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Sodium and Volume Disorders in Advanced Chronic Kidney Disease
Sodium and Volume Disorders in Advanced Chronic Kidney Disease Sana Khan, Matteo Floris, Antonello Pani, and Mitchell H. Rosner The kidney has a remarkable ability to modulate sodium and water excretion to maintain homeostasis despite a widely varying dietary intake. However, as glomerular filtration rate falls to less than 30 mL/min, this ability can be compromised leading to an increased risk for disorders of serum sodium and extracellular volume. In all cases, these disorders are associated with an increased rate of morbidity and mortality. Management strategies to both prevent and treat these conditions are available but requiring special attention to the unique circumstance of advanced CKD to maximize therapeutic response and prevent complications. Q 2016 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Sodium, Hyponatremia, Hypernatremia, Volume, Diuretics
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he kidney is the major regulator of both plasma sodium/osmolality and volume control. The former is controlled through variable water excretion and the latter through modulation of sodium excretion. As glomerular filtration rate (GFR) decreases and patients progress to worsening stages of CKD (stages 4 and 5), the ability to regulate these processes and retain tight control over both plasma sodium/osmolality and volume may become impaired. This inability to maintain homeostasis is most marked under stress conditions such as when comorbid conditions, such as heart failure, liver disease, or wide variations in dietary intake of sodium and water, interact to increase the risk for volume overload and either hyponatremia or hypernatremia. In all cases, the presence of volume overload, hyponatremia, or hypernatremia significantly increases the risk for mortality and poor outcomes.1-3 This highlights the importance of maintaining euvolemia and normal plasma sodium levels. SODIUM DISORDERS IN CKD Epidemiology of Sodium Disorders in CKD Hyponatremia (defined as a serum sodium , 135 meq/L) is one of the most common electrolyte disorders encountered in clinical practice, estimated to be present in 10% to 30% of acutely hospitalized patients.4,5 In the elderly population, hyponatremia is especially common and surveys of nursing home residents indicate a prevalence of hyponatremia as high as 30%.6 The presence of hyponatremia, no matter what the etiology may be, is associated with increased morbidity and mortality in ambulatory and hospitalized patients and may be regarded as an From the Division of Nephrology, University of Virginia Health System, Charlottesville, VA; and Department of Nephrology and Dialysis, G. Brotzu Hospital, Cagliari, Italy. Financial Disclosure: No authors have relevant conflict of interests or financial relationships to disclose. Address correspondence to Mitchell H. Rosner, MD, Division of Nephrology, University of Virginia Health System, Box 800133 HSC, Charlottesville, VA 22903. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2015.12.003
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important marker of severe disease.7 It is likely that the major mortality effect attributed to hyponatremia derives more from the underlying etiology leading to the electrolyte disorder rather than hyponatremia itself.5,8 The majority of these epidemiologic studies do not include data on the kidney function of these patients, so specific data on the association with or without CKD are not available except for a single study discussed below. Hypernatremia (defined as serum sodium . 145 meq/L) is much less common than hyponatremia, estimated to be 2% to 5% in acutely ill patients.9,10 This is likely because the fact that in the presence of a normal thirst sensation, most people are able to maintain serum sodium levels , 145 meq/L. It is only when thirst sensation is impaired (for instance, in patients who have serious disorders of cognition) or when water access is limited that hypernatremia occurs.11 This can be exacerbated by excessive urinary or other body water losses.12 As an example, patients with significant cognitive impairment who are hospitalized often have inadequate thirst sensation cannot easily ask for water and may not have ready access to fluids. Thus, these patients are prone to the development of hypernatremia. Although CKD is known to affect the ability of the kidneys to regulate water homeostasis, because of impaired diluting and concentrating mechanisms with progressive kidney disease, studies have indicated that dysnatremias resulting from worsening CKD alone are rare, even in patients with advanced CKD.2,13,14 A large observational study evaluated the prevalence of dysnatremias in 655,493 US veterans with non-dialysis-dependent CKD.15 At baseline, 13.5% of patients had hyponatremia (serum sodium , 136 mEq/L) and 2% had hypernatremia (serum sodium . 145 mEq/L). However, over a mean 5-year period of observation, 26% of all patients developed at least 1 episode of hyponatremia and 7% developed hypernatremia. The prevalence of hyponatremia did not have a strong correlation with CKD stage and was essentially similar in patients with Stage 3, Stage 4, and Stage 5 CKD (11%-12%).15 However, the prevalence of hypernatremia showed a significant increase with advancing CKD (up to maximum of 3.1% in stages 4 and 5). Attributing the dysnatremia solely to advancing CKD is difficult in these observational studies as patients had serum sodium levels measured in both the inpatient and
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outpatient setting, and the circumstances regarding the a greater load of solute filtration, decreased tubular measurement of the serum sodium were not known (ie, responsiveness to AVP, and an impaired countercurrent the laboratory values may have been obtained during an mechanism in disorders affecting the renal medulla.19-21 Animal models have additionally demonstrated acute illness, such as pneumonia). decreased urea recycling in the loop of Henle in CKD Mortality associated with dysnatremias in patients with models, which contributes to decreased medullary non-dialysis CKD was also studied in the large Veteran’s tonicity.22 Additionally, concentrating defects are more cohort described earlier.15 In this study, mortality was lowest in patients with a serum sodium between 140 and pronounced in those interstitial-prominent diseases 144 meq/L and then showed a linear increase with the affecting the renal medulla.22,23 Furthermore, many patients with CKD are taking loop diuretics that impair severity of both hyponatremia and hypernatremia that the development of a hypertonic medullary gradient. was present in all subgroups (including those with and Impaired ability to concentrate the urine typically leads without heart failure and liver disease). Patients with to excessive urine output (polyuria) and nocturia and in serum sodium levels , 130, 130 to 135, 145 to 149, and . the face of impaired thirst sensation or limited water 150 mEq/L compared with the reference level of 136 to access predisposes individuals to the development of 145 mEq/L had a statistically significant hazard ratio for hypernatremia. The fact that urine-concentrating ability all-cause mortality. The mortality association with hypois affected to a greater extent than diluting ability is supnatremia was not influenced by CKD stage. However, ported by the fact that the rate of hypernatremia the association of hypernatremia and mortality was increases with advancing CKD, whereas the rate of hypoactually lower in more advanced stages of CKD. The natremia does not.15 explanation for this apparent “protective” effect of advanced CKD on hypernatremia-related mortality is not clear, but the authors have speculated that this may Impaired Urinary Diluting Ability. Additionally, impaired be because of adaptation to urinary dilution, as maniincreased extracellular osmofested by an inability to CLINICAL SUMMARY lality in patients with more lower urine osmolality advanced CKD who experiappropriately, has been 1. As kidney function decreases, the ability to maintain ence a gradual accumulation observed in advanced kidplasma osmolality and volume within normal limits can of uremic solutes.15 This ney dysfunction.19,24 The be impaired and this is especially true during states of more gradual change in mechanisms for this stress such as heart or liver failure. extracellular osmolality aldisorder are less clear than 2. In patients with CKD, hyponatremia is far more common lows for cellular adaptation those of impaired urinary than hypernatremia. that can occur over a longer concentrating ability in 3. Treatment of hyponatremia and hypernatremia in the time frame. CKD. In order for dilute patient with CKD follows the same principles as for urine to be made, several Pathophysiology of patients with normal kidney function. mechanisms must be Sodium Disorders: The operative: (a) there must be 4. In patients with advanced CKD and volume overload, loop Role of CKD enough filtrate delivered to diuretics are the agents of choice to increase sodium Under normal circumstances, excretion. the distal nephron for sodium levels are maintained dilution and excretion, (b) because of a balance between the diluting segments of net water intake and excretion. Impaired concentrating the distal nephron must selectively reabsorb sodium and and diluting abilities occur with CKD that stress the ability lead to a fall in urine osmolality and finally, and (c) AVP of the body to maintain normonatremia.2 Typically with levels must fall and the collecting tubule must decrease CKD, the capacity to dilute the urine is maintained longer its permeability to water reabsorption and allow water to than the capacity to concentrate the urine, but as patients be excreted (dilute urine). It is unlikely that limitations in reach ESRD, the urine osmolality reaches a constant level filtrate amount affect this process until very late CKD at approximately 300 mOsm/L (isosthenuria).16 At this (with GFRs ,5 mL/min), and it is most likely that CKD late stage, factors other than the urine-concentrating/ may be associated with defects in the diluting segment.2 diluting mechanism must take precedence to maintain This may be further exacerbated using thiazide diuretics, normal serum osmolality. These include the amount of wawith resulting natriuresis, and vasopressin release.25 The ter intake and the solute load and residual GFR.17 net result of these impairments in urine dilution is that the risk of hyponatremia may be increased. However, Urine Concentration Ability in CKD. The ability to concenbased on observational studies, this risk of hyponatremia trate urine is dependent on the presence of a hypertonic with advancing CKD is likely small.15 medullary interstitium and collecting tubule permeability Integrated Physiology of Impairments in Dilution/ that varies substantially under the influence of arginine Concentration in CKD vasopressin (AVP). Several factors have been thought to As an example of how these derangements in kidney contribute to impaired concentrating ability and subsefunction may lead to dysnatremias, it is instructive to quent isosthenuria that is characteristic of CKD.18 These include an osmotic diuresis from excess solute excretion look at typical urine osmolalities and water intakes. in remaining functional nephrons that are now carrying Under normal circumstances, with intact countercurrent
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mechanisms, urine osmolality can range from 50 to 1200 mOsm/kg H2O depending on the presence or absence of AVP. Thus, a fixed dietary solute load of 600 mOsm/d may be excreted in as little as 0.5 L urine (highly concentrated urine with an osmolality of 1200 mOsm/kg) or as much as 12 L of urine (maximally dilute urine with an osmolality of 50 mOsm/kg). Individuals with advanced CKD may be able to concentrate urine to 200 to 300 mOsm/kg H2O which will be relatively fixed. Hence, in a patient with advanced CKD (stages 4 and 5), the same 600-mOsm solute load would require generation of 2 to 3 L of urine output. In this scenario, where the ability of the kidney to alter the urine osmolality in response to varying dietary intake of fluids is limited, ingestion of less than 2 L of fluids per day would result in progressive negative water balance, and the subsequent development of hypernatremia. On the contrary, greater fluid intake more than 3 L/d and an inability to dilute urine result in progressive fluid retention and development of hyponatremia. This demonstrates the role of CKD in limiting the kidney flexibility to control water excretion in response to variable dietary water and solute intake. Additionally, underlying coexistent conditions that have impact on water handling, such as the nephrotic syndrome, liver disease, and congestive heart failure, may confound water balance in advanced CKD. For example, in these conditions, effective circulating volume is decreased that leads to neurohormonal activation with high levels of vasopressin, angiotensin II, and activation of the sympathetic nervous system. Depending on the water and sodium intake of the patient, this neurohormonal activation will increase the likelihood of dysnatremias, most likely hyponatremia. Concomitant diuretic use and medications that impair urinary concentration/ dilution also affect the risk of developing a dysnatremia in the face of CKD. Treatment of Sodium Disorders in CKD The treatment of sodium disorders in patients with CKD follows the same principles as the treatment of these disorders in patients without CKD. Some general principles are given in Tables 1 and 2.26 As mentioned previously, results
of a large epidemiologic study revealed lowest mortality in patients with sodium levels of 140 mEq/L and adjusted hazard ratios for the group , 130 and 130 to 135 mEq/L to be 1.93 and 1.28, respectively.15 Thus, gradual correction of serum sodium levels to 130 to 135 mEq/L appears to be a reasonable target in this population. There are several limitations that need to be considered when approaching therapeutic options in dysnatremias in CKD patients.2 Water restriction is a slow acting approach toward hyponatremia correction and often practiced in the outpatient setting. Frequent monitoring of serum sodium levels is required to prevent undesirable increases to hypernatremic levels. Similarly, close monitoring is needed in cases of normal saline infusion for correction of hypovolemic hyponatremia, given the high likelihood of sodium retention and resulting fluid overload. Several pharmacologic agents have been listed in Table 1. Loop diuretics are commonly used to enhance water excretion for hyponatremia correction. In CKD patients, it is important to monitor for signs of volume depletion and electrolyte abnormalities. Demeclocycline has been used in hyponatremia correction; however, it must be used with caution in CKD patients since it is renally excreted and has been shown to worsen renal insufficiency.48 Additionally, although vasopressin V2 receptor antagonists have been shown to correct hyponatremia, several trials have excluded patients with advanced CKD.49,50 Small studies have demonstrated safety of Tolvaptan use in advanced CKD; however, larger studies are needed to determine V2 receptor antagonist efficacy in advancing CKD.51 The role of kidney replacement therapy has been reported in correction of hyponatremia in CKD patient with confounding anuric AKI47; however, it has not been reported otherwise in stable CKD patients nor was it reported as a therapeutic option in the epidemiological study previously discussed.15 VOLUME DISORDERS IN CKD The control of extracellular volume is modulated through changes in kidney sodium excretion. The
Table 1. Treatment Options for Hyponatremia in CKD Treatment
Mechanism
Comments
Water restriction to 500 mL less than urine output Hypertonic saline
Decreases total body water, increasing ratio of sodium to water Increases ratio of sodium to water
Loop diuretics (often with sodium supplementation)
Increases rate of dilute urine production and combined with salt supplementation leads to net body water loss Increases osmolality of plasma and tubular fluid and increases renal water excretion
Slow acting, unpredictable, and compliance is difficult Treatment of choice for acute, symptomatic hyponatremia but risks overcorrection in patients with chronic hyponatremia Inexpensive but requires close monitoring to avoid volume depletion and other electrolyte abnormalities Effective and inexpensive but unpalatable and currently not readily available in the United States Potential for nephrotoxicity and slow to act Expensive, requires monitoring for first 48 h and limited to 30 d use due to concern of liver injury. May be less effective as GFR falls ,30 mL/min
Urea
Demeclocycline AVP receptor antagonists (tolvaptan and conivaptan)
Induced nephrogenic diabetes insipidus Directly antagonizes vasopressin type 2 receptor leading to excretion of dilute urine
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Table 2. Treatment of Hypernatremia in CKD Hypovolemic
Euvolemic
Correct volume deficit with isotonic saline until vital signs stabilize
Calculate water deficit and replace along with ongoing losses with hypotonic fluids or oral water If central diabetes insipidus: aqueous vasopressin
Calculate water deficit and replace along with ongoing losses with hypotonic fluids or oral water Treat underlying cause of water/volume loss
If nephrogenic diabetes inspidus: low salt diet, thiazide diuretics, amiloride, and stop any offending medications
major effector systems involved in this process are listed in Table 3 that delineates the major afferent sensors of volume and the efferent systems involved in modulation of kidney sodium excretion. Given the primacy of the kidney in the control of extracellular volume, it is not surprising that volume overload is increasingly common in patients with CKD. The typical clinical presentation is with signs and symptoms such dyspnea, peripheral edema, ascites, and reduced exercise tolerance often with concomitant hypertension. Although the prevalence of volume overload solely because of CKD is hard to determine, a study by Hung and colleagues in patients with CKD stages 3 to 5 demonstrated that only 48% were euvolemic by bioimpedance assessment.3,27 However, it is extremely difficult to dissociate volume overload solely because of advancing CKD from other comorbidities (such as systolic or diastolic heart failure, hypertension, and arterial stiffness). In fact, when measurements (using chromium-labeled red blood cells, exchangeable sodium, bromide or sulfate) of extracellular volume have been made in patients with CKD, the results are conflicting but overall show that extracellular fluid volume is usually normal, at least until GFR is profoundly decreased (, 10 mL/min).13,28 In terms of extracellular volume homeostasis, there is a vicious cycle that develops where CKD along with hypertension and heart failure lead to volume overload that further worsens hypertension, left ventricular hypertrophy, and kidney function. In fact, several studies have linked a patient’s relative hydration status as determined by either brain natriuretic peptide levels or bioimpedance spectroscopy with both mortality and CKD progression.3,27,29,30 For example, Tsai and
Hypervolemic Often iatrogenic and removal of offending agents Loop diuretics and calculate water deficit and replace along with ongoing losses with hypotonic fluids or oral water If renal failure, hemodialysis
have demonstrated that volume colleagues29 overload (using BIS) was both associated with a more rapid progression of CKD and the need to initiate kidney replacement therapy. Abnormal fluid status is also associated with an increased all-cause and cardiovascular mortality rate.3 There are several other factors that compound the difficulty of studying the independent effects of CKD on volume overload. Some patients may have expanded intravascular and extravascular volumes, whereas other patients may only have expanded extravascular volumes in the setting of normal or even lower intravascular volumes. This latter group includes patients with CKD and the nephrotic syndrome or advanced heart or liver failure. Thus, within the category of volume-overloaded patients, there are subtypes where the role of CKD may differ. Pathogenesis of Sodium Retention and Volume Overload in CKD Sodium balance is surprisingly well maintained in patients with CKD and GFRs ranging from 3 to 25 mL/min when sodium intake is varied 2-fold from 1400 to 2800 mg/d.32 This ability to modulate kidney sodium excretion is likely because of changes in tubular reabsorption/excretion (most likely in the proximal tubule, loop of Henle, and distal nephron) and in these studies was independent of aldosterone.31,52 In general, it has been hypothesized that in CKD, there is an adaptive response leading to an increase in sodium excretion per nephron in the setting of a constant sodium intake (fractional excretion of sodium is increased).32 The mechanisms responsible for this adaptation are not elucidated but may require some degree of subclinical volume expansion and elevation in mean arterial blood pressure to increase sodium excretion.33-35 This is a protective effect against the
Table 3. Control Systems Involved in Extracellular Volume Regulation Afferent Sensor Systems - Baroreceptors (arterial circulation, aortic arch, carotid sinuses, cardiac atria, and renal arteries) - Sympathetic nervous system is major communication node between arterial baroreceptors and kidney
Efferent Effector Systems -
Sympathetic nervous system Renin Angiotensin II Aldosterone Prostaglandins Vasopressin Endothelin Nitric oxide Natriuretic peptides
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development of continued sodium retention and edema formation. However, it appears that the time constant over which changes in fractional excretion of sodium can change is limited, and thus, if sodium intake is suddenly increased or decreased, the kidneys cannot immediately adjust and, thus, volume expansion or depletion is more likely.28,32 Clinically, this translates into the observation that if changes in sodium intake are introduced slowly and stepwise in patient with CKD, volume expansion/ depletion does not typically occur. However, rapid changes in sodium intake are not well tolerated and lead to volume disorders. Volume disorders in advanced CKD are often part of syndromes resulting from underlying comorbid conditions, including cirrhosis, cardiorenal syndrome, nephrotic syndrome. Cardiorenal syndrome in particular involves a complex pathophysiology involving reninangiotensin system activation, sympathetic nervous system, and hemodynamic alterations.54 Multifactorial cardiorenal interactions involving arterial underfilling because of ventricular contractile dysfunction, decreased GFR, insufficient pressure natriuresis, and renal venous hypertension, all contribute to volume overload, with subsequent volume overload and worsening of cardiac and kidney dysfunction.54,55 Management of Volume Disorders in CKD Given that the primary effect of diuretics is to inhibit tubular sodium reabsorption resulting in an increase in sodium excretion, a decrease in ECF volume expansion, and a drop in blood pressure, these agents are the mainstay for the treatment of CKD-related volume expansion. Diuretics are used in CKD patients to manage edema, control blood pressure, potentiate the effects of other antihypertensive agents including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers and to aid in correction of metabolic acidosis and hyperkalemia. There are 3 main classes of diuretics: loop diuretics, thiazide diuretics, and potassium sparing (K1 sparing) diuretics. Loop diuretics, such as furosemide, bumetanide, and torsemide, act by inhibiting the Na1-K1-2Cl2 cotransporter in the thick ascending limb of the loop of Henle, thus enhancing sodium and water clearance. The maximally effective doses lead to an almost complete block of sodium reabsorption in the loop of Henle (z20%-25% of filtered sodium). Loop diuretics circulate bound to albumin and are secreted into tubular fluid by organic anion transporters in the proximal tubule. Because patients whose GFR is ,15 mL/min secrete only 10% to 20% of the amount of loop diuretic that is secreted by patients with normal GFR treated with a similar dose, the dose of diuretic administered to achieve effective tubular concentration must be increased proportionately.36 For example, CKD stages 4 to 5 patients should be started at a dose of 40 to 80 mg once daily and then titrated upward by 25% to 50% weekly depending on the desired effects on lowering ECF volume.37 The greatest natriuretic response is observed with intravenous (IV) doses of 160 to 200 mg of furosemide or equivalent doses of bumetanide (6-8 mg) and torsemide (80-100 mg).38,39
The decrease in kidney function does not influence the bioavailability of loop diuretics (z50%) but can significantly prolong the relatively short half-life of these drugs.40 Given the primacy of volume expansion and its role in hypertension in late-stage CKD, loop diuretics also play a significant role in the management of hypertension in advanced stages of CKD. Thiazide diuretics, such as hydrochlorothiazide, reduce sodium reabsorption in the distal tubule by inhibiting the apical Na1-Cl-cotransport system. Although they are the diuretics of choice in patients with normal or mild reductions of kidney function, the effect on natriuresis in subjects with GFR ,50 mL/min is lower compared with loop diuretics.40 When used alone, thiazides become less effective in patients with GFR ,35 mL/min, and higher doses are needed if kidney function is compromised.41 Because of their compartmentalization into red blood cells, long-acting thiazide-like diuretics, such as metolazone and chlorthalidone, are associated with more sustained lowlevel diuresis and tend to be more effective in advanced stages of CKD than hydrochlorothiazide.42 In patients with inadequate natriuresis in response to maximal doses of loop diuretics, sequential nephron blockade with thiazide diuretics has been shown to have a synergistic effect, although at the cost of a higher risk for volume depletion and electrolyte disorders.43,53 Potassium-sparing diuretics act primarily at the cortical part of the collecting duct and are divided into 2 subgroups: inhibitors of the epithelial sodium channels in the luminal membrane, such as amiloride and triamterene, and aldosterone receptor antagonists, such as spironolactone and eplerenone. These agents must be used cautiously in CKD patients because of the risk of hyperkalemia, and they tend to have small effects on decreasing extracellular volume.40 However, aldosterone receptor antagonists are increasingly being used in patients with CKD because of their antiproteinuric effects and cardioprotective benefits.44 Initiation of therapy with low doses is recommended along with slow-dose titration and frequent monitoring of potassium levels.37 Although exceeding the ceiling dose for diuretics acting on the same transport mechanisms will not result in an incremental diuretic response, the combination of diuretics acting on separate nephron sites (sequential nephron blockade) may be synergistic and lead to significant decreases in extracellular volume. The most commonly used combination in clinical practice is the association of a loop diuretic with a thiazide or thiazide-like drug. The combination of furosemide-metolazone is particularly effective in patients that require large volume fluid removal.45 Finally, in those patients with significant, symptomatic volume overload and advanced CKD, continuous IV infusion of loop diuretics may confer additional benefits. Greater sodium excretion has been observed in patients with advanced CKD treated with continuous rather than bolus loop diuretic infusion.46 Moreover, continuous infusion of loop diuretics may be associated with lower peak plasma concentrations than high-dose IV dosing which should lead to fewer dose-related side effects, such as ototoxicity.
Sodium and Volume Disorders
At some point, patients with very advanced, usually Stage 5, CKD will not respond to diuretic therapy and may develop refractory volume overload despite dietary sodium restriction. This is an indication to start kidney replacement therapy with either peritoneal dialysis or hemodialysis. SUMMARY Disorders of sodium and water balance become more common as CKD advances. However, the amazing ability of the kidney to adapt to widely varying sodium and water intakes limits these disorders to later stages (4 and 5) of CKD. Attention to the development of these issues and early, aggressive therapy to manage these problems is critical as they (hypernatremia, hyponatremia, extracellular volume overload) are associated with increased morbidity and mortality. Effective therapies exist to treat these disorders, but as CKD evolves, the most effective therapy may be kidney replacement therapy along with strict dietary control of water and sodium intake. REFERENCES 1. Zaino CJ, Meheshwani AV, Goldfarb DS. Impact of mild chronic hyponatremia on falls, fractures, osteoporosis and death. Am J Orthop (Belle Mead NJ). 2013;42(11):522-527. 2. Combs S, Berl T. Dysnatremia in patients with kidney disease. Am J Kidney Dis. 2014;63(2):294-303. 3. Hung SC, Kuo KL, Peng CH, et al. Volume overload correlates with cardiovascular risk factors in patients with chronic kidney disease. Kidney Int. 2014;85(3):703-709. 4. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006;119(7 suppl 1):S30-S35. 5. Schrier RW, Sharma S, Shchekochikhin D. Hyponatraemia: more than just a marker of disease severity? Nat Rev Nephrol. 2013;9(1):37-50. 6. Cowen LE, Hodak SP, Verbalis JG. Age-associated abnormalities of water homeostasis. Endocrinol Metab Clin North Am. 2013;42(2):346-370. 7. Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med. 2010;170(3):294-302. 8. Chawla A, Sterns RH, Nigwekar SU, Cappuccio JD. Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol. 2011;6(5):960-965. 9. Arampatzis S, Frauchiger B, Fiedler GM, et al. Characteristics, symptoms, and outcome of severe dysnatremias present on hospital admission. Am J Med. 2012;125(11):1125.e1-1125.e7. 10. Gucyetmez B, Ayyildiz AC, Ogan A, et al. Dysnatremia on intensive care unit admission is a stronger risk factor when associated with organ dysfunction. Minerva Anestesiol. 2014;80(10):1096-1104. 11. Shah MK, Workeneh B, Taffet GE. Hypernatremia in the geriatric population. Clin Interv Aging. 2014;9:1987-1992. 12. Verbalis JG. Disorders of water metabolism: diabetes insipidus and the syndrome of inappropriate antidiuretic hormone secretion. Handb Clin Neurol. 2014;124:37-52. 13. Mitch WE, Wilcox CS. Disorders of body fluids, sodium and potassium in chronic renal failure. Am J Med. 1982;72(3):536-550. 14. Wallia R, Greenberg A, Piraino B, et al. Serum electrolyte patterns in end-stage renal disease. Am J Kidney Dis. 1986;8(2):98-104. 15. Kovesdy CP, Lott EH, Lu JL, et al. Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation. 2012;125(5):677-684. 16. Tuso PJ, Nissenson AR, Danovitch GM. Electrolyte disorders in chronic renal failure. In: Narins RG, ed. Maxwell & Kleeman’s Clinical Disorders of Fluid and Electrolyte Metabolism. New York, NY: McGraw-Hill, Inc.; 1994:1195-1211.
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17. Kovesdy CS. Significance of hypo- and hypernatremia in chronic kidney disease. Nephrol Dial Transplant. 2012;27(3):891-898. 18. Tannen RL, Regal EM, Dunn MJ, et al. Vasopressin resistant hyposthenuria in advanced chronic renal disease. N Engl J Med. 1969;280(21):1135-1141. 19. Kleeman CD, Adams DA, Maxwell MH. An evaluation of maximal water diuresis in chronic renal disease: I. Normal solute intake. J Lab Clin Med. 1961;58:169-184. 20. Fine LG, Schlondorff D, Trizna W, et al. Functional profile of the isolated uremic nephron:impaired water permeability and adenylate cyclase responsiveness of the cortical collecting tubule to vasopressin. J Clin Invest. 1978;61(6):1519-1527. 21. Gilbert RM, Weber H, Turshin L, et al. A study of the intrarenal recycling of urea in the rat with chronic experimental pyelonephritis. J Clin Invest. 1976;58(6):1348-1357. 22. Hatch FE, Culbertson JW, Diggs LW. Nature of the renal concentrating defect in sickle cell disease. J Clin Invest. 1967;46(3):336-345. 23. Zittema D, Boertien WE, van Beek AP. Vasopressin, copeptin, and renal concentrating capacity in patients with autosomal dominant polycystic kidney disease without renal impairment. Clin J Am Soc Nephrol. 2012;7(6):906-913. 24. Bricker NS, Dewey RR, Lubowitz H, Stokes J, Kirkensgaard T. Observations of the concentrating and diluting mechanisms of the diseased kidney. J Clin Invest. 1959;38(3):516-523. 25. Hix JK, Silver S, Sterns RH. Diuretic-associated hyponatremia. Semin Nephrol. 2011;31(6):553-566. 26. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1-S42. 27. Tsai YC, Tsai JC, Chen SC, et al. Association of fluid overload with kidney disease progression in advanced CKD: a prospective cohort study. Am J Kidney Dis. 2014;63(1):68-75. 28. Paller MS. Sodium metabolism in chronic kidney disease. In: Kimmel PL, Rosenberg ME, eds. Chronic Kidney Disease. San Diego, CA: Elsevier; 2015:375-380. 29. Tsai YC, Chiu YW, Tsai JC, et al. Association of fluid overload with cardiovascular morbidity and all-cause mortality in stages 4 and 5 CKD. Clin J Am Soc Nephrol. 2014;10(1):39-46. 30. Wabel P, Moissl U, Chamney P, et al. Towards improved cardiovascular management: the necessity of combining blood pressure and fluid overload. Nephrol Dial Transplant. 2008;23(9):2965-2971. 31. Slatopolsky E, Elkan IO, Weerts C, Bricker NS. Studies of the characteristics of the control system governing sodium excretion in uremic man. J Clin Invest. 1968;47(3):521-530. 32. Danovitch GM, Bourgoignie J, Bricker NS. Reversibility of the “salt-losing” tendency of chronic renal failure. N Engl J Med. 1977;296(1):14-19. 33. Muntner P, Anderson A, Charleston J, et al. Hypertension awareness, treatment, and control in adults with CKD: results from the Chronic Renal Insufficiency Cohort (CRIC) Study. Am J Kidney Dis. 2010;55(3):441-451. 34. Agarwal R. Hypertension in chronic kidney disease and dialysis: pathophysiology and management. Cardiol Clin. 2005;23:237-248. 35. Vasavada N, Agarwal R. Role of excess volume in the pathogenesis of hypertension in chronic kidney disease. Kidney Int. 2003;64(5):1772-1779. 36. Brater DC. Pharmacology of diuretics. Am J Med Sci. 2000;319(1):38-50. 37. Kidney Disease Outcomes Quality I. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(5 Suppl 1):S1-S290. 38. Voelker JR, Cartwright-Brown D, Anderson S, et al. Comparison of loop diuretics in patients with chronic renal insufficiency. Kidney Int. 1987;32(4):572-578. 39. Rudy DW, Gehr TW, Matzke GR, et al. The pharmacodynamics of intravenous and oral torsemide in patients with chronic renal insufficiency. Clin Pharmacol Ther. 1994;56(1):39-47.
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40. Sica DA. Diuretic use in renal disease. Nat Rev Nephrol. 2012;8(2):100-109. 41. Knauf H, Mutschler E. Diuretic effectiveness of hydrochlorothiazide and furosemide alone and in combination in chronic renal failure. J Cardiovasc Pharmacol. 1995;26(3):394-400. 42. Dargie HJ, Allison ME, Kennedy AC, et al. High dosage metolazone in chronic renal failure. Br Med J. 1972;4(5834):196-198. 43. Wollam GL, Tarazi RC, Bravo EL, et al. Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am J Med. 1982;72(6):929-938. 44. Sica DA. The risks and benefits of aldosterone antagonists. Curr Heart Fail Rep. 2005;2(2):65-71. 45. Sica DA, Gehr TW. Diuretic use in stage 5 chronic kidney disease and end-stage renal disease. Curr Opin Nephrol Hypertens. 2003;12(5):483-490. 46. Rudy DW, Voelker JR, Greene PK, et al. Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy. Ann Intern Med. 1991;115(5):360-366. 47. Bender FH. Successful treatment of severe hyponatremia in a patient with renal failure using continuous venovenous hemodialysis. Am J Kidney Dis. 1998;32(5):829-831. 48. Braden GL, Geheb MA, Shook A, et al. Demecloclyin-induced natriuresis and renal insufficiency: in vivo and in vitro studies. Am J Kidney Dis. 1985;5(5):270-277.
49. Rozen-Zvi B, Yahav D, Gheorghiade M, et al. Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis. Am J Kidney Dis. 2010;56(2):325-327. 50. Schrier RW, Gross P, Gheroghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist for hyponatremia. N Engl J Med. 2006;355(20):2099-2112. 51. Otsuka T, Sakai Y, Murasawa T, et al. The effects of tolvaptan in patients with severe chronic kidney disease complicated by congestive heart failure. Clin Exp Nephrol. 2013;17(6):834-838. 52. Bank N, Aynedjian HS. Individual nephron function in experimental bilateral pyelonephritis. I. Glomerular filtration rate and proximal tubular sodium, potassium and water reabsorption. J Lab Clin Med. 1966;68(5):713-727. 53. Flliser D, Schroter M, Nerubeck M, et al. Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure. Kidney Int. 1994;46(2):482-488. 54. Tsuruya K, Eriguchi M. Cardiorenal syndrome in chronic kidney disease. Curr Opin Nephrol Hypertens. 2015;24(2):154-162. 55. Heywood JT, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail. 2007;13(6):422-430.
T
he kidney is the major regulator of both plasma sodium/osmolality and volume control. The former is controlled through variable water excretion and the latter through modulation of sodium excretion. As glomerular filtration rate (GFR) decreases and patients progress to worsening stages of CKD (stages 4 and 5), the ability to regulate these processes and retain tight control over both plasma sodium/osmolality and volume may become impaired. This inability to maintain homeostasis is most marked under stress conditions such as when comorbid conditions, such as heart failure, liver disease, or wide variations in dietary intake of sodium and water, interact to increase the risk for volume overload and either hyponatremia or hypernatremia. In all cases, the presence of volume overload, hyponatremia, or hypernatremia significantly increases the risk for mortality and poor outcomes.1-3 This highlights the importance of maintaining euvolemia and normal plasma sodium levels. SODIUM DISORDERS IN CKD Epidemiology of Sodium Disorders in CKD Hyponatremia (defined as a serum sodium , 135 meq/L) is one of the most common electrolyte disorders encountered in clinical practice, estimated to be present in 10% to 30% of acutely hospitalized patients.4,5 In the elderly population, hyponatremia is especially common and surveys of nursing home residents indicate a prevalence of hyponatremia as high as 30%.6 The presence of hyponatremia, no matter what the etiology may be, is associated with increased morbidity and mortality in ambulatory and hospitalized patients and may be regarded as an From the Division of Nephrology, University of Virginia Health System, Charlottesville, VA; and Department of Nephrology and Dialysis, G. Brotzu Hospital, Cagliari, Italy. Financial Disclosure: No authors have relevant conflict of interests or financial relationships to disclose. Address correspondence to Mitchell H. Rosner, MD, Division of Nephrology, University of Virginia Health System, Box 800133 HSC, Charlottesville, VA 22903. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2015.12.003
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important marker of severe disease.7 It is likely that the major mortality effect attributed to hyponatremia derives more from the underlying etiology leading to the electrolyte disorder rather than hyponatremia itself.5,8 The majority of these epidemiologic studies do not include data on the kidney function of these patients, so specific data on the association with or without CKD are not available except for a single study discussed below. Hypernatremia (defined as serum sodium . 145 meq/L) is much less common than hyponatremia, estimated to be 2% to 5% in acutely ill patients.9,10 This is likely because the fact that in the presence of a normal thirst sensation, most people are able to maintain serum sodium levels , 145 meq/L. It is only when thirst sensation is impaired (for instance, in patients who have serious disorders of cognition) or when water access is limited that hypernatremia occurs.11 This can be exacerbated by excessive urinary or other body water losses.12 As an example, patients with significant cognitive impairment who are hospitalized often have inadequate thirst sensation cannot easily ask for water and may not have ready access to fluids. Thus, these patients are prone to the development of hypernatremia. Although CKD is known to affect the ability of the kidneys to regulate water homeostasis, because of impaired diluting and concentrating mechanisms with progressive kidney disease, studies have indicated that dysnatremias resulting from worsening CKD alone are rare, even in patients with advanced CKD.2,13,14 A large observational study evaluated the prevalence of dysnatremias in 655,493 US veterans with non-dialysis-dependent CKD.15 At baseline, 13.5% of patients had hyponatremia (serum sodium , 136 mEq/L) and 2% had hypernatremia (serum sodium . 145 mEq/L). However, over a mean 5-year period of observation, 26% of all patients developed at least 1 episode of hyponatremia and 7% developed hypernatremia. The prevalence of hyponatremia did not have a strong correlation with CKD stage and was essentially similar in patients with Stage 3, Stage 4, and Stage 5 CKD (11%-12%).15 However, the prevalence of hypernatremia showed a significant increase with advancing CKD (up to maximum of 3.1% in stages 4 and 5). Attributing the dysnatremia solely to advancing CKD is difficult in these observational studies as patients had serum sodium levels measured in both the inpatient and
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outpatient setting, and the circumstances regarding the a greater load of solute filtration, decreased tubular measurement of the serum sodium were not known (ie, responsiveness to AVP, and an impaired countercurrent the laboratory values may have been obtained during an mechanism in disorders affecting the renal medulla.19-21 Animal models have additionally demonstrated acute illness, such as pneumonia). decreased urea recycling in the loop of Henle in CKD Mortality associated with dysnatremias in patients with models, which contributes to decreased medullary non-dialysis CKD was also studied in the large Veteran’s tonicity.22 Additionally, concentrating defects are more cohort described earlier.15 In this study, mortality was lowest in patients with a serum sodium between 140 and pronounced in those interstitial-prominent diseases 144 meq/L and then showed a linear increase with the affecting the renal medulla.22,23 Furthermore, many patients with CKD are taking loop diuretics that impair severity of both hyponatremia and hypernatremia that the development of a hypertonic medullary gradient. was present in all subgroups (including those with and Impaired ability to concentrate the urine typically leads without heart failure and liver disease). Patients with to excessive urine output (polyuria) and nocturia and in serum sodium levels , 130, 130 to 135, 145 to 149, and . the face of impaired thirst sensation or limited water 150 mEq/L compared with the reference level of 136 to access predisposes individuals to the development of 145 mEq/L had a statistically significant hazard ratio for hypernatremia. The fact that urine-concentrating ability all-cause mortality. The mortality association with hypois affected to a greater extent than diluting ability is supnatremia was not influenced by CKD stage. However, ported by the fact that the rate of hypernatremia the association of hypernatremia and mortality was increases with advancing CKD, whereas the rate of hypoactually lower in more advanced stages of CKD. The natremia does not.15 explanation for this apparent “protective” effect of advanced CKD on hypernatremia-related mortality is not clear, but the authors have speculated that this may Impaired Urinary Diluting Ability. Additionally, impaired be because of adaptation to urinary dilution, as maniincreased extracellular osmofested by an inability to CLINICAL SUMMARY lality in patients with more lower urine osmolality advanced CKD who experiappropriately, has been 1. As kidney function decreases, the ability to maintain ence a gradual accumulation observed in advanced kidplasma osmolality and volume within normal limits can of uremic solutes.15 This ney dysfunction.19,24 The be impaired and this is especially true during states of more gradual change in mechanisms for this stress such as heart or liver failure. extracellular osmolality aldisorder are less clear than 2. In patients with CKD, hyponatremia is far more common lows for cellular adaptation those of impaired urinary than hypernatremia. that can occur over a longer concentrating ability in 3. Treatment of hyponatremia and hypernatremia in the time frame. CKD. In order for dilute patient with CKD follows the same principles as for urine to be made, several Pathophysiology of patients with normal kidney function. mechanisms must be Sodium Disorders: The operative: (a) there must be 4. In patients with advanced CKD and volume overload, loop Role of CKD enough filtrate delivered to diuretics are the agents of choice to increase sodium Under normal circumstances, excretion. the distal nephron for sodium levels are maintained dilution and excretion, (b) because of a balance between the diluting segments of net water intake and excretion. Impaired concentrating the distal nephron must selectively reabsorb sodium and and diluting abilities occur with CKD that stress the ability lead to a fall in urine osmolality and finally, and (c) AVP of the body to maintain normonatremia.2 Typically with levels must fall and the collecting tubule must decrease CKD, the capacity to dilute the urine is maintained longer its permeability to water reabsorption and allow water to than the capacity to concentrate the urine, but as patients be excreted (dilute urine). It is unlikely that limitations in reach ESRD, the urine osmolality reaches a constant level filtrate amount affect this process until very late CKD at approximately 300 mOsm/L (isosthenuria).16 At this (with GFRs ,5 mL/min), and it is most likely that CKD late stage, factors other than the urine-concentrating/ may be associated with defects in the diluting segment.2 diluting mechanism must take precedence to maintain This may be further exacerbated using thiazide diuretics, normal serum osmolality. These include the amount of wawith resulting natriuresis, and vasopressin release.25 The ter intake and the solute load and residual GFR.17 net result of these impairments in urine dilution is that the risk of hyponatremia may be increased. However, Urine Concentration Ability in CKD. The ability to concenbased on observational studies, this risk of hyponatremia trate urine is dependent on the presence of a hypertonic with advancing CKD is likely small.15 medullary interstitium and collecting tubule permeability Integrated Physiology of Impairments in Dilution/ that varies substantially under the influence of arginine Concentration in CKD vasopressin (AVP). Several factors have been thought to As an example of how these derangements in kidney contribute to impaired concentrating ability and subsefunction may lead to dysnatremias, it is instructive to quent isosthenuria that is characteristic of CKD.18 These include an osmotic diuresis from excess solute excretion look at typical urine osmolalities and water intakes. in remaining functional nephrons that are now carrying Under normal circumstances, with intact countercurrent
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mechanisms, urine osmolality can range from 50 to 1200 mOsm/kg H2O depending on the presence or absence of AVP. Thus, a fixed dietary solute load of 600 mOsm/d may be excreted in as little as 0.5 L urine (highly concentrated urine with an osmolality of 1200 mOsm/kg) or as much as 12 L of urine (maximally dilute urine with an osmolality of 50 mOsm/kg). Individuals with advanced CKD may be able to concentrate urine to 200 to 300 mOsm/kg H2O which will be relatively fixed. Hence, in a patient with advanced CKD (stages 4 and 5), the same 600-mOsm solute load would require generation of 2 to 3 L of urine output. In this scenario, where the ability of the kidney to alter the urine osmolality in response to varying dietary intake of fluids is limited, ingestion of less than 2 L of fluids per day would result in progressive negative water balance, and the subsequent development of hypernatremia. On the contrary, greater fluid intake more than 3 L/d and an inability to dilute urine result in progressive fluid retention and development of hyponatremia. This demonstrates the role of CKD in limiting the kidney flexibility to control water excretion in response to variable dietary water and solute intake. Additionally, underlying coexistent conditions that have impact on water handling, such as the nephrotic syndrome, liver disease, and congestive heart failure, may confound water balance in advanced CKD. For example, in these conditions, effective circulating volume is decreased that leads to neurohormonal activation with high levels of vasopressin, angiotensin II, and activation of the sympathetic nervous system. Depending on the water and sodium intake of the patient, this neurohormonal activation will increase the likelihood of dysnatremias, most likely hyponatremia. Concomitant diuretic use and medications that impair urinary concentration/ dilution also affect the risk of developing a dysnatremia in the face of CKD. Treatment of Sodium Disorders in CKD The treatment of sodium disorders in patients with CKD follows the same principles as the treatment of these disorders in patients without CKD. Some general principles are given in Tables 1 and 2.26 As mentioned previously, results
of a large epidemiologic study revealed lowest mortality in patients with sodium levels of 140 mEq/L and adjusted hazard ratios for the group , 130 and 130 to 135 mEq/L to be 1.93 and 1.28, respectively.15 Thus, gradual correction of serum sodium levels to 130 to 135 mEq/L appears to be a reasonable target in this population. There are several limitations that need to be considered when approaching therapeutic options in dysnatremias in CKD patients.2 Water restriction is a slow acting approach toward hyponatremia correction and often practiced in the outpatient setting. Frequent monitoring of serum sodium levels is required to prevent undesirable increases to hypernatremic levels. Similarly, close monitoring is needed in cases of normal saline infusion for correction of hypovolemic hyponatremia, given the high likelihood of sodium retention and resulting fluid overload. Several pharmacologic agents have been listed in Table 1. Loop diuretics are commonly used to enhance water excretion for hyponatremia correction. In CKD patients, it is important to monitor for signs of volume depletion and electrolyte abnormalities. Demeclocycline has been used in hyponatremia correction; however, it must be used with caution in CKD patients since it is renally excreted and has been shown to worsen renal insufficiency.48 Additionally, although vasopressin V2 receptor antagonists have been shown to correct hyponatremia, several trials have excluded patients with advanced CKD.49,50 Small studies have demonstrated safety of Tolvaptan use in advanced CKD; however, larger studies are needed to determine V2 receptor antagonist efficacy in advancing CKD.51 The role of kidney replacement therapy has been reported in correction of hyponatremia in CKD patient with confounding anuric AKI47; however, it has not been reported otherwise in stable CKD patients nor was it reported as a therapeutic option in the epidemiological study previously discussed.15 VOLUME DISORDERS IN CKD The control of extracellular volume is modulated through changes in kidney sodium excretion. The
Table 1. Treatment Options for Hyponatremia in CKD Treatment
Mechanism
Comments
Water restriction to 500 mL less than urine output Hypertonic saline
Decreases total body water, increasing ratio of sodium to water Increases ratio of sodium to water
Loop diuretics (often with sodium supplementation)
Increases rate of dilute urine production and combined with salt supplementation leads to net body water loss Increases osmolality of plasma and tubular fluid and increases renal water excretion
Slow acting, unpredictable, and compliance is difficult Treatment of choice for acute, symptomatic hyponatremia but risks overcorrection in patients with chronic hyponatremia Inexpensive but requires close monitoring to avoid volume depletion and other electrolyte abnormalities Effective and inexpensive but unpalatable and currently not readily available in the United States Potential for nephrotoxicity and slow to act Expensive, requires monitoring for first 48 h and limited to 30 d use due to concern of liver injury. May be less effective as GFR falls ,30 mL/min
Urea
Demeclocycline AVP receptor antagonists (tolvaptan and conivaptan)
Induced nephrogenic diabetes insipidus Directly antagonizes vasopressin type 2 receptor leading to excretion of dilute urine
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Table 2. Treatment of Hypernatremia in CKD Hypovolemic
Euvolemic
Correct volume deficit with isotonic saline until vital signs stabilize
Calculate water deficit and replace along with ongoing losses with hypotonic fluids or oral water If central diabetes insipidus: aqueous vasopressin
Calculate water deficit and replace along with ongoing losses with hypotonic fluids or oral water Treat underlying cause of water/volume loss
If nephrogenic diabetes inspidus: low salt diet, thiazide diuretics, amiloride, and stop any offending medications
major effector systems involved in this process are listed in Table 3 that delineates the major afferent sensors of volume and the efferent systems involved in modulation of kidney sodium excretion. Given the primacy of the kidney in the control of extracellular volume, it is not surprising that volume overload is increasingly common in patients with CKD. The typical clinical presentation is with signs and symptoms such dyspnea, peripheral edema, ascites, and reduced exercise tolerance often with concomitant hypertension. Although the prevalence of volume overload solely because of CKD is hard to determine, a study by Hung and colleagues in patients with CKD stages 3 to 5 demonstrated that only 48% were euvolemic by bioimpedance assessment.3,27 However, it is extremely difficult to dissociate volume overload solely because of advancing CKD from other comorbidities (such as systolic or diastolic heart failure, hypertension, and arterial stiffness). In fact, when measurements (using chromium-labeled red blood cells, exchangeable sodium, bromide or sulfate) of extracellular volume have been made in patients with CKD, the results are conflicting but overall show that extracellular fluid volume is usually normal, at least until GFR is profoundly decreased (, 10 mL/min).13,28 In terms of extracellular volume homeostasis, there is a vicious cycle that develops where CKD along with hypertension and heart failure lead to volume overload that further worsens hypertension, left ventricular hypertrophy, and kidney function. In fact, several studies have linked a patient’s relative hydration status as determined by either brain natriuretic peptide levels or bioimpedance spectroscopy with both mortality and CKD progression.3,27,29,30 For example, Tsai and
Hypervolemic Often iatrogenic and removal of offending agents Loop diuretics and calculate water deficit and replace along with ongoing losses with hypotonic fluids or oral water If renal failure, hemodialysis
have demonstrated that volume colleagues29 overload (using BIS) was both associated with a more rapid progression of CKD and the need to initiate kidney replacement therapy. Abnormal fluid status is also associated with an increased all-cause and cardiovascular mortality rate.3 There are several other factors that compound the difficulty of studying the independent effects of CKD on volume overload. Some patients may have expanded intravascular and extravascular volumes, whereas other patients may only have expanded extravascular volumes in the setting of normal or even lower intravascular volumes. This latter group includes patients with CKD and the nephrotic syndrome or advanced heart or liver failure. Thus, within the category of volume-overloaded patients, there are subtypes where the role of CKD may differ. Pathogenesis of Sodium Retention and Volume Overload in CKD Sodium balance is surprisingly well maintained in patients with CKD and GFRs ranging from 3 to 25 mL/min when sodium intake is varied 2-fold from 1400 to 2800 mg/d.32 This ability to modulate kidney sodium excretion is likely because of changes in tubular reabsorption/excretion (most likely in the proximal tubule, loop of Henle, and distal nephron) and in these studies was independent of aldosterone.31,52 In general, it has been hypothesized that in CKD, there is an adaptive response leading to an increase in sodium excretion per nephron in the setting of a constant sodium intake (fractional excretion of sodium is increased).32 The mechanisms responsible for this adaptation are not elucidated but may require some degree of subclinical volume expansion and elevation in mean arterial blood pressure to increase sodium excretion.33-35 This is a protective effect against the
Table 3. Control Systems Involved in Extracellular Volume Regulation Afferent Sensor Systems - Baroreceptors (arterial circulation, aortic arch, carotid sinuses, cardiac atria, and renal arteries) - Sympathetic nervous system is major communication node between arterial baroreceptors and kidney
Efferent Effector Systems -
Sympathetic nervous system Renin Angiotensin II Aldosterone Prostaglandins Vasopressin Endothelin Nitric oxide Natriuretic peptides
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development of continued sodium retention and edema formation. However, it appears that the time constant over which changes in fractional excretion of sodium can change is limited, and thus, if sodium intake is suddenly increased or decreased, the kidneys cannot immediately adjust and, thus, volume expansion or depletion is more likely.28,32 Clinically, this translates into the observation that if changes in sodium intake are introduced slowly and stepwise in patient with CKD, volume expansion/ depletion does not typically occur. However, rapid changes in sodium intake are not well tolerated and lead to volume disorders. Volume disorders in advanced CKD are often part of syndromes resulting from underlying comorbid conditions, including cirrhosis, cardiorenal syndrome, nephrotic syndrome. Cardiorenal syndrome in particular involves a complex pathophysiology involving reninangiotensin system activation, sympathetic nervous system, and hemodynamic alterations.54 Multifactorial cardiorenal interactions involving arterial underfilling because of ventricular contractile dysfunction, decreased GFR, insufficient pressure natriuresis, and renal venous hypertension, all contribute to volume overload, with subsequent volume overload and worsening of cardiac and kidney dysfunction.54,55 Management of Volume Disorders in CKD Given that the primary effect of diuretics is to inhibit tubular sodium reabsorption resulting in an increase in sodium excretion, a decrease in ECF volume expansion, and a drop in blood pressure, these agents are the mainstay for the treatment of CKD-related volume expansion. Diuretics are used in CKD patients to manage edema, control blood pressure, potentiate the effects of other antihypertensive agents including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers and to aid in correction of metabolic acidosis and hyperkalemia. There are 3 main classes of diuretics: loop diuretics, thiazide diuretics, and potassium sparing (K1 sparing) diuretics. Loop diuretics, such as furosemide, bumetanide, and torsemide, act by inhibiting the Na1-K1-2Cl2 cotransporter in the thick ascending limb of the loop of Henle, thus enhancing sodium and water clearance. The maximally effective doses lead to an almost complete block of sodium reabsorption in the loop of Henle (z20%-25% of filtered sodium). Loop diuretics circulate bound to albumin and are secreted into tubular fluid by organic anion transporters in the proximal tubule. Because patients whose GFR is ,15 mL/min secrete only 10% to 20% of the amount of loop diuretic that is secreted by patients with normal GFR treated with a similar dose, the dose of diuretic administered to achieve effective tubular concentration must be increased proportionately.36 For example, CKD stages 4 to 5 patients should be started at a dose of 40 to 80 mg once daily and then titrated upward by 25% to 50% weekly depending on the desired effects on lowering ECF volume.37 The greatest natriuretic response is observed with intravenous (IV) doses of 160 to 200 mg of furosemide or equivalent doses of bumetanide (6-8 mg) and torsemide (80-100 mg).38,39
The decrease in kidney function does not influence the bioavailability of loop diuretics (z50%) but can significantly prolong the relatively short half-life of these drugs.40 Given the primacy of volume expansion and its role in hypertension in late-stage CKD, loop diuretics also play a significant role in the management of hypertension in advanced stages of CKD. Thiazide diuretics, such as hydrochlorothiazide, reduce sodium reabsorption in the distal tubule by inhibiting the apical Na1-Cl-cotransport system. Although they are the diuretics of choice in patients with normal or mild reductions of kidney function, the effect on natriuresis in subjects with GFR ,50 mL/min is lower compared with loop diuretics.40 When used alone, thiazides become less effective in patients with GFR ,35 mL/min, and higher doses are needed if kidney function is compromised.41 Because of their compartmentalization into red blood cells, long-acting thiazide-like diuretics, such as metolazone and chlorthalidone, are associated with more sustained lowlevel diuresis and tend to be more effective in advanced stages of CKD than hydrochlorothiazide.42 In patients with inadequate natriuresis in response to maximal doses of loop diuretics, sequential nephron blockade with thiazide diuretics has been shown to have a synergistic effect, although at the cost of a higher risk for volume depletion and electrolyte disorders.43,53 Potassium-sparing diuretics act primarily at the cortical part of the collecting duct and are divided into 2 subgroups: inhibitors of the epithelial sodium channels in the luminal membrane, such as amiloride and triamterene, and aldosterone receptor antagonists, such as spironolactone and eplerenone. These agents must be used cautiously in CKD patients because of the risk of hyperkalemia, and they tend to have small effects on decreasing extracellular volume.40 However, aldosterone receptor antagonists are increasingly being used in patients with CKD because of their antiproteinuric effects and cardioprotective benefits.44 Initiation of therapy with low doses is recommended along with slow-dose titration and frequent monitoring of potassium levels.37 Although exceeding the ceiling dose for diuretics acting on the same transport mechanisms will not result in an incremental diuretic response, the combination of diuretics acting on separate nephron sites (sequential nephron blockade) may be synergistic and lead to significant decreases in extracellular volume. The most commonly used combination in clinical practice is the association of a loop diuretic with a thiazide or thiazide-like drug. The combination of furosemide-metolazone is particularly effective in patients that require large volume fluid removal.45 Finally, in those patients with significant, symptomatic volume overload and advanced CKD, continuous IV infusion of loop diuretics may confer additional benefits. Greater sodium excretion has been observed in patients with advanced CKD treated with continuous rather than bolus loop diuretic infusion.46 Moreover, continuous infusion of loop diuretics may be associated with lower peak plasma concentrations than high-dose IV dosing which should lead to fewer dose-related side effects, such as ototoxicity.
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At some point, patients with very advanced, usually Stage 5, CKD will not respond to diuretic therapy and may develop refractory volume overload despite dietary sodium restriction. This is an indication to start kidney replacement therapy with either peritoneal dialysis or hemodialysis. SUMMARY Disorders of sodium and water balance become more common as CKD advances. However, the amazing ability of the kidney to adapt to widely varying sodium and water intakes limits these disorders to later stages (4 and 5) of CKD. Attention to the development of these issues and early, aggressive therapy to manage these problems is critical as they (hypernatremia, hyponatremia, extracellular volume overload) are associated with increased morbidity and mortality. Effective therapies exist to treat these disorders, but as CKD evolves, the most effective therapy may be kidney replacement therapy along with strict dietary control of water and sodium intake. REFERENCES 1. Zaino CJ, Meheshwani AV, Goldfarb DS. Impact of mild chronic hyponatremia on falls, fractures, osteoporosis and death. Am J Orthop (Belle Mead NJ). 2013;42(11):522-527. 2. Combs S, Berl T. Dysnatremia in patients with kidney disease. Am J Kidney Dis. 2014;63(2):294-303. 3. Hung SC, Kuo KL, Peng CH, et al. Volume overload correlates with cardiovascular risk factors in patients with chronic kidney disease. Kidney Int. 2014;85(3):703-709. 4. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006;119(7 suppl 1):S30-S35. 5. Schrier RW, Sharma S, Shchekochikhin D. Hyponatraemia: more than just a marker of disease severity? Nat Rev Nephrol. 2013;9(1):37-50. 6. Cowen LE, Hodak SP, Verbalis JG. Age-associated abnormalities of water homeostasis. Endocrinol Metab Clin North Am. 2013;42(2):346-370. 7. Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med. 2010;170(3):294-302. 8. Chawla A, Sterns RH, Nigwekar SU, Cappuccio JD. Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol. 2011;6(5):960-965. 9. Arampatzis S, Frauchiger B, Fiedler GM, et al. Characteristics, symptoms, and outcome of severe dysnatremias present on hospital admission. Am J Med. 2012;125(11):1125.e1-1125.e7. 10. Gucyetmez B, Ayyildiz AC, Ogan A, et al. Dysnatremia on intensive care unit admission is a stronger risk factor when associated with organ dysfunction. Minerva Anestesiol. 2014;80(10):1096-1104. 11. Shah MK, Workeneh B, Taffet GE. Hypernatremia in the geriatric population. Clin Interv Aging. 2014;9:1987-1992. 12. Verbalis JG. Disorders of water metabolism: diabetes insipidus and the syndrome of inappropriate antidiuretic hormone secretion. Handb Clin Neurol. 2014;124:37-52. 13. Mitch WE, Wilcox CS. Disorders of body fluids, sodium and potassium in chronic renal failure. Am J Med. 1982;72(3):536-550. 14. Wallia R, Greenberg A, Piraino B, et al. Serum electrolyte patterns in end-stage renal disease. Am J Kidney Dis. 1986;8(2):98-104. 15. Kovesdy CP, Lott EH, Lu JL, et al. Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation. 2012;125(5):677-684. 16. Tuso PJ, Nissenson AR, Danovitch GM. Electrolyte disorders in chronic renal failure. In: Narins RG, ed. Maxwell & Kleeman’s Clinical Disorders of Fluid and Electrolyte Metabolism. New York, NY: McGraw-Hill, Inc.; 1994:1195-1211.
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