REVIEW

European Journal of Heart Failure (2014) 16, 133–142 doi:10.1002/ejhf.35

The kidney in congestive heart failure: ‘are natriuresis, sodium, and diuretics really the good, the bad and the ugly?’ Frederik H. Verbrugge1,2, Matthias Dupont1, Paul Steels3, Lars Grieten1,3, Quirine Swennen3, W.H. Wilson Tang4, and Wilfried Mullens1,3* 1 Department

of Cardiology, Ziekenhuis Oost-Limburg, Genk, 3600, Belgium; 2 Doctoral School for Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; and 4 Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

3 Biomedical

Received 16 May 2013; revised 21 June 2013; accepted 9 August 2013 ; online publish-ahead-of-print 9 December 2013

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron’s function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy-refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter-regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction—although not by conventional GFR measurements—is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function.

.......................................................................................................... Congestive heart failure • Diuretics • Kidney • Natriuretic peptides • Sodium

Introduction Sodium is the most abundant cation in the extracellular compartment of the body. Therefore, it makes the largest contribution to overall osmolality of the extracellular fluid; hence, where sodium goes, water follows. As sodium is freely filtered by the glomerulus, ∼25 500 mmol reaches the renal tubules each day, i.e. the product of the glomerular filtration rate (GFR; ∼180 L/day) and sodium plasma concentration (∼142 mmol/L). From an evolutionary point of view, to make terrestrial life possible, the organism consequently had to invest heavily in sodium-preserving strategies. Indeed, the renal tubules normally reabsorb >99% of filtered sodium, while

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only a tiny fraction is excreted in the urine.1 However, this tiny fraction is highly regulated to mimic dietary intake and so preserve extracellular volume homeostasis. Importantly, because of the large amount of sodium recycled through the kidneys, even minute variations in the fractional reabsorptive rate have the potential to change total body sodium and thus extracellular volume. Patients with congestive heart failure (CHF) demonstrate increased sodium avidity and extracellular volume overload, i.e. congestion, and this is their most frequent reason for hospital admission.2 This review will discuss renal sodium handling in the context of CHF. We will argue why natriuresis should be a major treatment target in CHF, and how it might be used to tailor decongestive therapies with

*Corresponding author. Tel: +32 89 32 70 87, Fax: +32 89 32 79 18, Email: [email protected]

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Glomerular filtration rate vs. natriuresis in congestive heart failure The GFR is a strong predictor of all-cause mortality in ambulatory CHF patients, even outperforming left ventricular ejection fraction (LVEF) in that respect.3 This should not be surprising, as whole kidney GFR—often used synonymously for renal function—largely reflects the number of functionally intact glomeruli in this case. As such, whole kidney GFR is a marker of renal reserve. Importantly, whole kidney GFR constitutes the sum of the individual contributions from each functionally intact glomerulus, i.e. single nephron GFR (snGFR). In contrast to the ambulatory setting, factors that influence snGFR, such as altered haemodynamics (both systemic and intrarenal), neurohumoral activation, volume overload, and misdistribution, are more prominent in decompensated CHF. Indeed, depending on contextual factors, decreases in whole kidney GFR are associated with worse, neutral, or even better clinical outcome in decompensated CHF.4 – 6 On the other hand, persistent congestion, as a reflection of the inability of the kidneys to preserve sodium homeostasis, has been more consistently associated with higher mortality and more frequent readmissions in CHF.7 Both impaired GFR and alterations in the fractional reabsorptive rate of sodium—essentially a function of the renal tubules—are equally important in emerging therapy-refractory congestion. Therefore, focusing on natriuresis and sodium balance in addition to GFR might be a more successful strategy to achieve decongestion while preserving renal function.

Renal sodium handling in congestive heart failure The glomerulus and intrarenal haemodynamics As sodium is freely filtered by the glomerulus, whole kidney GFR is an important determinant of natriuresis, depending on the number of functional glomeruli (i.e. the degree of chronic kidney disease) and the snGFR. The latter is determined by the area and permeability characteristics of the glomerular filtration barrier and Starling forces in the glomerular capillary and Bowman’s space.8 In humans, snGFR cannot be measured directly, but a value of ∼40–70 nL/min in healthy persons can be estimated by dividing whole kidney GFR by the number of glomeruli. Intrinsic autoregulation mechanisms keep the snGFR within narrow limits. First, renal blood flow (RBF) is kept constant, irrespective of a varying mean arterial blood pressure between 70 and 150 mmHg, by mediating afferent arteriolar resistance.9 A second mechanism called the tubuloglomerular feedback protects

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the goal of preserving renal function. Therefore, contemporary insights into the pathophysiology of CHF will be linked to a review of older but nevertheless important concepts on renal physiology and sodium handling.

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the glomerulus from hyperfiltration by keeping the chloride load presented to Henle’s loop, i.e. the snGFR, constant.10 Rising chloride concentrations in macula densa cells at the end of the thick ascending limb of Henle’s loop (TAL) stimulate paracrine release of adenosine and ATP, triggering vasoconstriction of the afferent arteriole through A1 receptors.11 On the other hand, because of a feedback mechanism which is called the glomerulotubular balance, increased filtration in the glomerulus is met by increased reabsorption in the proximal renal tubules.12 This bilateral crosstalk between the glomerulus and the macula densa ensures that in normal homeostasis, the sodium load at the macula densa is kept constant with a stable snGFR. Finally, because of the high filtration coefficient of the glomerular filtration barrier and the rising colloid osmotic pressure alongside glomerular capillaries, the snGFR is relatively well maintained when the RBF drops, by an increase in the filtration fraction (FF), even without neurohumoral interference, until filtration equilibrium is reached (Figure 1). A recent study in contemporary CHF patients shows that the FF is increased at 28%, even in patients treated with an ACE inhibitor, which counteracts efferent arteriolar vasoconstriction and promotes RBF.13 Nevertheless, a variety of reasons might contribute to impaired GFR in CHF. First, as CHF and chronic kidney diseases share common risk factors, a lower number of functionally active glomeruli might already result in a lower GFR on the whole kidney level. Moreover, especially in decompensated CHF, snGFR is often decreased. According to the laws of haemodynamics, the renal arteriovenous pressure difference, i.e. renal arterial minus venous pressure, and total renal vascular resistance determine RBF and consequently snGFR. Because of the explained autoregulation, only a severe drop in mean arterial blood pressure is expected to influence RBF. However, as aggressive decongestive therapy might result in intravascular underfilling, such drops do occur in the context of CHF, and are indeed associated with decreased GFR.14,15 Moreover, activation of the sympathetic nervous system in CHF increases vasoconstriction at the level of the glomerular arterioles, leading to a decrease in RBF and GFR.16 Furthermore, it has now been clearly established that backward failure leading to increased central venous pressure is another cause of kidney dysfunction in CHF, especially when cardiac output is low.17 – 19 It was already demonstrated in 1950 that human patients with CHF have renal venous hypertension.20 Several reports have subsequently confirmed that RBF decreases when renal venous pressure is increased and, indeed, measurements in human patients with advanced CHF have shown that RBF is regularly decreased, yet with an increased FF of up to 60%.21 – 24 Finally, neurohumoral activation in CHF contributes to both low RBF and high FF, most obviously through increased systemic and local levels of angiotensin II, which stimulates vasoconstriction and increases renal vascular resistance, predominantly in the efferent arteriole.25

The proximal tubules The fractional reabsorptive rate of sodium in the renal tubules is another major determinant of natriuresis. Because of the glomerulotubular balance—a process largely determined by Starling forces—a relatively constant fraction of sodium (∼75%) is © 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology

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Renal sodium handling in congestive heart failure

Figure 1 Filtration equilibrium: the physiological maximum of filtration fraction (FF). The value of the single nephron glomerular filtration

reabsorbed in renal tubules proximally from the macula densa.26 Different transporters on the luminal membrane of proximal tubular cells mediate sodium uptake (Figure 2A). Subsequently, sodium is pumped out into the renal interstitium by Na+ /K+ -ATPases on the basolateral membrane. Because the wall of proximal tubules is freely permeable to water, passive movement of water accompanies active reabsorption of sodium to maintain osmotic equilibrium. Peritubular capillaries ultimately take up interstitial sodium in an iso-osmotic process determined by Starling forces.27 This is of great importance because sodium otherwise leaks back into the tubular lumen.28 Thus, Starling forces across the peritubular

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rate (snGFR) depends on the area and permeability characteristics of the glomerular membrane and Starling forces in the glomerular capillary and Bowman’s space favouring (green) and opposing (red) ultrafiltration. In normal circumstances, snGFR is 40–70 nL/min with the FF being 20–25%. Because of the high renal blood flow (RBF), 𝜋 GC rises slowly from the proximal to the distal end of the glomerular capillary. Therefore, an ultrafiltration pressure gradient prevails over the entire length of the glomerular capillary. When RBF—and thus renal plasma flow (RPF)—decreases, the plasma volume that is exposed to the ultrafiltration pressure gradient at any given time per area unit of the capillary wall is smaller. Consequently, this leads to a faster increase of 𝜋 GC along the course of the glomerular capillary, which results in an increased 𝜋 GC at the level of the efferent arteriole (EA) and hence a rise in FF. The rise in FF will attenuate the absolute drop in snGFR, even without neurohumoral interference or changing PGC . However, from the point where filtration equilibrium is reached, when the maximum FF is achieved at ∼60%, a further decrease in RPF causes snGFR to drop linearly as the ultrafiltration pressure gradient can no longer be maintained over the entire length of the glomerular capillary, which results in part of this capillary no longer used for ultrafiltration (wasted capillary). AA, afferent arteriole; Hct, haematocrit; PB , hydrostatic pressure in Bowman’s space; PGC , glomerular capillary hydrostatic pressure; 𝜋 B , colloid osmotic pressure in Bowman’s space; 𝜋 GC , glomerular capillary colloid osmotic pressure.

© 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology

capillaries, not directly influenced by neurohumoral activation but rather determined by local haemodynamics of the microcirculation, ultimately drive net sodium reabsorption in the proximal tubules. In CHF, important alterations in peritubular Starling forces might occur (Figure 2B). First, increased FF, which might already be present before a substantial decrease in GFR, raises peritubular capillary oncotic pressure. Secondly, in the presence of renal venous hypertension, i.e. congestion, substantial alterations in both the hydrostatic and colloid osmotic pressure of the renal interstitium take place. It was already demonstrated in 1956 by Gottschalk and Mylle that the hydrostatic pressure of the renal interstitium

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A

B

Figure 2 The proximal tubules: passive sodium reabsorption by Starling forces. (A) Different transporters mediate active transport of sodium across the luminal side of proximal tubular cells. However, because the proximal tubules have a very leaky epithelium, back flux to the lumen is easily possible and nett sodium reabsorption is rather determined by passive Starling forces between the peritubular capillaries and renal interstitium, irrespective of neurohumoral interference. (B) In congestive heart failure, because of an increased filtration fraction, 𝜋 PC is higher, which stimulates sodium and water reabsorption. Moreover, when congestion is present and because the kidney is an encapsulated organ, PIF and PPC will both be increased, whereas 𝜋 IF will drop because of increased lymph flow, which washes out interstitial proteins. This further facilitates nett sodium and water reabsorption. AA, amino acid; Glu, glucose; PIF , interstitial fluid hydrostatic pressure; PPC , peritubular capillary hydrostatic pressure; 𝜋 IF , interstitial fluid colloid osmotic pressure; 𝜋 PC , peritubular capillary colloid osmotic pressure.

rises in parallel with the renal venous pressure.29 However, because the kidney is an encapsulated organ, the hydrostatic pressure is equally elevated inside the lumen of peritubular capillaries.29 Yet, while increased hydrostatic pressure slightly increases fractional sodium excretion in a state of hydropenia, the opposite is true in the case of volume expansion.30 This might be explained by an

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increased renal lymph flow, washing out interstitial proteins and decreasing colloid osmotic pressure in the renal interstitium when congestion is present. Indeed, lymph flow massively increases, even exceeding urinary flow in the ureter, in a state of renal venous hypertension.31,32 Moreover, increased peritubular protein concentration is significantly correlated to fractional reabsorption in the proximal tubules in the presence of extracellular volume expansion.33 Finally, peritubular capillaries, although highly permeable to water, are virtually impermeable to plasma proteins, which explains why intracapillary colloid osmotic pressure remains high.27 Together, these changes facilitate sodium and water reabsorption by the peritubular capillaries from the renal interstitium surrounding the proximal tubules and diminish back flux into their lumen. As a result, the fractional reabsorption of sodium in the proximal tubules in CHF exceeds its normal value, which is especially important if the absolute amount of sodium delivered is already low because of low snGFR. A low absolute amount of sodium delivered to the distal nephron has important therapeutic implications because it is the place where commonly used loop and thiazidetype diuretics as well as endogenous natriuretic peptides act.

The macula densa The distal part of the TAL contains some highly specialized cells that lie in close proximity to the afferent arteriole (Figure 3A). These cells, which form the macula densa and are responsible for the tubuloglomerular feedback if they are presented with an increased chloride load, also respond to reduced chloride delivery by increasing cyclo-oxygenase-2 (COX-2) and nitric oxide synthase I (NOS I) activity, leading to paracrine prostaglandin E2 (PGE2 ) and nitric oxide (NO) secretion.11 Both PGE2 and NO work in concert to stimulate renin release by granulosa cells of the afferent arteriole and further activation of the renin–angiotensin–aldosterone axis. High angiotensin II levels facilitate catecholamine release by the sympathetic nervous system and release of arginine vasopressin by the posterior pituitary gland. As angiotensin II and increased sympathetic nerve activity (through alpha-adrenergic receptors) as well as arginine vasopressin all stimulate apical Na+ –H+ exchangers and basolateral Na+ /K+ -ATPases in the renal tubules, fractional sodium reabsorption is promoted. In CHF, because of increased fractional sodium reabsorption in the proximal tubules, chloride delivery to the macula densa is reduced, which causes a vicious cycle of worsening congestion and harmful neurohumoral activation that might ultimately drive disease progression (Figure 3B). In addition, loop diuretics used to treat congestion in CHF directly inhibit the Na+ /K+ /2Cl – cotransporter on the luminal side of the TAL as well as in the macula densa. The latter further depletes intracellular chloride levels in the macula densa and will sustain harmful neurohumoral activation.

The distal convoluted tubules and collecting ducts The distal convoluted tubules (DCTs) and collecting ducts constitute the most distal part of the nephron and reabsorb only a minor fraction (≤10%) of the total amount of sodium filtered by © 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology

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A

B

the glomerulus. In contrast to the part of the nephron proximal to the macula densa, where net fractional sodium reabsorption is normally kept relatively constant, distal fractional reabsorptive rates can vary substantially depending on tubular flow rate, and levels of aldosterone and arginine vasopressin.34 – 36 Therefore, it is the distal nephron which determines the urinary sodium concentration and osmolality. However, a prerequisite to achieve this function of maintaining a neutral sodium balance is an adequate sodium delivery to the distal nephron. In CHF, because of increased fractional reabsorption in the proximal tubules and often decreased snGFR, tubular flow might be low in the distal part of the nephron despite significant volume overload. Moreover, aldosterone and arginine vasopressin levels are high, which further stimulates reabsorption of the remaining tubular fluid. In addition, decreased distal tubular flow causes aldosterone breakthrough. Paradoxically, administration of large amounts of exogenous aldosterone to normal individuals does not cause oedema, because after the initial sodium-retaining effects of aldosterone, urinary sodium excretion increases to balance intake.37 This aldosterone escape arises because the distal nephron cannot fully reabsorb the increased sodium load resulting from increased filtration due to volume expansion and

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Figure 3 The macula densa: tubuloglomerular feedback vs. unrestrained neurohumoral activation in congestive heart failure. (A) Normally, the macula densa senses increased chloride delivery because active chloride transport consumes ATP, which is further downgraded to adenosine. Adenosine, which is released from macula densa cells, has a paracrine effect on the afferent arteriole, where it causes vasoconstriction. Through this tubuloglomerular feedback, the nephron is protected against hyperfiltration. (B) In congestive heart failure, chloride delivery to the macula densa is diminished and intracellular chloride levels are low. This stimulates NOS I and COX-2 activation and release of NO and PGE2 . The latter two work in concert to act upon granulosa cells of the afferent arteriole to cause renin release and vasodilation through relaxation of smooth muscle cells. Renin activates angiotensin II, which initiates a vicious cycle of neurohumoral activation and congestion. Notably, furosemide inhibits the Na+ /K+ /2Cl – co-transporter, further exacerbating low intracellular chloride levels in the macula densa and consequently neurohumoral activation. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; COX-2, cyclo-oxygenase-2; FF, filtration fraction; NO, nitric oxide; NOS I; nitric oxide synthetase; PGE2 , prostaglandin E2 .

© 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology

up-regulation of natriuretic peptides. Importantly, when fractional sodium reabsorption in the proximal tubules is greatly enhanced in CHF, distal sodium delivery remains low. Consequently, aldosterone breakthrough is observed, which leads to secondary hyperaldosteronism despite treatment with an adequately dosed renin-angiotensin system inhibitor.38 Additionally, the distal nephron plays an important role in emerging loop diuretic resistance. It is well known that with repeated dosing of loop diuretics, diuretic efficacy decreases, i.e. the socalled braking phenomenon. Importantly, intrinsic renal adaptions occur with prolonged exposure to loop diuretics. Already after a few days, hypertrophy of distal tubular cells is evident, causing increased local sodium uptake and aldosterone secretion.39 In this setting, combinational diuretic therapy with thiazide-type diuretics is able to overcome loop diuretic resistance.40

Failing natriuretic peptides in congestive heart failure The natriuretic peptides constitute a major counter-regulating system that decreases tubular sodium reabsorption to achieve a

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negative sodium balance when there is volume overload. Atrial natriuretic peptide and B-type natriuretic peptide (BNP) were the first to be discovered and are produced by cardiac myocytes when wall tension is increased. However, the natriuretic peptide family in humans count at least four other members (C-type, Dtype, V-type, and urodilatin), and other peptides with structural similarities are produced, for instance, by the gut (guanylin and uroguanylin).41,42 Natriuretic peptides exert their function through interactions with high-affinity receptors on the surface of target cells. Three natriuretic peptide receptors (A, B, and C) have been described, and all are activators of guanylyl cyclase, which means they mediate their effects through stimulation of the second messenger cyclic guanosine monophosphate (cGMP). In the kidney, natriuretic peptides increase RBF, cause a relaxation of mesangial cells which increases the filtration area of the glomerulus, and reduce fractional sodium reabsorption in the renal tubules.43 Interestingly, natriuretic peptide receptors in the renal tubules are predominantly expressed in the distal part of the nephron.44 This might explain why in advanced CHF—with greatly enhanced proximal sodium reabsorption—they eventually fail to elicit potent natriuresis. Indeed, a recent subanalysis from the Acute Study of Clinical Effectiveness of Nesiritide in Subjects With Decompensated Heart

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Failure (ASCEND-HF) demonstrates that nesiritide, a recombinant BNP, did not increase diuresis- and presumably natriuresis - in patients with advanced CHF.45 In an elegantly executed experiment, involving 38 patients with pre-clinical systolic/diastolic dysfunction (asymptomatic individuals with normal haemodynamics and GFR), McKie et al. have recently provided more compelling evidence that impaired natriuresis might be a factor driving disease progression in CHF, rather than merely a consequence of neurohumoral activation secondary to cardiac dysfunction.46,47 They were able to demonstrate that such patients have a blunted natriuretic response upon volume expansion, which could be restored after administration of exogenous SQ BNP (Scios, Mountain View, CA, USA). The authors have raised the interesting hypothesis that lack of an adaptive increase in tubular cGMP upon volume loading might be involved from the beginning of the disease process. There are several potential reasons for inadequate cGMP activation in patients with pre-clinical CHF (Figure 4). First, the natriuretic peptide receptor type A is downregulated in CHF.48 Secondly, there is an up-regulation of neutral endopeptidase, which degrades natriuretic peptides and is found most abundantly in renal tubular cells.49 Finally, there is some evidence of augmented phosphodiesterase 5 (PDE5) activity in

Figure 4 Natriuretic peptides: causes of impaired renal sensitivity. PDE5, phosphodiesterase 5; RBF, renal blood flow.

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the renal tubules in CHF, which is responsible for an increased breakdown of cGMP.50 Interestingly, the PDE5 inhibitor tadalafil abolishes the decrease in natriuresis seen with intra-abdominal pressure elevation in a rat model of CHF.51 Increased intraabdominal pressure is not uncommon in humans with CHF, related to systemic congestion and correlated to worse GFR.52 Conclusively, intrinsic kidney changes, presumably in the renal tubules—and thus not detected by markers of GFR—might cause the blunted response to natriuretic peptides found in pre-clinical stages of CHF. Eventually, when the disease progresses, greatly enhanced proximal sodium reabsorption, because of decreased RBF and neurohumoral activation, further precludes the beneficial effects of natriuretic peptides in the distal nephron.

Hyponatraemia: marker for increased proximal sodium reabsorption? Hyponatraemia is a common finding in advanced CHF and is closely correlated to poor outcome.53 It is less clear if this correlation represents a causal association or if hyponatraemia is just a marker of more advanced disease. Indeed, studies which have assessed the prognostic importance of changes in serum sodium concentration have yielded conflicting results.54,55 Moreover, vasopressin antagonists increase free water excretion—without influence on sodium homeostasis—thereby correcting hyponatraemia, but have failed to demonstrate any benefits in patients with CHF.56 Generally, hyponatraemia in CHF is assumed to be the direct consequence of increased arginine vasopressin levels causing free water retention. However, an intriguing study by Bell et al. published in 1964 challenges this idea. In this study, it is demonstrated that impaired free water clearance in CHF patients might be reversed by administration of mannitol, an osmotic diuretic.57 The proposed explanation for this phenomenon is that osmotic diuretics enhance tubular flow, increasing the amount of tubular fluid offered to the distal nephron. Importantly, the distal nephron is essential for diluting urine as sodium is reabsorbed while the tubular wall is impermeable to water. Similar findings in patients with advanced cirrhosis, another condition where RBF is low and proximal sodium reabsorption increased, further support this hypothesis.58 Thus, in both CHF and cirrhosis, insufficient tubular flow through the distal nephron might contribute to additional free water retention, which might ultimately manifest as hyponatraemia despite increased total body sodium.

Future perspectives and therapeutic implications Renal function assessment: alternatives to serum creatinine Renal function in the context of decongestive therapies for decompensated CHF is traditionally monitored through serum creatinine levels. The limitations of serum creatinine as a biomarker for GFR

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are well known, largely because of variable production (dependent on age, sex, muscle mass, and ethnicity), dependency on the diet, and tubular secretion.59 These shortcomings are partly overcome by the application of formulas such as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, which is currently considered the most accurate.60 Alternatively, new biomarkers such as cystatin C, which might better reflect GFR, have the potential to improve risk stratification of renal dysfunction in CHF.61 However, even the most accurate measurement of GFR is a poor marker of structural damage to the nephron in decompensated CHF, as many reversible factors in this context might influence snGFR. Urinary albumin, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and N-acetyl-𝛽-D-glucosaminidase (NAG) are proposed to improve the diagnosis of acute kidney injury (AKI) during decongestive treatment for CHF as they better reflect glomerular and tubular damage.62 Importantly in this respect, our group found that urinary NGAL levels are increased in decompensated CHF patients who experience a rise in serum creatinine, but in a range much lower than in patients with AKI through a direct nephrotoxic insult (e.g. contrast nephropathy).63 This is somewhat reassuring, although, if tubular markers are effectively increased, this is associated with worse outcome.64 Alternatively, as persistent congestion is more consistently associated with worse outcome than short-term changes in GFR, guiding therapy by assessing natriuresis—which reflects both glomerular and tubular function—might be a more successful strategy to achieve decongestion.7 Possibly, fractional sodium and chloride excretion might be helpful to assess tubular function and efficacy of diuretics. However, this remains only a hypothesis, which should be an area of future research.

Loop diuretic resistance and combinational diuretic therapy While loop diuretics remain the most frequently applied therapy in decompensated CHF, there are several reasons why this medication class might lose its efficiency or even be harmful. To enable secretion by the proximal tubules and reach their target of action—the Na+ /K+ /2Cl – symporter on the luminal side of the TAL—loop diuretics need sufficient plasma concentrations, especially if renal function is compromised.65 Additionally, gastrointestinal absorption may be delayed in the case of marked congestion with gut oedema. Newer agents such as bumetanide and torsemide have a better oral bioavailability and might be preferred over furosemide in these cases. Moreover, torsemide has a significantly longer half-life, which limits episodes of postdiuretic rebound sodium retention. Limited evidence from small studies indeed suggests better functional capacity and improved survival of CHF patients treated with torsemide compared with furosemide.66 – 68 Alternatively, loop diuretics can be administered in a higher dose or by continuous instead of bolus infusion, which is associated with some theoretical advantages. However, in the recent Diuretic Optimization Strategies Evaluation (DOSE) trial, both strategies yielded no significant benefit in patients admitted with decompensated CHF.69 In addition, there are some concerns

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From a pathophysiological perspective, it might be interesting to enhance loop diuretic responsiveness through combinational diuretic therapy. First, thiazide-type diuretics might overcome loop diuretic responsiveness caused by distal tubular hypertrophy (i.e. the braking phenomenon).40 Secondly, mineralocorticoid receptor antagonists are an established treatment for symptomatic CHF and counteract aldosterone breakthrough.73,74 Finally, targeting sodium reabsorption in the proximal tubules might have some potential benefits in decompensated CHF as it is the place where most sodium is reabsorbed. Greater delivery of chloride to macula densa cells will decrease renin production, terminating neurohumoral activation. Moreover, endogenous natriuretic peptides (acting in the distal nephron) will possibly regain their effects. Particularly when hyponatraemia, low RBF, and low fractional sodium excretion are present, tailored decongestive therapy should target the proximal tubules. While novel therapies are awaited, two currently available approaches might be considered, though they require more investigation in randomized clinical trials. First, acetazolamide is an old and largely forgotten diuretic targeting the proximal tubules. It exerts its diuretic effect through inhibition of carbonic anhydrase, resulting in urinary sodium bicarbonate wasting. Remarkably, in a small study of nine patients with advanced CHF and diuretic resistance, therapy with acetazolamide was able to elicit potent diuresis.75 Secondly, osmotic diuretics such as mannitol decrease proximal sodium reabsorption and cause an even greater free water diuresis, making them an appealing option when hyponatraemia is present.76 Yet, as the evidence regarding the use of acetazolamide or osmotic diuretics in CHF remains limited to two small, observational studies, findings should be considered hypothesisgenerating and must be further assessed in future randomized clinical trials.

Vasodilator therapy to improve renal blood flow As explained, increased RBF is associated with a decrease in FF and consequently less proximal sodium reabsorption and neurohumoral activation. Interestingly, ACE inhibitors cause an increased RBF, predominantly because of vasodilation of the efferent arteriole, which might cause a drop in GFR (and FF) that is not associated with worse outcome.6 In this respect, it is intriguing to observe that in the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin has emerged as the first therapy potentially reducing all-cause mortality in patients with decompensated CHF.77 Importantly, serelaxin is recombinant human relaxin-2, which is normally produced by women during pregnancy and increases RBF. In the RELAXAHF trial, treatment with serelaxin was associated with favourable renal outcomes.78 Another study by Cotter et al. has suggested that a lower dose of diuretics is needed to achieve decongestion when vasodilator therapy is added.79 Specific data regarding the role of vasodilators to improve renal function in patients with cardio-renal syndrome are lacking, but low-dose dopamine and nesiritide, both sharing renal vasodilator properties, are currently

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regarding the adverse effects of high-dose loop diuretics, such as intravascular volume depletion, neurohumoral activation (Figure 3), potassium and magnesium wasting, and hyperuricaemia.70 – 72

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under investigation in the ROSE AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure) trial (NCT01132846).

Renal sympathetic denervation and vagal stimulation Excess orthosympathetic activity and withdrawal of parasympathetic tone are characteristic features of CHF.80 Orthosympathetic activation directly stimulates renin secretion, decreases RBF, and increases tubular sodium reabsorption.16 Therefore, it has a major impact on the potency of the kidneys to elicit natriuresis. Denervation of renal nerves has been shown to lead to a decrease in sympathetic outflow, probably as the result of interruption of afferent fibres that contribute to sympathetic activation.81 Alternatively, vagal stimulation is currently explored as a treatment for CHF because of its sympatholytic effects.82 Yet, the exact role of both treatment modalities in CHF remains to be elucidated.

Ultrafiltration and peritoneal dialysis As mechanical fluid removal through ultrafiltration removes more sodium for the same amount of water when compared with diuretics, it has the potential to relieve volume overload more efficiently.83 However, because of the potential complications associated with a central venous access and the rather disappointing results of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial, most experts currently consider ultrafiltration only indicated in the case of overt systemic congestion, refractory to combination diuretic therapy and with careful regulation of the ultrafiltration rate to avoid intravascular volume depletion.84 Analogously in the ambulatory setting, peritoneal dialysis may offer an efficient and safe alternative to achieve decongestion in patients with a strong tendency for volume overload despite adequate diuretic treatment. Continuous ambulatory peritoneal dialysis has a minimal impact on central haemodynamics and neurohumoral activation, which might explain its success in preliminary clinical studies with CHF patients.85,86 However, those results from small observational studies should be confirmed first by large randomized clinical trials before a definitive recommendation can be made.

Conclusions Increased sodium avidity and a tendency to extracellular volume overload are the most frequent reason for hospitalizations in patients with CHF (the ‘bad’). Achieving a balanced natriuresis is key in CHF and reflects the nephron’s function as a whole (the ‘good’), in contrast to serum creatinine, which only reflects glomerular filtration. As different reasons contribute to diminished natriuretic efficiency of loop diuretics in CHF, tailored use of combinational diuretic therapy and new emerging treatment options to achieve thorough decongestion may offer preferable alternatives to blind up-titration of loop diuretics (the ‘ugly’). © 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology

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Funding No grants, contracts or other forms of financial support were given to support publication of this manuscript. F.H.V., L.G., and WM. are researchers for the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital. Conflict of interest: none declared.

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© 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology

The kidney in congestive heart failure: 'are natriuresis, sodium, and diuretics really the good, the bad and the ugly?'.

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion,...
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