could induce fibrogenic mechanisms20Another hypothesis that has been put forward is that an increased fluid intake leads to intravascular volume expansion and eventually to an increase in blood pressure (BP), which is one of the major factors of kidney disease progression 21

This does not mean that it is beneficial for the kidney to restrict fluid intake. However, we advocate that there is no advantage to increasing the daily fluid intake above what the thirst sensation tells you. The thirst mechanism is one of the most delicately regulated body systems and works

(food +oxidation - water loss; ml) 200 200

Drinking (ml) 470 1140


So far we have dealt with the fact that increasing the fluid intake does not increase kidney function, but is there evidence that an increased fluid intake may even harm the kidney? In humans, there had been no prospective study of the effect of fluid intake on kidney disease progression. However, a retrospective analysis of the Modification of Diet in Renal Disease and a prospective cohort study by Tsai,Y.C et al shown that increased fluid is harmful to kidney function.



Patients with CKD should not "push fluids:' Normal thirst guided intake should determine water intake, unless there is a specific reason to increase fluid intake. There is no evidence of a beneficial effect of a high fluid intake. Indeed, studies from Tsai and colleagues suggest that increased volume status promotes CKD progression. These data are consistent with the findings of MDRD study.



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