Pathophysiology of Sodium Retention and Wastage

Extracellular fluid (ECF) volume is determined by the balance between sodium intake and renal excretion of sodium. Under normal circumstances, wide variations in salt intake lead to parallel changes in renal salt excretion, such that ECF volume is maintained within narrow limits. This relative constancy of ECF volume is achieved by a series of afferent sensing systems, central integrative pathways, and renal and extrarenal effector mechanisms acting in concert to modulate sodium excretion by the kidney.

Introduction

In the major edematous states, effector mechanisms responsible for sodium retention behave in a more-or-less nonsuppressible manner, resulting in either subtle or overt expansion of ECF volume. In some instances, an intrinsic abnormality of the kidney leads to primary retention of sodium, resulting in expansion of ECF volume. In other instances, the kidney retains sodium secondarily as a result of an actual or sensed reduction in effective circulatory volume.

Renal sodium wastage can be defined as the inability of the kidney to conserve sodium to such an extent that continued loss of sodium into the urine leads to contraction of intravascular volume and hypotension. Renal sodium wastage occurs in circumstances where renal sodium transport is pharmacologically interrupted (administration of diuretics), where the integrity of renal tubular function is breached (tubulointerstitial renal disease) or when mineralocorticoid activity or tubular responsiveness are diminished or absent.

Sodium Intake and Sodium Balance

Under normal circumstances, renal excretion of sodium is regulated so that balance is maintained between intake and output, and ECF volume is stabilized. A subject maintained on a normal-sodium diet is in balance when body weight is constant, and sodium intake and output are equal. When the diet is abruptly decreased, a transient negative sodium balance ensues. A slight contraction of ECF volume signals activation of sodium-conserving mechanisms, which lead to decreases in urinary sodium excretion. After a few days, sodium balance is achieved and ECF volume and weight are stabilized, albeit at a lower value. If sodium intake is increased to the previous normal values, transient positive sodium balance leads to expansion of ECF volume, thereby suppressing those mechanisms that enhanced sodium reabsorption. A new steady-state is reached when ECF volume has risen sufficiently so that sodium excretion now equals intake ( Figure 38.1 ). In both directions a steady-state is achieved, whereby sodium intake equals output, while ECF volume is expanded during salt loads and shrunk during salt restriction. The kidney behaves as though ECF volume is the major regulatory element modulating sodium excretion.

Figure 38.1, Changes in body weight in response to abrupt changes in dietary salt demonstrating the ability of a normal subject to maintain salt balance with only minimal changes in extracellular fluid volume.

The major edematous states – congestive heart failure, cirrhosis of the liver, and nephrotic syndrome – depart strikingly from those constraints. These states are characterized by persistent renal salt retention despite progressive expansion of ECF volume. Unrelenting sodium reabsorption is not the result of diminished sodium intake or even in most cases diminished plasma volume, as dietary salt is adequate and total ECF and plasma volumes are expanded. Renal sodium excretion no longer parallels changes in ECF volume; rather, the kidney behaves as if sensing a persistent low-volume stimulus. Some critical component of ECF volume remains underfilled.

Primary and Secondary Edema

A common feature of the major edematous states is persistent renal salt retention despite progressive expansion of both plasma and ECF volume. Two themes have been proposed to explain the persistent salt retention that characterizes the major edematous states: salt retention may be a primary abnormality of the kidney or a secondary response to some disturbance in circulation.

Primary edema (overflow, overfill, nephritic) refers to expansion of ECF volume and subsequent edema formation consequent to a primary defect in renal sodium excretion. Increased ECF volume and expansion of its subcompartments result in manifestations of a well-filled circulation. Hypertension and increased cardiac output are commonly present. The mechanisms normally elicited in response to an underfilled circulation are suppressed (↓ renin–angiotensin–aldosterone,↓antidiuretic hormone (ADH),↓activity of sympathetic nerves,↓circulating catecholamines). Acute post-streptococcal glomerulonephritis and acute or advanced chronic kidney disease are disorders in which edema formation is primary in origin.

Secondary edema (underfill) results from the response of normal kidneys to actual or sensed underfilling of the circulation. In this form of edema, a primary disturbance within the circulation secondarily triggers renal mechanisms for sodium retention. Those systems that normally serve to defend the circulation are activated (rises in renin–angiotensin–aldosterone, ADH, activity of sympathetic nerves, and circulating catecholamines). The renal response in underfill edema is similar to that in normal subjects placed on a low-salt diet, that is, low fractional excretion of sodium, increased filtration fraction, and prerenal azotemia. Despite these similarities, a number of critical features distinguish these two states: (1) sodium balance is positive in underfill edema while salt-restricted normal subjects are in balance; and (2) administration of salt to sodium-restricted normals transiently expands ECF volume, after which sodium excretion equals intake, whereas in underfill edema, ECF volume expands progressively consequent to unyielding salt retention; and features of an underfilled circulation persist in underfill edema, while the circulation is normalized in normals.

The circulatory compartment that signals persistent activation of sodium-conserving mechanisms in secondary edema is not readily identifiable. Cardiac output may be high (arteriovenous shunts) or low (dilated cardiomyopathy). Similarly, plasma volume may be increased (arteriovenous shunts and heart failure) or decreased (some cases of nephrotic syndrome). The body fluid compartment ultimately responsible for signaling a volume-regulatory reflex leading to renal sodium retention is effective arterial blood volume (EABV). EABV identifies that critical component of arterial blood volume, actual or sensed, that regulates sodium reabsorption by the kidney. In both normal circumstances and the major edematous states, the magnitude of EABV is the major determinant of renal salt and water handling.

Concept of Effective Arterial Blood volume

In order to explain adequately persistent sodium retention in underfill edema, two cardinal features must exist. First, there must be a persistent low-volume stimulus sensed by the kidney that is then translated into persistent, indeed often unrelenting, retention of sodium despite adequate salt intake and overexpansion of ECF volume. Second, there must be a disturbance in those forces that partition retained fluid into the various subcompartments of the ECF space, resulting in an inability to terminate the low-volume stimulus. The first feature can be ascribed to a shrunken EABV, a feature common to all major edematous states. The second feature can be attributed to a disruption in Starling forces, which normally dictate the distribution of fluid within the extracellular compartment. A disturbance in the circulation exists such that retained fluid is unable to restore EABV but rather is sequestered, resulting in edema formation.

Fluctuations in EABV are modulated by two key determinants: (1) filling of the arterial tree (normally determined by venous return and cardiac output); and (2) peripheral resistance (a factor influenced by compliance of the vasculature and degree of arteriolar runoff). A reduction in EABV can be the result of decreased arterial blood volume owing to low cardiac output, as in congestive heart failure. Conversely, EABV can be reduced in the face of increased arterial blood volume when there is excessive peripheral runoff, as seen in arteriovenous shunting and vasodilation. Increased compliance of the arterial vasculature in which arterial blood volume is reduced relative to the holding capacity of the vascular tree results in decreased EABV. For example, administration of salt to a subject with a highly compliant or “slack” circulation (as in pregnancy or cirrhosis) results in a sluggish natriuretic response, in contrast to a high resistance or “tight” circulation (as in primary aldosteronism or accelerated hypertension) in which salt administration causes prompt natriuresis.

Under normal circumstances, EABV is well-correlated with ECF volume. Figure 38.1 depicts the relationship between subcompartments of ECF volume and renal sodium excretion in both normal and edematous states. Under normal circumstances, subcompartments of ECF volume freely communicate in response to changes in dietary sodium, such that expansion or shrinkage of these compartments occurs in concert ( Figure 38.2 , states 1A and 1B). In steady-state conditions, sodium intake and output are in balance; the set point at which balance is attained is dictated by salt intake.

Figure 38.2, Concept of effective arterial blood volume and effect of fluid distributory disturbances on sodium balance and sodium excretion.

By contrast, major edematous states are characterized by a shrunken EABV, which cannot be filled despite expansion of one or more subcompartments. No longer is EABV well-correlated with total ECF volume and salt intake. Due to a disturbance in the forces that normally partition fluid into the various subcompartments of ECF space, EABV remains contracted even though total ECF volume is greatly expanded. Activation of sodium-conserving mechanisms persists, despite plentiful salt intake. Such derangements in fluid distribution can be categorized as disturbances in Starling forces within the interstitial space, between interstitial space and vascular tree, and disturbances within the circulation. These disturbances are summarized next.

1.
Trapped fluid ( Figure 38.2 , state 2A). In the first type of disturbance, fluid is trapped within a pathologic compartment such that it cannot contribute to effective extracellular volume, that is, volume capable of filling interstitial and vascular spaces. Decrease in effective extracellular volume leads to decreases in total blood volume, arterial blood volume, and EABV, and renal sodium retention is stimulated. Retention of salt and water cannot re-expand effective extracellular volume, as fluid is sequestered into an abnormal fluid compartment behind the “Starling block” within the interstitial space. Such spacing of fluid into inflamed tissue, vesicles and bullae, peritonitis, necrotizing pancreatitis, rhabdomyolysis, and burns functionally behaves as if lost from the body.
2.
Reduced oncotic pressure. A reduction in the circulating level of albumin can lead to a second type of fluid maldistribution. Decreased plasma oncotic pressure allows fluid to translocate from the vascular compartment to the interstitial space. Reductions in total blood volume, arterial blood volume, and EABV lead to sodium retention. The retained salt and water, owing to a “Starling block” across the capillary bed, leaks into the interstitial space.
3.
Vascular disturbances ( Figure 38.2 , states 2B and 2C). A third type of fluid distributory disturbance results from abnormalities within the circulation, and can be of two types. The prototypical example of the first type is congestive heart failure. A failing ventricle results in decreased cardiac output and high diastolic intraventricular pressures. Venous return is impeded, with consequent reductions in arterial blood volume and EABV. Sodium retention is stimulated, but arterial blood volume and EABV remain contracted due to a circulatory block across the heart. In consequence, venous volume expands and leads to transudation of fluid into the interstitial space. The second type of circulatory abnormality that leads to fluid maldistribution is exemplified by arteriovenous shunting (e.g., Paget’s disease, beriberi, thyrotoxicosis, anemia, cirrhosis). Widespread shunting through multiple small arteriovenous communications results in increased venous return, thereby augmenting cardiac output and arterial filling. However, arterial runoff and vasodilation lead to underperfusion of some critical area in the microcirculation. The circulatory block lies between the arterial blood volume and EABV.

What distinguishes secondary edematous states from the normal circumstance is an inability to expand EABV owing to Starling or circulatory blocks within the extracellular space. Normally, the system of volume regulation behaves as an open system, such that fluctuations in one compartment are quickly translated into parallel changes in other compartments; total ECF volume and EABV are closely related. In contrast, volume regulation in underfill edema can be regarded as clamped; EABV remains shrunken despite expansion of the subcompartments of the extracellular space. EABV becomes dissociated from total ECF volume; salt retention becomes unrelenting and salt administration cannot re-expand the contracted EABV.

The reader is referred to the fourth edition of this book, in which a comprehensive discussion is provided on the afferent and efferent mechanisms involved in the regulation of extracellular fluid volume under normal circumstances. An overview of renal sodium handling in each segment of the nephron was also provided in that discussion. In this edition, the chapter will focus exclusively on the pathophysiology of the major edematous and salt-wasting states.

Congestive Heart Failure

The fundamental abnormality underlying congestive heart failure is an inability of the heart to maintain its function as a pump. As a result, a series of complex compensatory reflexes are initiated that serve to defend the circulation. The renal response to a failing myocardium is retention of salt and water resulting in expansion of ECF volume. If myocardial dysfunction is mild, expansion of ECF volume leads to increased left ventricular end-diastolic volume, which raises cardiac output according to the dictates of the Frank–Starling principle. In this state of compensated congestive heart failure, salt intake and output come into balance, but at the expense of an expanded ECF volume. Further deterioration in ventricular function leads to further renal retention of salt and water. There is progressive expansion of ECF volume and features of a congested circulation become manifest: peripheral edema, engorged neck veins, and pulmonary edema. Despite massive overexpansion of ECF volume, the kidneys behave as though they were responding to a low-volume stimulus. In subsequent sections, a detailed analysis of the afferent and efferent regulatory limbs in congestive heart failure will be provided.

Afferent Sensing Mechanisms in Congestive Heart Failure

Low and High Pressure Baroreceptors

A characteristic feature in many forms of congestive heart failure is increased stretch and transmural pressure within the cardiac atria. These alterations would normally provide afferent signals that suppress sympathetic outflow and decrease the release of renin and ADH, and ultimately result in a diuretic and natriuretic response. In congestive heart failure, this afferent signaling mechanism is markedly perturbed. Despite the presence of venous congestion and elevated cardiac filling pressures, sympathetic nervous activity and serum concentrations of renin and ADH are increased and urinary salt excretion is blunted. Both clinical and experimental studies are consistent with a decrease in sensitivity of the pressure-sensitive receptors in the cardiac atria.

Increased renal sympathetic nerve activity in cardiac failure has also been attributed to impaired arterial baroreceptor function. High pressure baroreceptors in the carotid sinus and aortic arch normally exert a tonic inhibitory effect on central nervous system sympathetic outflow. Although the precise mechanism for the sympathoexcitation is not known, a sustained reduction in arterial pressure is unlikely to be the sole explanation, since arterial pressure is usually normal in congestive heart failure. Rather, sympathetic tone becomes insensitive to manipulations that normally suppress or enhance its activity. For example, infusion of nitroprusside increases both the heart rate and the circulating norepinephrine levels in normal subjects, whereas equivalent hypotensive doses in subjects with congestive heart failure elicit a blunted response. Similarly, patients with heart failure show less bradycardia when arterial pressure is raised by infusion of phenylephrine. Such alterations in baroreflex function may result from abnormalities peripherally or alterations in central autonomic regulatory centers.

Several observations suggest angiotensin II may contribute to the depressed baroreflex sensitivity in heart failure. Angiotensin II has been shown to upwardly reset the arterial baroreflex control of heart rate in the rabbit, independent of a change in arterial pressure. In the rat, increased levels of endogenous angiotensin II produced by changes in dietary salt intake tonically increase the basal level of renal sympathetic nerve activity, and upwardly reset the arterial baroreflex control of renal sympathetic nerve activity. In experimental models, administration of an angiotensin II receptor blocker can reverse these changes and improve the sensitivity of the arterial baroreflex mechanism. Interestingly, captopril administered to patients with congestive heart failure restores the normal hemodynamic response to postural tilt and infusion of vasoconstrictive agents.

Cardiac Output

A reduction in cardiac output has been suggested as the afferent signal that leads to Na retention in heart failure. When cardiac output is reduced by constriction of the abdominal or thoracic vena cava, urinary sodium excretion is typically decreased. Restoring cardiac output to normal by autologous blood transfusion ameliorates renal salt retention, despite persistently elevated venous and hepatic pressures. By contrast, rats with small-to-moderate myocardial infarctions have normal capacities to increase cardiac output in response to volume loads, and yet renal sodium excretion remains blunted in these animals. Even when cardiac output is increased above normal, as with the creation of an arteriovenous fistula in dogs, clinical findings of ascites and peripheral and pulmonary edema develop. Despite increased cardiac output, levels of renin, aldosterone, and ANP are high. Thus, the signal which initiates renal salt retention in congestive heart failure cannot originate solely from a decrease in cardiac output.

Other Sensors

Other afferent sensing mechanisms potentially active in congestive heart failure include intrahepatic baroreceptors and mechanoreceptors within the kidney. Chemosensitive receptors that respond to changing levels of metabolic breakdown products may participate in sensing of ECF volume. One such sensing mechanism may relate to the cardiac sympathetic afferent reflex. The reflex begins with sympathetic afferent fibers that respond to changes in cardiac pressure and dimension or substances that may accumulate in ischemia or heart failure. The reflex is excitatory in nature, such that activation of the afferent fibers leads to increased central sympathetic outflow. In summary, a contracted EABV serves as the afferent signal that elicits activation of effector mechanisms resulting in sodium retention. As with other edematous disorders, the exact volume compartment that comprises EABV has not been elucidated ( Figure 38.3 ).

Figure 38.3, Summary of pathways leading to renal sodium retention in low- and high-output congestive heart failure

Effector Mechanisms in Congestive Heart Failure

Nephron Sites of Renal Sodium Retention

Renal sodium handling in the setting of congestive heart failure is similar to that which occurs in an otherwise normal individual who is volume-depleted. Activation of effector mechanisms lead to alterations in renal hemodynamics and tubular transport mechanisms that culminate in renal salt retention.

Renal hemodynamics in congestive heart failure are characterized by reduced renal plasma flow and a well-preserved glomerular filtration rate, such that filtration fraction is typically increased. In a rat model of myocardial infarction, Hostetter et al. found a positive correlation between the decline in renal plasma flow and the degree to which left ventricular function was impaired. The glomerular filtration rate remained well-preserved as a result of an increased filtration fraction, except in animals with a severely compromised left ventricle. When examined at the level of the single nephron, these hemodynamic changes were found to be the result of a disproportionate increase in efferent arteriolar vasoconstriction and increased glomerular capillary hydraulic pressure. Treatment with an angiotensin-converting enzyme inhibitor caused a decline in filtration fraction and efferent arteriolar resistance, suggesting an important role for angiotensin II in mediating efferent arteriolar constriction.

Changes in glomerular and proximal tubular function in heart failure are similar to those that result from infusion of angiotensin II or norepinephrine. Angiotensin II, catecholamines, and renal nerves are all capable of increasing both the afferent and the efferent arteriolar tone, but predominantly act on the latter. These changes serve to maintain glomerular filtration rate near normal as renal plasma flow declines secondary to impaired cardiac function. As cardiac function progressively declines and the reduction in renal plasma flow becomes severe, the glomerular filtration rate will begin to fall. At this point there is an inadequate rise in filtration fraction, because efferent arteriolar vasoconstriction can no longer offset the intense afferent arteriolar constriction. Higher plasma catecholamines and further increases in sympathetic nerve activity acting to provide circulatory stability result in greater constriction of the afferent arteriole, such that glomerular plasma flow and transcapillary hydraulic pressure are reduced. In this setting, the glomerular filtration rate becomes dependent on afferent arteriolar flow.

These observations are similar to what has been observed in human subjects with varying degrees of left ventricular function. As left ventricular function declines, the glomerular filtration rate is initially maintained by an increased filtration fraction. However, in patients with severely depressed left ventricular function, a progressive decline in renal blood flow becomes associated with a fall in glomerular filtration rate due to an inadequate rise in filtration fraction. In this setting, administration of an ACE inhibitor can result in a further lowering of the glomerular filtration rate, even though systemic arterial pressure remains fairly constant.

Both experimental and clinical studies support the proximal nephron as a major site of increased sodium reabsorption in the setting of congestive heart failure. In human subjects, clearance techniques have primarily been employed to demonstrate the contribution of the proximal nephron. For example, infusion of mannitol was shown to increase free water excretion to a greater extent in patients with congestive heart failure as compared to normal controls. Since mannitol inhibits fluid reabsorption proximal to the diluting segment, it was inferred that enhanced free water clearance was reflective of augmented delivery of Na from the proximal tubule to the diluting segment. In dogs with an arteriovenous fistula, there is a failure to escape from the Na-retaining effects of deoxycorticosterone acetate. In addition, these animals do not develop hypokalemia in contrast to normal controls. The absence of hypokalemia in the setting of mineralocorticoid excess is best explained by decreased delivery of Na to the distal nephron due to enhanced proximal Na reabsorption. Alterations in peritubular hydrostatic and oncotic forces, as well as direct effects of various neurohormonal effectors, account for enhanced proximal sodium and water absorption in this setting.

Clearance and micropuncture studies are also consistent with enhanced sodium reabsoption in the distal tubule in states of congestive heart failure. The loop of Henle has been identified as a site of enhanced sodium reabsoption in dogs with chronic vena cava obstruction and rats with an arteriovenous fistula.

Renin–Angiotensin–Aldosterone System

The renin–angiotensin–aldosterone system is activated when the heart fails as a pump. Components of this system serve to compensate for decreased cardiac output by stabilizing the circulation and expanding ECF volume.

Several mechanisms are activated in the setting of a failing myocardium which serve to increased renin release. Diminished pressure in the afferent arteriole enhances renin release via a baroreceptor mechanism, the sensitivity of which is heightened consequent to augmented baseline sympathetic nerve activity. Enhanced salt and water reabsorption in the proximal tubule and loop of Henle diminishes sodium chloride concentration at the macula densa, providing a stimulatory signal for renin release by way of the tubuloglomerular feedback mechanism. Finally, increased sympathetic nerve activity directly enhances renin release via stimulation of β-adrenergic receptors on the juxtaglomerular cells.

Renin acts on angiotensinogen synthesized in the liver and elsewhere to produce the decapeptide, angiotensin I. Angiotensin I is converted to angiotensin II by the angiotensin-converting enzyme present in the lungs, kidney, and blood vessels throughout the circulation.

Angiotensin II plays a pivotal role in glomerular and proximal tubule function in models of congestive heart failure ( Figure 38.4 ). By selectively increasing efferent arteriolar tone, adjustments in the glomerular and postglomerular circulatory network favor net reabsorption in the proximal tubule. Increased filtration fraction leads to increased peritubular oncotic pressure, and in combination with decreased peritubular hydrostatic pressure net sodium reabsorption is enhanced. Angiotensin II also stimulates salt and water reabsorption through a direct effect on proximal tubular cells. Increased efferent arteriolar resistance increases glomerular capillary hydrostatic pressure, mitigating any fall in GFR that would otherwise occur from decreased renal blood flow. In clinical, as well as experimental, models of heart failure, administration of ACE inhibitors improves renal blood flow and increases urinary sodium excretion, consistent with important angiotensin II-mediated effects on the renal microvasculature.

Figure 38.4, Pathways by which angiotensin II regulates renal sodium excretion in response to a decrease in effective arterial blood volume.

Angiotensin II also contributes to renal salt and water retention through effects mediated by increased renal sympathetic nerve activity. As previously mentioned, angiotensin II decreases the sensitivity of the baroreflex mechanism such that a higher pressure is required to decrease central sympathetic outflow. In addition, angiotensin II directly stimulates sympathetic outflow at the level of the central nervous system. Chronic administration of an ACE inhibitor to patients with congestive heart failure reduces central sympathetic outflow and improves the sympathoinhibitory response to baroreflex stimulation.

Angiotensin II also influences renal salt and water handling in the distal nephron, primarily through stimulatory effects on aldosterone release in the adrenal gland. Aldosterone acts primarily on the collecting duct to promote tubular reabsorption of sodium. Aldosterone-stimulated sodium reabsorption generates a luminal-negative voltage that secondarily enhances excretion of hydrogen and potassium ions. The magnitude of potassium secretion will depend on the volume and composition of filtrate reaching the collecting duct. In this regard, patients with heart failure rarely manifest hypokalemia and alkalosis, despite oversecretion of mineralocorticoid, unless distal sodium delivery is increased by use of a diuretic. In the absence of diuretic therapy, distal delivery of sodium is low due to enhanced proximal reabsorption mediated by angiotensin II, sympathetic nerves, and peritubular physical factors. Thus, although plasma renin and aldosterone levels are frequently elevated in heart failure, there is conflicting data as to the importance of aldosterone in mediating renal salt retention.

Conflicting data regarding the importance of the renin–angiotensin–aldosterone system in the generation of cardiac edema is best resolved when analyzed with respect to severity of heart failure. The initial response to constriction of the pulmonary artery or thoracic inferior vena cava in dogs is a reduction in blood pressure, and increases in renin and aldosterone levels. During this acute phase there is avid renal sodium retention, and stability of blood pressure is critically dependent on circulating angiotensin II. Over several days plasma volume and body weight increase, while renin, aldosterone, and sodium balance return to control values. During the acute phase, administration of a converting enzyme inhibitor results in hypotension, while no effect on blood pressure is observed during this chronic phase. If plasma renin and aldosterone fail to decrease due to severe impairment of cardiac output, then converting enzyme inhibitor-induced hypotension persists.

A similar pattern is seen in dogs with an arteriovenous fistula. In the early phase of this high-output cardiac failure model, significant elevations in renin and aldosterone levels occur, and renal sodium retention is marked. Several days later, after development of peripheral edema and ascites, renin and aldosterone levels return to baseline and daily sodium excretion begins to match dietary intake.

A similar relationship between the renin–angiotensin–aldosterone system and stage and severity of congestive heart failure exists in humans. This relationship may explain why renal function improves in some patients treated with ACE inhibitors, whereas renal function deteriorates in others. In subjects whose renal function worsens after administration of the drug, there is a greater fall in mean right atrial pressure, left ventricular filling pressure, mean arterial pressure, and systemic vascular resistance as compared to subjects with stable renal function. In addition, plasma renin activity increases to a greater extent. These changes suggest a more contracted EABV and greater dependency of systemic vascular resistance on circulating angiotensin II in patients with ACE inhibitor-induced renal dysfunction.

In summary, during severe decompensated left ventricular failure, decreased EABV elicits release of renin with consequent activation of angiotensin II and aldosterone. Acutely, increased circulating levels of angiotensin II serve to maintain systemic blood pressure and augment renal sodium reabsorption. Salt retention is the result of hemodynamic and direct effects of angiotensin II at the level of the proximal tubule, and enhanced sodium reabsorption in the distal nephron primarily mediated by increased aldosterone. As ECF volume expands, renin, angiotensin II, and aldosterone become suppressed, although not necessarily to normal levels. Maintenance of systemic blood pressure is more dependent on volume rather than angiotensin II. Sodium balance is now achieved, but at the expense of increased steady-state ECF volume. ACE inhibitor therapy is not associated with deleterious effects on renal function at this stage of the disease. Should further deterioration in cardiac function ensue, persistent activation of the renin–angiotensin–aldosterone system may result, such that systemic blood pressure remains dependent on circulating angiotensin II despite expansion of ECF volume. In this setting, ACE inhibitor therapy can precipitate hypotension and significant reductions in the glomerular filtration rate. One has to consider this sequential change in renin to volume dependency of mean arterial blood pressure in attempting to predict net renal and hemodynamic effects of converting enzyme inhibition.

Sympathetic Nervous System

The sympathetic nervous system is activated in congestive heart failure. Plasma norepinephrine levels are elevated, and concentrations correlate with the degree of left ventricular dysfunction. Direct nerve recordings demonstrate a direct relationship between central sympathetic nerve outflow and left ventricular filling pressures.

Increased sympathetic tone influences renal reabsorption of salt and water by indirect, as well as direct, mechanisms ( Figure 38.5 ). Glomerular hemodynamics are affected similarly to that produced by angiotensin II. In addition, sympathetic nerves directly stimulate tubular reabsorption of salt and water in both the proximal and the distal nephron.

Figure 38.5, Pathways by which sympathetic nerves regulate renal sodium excretion in response to a decrease in effective arterial blood volume.

Increased sympathetic nerve activity stimulates renin release. The subsequent formation of angiotensin II provides a positive feedback loop leading to further increases in sympathetic nerve activity. Angiotensin II sensitizes tissues to the actions of catecholamines, and acts synergistically with renal nerves in modulating renal blood flow.

Arginine Vasopressin

Increased circulating levels of AVP is a characteristic finding in patients with congestive heart failure. The nonosmotic release of AVP plays an important role in the development of hyponatremia, which in turn is a well-defined predictor of mortality in heart failure patients. In experimental heart failure, there is upregulation of the mRNA for vasopressin in the hypothalamus. In addition, there is increased expression of the mRNA and the protein for the aquaporin-2 water channel. In a rat model of heart failure, selective antagonism of the V-2 receptor is associated with a significant improvement in free water clearance. Administration of a V-2 receptor antagonist to patients with congestive heart failure is associated with a significant reduction in body weight and improvement in dyspnea, but has not been shown to reduce mortality.

Prostaglandins

Increased production of prostaglandins plays an important role in maintaining circulatory homeostasis in congestive heart failure. In response to decreases in cardiac output, neurohumoral vasoconstrictor forces (i.e., the renin–angiotensin–aldosterone system, the neurosympathoadrenal axis) participate in the maintenance of systemic arterial pressure, and result in increased total peripheral vascular resistance. These same vasoconstrictors stimulate the renal production of vasodilatory prostaglandins, such that the rise in renal vascular resistance is less than that seen in the periphery. Vasodilatory prostaglandins function in a counter-regulatory role, attenuating the fall in renal blood flow and glomerular filtration rate that would otherwise occur if vasoconstrictor forces were left unopposed.

Renal prostaglandins also serve to moderate salt and water retention that would otherwise occur in the setting of unopposed activation of effector mechanisms such as angiotensin II, aldosterone, renal sympathetic nerves, and ADH. The importance of prostaglandins in modulating renal hemodynamics, sodium excretion, and circulatory homeostasis progressively increases in proportion to the severity of the heart failure ( Figure 38.6 ).

Figure 38.6, Renal prostaglandins moderate the effect of various effector mechanisms, thereby allowing renal function to be well-maintained in the setting of increased systemic vasoconstrictor input.

Natriuretic Peptides

Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are circulating hormones which are primarily synthesized in the cardiac atria and ventricles respectively. The synthesis and release of these peptides provide a mechanism whereby cardiac atria and ventricles serve both an afferent and efferent function in the control of ECF volume. Levels of ANP are elevated and correlate with the severity of disease in humans and experimental animals with heart failure.

The natriuretic and vasodilatory properties of ANP suggest that this peptide plays an important counter-regulatory role in congestive heart failure. However, attempts to use ANP therapeutically in congestive heart failure have produced disappointing results. ANP infused in patients with heart failure causes only a minimal change in fractional sodium excretion and urine flow rates, as compared to the robust response in normal controls. The mechanism of renal nonresponsiveness in heart failure is not entirely clear. A downregulation of receptors due to sustained exposure to high levels of ANP or altered intrarenal hemodynamics are possibilities. Decreased delivery of sodium to the distal nephron where ANP normally exerts its natriuretic effect is also a likely cause of resistance. While ANP levels are uniformly elevated in congestive heart failure, potentially beneficial natriuretic properties are overwhelmed by more powerful antinatriuretic effector mechanisms.

Similar to ANP, plasma levels of BNP are elevated in congestive heart failure, and in proportion to the severity of systolic and diastolic dysfunction. Infusion of BNP is associated with a significant reduction in pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, and mean arterial pressure, as well as an increase in cardiac index. These hemodynamic benefits are accompanied by significant increases in urinary volume and sodium excretion, in some but not all studies. Infusion of BNP can be associated with hypotension, particularly when given with other vasodilators. Measurement of plasma BNP levels is often utilized as a diagnostic tool to differentiate between cardiac versus other causes of pulmonary congestion. In addition, BNP levels can be used as a prognostic indicator and a marker reflecting the degree of cardiac dysfunction.

Endothelin and Nitric Oxide

Circulating levels of endothelin are increased in congestive heart failure, and correlate positively with the degree of myocardial dysfunction. Studies in which endothelin antagonists have been administered suggest this substance may play a role in the pathophysiology of cardiac failure. In a randomized, double-blind study of human subjects with heart failure, infusion of an ETa and ETb receptor blocker (bosentan) was associated with a reduction in right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and mean arterial pressure. In a dog model of heart failure, ETa blockade alone lead to a reduction in cardiac filling pressures and increased cardiac output. These hemodynamic changes were associated with an increase in GFR and renal plasma flow, as well as increased urinary sodium excretion. By contrast, administration of an ETb receptor blocker caused an increase in cardiac filling pressures and a decrease in cardiac output, suggesting endogenous endothelins adversely effect cardiac hemodynamics and cause fluid retention, primarily through ETa receptors.

Nitric oxide production is increased in congestive heart failure. Increased release of nitric oxide from resistance vessels may partly antagonize neurohumoral vasoconstrictor forces. Inhibiting nitric oxide production in heart failure patients causes a significant increase in pulmonary and systemic vascular resistance, as well as a decline in cardiac output. In the renal vasculature, nitric oxide production is also increased; however, the renal vasodilatory response to nitric oxide is impaired. Administration of an angiotensin receptor antagonist restores nitric oxide-mediated renal vasodilation, suggesting angiotensin II plays a contributory role in this defect.

Cirrhosis

Renal sodium excretion is normally regulated so that extracellular fluid (ECF) volume is maintained within normal limits. Any maneuver that increases ECF volume will lead to a prompt and sustained natriuresis until the volume returns to normal. In patients with cirrhosis, this homeostatic mechanism becomes deranged such that large increases in ECF volume are accompanied by continued renal salt retention, resulting in edema and ascites formation.

Presinusoidal Versus Postsinusoidal Obstruction and Ascites Formation

In patients with cirrhosis, the kidneys are normal but are signaled to retain salt in an unrelenting manner. The critical event in the generation of this signal is development of hepatic venous outflow obstruction. In the normal state, the portal circulation is characterized by high flow, low pressure, and low resistance. The imposition of a resistance into this high-flow vasculature will uniformly raise portal pressure, but development of ascites is critically dependent on location of the resistance. Conditions associated with presinusoidal vascular obstruction, such as portal vein thrombosis and schistosomiasis, raise portal pressure but are not generally associated with ascites. By contrast, hepatic diseases such as Laennec’s cirrhosis and Budd Chiari syndrome cause early postsinusoidal vascular obstruction, and are associated with marked degrees of salt retention, anasarca, and ascites. Thus, during the development of the cirrhotic process, ascites will accumulate primarily when the pathologic process is associated with hepatic venous outflow obstruction and sinusoidal hypertension.

This distinction between presinusoidal and postsinusoidal obstruction can best be explained by comparing the characteristics of fluid exchange in capillaries of the splanchnic bed versus those in the hepatic sinusoids. The intestinal capillaries are similar to those in the peripheral tissues, in that they have continuous membranes with small pores such that a barrier exists, preventing plasma proteins from moving into the interstitial space. An increase in capillary hydrostatic pressure will cause the movement of a protein-poor fluid to enter the interstitial compartment and decrease the interstitial protein concentration. Interstitial protein concentration is further reduced by an acceleration in lymph flow that is stimulated by the fluid movement. As a result, the interstitial oncotic pressure falls, and the plasma oncotic pressure remains unchanged. The net oncotic force therefore rises and offsets the increase in hydrostatic force, providing a buffer against excessive fluid filtration. The fall in intestinal lymph protein concentration is maximal at relatively low pressures, and is much greater than that observed from the cirrhotic liver. Thus, the increase in net oncotic force associated with dilution of the interstitial protein and accelerated lymph flow contribute to the protection against ascites in patients whose only abnormality is portal hypertension.

The situation across the liver sinusoids is quite different. Hepatic sinusoids, unlike capillaries elsewhere in the body, are extremely permeable to protein. As a result, colloid osmotic pressure exerts little influence on movement of fluid. Rather, direction of fluid movement is determined almost entirely by changes in sinusoidal hydraulic pressure. Thus, efflux of protein-rich filtrate into the space of Disse is critically dependent on hepatic venous pressures. Obstruction to hepatic venous outflow will lead to large increments in the formation of hepatic lymph and flow through the thoracic duct. Unlike the intestinal capillaries, there is little or no restriction in the movement of protein into the interstitium, such that the protein concentration of hepatic lymph will quickly approach that of plasma. As a result, no significant oncotic gradient develops between plasma and the interstitium at high sinusoidal pressures and flow.

When sinusoidal pressure increases to such a degree that hepatic lymph formation exceeds the capacity of the thoracic duct to return fluid to the circulation, interstitial fluid weeps off the liver into the peritoneal space and forms ascites. Lymph formation in the setting of cirrhosis can be more than 20-fold greater than that which occurs under normal circumstances. Whereas in normal humans 1–1.5 liters/day of lymph are returned to the circulation, subjects with cirrhosis, even without ascites, may have lymph flow through the thoracic duct as high as 15–20 liters/day. The predominance of hepatically-produced lymph to overall lymph production is illustrated by studies in experimental animals with cirrhosis. Barrowman and Granger found a 29-fold increase in hepatic lymph flow, while only a three-fold increase was noted in the splanchnic lymphatics. Eleven of 19 animals had normal flows of intestinal lymph, while all the cirrhotic animals had increased flows in liver lymph.

Conditions associated with the rapid onset of postsinusoidal obstruction, such as acute right-sided congestive heart failure and Budd–Chiari syndrome, initially give rise to ascitic fluid that has a high protein concentration that may even approach that of plasma. This high protein concentration is reflective of the liver being the predominant source of the ascitic fluid. However, over time the protein content of ascites in these conditions begins to decrease. Witte et al. measured the total protein in ascitic, pleural, and peripheral edema fluid in acute and chronic heart failure patients. In the setting of acute heart failure, the mean concentration of protein in ascitic fluid was approximately 5 g/dl. By contrast, the protein concentration in ascitic fluid of chronic congestive heart failure patients was 2.7 g/dl. A lower protein concentration is also typical of conditions such as Laennec’s cirrhosis, in which postsinusoidal obstruction develops slowly.

Two phenomena contribute to this change in ascitic fluid protein concentration. If the hepatic sinusoids are subject to an increased hydrostatic pressure for a long period of time, they begin to assume the anatomic and functional characteristics of capillaries found elsewhere in the body, a process referred to as capillarization. This change leads to a decrease in albumin permeability, such that oncotic forces begin to play some role in hepatic lymph formation. At the same time, hypoalbuminemia develops secondary to decreased hepatic synthesis, as well as dilution secondary to ECF volume expansion. As a result, the protein content of hepatic lymph, although still high, falls to approximately 50–55% of plasma values.

The second factor contributing to the lower ascitic protein concentration is the superimposition of portal hypertension. Early in the development of portal hypertension when plasma protein concentration is normal only minimal amounts of ascitic fluid are derived from the splanchnic bed, due to the buffering effect of increased net oncotic force opposing fluid filtration. Extremely high hydrostatic pressures are required to produce significant amounts of ascitic fluid in the setting of normal plasma protein concentrations. By contrast, less and less hydrostatic pressure is required for the formation of ascitic fluid, as the plasma albumin concentration decreases and the net osmotic force declines. In this setting, the splanchnic bed begins to make a greater contribution to the generation of ascites, and the fluid is characterized by a low protein concentration.

The development of portal hypertension is also associated with changes in the splanchnic circulation that secondarily lead to increased lymph production in the splanchnic bed. The importance of the splanchnic lymphatic pool in the generation of ascites is reflected by the fact that in most instances ascitic fluid is transudative and characterized by a protein concentration of approximately 2.5 g/dl. Classically, portal hypertension was considered to be the sole result of increased resistance to portal venous flow. However, studies in experimental models suggest that increased portal venous flow resulting from generalized splanchnic arteriolar vasodilation also plays a role in the genesis of increased portal pressure. This vasodilation leads to changes in the splanchnic microcirculation that may predispose to increased filtration of fluid. For example, an acute elevation of venous pressure in the intestine normally elicits a myogenic response that leads to a reduction in blood flow. This decrease in flow is thought to serve a protective role against the development of bowel edema. However, in chronic portal hypertension this myogenic response is no longer present. In this setting, arteriolar resistance is reduced, such that capillary pressure and filtration are increased. The loss of this autoregulatory mechanism may account for the greater increase in intestinal capillary pressure and lymph flow seen under conditions of chronic portal hypertension when compared to acute increases in portal pressure of the same magnitude. The potential causes of splanchnic arteriolar vasodilation are discussed below.

The importance of portal hypertension in the pathogenesis of ascites is highlighted by several observations. First, patients with ascites have significantly higher portal pressures as compared to those without ascites. Although the threshold for ascites development is not clearly defined, it is unusual for ascites to develop with a pressure below 12 mmHg. Gines found that only 4 of 99 cirrhotic patients with ascites had a portal pressure <12 mmHg, as estimated by hepatic venous wedged pressure. Second, portal pressure correlates inversely with urinary sodium excretion. Third, maneuvers designed to reduce portal pressure are known to have a favorable effect on the development of ascites. For example, surgical portosystemic shunts used in the treatment of variceal bleeding reduce portal pressure, and are associated with a lower probability of developing ascites during follow-up. Both side-to-side and end-to-side portocaval anastomosis have been shown effective in the management of refractory ascites in cirrhosis. Recent studies also suggest that reducing portal pressure with a transjugular intrahepatic portasystemic shunt has a beneficial effect on ascites.

In summary, ascites develops when the production of lymph from either or both the hepatic sinusoids and the splanchnic circulation exceeds the transport capacity of the lymphatics. In this setting, fluid will begin to weep from the surface of the liver and the splanchnic capillary bed, and accumulate as ascites. The final protein concentration measured in the peritoneal fluid is determined by the sum of the two contributing pools of fluid; one relatively high in protein originating in the liver and the other, a low protein filtered across splanchnic capillaries. Hepatic venous outflow obstruction leading to increased sinusoidal pressure and portal hypertension are the major determinants of whether lymph production will be of a magnitude sufficient for ascitic fluid to accumulate. Increased sinusoidal pressure is also related to the subsequent development of renal salt retention. The mechanism by which sinusoidal hypertension signals the kidney to retain sodium is discussed in the following section.

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