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

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European Journal of Heart Failure (2014) 16, doi: /ejhf.35 REVIEW The kidney in congestive heart failure: are natriuresis, sodium, and diuretics really the good, the bad and the ugly? Frederik
European Journal of Heart Failure (2014) 16, doi: /ejhf.35 REVIEW The kidney in congestive heart failure: are natriuresis, sodium, and diuretics really the good, the bad and the ugly? Frederik H. Verbrugge 1,2, Matthias Dupont 1, Paul Steels 3, Lars Grieten 1,3, Quirine Swennen 3, W.H. Wilson Tang 4, and Wilfried Mullens 1,3 * 1 Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, 3600, Belgium; 2 Doctoral School for Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; 3 Biomedical 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 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.... Keywords 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, 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... 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: , Fax: , 134 F. H. Verbrugge et al. 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. 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 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... 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 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% 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 Renal sodium handling in congestive heart failure 135 Figure 1 Filtration equilibrium: the physiological maximum of filtration fraction (FF). The value of the single nephron glomerular filtration 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 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 P GC. 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; P B, hydrostatic pressure in Bowman s space; P GC, glomerular capillary hydrostatic pressure; π B, colloid osmotic pressure in Bowman s space; π GC, glomerular capillary colloid osmotic pressure. 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... 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 136 F. H. Verbrugge et al. 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, P IF and P PC 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; P IF, interstitial fluid hydrostatic pressure; P PC, 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... 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 E 2 (PGE 2 )and nitric oxide (NO) secretion. 11 Both PGE 2 andnoworkinconcert 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 Renal sodium handling in congestive heart failure 137 A B 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 PGE 2. 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,
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