Chapter 13 Water, electrolytes and acid–base balance
In normal, healthy people, the total body water constitutes 50–60% of lean bodyweight in men and 45–50% in women. In a healthy 70 kg male, total body water is approximately 42 L. This is contained in three major compartments:
The intracellular and interstitial fluids are separated by the cell membrane; the interstitial fluid and plasma are separated by the capillary wall (Fig. 13.1). In the absence of solute, water molecules move randomly and in equal numbers in either direction across a semi-permeable membrane. However, if solutes are added to one side of the membrane, the intermolecular cohesive forces reduce the activity of the water molecules. As a result, water tends to stay in the solute-containing compartment because there is less free diffusion across the membrane. This ability to hold water in the compartment can be measured as the osmotic pressure.
Figure 13.1 Distribution of water between the vascular and extravascular (interstitial) spaces. This is determined by the equilibrium between hydrostatic pressure, which tends to force fluid out of the capillaries, and oncotic pressure, which acts to retain fluid within the vessel. The net flow of fluid outwards is balanced by ‘suction’ of fluid into the lymphatics, which returns it to the bloodstream. Similar principles govern the volume of the peritoneal and pleural spaces.
Osmotic pressure is the primary determinant of the distribution of water among the three major compartments. The concentrations of the major solutes in the compartments differ, each having one solute that is primarily limited to that compartment and therefore determines its osmotic pressure:
Regulation of the plasma volume is somewhat more complicated because of the tendency of the plasma proteins to hold water in the vascular space by an oncotic effect which is, in part, counterbalanced by the hydrostatic pressure in the capillaries that is generated by cardiac contraction (Fig. 13.1). The composition of intracellular and extracellular fluids is shown in Table 13.1.
A characteristic of an osmotically active solute is that it cannot freely leave its compartment. The capillary wall, for example, is relatively impermeable to plasma proteins, and the cell membrane is ‘impermeable’ to Na+ and K+ because the Na+/K+-ATPase pump largely restricts Na+ to the extracellular fluid and K+ to the intracellular fluid. By contrast, Na+ freely crosses the capillary wall and achieves similar concentrations in the interstitium and plasma; as a result, it does not contribute to fluid distribution between these compartments. Similarly, urea crosses both the capillary wall and the cell membrane and is osmotically inactive. Thus, the retention of urea in renal failure does not alter the distribution of the total body water.
A conclusion from these observations is that body Na+ stores are the primary determinant of the extracellular fluid volume. Thus, the extracellular volume – and therefore tissue perfusion – are maintained by appropriate alterations in Na+ excretion. For example, if Na+ intake is increased, the extra Na+ will initially be added to the extracellular fluid. The associated increase in extracellular osmolality will cause water to move out of the cells, leading to extracellular volume expansion. Balance is restored by excretion of the excess Na+ in the urine.
Figure 13.2 shows the relative effects on the compartments of the addition of identical volumes of water, saline and colloid solutions. Thus, 1 L of water given intravenously as 5% glucose is distributed equally into all compartments, whereas the same amount of 0.9% saline remains in the extracellular compartment. The latter is thus the correct treatment for extracellular water depletion – sodium keeping the water in this compartment. The addition of 1 L of colloid with its high oncotic pressure stays in the vascular compartment and is a treatment for hypovolaemia.
The extracellular volume is determined by the sodium concentration. The regulation of extracellular volume is dependent upon a tight control of sodium balance, which is exerted by normal kidneys. Renal Na+ excretion varies directly with the effective circulating volume. In a 70 kg man:
Figure 13.3 Regulation of extracellular volume. (a) Sequence of events in which a decrease in cardiac output or peripheral arterial dilatation initiates renal sodium and water retention. (b) Mechanism of impaired escape from the actions of aldosterone and resistance to atrial natriuretic peptides (ANP).
(Modified from Schrier RW. Renal and Electrolyte Disorders, 7th edn. Philadelphia: Lippincott Williams and Wilkins; 2010, with permission.)
The unifying hypothesis of extracellular volume regulation in health and disease proposed by Schrier states that the fullness of the arterial vascular compartment – or the so-called effective arterial blood volume (EABV) – is the primary determinant of renal sodium and water excretion. Thus effective arterial blood volume constitutes effective circulatory volume for the purposes of body fluid homeostasis.
The fullness of the arterial compartment depends upon a normal ratio between cardiac output and peripheral arterial resistance. Thus, diminished EABV is initiated by a fall in cardiac output or a fall in peripheral arterial resistance (an increase in the holding capacity of the arterial vascular tree). When the EABV is expanded, the urinary Na+ excretion is increased and can exceed 100 mmol/L. By contrast, the urine can be rendered virtually free of Na+ in the presence of EABV depletion and normal renal function.
These changes in Na+ excretion can result from alterations both in the filtered load, determined primarily by the glomerular filtration rate (GFR), and in tubular reabsorption, which is affected by multiple factors. In general, it is changes in tubular reabsorption that constitute the main adaptive response to fluctuations in the effective circulating volume. How this occurs can be appreciated from Table 13.2 and Figure 13.4 and Figure 12.2 (see p. 563), which depicts the sites and determinants of segmental Na+ reabsorption. Although the loop of Henle and distal tubules make a major overall contribution to net Na+ handling, transport in these segments primarily varies with the amount of Na+ delivered; that is, reabsorption is flow-dependent. In comparison, the neurohumoral regulation of Na+ reabsorption according to body needs occurs primarily in the proximal tubules and collecting ducts.
Intrarenal receptors. Receptors in the walls of the afferent glomerular arterioles respond, via the juxtaglomerular apparatus, to changes in renal perfusion, and control the activity of the renin-angiotensin-aldosterone system (see p. 1006). In addition, sodium concentration in the distal tubule and sympathetic nerve activity alter renin release from the juxtaglomerular cells. Prostaglandins I2 and E2 are also generated within the kidney in response to angiotensin II, acting to maintain glomerular filtration rate and sodium and water excretion, modulating the sodium-retaining effect of this hormone.
Extrarenal receptors. These are located in the vascular tree in the left atrium and major thoracic veins, and in the carotid sinus body and aortic arch. These volume receptors respond to a slight reduction in effective circulating volume and result in increased sympathetic nerve activity and a rise in catecholamines. In addition, volume receptors in the cardiac atria control the release of a powerful natriuretic hormone – atrial natriuretic peptide (ANP) – from granules located in the atrial walls (see p. 943).
High-pressure arterial receptors (carotid, aortic arch, juxtaglomerular apparatus) predominate over low-pressure volume receptors in volume control in mammals. The low-pressure volume receptors are distributed in thoracic tissues (cardiac atria, right ventricle, thoracic veins, pulmonary vessels) and their role in the volume regulatory system is marginal.
A salt load, for example, leads to an increase in the effective circulatory and extracellular volume, raising both renal perfusion pressure, and atrial and arterial filling pressure. The increase in the renal perfusion pressure reduces the secretion of renin, and subsequently that of angiotensin II and aldosterone (see Fig. 12.5), whereas the rise in atrial and arterial filling pressure increases the release of ANP. These factors combine to reduce Na+ reabsorption in the collecting duct, thereby promoting excretion of excess Na+.
By contrast, in patients on a low Na+ intake or in those who become volume-depleted as a result of vomiting and diarrhoea, the ensuing decrease in effective volume enhances the activity of the renin-angiotensin-aldosterone system and reduces the secretion of ANP. The net effect is enhanced Na+ reabsorption in the collecting ducts, leading to a fall in Na+ excretion. This increases the extracellular volume towards normal.
With more marked hypovolaemia, a decrease in GFR leads to an increase in proximal and thin ascending limb Na+ reabsorption which contributes to Na+ retention. This is brought about by enhanced sympathetic activity acting directly on the kidneys and indirectly by stimulating the secretion of renin/angiotensin II (see Fig. 13.3b) and non-osmotic release of antidiuretic hormone (ADH), also called vasopressin. The pressure natriuresis phenomenon may be the final defence against changes in the effective circulating volume. Marked persistent hypovolaemia leads to systemic hypotension and increased salt and water absorption in the proximal tubules and ascending limb of Henle. This process is partly mediated by changes in renal interstitial hydrostatic pressure and local prostaglandin and nitric oxide production.
Sodium and water are retained despite increased extracellular volume in oedematous conditions such as cardiac failure, hepatic cirrhosis and hypoalbuminaemia. Here the principal mediator of salt and water retention is the concept of arterial underfilling due either to reduced cardiac output or diminished peripheral arterial resistance. Arterial underfilling in these settings leads to reduction of pressure or stretch (i.e. ‘unloading’ of arterial volume receptors), which results in activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system and non-osmotic release of ADH. These neurohumoral mediators promote salt and water retention in the face of increased extracellular volume. The common nature of the degree of arterial fullness and neurohumoral pathway in the regulation of extracellular volume in health and disease states forms the basis of Schrier’s unifying hypothesis of volume homeostasis (Fig. 13.3a).
Not only is the activity of the renin-angiotensin-aldosterone system increased in oedematous conditions such as cardiac failure, hepatic cirrhosis and hypoalbuminaemia, but also the action of aldosterone is more persistent than in normal subjects and patients with Conn’s syndrome, who have increased aldosterone secretion (see p. 989).
In normal subjects, high doses of mineralocorticoids initially increase renal sodium retention so that the extracellular volume is increased by 1.5–2 L. However, renal sodium retention then ceases, sodium balance is re-established, and there is no detectable oedema. This escape from mineralocorticoid-mediated sodium retention explains why oedema is not a characteristic feature of primary hyperaldosteronism (Conn’s syndrome). The escape is dependent on an increase in delivery of sodium to the site of action of aldosterone in the collecting ducts. The increased distal sodium delivery is achieved by high extracellular volume-mediated arterial overfilling. This suppresses sympathetic activity and angiotensin II generation, and increases cardiac release of ANP with resultant increase in renal perfusion pressure and GFR. The net result of these events is reduced sodium absorption in the proximal tubules and increased distal sodium delivery which overwhelms the sodium-retaining actions of aldosterone.
In patients with the above oedematous conditions, e.g. heart failure, escape from the sodium-retaining actions of aldosterone does not occur and therefore they continue to retain sodium in response to aldosterone. Accordingly they have substantial natriuresis when given spironolactone, which blocks mineralocorticoid receptors. Alpha-adrenergic stimulation and elevated angiotensin II increase sodium transport in the proximal tubule, and reduced renal perfusion and GFR further increases sodium absorption from the proximal tubules by presenting less sodium and water in the tubular fluid. Sodium delivery to the distal portion of the nephron, and thus the collecting duct, is reduced. Similarly, increased cardiac ANP release in these conditions requires optimum sodium concentration at the site of its action in the collecting duct for its desired natriuretic effects. Decreased sodium delivery to the collecting duct is therefore the most likely explanation for the persistent aldosterone-mediated sodium retention, absence of escape phenomenon and resistance to natriuretic peptides in these patients (Fig. 13.3b).
Body water homeostasis is affected by thirst and the urine concentrating and diluting functions of the kidney. These in turn are controlled by intracellular osmoreceptors, principally in the hypothalamus, to some extent by volume receptors in capacitance vessels close to the heart, and via the renin-angiotensin system. Of these, the major and best-understood control is via osmoreceptors. Changes in the plasma Na+ concentration and osmolality are sensed by osmoreceptors that influence both thirst and the release of ADH (vasopressin) from the supraoptic and paraventricular nuclei of the anterior hypothalamus.
ADH plays a central role in urinary concentration by increasing the water permeability of the normally impermeable cortical and medullary collecting ducts. There are three major G-protein coupled receptors for vasopressin (ADH):
Activation of the V1A receptors induces vasoconstriction while V1B receptors appear to mediate the effect of ADH on the pituitary, facilitating the release of ACTH. The V2 receptors mediate the antidiuretic response as well as other functions.
The ability of ADH to increase the urine osmolality is related indirectly to transport in the ascending limb of the loop of Henle, which reabsorbs NaCl without water. This process, which is the primary step in the countercurrent mechanism, has two effects: it makes the tubular fluid dilute and the medullary interstitium concentrated. In the absence of ADH, little water is reabsorbed in the collecting ducts, and a dilute urine is excreted. By contrast, the presence of ADH promotes water reabsorption in the collecting ducts down the favourable osmotic gradient between the tubular fluid and the more concentrated interstitium. As a result, there is an increase in urine osmolality and a decrease in urine volume.
Intercalated cells, in comparison, do not transport NaCl (since they have a lower level of Na+/K+-ATPase activity) but play a role in hydrogen and bicarbonate handling and in potassium reabsorption in states of potassium depletion.
The ADH-induced increase in collecting duct water permeability occurs primarily in the principal cells. ADH acts on V2 (vasopressin) receptors located on the basolateral surface of principal cells, resulting in the activation of adenyl cyclase. This leads to protein kinase activation and to preformed cytoplasmic vesicles that contain unique water channels (called aquaporins) moving to and then being inserted into the luminal membrane. Four renal aquaporins have been well characterized and are localized in different areas of the cells of the collecting duct. The water channels span the luminal membrane and permit water movement into the cells down a favourable osmotic gradient (Fig. 13.5). This water is then rapidly returned to the systemic circulation across the basolateral membrane. When the ADH effect has worn off, the water channels aggregate within clathrin-coated pits, from which they are removed from the luminal membrane by endocytosis and returned to the cytoplasm. A defect in any step in this pathway, such as in attachment of ADH to its receptor or the function of the water channel, can cause resistance to the action of ADH and an increase in urine output. This disorder is called nephrogenic diabetes insipidus.
Figure 13.5 Aquaporin-mediated water transport in the renal collecting duct. Stimulation of the vasopressin 2 receptor causes cAMP-mediated insertion of the aquaporin into the apical membrane, allowing water transport down the osmotic gradient.
(Adapted from Connolly DL, Shanahan CM, Weissberg PL. Water channels in health and disease. Lancet 1996; 347:211, with permission from Elsevier.)
In addition to influencing the rate of water excretion, ADH plays a central role in osmoregulation because its releaseis directly affected by the plasma osmolality. At a plasma osmolality of <275 mosmol/kg, which usually represents a plasma Na+ concentration of <135–137 mmol/L, there is essentially no circulating ADH. As the plasma osmolality rises above this threshold, however, the secretion of ADH increases progressively.
1. Ingestion of a water load leads to an initial reduction in the plasma osmolality, thereby diminishing the release of ADH. The ensuing reduction in water reabsorption in the collecting ducts allows the excess water to be excreted in a dilute urine.
2. Water loss resulting from sweating is followed by, in sequence, a rise in both plasma osmolality and ADH secretion, enhanced water reabsorption, and the appropriate excretion of a small volume of concentrated urine. This renal effect of ADH minimizes further water loss but does not replace the existing water deficit. Thus, optimal osmoregulation requires an increase in water intake, which is mediated by a concurrent stimulation of thirst. The importance of thirst can also be illustrated by studies in patients with central diabetes insipidus, who are deficient in ADH. These patients often complain of marked polyuria, which is caused by the decline in water reabsorption in the collecting ducts. However, they do not typically become hypernatraemic, because urinary water loss is offset by the thirst mechanism.
A common misconception is that regulation of the plasma Na+ concentration is closely correlated with the regulation of Na+ excretion. However, it is related to volume regulation, which has different sensors and effectors (volume receptors) from those involved in water balance and osmoregulation (osmoreceptors).
A water load is rapidly excreted (in 4–6 h) by inhibition of ADH release so that there is little or no water reabsorption in the collecting ducts. This process is normally so efficient that volume regulation is not affected and there is no change in ANP release or in the activity of the renin-angiotensin-aldosterone system. Thus, a dilute urine is excreted, and there is little alteration in the excretion of Na+.
0.9% saline administration, by contrast, causes an increase in volume but no change in plasma osmolality. In this setting, ANP secretion is increased, aldosterone secretion is reduced and ADH secretion does not change. The net effect is the appropriate excretion of the excess Na+ in a relatively iso-osmotic urine.
In some cases, both volume and osmolality are altered and both pathways are activated. For example, if a person with normal renal function eats salted potato chips and peanuts without drinking any water, the excess Na+ will increase the plasma osmolality, leading to osmotic water movement out of the cells and increased extracellular volume. The rise in osmolality will stimulate both ADH release and thirst (the main reason why many restaurants and bars supply free salted foods), whereas the hypervolaemia will enhance the secretion of ANP and suppress that of aldosterone. The net effect is increased excretion of Na+ without water.
This principle of separate volume and osmoregulatory pathways is also evident in the syndrome of inappropriate ADH secretion (SIADH). Patients with SIADH (see p. 993) have impaired water excretion and hyponatraemia (dilutional) caused by the persistent presence of ADH. However, the release of ANP and aldosterone is not impaired and, thus, Na+ handling remains intact. These findings have implications for the correction of the hyponatraemia in this setting which initially requires restriction of water intake.
ADH is also secreted by non-osmotic stimuli such as stress (e.g. surgery, trauma), markedly reduced effective circulatory volume (e.g. cardiac failure, hepatic cirrhosis), psychiatric disturbance and nausea, irrespective of plasma osmolality. This is mediated by the effects of sympathetic overactivity on supraoptic and paraventricular nuclei. In addition to water retention, ADH release in these conditions promotes vasoconstriction owing to the activation of V1A (vasopressin) receptors distributed in the vascular smooth muscle cells.
Most cells respond to swelling or shrinkage by activating specific metabolic or membrane-transport processes that return cell volume to its normal resting state. Within minutes after exposure to hypotonic solutions and resulting cell swelling, a common feature of many cells is the increase in plasma membrane potassium and chloride conductance. Although extrusion of intracellular potassium certainly contributes to a regulatory volume decrease, the role of chloride efflux itself is modest, given the relatively low intracellular chloride concentration. Other intracellular osmolytes, such as taurine and other amino acids, are transported out of the cell to achieve a regulatory volume decrease. By contrast, these regulatory mechanisms are operative in reverse to protect cell volume under hypertonic conditions, as is the case in the renal medulla. The tubular cells at the tip of renal papillae, which are constantly exposed to a hypertonic extracellular milieu, maintain their cell volume on a long-term basis by actively taking up smaller molecules, such as betaine, taurine and myoinositol, and by synthesizing more sorbitol and glycerophosphocholine.
Increased extracellular volume occurs in numerous disease states. The physical signs depend on the distribution of excess volume and on whether the increase is local or systemic. According to Starling principles, distribution depends on:
Peripheral oedema is caused by expansion of the extracellular volume by at least 2 L (15%). The ankles are normally the first part of the body to be affected, although they may be spared in patients with lipodermatosclerosis (where the skin is tethered and cannot expand to accommodate the oedema). Oedema may be noted in the face, particularly in the morning. In a patient in bed, oedema may accumulate in the sacral area. Expansion of the interstitial volume also causes pulmonary oedema, pleural effusion, pericardial effusion and ascites. Expansion of the blood volume (overload) causes a raised jugular venous pressure, cardiomegaly, added heart sounds, basal crackles as well as a raised arterial blood pressure in certain circumstances.
Extracellular volume expansion is due to sodium chloride retention. Increased oral salt intake does not normally cause volume expansion because of rapid homeostatic mechanisms which increase salt excretion. However, a rapid intravenous infusion of a large volume of saline will cause volume expansion. Most causes of extracellular volume expansion are associated with renal sodium chloride retention.
Reduction in cardiac output and the consequent fall in effective circulatory volume and arterial filling lead to activation of the renin-angiotensin-aldosterone system, non-osmotic release of ADH, and increased activity of the renal sympathetic nerves via volume receptors and baroreceptors (Fig. 13.3a). Sympathetic overdrive also indirectly augments ADH and renin-angiotensin-aldosterone response in these conditions. The cumulative effect of these mediators results in increased peripheral and renal arteriolar resistance and water and sodium retention. These factors result in extracellular volume expansion and increased venous pressure, causing oedema formation.
The mechanism is complex, but involves peripheral vasodilatation (possibly owing to increased nitric oxide generation) resulting in reduced effective arterial blood volume (EABV) and arterial filling. This leads to an activation of a chain of events common to cardiac failure and other conditions with marked peripheral vasodilatation (Fig. 13.3). The cumulative effect results in increased peripheral and renal resistance, water and sodium retention, and oedema formation.
Interstitial oedema is a common clinical finding with hypoalbuminaemia, particularly in the nephrotic syndrome. Expansion of the interstitial compartment is secondary to the accumulation of sodium in the extracellular compartment. This is due to an imbalance between oral (or parenteral) sodium intake and urinary sodium output, as well as alterations of fluid transfer across capillary walls. The intrarenal site of sodium retention is the cortical collecting duct (CCD) where Na+/K+-ATPase expression and activity are increased threefold along the basolateral surface (Fig. 13.4). In addition, amiloride-sensitive epithelial sodium channel activity is also increased in the CCD. The renal sodium retention should normally be counterbalanced by increased secretion of sodium in the inner medullary collecting duct, brought about by the release of ANP. This regulatory pathway is altered in patients with nephrotic syndrome by enhanced kidney specific catabolism of cyclic GMP (the second messenger for ANP) following phosphodiesterase activation.
Oedema generation was classically attributed to the decrease in the plasma oncotic pressure and the subsequent increase in the transcapillary oncotic gradient. However, the oncotic pressure and transcapillary oncotic gradient remain unchanged and the transcapillary hydrostatic pressure gradient is not altered. Conversely, capillary hydraulic conductivity (a measure of permeability) is increased. This is determined by intercellular macromolecular complexes between the endothelial cells consisting of tight junctions (made of occludins, claudins and ZO proteins) and adherens junctions (made of cadherin, catenins and actin cytoskeleton). Elevated TNF-α levels in nephrotic syndrome activate protein kinase C, which changes phosphorylation of occludin and capillary permeability. In addition, increased circulating ANP can increase capillary hydraulic conductivity by altering the permeability of intercellular junctional complexes. Furthermore, reduction in effective circulatory volume and the consequent fall in cardiac output and arterial filling can lead to a chain of events as in cardiac failure and cirrhosis (see above and Fig. 13.3). These factors result in extracellular volume expansion and oedema formation.
A decreased GFR decreases the renal capacity to excrete sodium. This may be acute, as in the acute nephritic syndrome (see p. 582), or may occur as part of the presentation of chronic kidney disease. In end-stage renal failure, extracellular volume is controlled by the balance between salt intake and its removal by dialysis.
Thiazolidinediones (TZD) (see p. 1011) are widely used to treat type 2 diabetes. Their mechanism of action is attributed to binding and activation of the PPAR-γ system. PPARs are nuclear transcription factors essential to the control of energy metabolism that are modulated via binding with tissue-specific fatty acid metabolites. Of the three PPAR isoforms, γ has been extensively studied and is expressed at high levels in adipose and liver tissues, macrophages, pancreatic-β cells and principal cells of the collecting duct. These drugs have been asociated with salt and water retention and are contraindicated in patients with heart failure. Recent evidence suggests that TZD-induced oedema (like insulin) is also due to upregulation of epithelial Na transporter channel (ENaC) but by different pathways. Diuretics of choice for TZD-induced oedema are amiloride and triamterene.
Substantial amounts of sodium and water may accumulate in the body without clinically obvious oedema or evidence of raised venous pressure. In particular, several litres may accumulate in the pleural space or as ascites; these spaces are then referred to as ‘third spaces’. Bone may also act as a ‘sink’ for sodium and water.
Initiation of insulin treatment for type 1 diabetes and refeeding after malnutrition are both associated with the development of transient oedema. The mechanism is complex but involves upregulation of ENaC in the principal cell of the collecting duct. This transporter is amiloride sensitive which makes amiloride or triamterene the diuretic of choice in insulin-induced oedema.
Oedema may result from increased capillary pressure owing to relaxation of precapillary arterioles. The best example is the peripheral oedema caused by dihydropyridine calcium-channel blockers such as nifedipine which affects up to 10% of the patients. Oedema is usually resolved by stopping the offending drug.
Oedema is also caused by increased interstitial oncotic pressure as a result of increased capillary permeability to proteins. This can occur as part of a rare complement-deficiency syndrome; with therapeutic use of interleukin 2 in cancer chemotherapy; or in ovarian hyperstimulation syndrome (see p. 981).
This, by definition, occurs in women without heart failure, hypoalbuminaemia, renal or endocrine disease. Oedema is intermittent and often worse in the premenstrual phase. The condition remits after the menopause. Patients complain of swelling of the face, hands, breasts and thighs, and a feeling of being bloated. Sodium retention during the day and increased sodium excretion during recumbency are characteristic; an abnormal fall in plasma volume on standing caused by increased capillary permeability to proteins may be the cause of this. The oedema may respond to diuretics, but returns when they are stopped. A similar syndrome of diuretic-dependent sodium retention can be caused by abuse of diuretics, for instance as part of an attempt to lose weight; but not all women with idiopathic oedema admit to having taken diuretics, and the syndrome was described before diuretics were introduced for clinical use, so the cause remains unclear.
This does not reflect disturbances of extracellular volume control per se, but can cause clinical confusion. Examples are ankle oedema due to venous damage following thrombosis or surgery, ankle or leg oedema due to immobility, oedema of the arm due to subclavian thrombosis, and facial oedema due to superior vena caval obstruction.
Sodium restriction has only a limited role, but is useful in patients who are resistant to diuretics. Sodium intake can easily be reduced to approximately 100 mmol (2 g) daily; reductions below this are often difficult to achieve without affecting the palatability of food.
Manoeuvres that increase venous return (e.g. strict bed rest or water immersion) stimulate salt and water excretion by effects on cardiac output and ANP release, but they are seldom of practical value.
The mainstay of treatment is the use of diuretic agents, which increase sodium, chloride and water excretion in the kidney (Table 13.3). These agents act by interfering with membrane ion pumps which are present on numerous cell types; they mostly achieve specificity for the kidney by being secreted into the proximal tubule, resulting in much higher concentrations in the tubular fluid than in other parts of the body.
These potent diuretics are useful in the treatment of any cause of systemic extracellular volume overload. They stimulate excretion of both sodium chloride and water by blocking the sodium-potassium-2-chloride (NKCC2) channel in the thick ascending limb of Henle (Fig. 13.6) and are useful in stimulating water excretion in states of relative water overload. They also act by causing increased venous capacitance, resulting in rapid clinical improvement in patients with left ventricular failure, preceding the diuresis. Unwanted effects include:
Figure 13.6 Transport mechanisms in the thick ascending limb of the loop of Henle. Sodium chloride is reabsorbed in the thick ascending limb by the bumetanide-sensitive sodium-potassium-2-chloride cotransporter (NKCC2). The electroneutral transporter is driven by the low intracellular sodium and chloride concentrations generated by the Na+/K+-ATPase and the kidney-specific basolateral chloride channel (ClC-Kb). The availability of luminal potassium is rate-limiting for NKCC2, and recycling of potassium through the ATP-regulated potassium channel (ROMK – renal outer medulla K+ channel) ensures the efficient functioning of the NKCC2 and generates a lumen-positive transepithelial potential. Genetic studies have identified putative loss of function mutations in the genes encoding NKCC2 1, ROMK 2, ClC-Kb 3, and barttin 4 in subgroups of patients with Bartter’s syndrome. In contrast to the normal condition, loss of function of NKCC2 impairs reabsorption of sodium and potassium. Inactivation of the basolateral ClC-Kb and barttin reduces transcellular reabsorption of chloride. Loss of function of any of these will reduce the transepithelial potential and thus decrease the driving force for the paracellular reabsorption of cations (K+, Mg2+, Ca2+ and Na+). Paracellin-1 is necessary for the paracellular transport of Ca2+ and Mg2+. In most patients with Bartter’s syndrome, urinary calcium excretion is increased. Hypercalcaemia or increased activation of calcium-sensing receptor inactivates ROMK and causes Bartter’s syndrome. Ka and Kb, kidney-specific basolateral chloride channel. ROMK, renal outer medullary potassium channel.
There is little to choose between the drugs in this class. Bumetanide has a better oral bioavailability than furosemide, particularly in patients with severe peripheral oedema, and has more beneficial effects than furosemide on venous capacitance in left ventricular failure.
These are less potent than loop diuretics. They act by blocking a sodium chloride channel in the distal convoluted tubule (Fig. 13.7). They cause relatively more urate retention, glucose intolerance and hypokalaemia than loop diuretics. They interfere with water excretion and may cause hyponatraemia, particularly if combined with amiloride or triamterene. This effect is clinically useful in diabetes insipidus. Thiazides reduce peripheral vascular resistance by mechanisms that are not completely understood but do not appear to depend on their diuretic action, and are widely used in the treatment of essential hypertension. They are also used extensively in mild to moderate cardiac failure. Thiazides reduce calcium excretion. This effect is useful in patients with idiopathic hypercalciuria, but may cause hypercalcaemia. Numerous agents are available, with varying half-lives but little else to choose between them. Metolazone is not dependent for its action on glomerular filtration, and therefore retains its potency in renal impairment.
Figure 13.7 Transport mechanisms in the distal convoluted tubule. Under normal conditions, sodium chloride is reabsorbed by the apical thiazide-sensitive sodium-chloride cotransporter (NCCT) in the distal convoluted tubule. The electroneutral transporter is driven by the low intracellular sodium and chloride concentrations generated by the Na+/K+-ATPase and an, as yet, undefined basolateral chloride channel. In this nephron segment, there is an apical calcium channel and a basolateral sodium-coupled exchanger. Physiological evidence indicates that the mechanisms for the transport of magnesium are similar to those for calcium. In Gitelman’s syndrome, putative loss of function mutations in the sodium-chloride cotransporter (NCCT (X)) lead to decreased reabsorption of sodium chloride and increased reabsorption of calcium. Functional overactivity of NCCT leads to Gordon’s syndrome by a new mechanism (see text). TRPM6, a member of the transient receptor potential family.
Aldosterone antagonists, which compete with aldosterone in the collecting ducts and reduce sodium absorption, e.g. spironolactone and eplerenone (which has a shorter half-life). Spironolactone is used in patients with heart failure because it significantly reduces the mortality in these patients by antagonizing the fibrotic effect of aldosterone on the heart. Eplerenone is devoid of antiandrogenic or antiprogesterone properties.
Amiloride and triamterene inhibit sodium uptake by blocking epithelial sodium channels in the collecting duct and reduce renal potassium excretion by reducing lumen-negative transepithelial voltage. They are mainly used as potassium-sparing agents with thiazide or loop diuretics.
Vasopressin V2 receptor antagonists are very useful agents in the treatment of conditions associated with elevated levels of vasopressin, such as heart failure, cirrhosis and SIADH (see p. 993). Non-peptide vasopressin V2 receptor antagonists are efficacious in producing free water diuresis in humans. Studies in patients with heart failure and cirrhosis suggest that such agents will allow normalization of serum osmolality with less water restriction (see p. 650).
Management. Intravenous administration of diuretics may establish a diuresis. High doses of loop diuretics are required to achieve adequate concentrations in the tubule if GFR is depressed. However, the daily dose of furosemide must be limited to a maximum of 2 g for an adult, because of ototoxicity. Intravenous albumin solutions restore plasma oncotic pressure temporarily in the nephrotic syndrome and allow mobilization of oedema but do not increase the natriuretic effect of loop diuretics.
Combinations of various classes of diuretics are extremely helpful in patients with resistant oedema. A loop diuretic plus a thiazide inhibit two major sites of sodium reabsorption; this effect may be further potentiated by addition of a potassium-sparing agent. Metolazone in combination with a loop diuretic is particularly useful in refractory congestive cardiac failure, because its action is less dependent on glomerular filtration. However, this potent combination can cause severe electrolyte imbalance. Both aminophylline and dopamine increase renal blood flow and may be useful in refractory cardiogenic sodium retention. In addition, theophyllines, by inhibiting phosphodiesterase activity in the inner medullary collecting duct, prolong the action of cyclic GMP (a second messenger of ANP).
Symptoms. Thirst, muscle cramps, nausea and vomiting, and postural dizziness occur. Severe depletion of circulating volume causes hypotension and impairs cerebral perfusion, causing confusion and eventual coma.
Loss of interstitial fluid leads to loss of skin elasticity (’turgor’) – the rapidity with which the skin recoils to normal after being pinched. Skin turgor decreases with age, particularly at the peripheries. The turgor over the anterior triangle of the neck or on the forehead is a very useful sign in all ages.
Loss of circulating volume leads to decreased pressure in the venous and (if severe) arterial compartments. Loss of up to 1 L of extracellular fluid in an adult may be compensated for by venoconstriction and may cause no physical signs.
Normally the blood pressure rises if a subject stands up, as a result of increased venous return due to venoconstriction (this maintains cerebral perfusion). Loss of extracellular fluid (underfill) prevents this and causes a fall in blood pressure. This is one of the earliest and most reliable signs of volume depletion, as long as the other causes of postural hypotension are excluded (Table 13.4).
This causes cold skin with empty peripheral veins, which are difficult to cannulate just when the patient needs intravenous therapy the most! This sign is often absent in sepsis, where peripheral vasodilatation contributes to effective hypovolaemia.
Septicaemia causes vasodilatation of both arterioles and veins, resulting in greatly increased capacitance of the vascular space. In addition, increased capillary permeability to plasma proteins leads to loss of fluid from the vascular space to the interstitium.
Blood tests are in general not helpful in the assessment of extracellular volume. Plasma urea may be raised owing to increased urea reabsorption and, later, to prerenal failure (when the creatinine rises as well), but this is very nonspecific. Urinary sodium is low if the kidneys are functioning normally, but is misleading if the cause of the volume depletion involves the kidneys (e.g. diuretics, intrinsic renal disease). Urine osmolality is high in volume depletion (owing to increased water reabsorption), but may also often mislead.
Assessment of volume status
The rational treatment of acute haemorrhage is the infusion of a combination of red cells and a plasma substitute or (if unavailable) whole blood. (Chronic anaemia causes salt and water retention rather than volume depletion by a mechanism common to conditions with peripheral vasodilatation.)
Loss of water and electrolytes, as occurs with vomiting, diarrhoea, or excessive renal losses, should be treated by replacement of the loss. If possible, this should be with oral water and sodium salts. These are available as slow sodium (600 mg, approximately 10 mmol each of Na+ and Cl− per tablet), the usual dose of which is 6–12 tablets/day with 2–3 L of water. It is used in mild or chronic salt and water depletion, such as that associated with renal salt wasting.
Sodium bicarbonate (500 mg, 6 mmol each of Na+ and HCO3− per tablet) is used in doses of 6–12 tablets/day with 2–3 L of water. This is used in milder chronic sodium depletion with acidosis (e.g. chronic kidney disease, post-obstructive renal failure, renal tubular acidosis). Sodium bicarbonate is less effective than sodium chloride in causing positive sodium balance. Oral rehydration solutions are described in Box 4.10.
Intravenous fluids are sometimes required (Table 13.6). Rapid infusion (e.g. 1000 mL per hour or even faster) is necessary if there is hypotension and evidence of impaired organ perfusion (e.g. oliguria, confusion); in these situations, plasma expanders (colloids) are often used in the first instance to restore an adequate circulating volume (see p. 887). Repeated clinical assessments are vital in this situation, usually complemented by frequent measurements of central venous pressure (see p. 872, for the management of shock). Severe hypovolaemia induces venoconstriction, which maintains venous return; over-rapid correction does not give time for this to reverse, resulting in signs of circulatory overload (e.g. pulmonary oedema) even if a total body extracellular fluid (ECF) deficit remains. In less severe ECF depletion (such as in a patient with postural hypotension complicating acute tubular necrosis), the fluid should be replaced at a rate of 1000 mL every 4–6 h, again with repeated clinical assessment. If all that is required is avoidance of fluid depletion during surgery, 1–2 L can be given over 24 h, remembering that surgery is a stimulus to sodium and water retention and that over-replacement may be as dangerous as under-replacement. Regular monitoring by fluid balance charts, bodyweight and plasma biochemistry is mandatory.
This causes extracellular volume depletion only in severe cases, because the loss is spread evenly among all the compartments of body water. In the rare situations where there is a true deficiency of water alone, as in diabetes insipidus or in a patient who is unable to drink (e.g. after surgery), the correct treatment is to give water.
These are best thought of as disorders of body water content. As discussed above, sodium content is regulated by volume receptors; water content is adjusted to maintain, in health, a normal osmolality and (in the absence of abnormal osmotically active solutes) a normal sodium concentration. Disturbances of sodium concentration are caused by disturbances of water balance.
|Extrarenal (urinary sodium <20 mmol/L)||Kidney (urinary sodium >20 mmol/L)|
Oliguric kidney injury
Rarely, hyponatraemia may be a ‘pseudo-hyponatraemia’. This occurs in hyperlipidaemia (either high cholesterol or high triglyceride) or hyperproteinaemia where there is a spuriously low measured sodium concentration, the sodium being confined to the aqueous phase but having its concentration expressed in terms of the total volume of plasma. In this situation, plasma osmolality is normal and therefore treatment of ‘hyponatraemia’ is unnecessary. Note: Artefactual ‘hyponatraemia’, caused by taking blood from the limb into which fluid of low sodium concentration is being infused, should be excluded.
This is due to salt loss in excess of water loss; the causes are listed in Table 13.7. In this situation, ADH secretion is initially suppressed (via the hypothalamic osmoreceptors); but as fluid volume is lost, volume receptors override the osmoreceptors and stimulate both thirst and the release of ADH. This is an attempt by the body to defend circulating volume at the expense of osmolality.
With extrarenal losses and normal kidneys, the urinary excretion of sodium falls in response to the volume depletion, as does water excretion, leading to concentrated urine containing <10 mmol/L of sodium. However, in salt-wasting kidney disease, renal compensation cannot occur and the only physiological protection is increased water intake in response to thirst.
With sodium depletion the clinical picture is usually dominated by features of volume depletion (see p. 638). The diagnosis is usually obvious where there is a history of gut losses, diabetes mellitus or diuretic abuse. Examination of the patient is often more helpful than the biochemical investigations, which include plasma and urine electrolytes and osmolality.
Table 13.10 shows the potential daily losses of water and electrolytes from the gut. Losses due to renal or adrenocortical disease may be less easily identified but a urinary sodium concentration of >20 mmol/L, in the presence of clinically evident volume depletion, suggests a renal loss.