CHAPTER OUTLINE

The sodium content of a normal adult is 55–65 mmol/kg body weight. The concentration of sodium in plasma is ~ 140 mmol/L (~ 152 mmol/kg). Under physiological conditions, the control of the ECF volume is through the control of functioning or effective plasma volume (that part of the plasma volume actively perfusing tissues). There are a variety of afferent mechanisms to monitor effective plasma volume (and thus ECF volume), which include intrathoracic volume receptors such as atrial stretch receptors, hepatic volume receptors, arterial baroreceptors, intrarenal baroreceptors and, possibly, tissue receptors monitoring tissue perfusion. Whatever the actual or relative function of all these sensory systems, their resultant influence is fine control over the renal conservation of sodium and the appetite for oral sodium intake.

Sodium intake varies considerably between different human cultural and ethnic groups. Variations in intake between 5 and 500 mmol/24 h have been recorded and physiological mechanisms balance this with the renal excretion of sodium. Sodium delivery to the renal tubules is a function of plasma sodium concentration and the glomerular filtration rate (GFR). Every 24 h, the kidneys of an average healthy adult male will filter in excess of 24 000 mmol of sodium, most of which is reabsorbed in the tubules so that, in health, sodium balance is achieved. In a healthy individual, renal sodium conservation can be extremely efficient, with urine sodium concentration falling to < 1 mmol/L urine. Conversely, when sodium intake is excessive, the capacity to excrete sodium can result in urine sodium concentrations up to 300 mmol/L urine.

Under normal physiological conditions, approximately 80% of the sodium in the glomerular filtrate is reabsorbed in the proximal tubules. The protein concentration of the blood within the post-glomerular peritubular capillary beds is believed to exert a strong oncotic pressure on fluid in the proximal tubules, and this in turn helps to regulate the volume of fluid reabsorbed. This process contributes to the autoregulation of filtration and reabsorption known as glomerulo–tubular balance. There has been considerable physiological interest in the control of proximal tubular sodium reabsorption and other intrinsic renal control mechanisms, such as redistribution of filtering activity from superficial nephrons (relatively salt-losing) to juxtamedullary nephrons (relatively salt-retaining). However, to date, the major humoral influences on sodium reabsorption appear to reside in the distal tubules and collecting ducts.

Aldosterone acts through the specific nuclear mineralocorticoid receptor, which is protected from cortisol (for which it has equal affinity) through the intracellular production of 11β-hydroxysteroid dehydrogenase (11β-HSD). This enzyme converts cortisol to cortisone, for which the receptor has weak affinity. The response within the principal cells lining the distal tubules and collecting ducts is the apical influx of sodium via epithelial Na⁺ channel (ENaC) stimulation and its efflux via basolateral Na⁺,K⁺-ATPase. The net effect is active sodium reabsorption in exchange for potassium. In addition, angiotensin II has direct vasoconstrictive actions, thus having an immediate influence on effective plasma volume.

Glomerular filtration and the action of aldosterone do not constitute the complete control over renal sodium excretion within mammalian systems. The existence of a third factor (or factors) had been proposed for 20 years prior to the identification of a specific natriuretic factor in 1981. This factor was originally identified in rat cardiac atria and was termed atrial natriuretic factor (now known as atrial natriuretic peptide, ANP). Since then, a further two natriuretic peptides have been identified in humans. Circulating ANP is a 28 amino acid (AA) peptide with a 17 AA ring structure formed by a disulphide bridge between cysteines at positions 7 and 23: the gene for the ANP precursor molecule is located on the short arm of chromosome 1. Three exons code for a 151 AA peptide (preproANP) which, following removal of the signal peptide, results in a 126 AA peptide (proANP) – the main storage form. On secretion into the circulation, proANP is cleaved into the N-terminal 1–98 peptide (NT-proANP), and the biologically active 99–126 peptide (ANP). The major stimulus to the secretion of ANP is atrial stretch and the major sites of synthesis are the atria.

In 1990, a further ‘natriuretic peptide’ was described in porcine brain and termed C-type natriuretic peptide (CNP). The gene for CNP is coded on chromosome 4. Although CNP has been identified in human plasma, this peptide is mediated through a different receptor and does not have direct natriuretic function, but acts primarily as an antiproliferative regulator in the vascular cell system and as a neuropeptide.

There is no doubt that ANP, and to a lesser extent BNP, has important physiological functions in relation to sodium balance. Simple experiments can readily demonstrate changes in ANP and BNP concentrations in relation to dietary sodium intake, and the interaction of ANP and BNP with the renin–angiotensin–aldosterone axis results in a dual ‘fine-tuning’ system of sodium control, using afferent information obtained from the heart and kidneys simultaneously. However, unlike the situation with the renin–angiotensin–aldosterone axis, no primary disorders of natriuretic hormone excess or deficiency have yet been identified with certainty. Because the major stimulus to the release of ANP and BNP is cardiac wall stretch, the major current clinical utility of measuring these peptides, particularly BNP and NT-proBNP, is in the diagnosis and monitoring of cardiac failure.

The renal conservation of sodium is remarkably efficient, but when sustained, non-renal losses occur under physiological conditions, such as through sweating due to prolonged vigorous physical activity or as a result of prolonged exposure to high ambient temperature, then a mechanism for increasing sodium intake comes into play – the salt appetite. That such a mechanism exists in humans can be observed in pathological states of impaired sodium conservation such as Addison disease. However, accurately defining the sodium appetite in humans under physiological conditions is a subjective and difficult task. Salt intakes are largely conditioned by traditions of food intake and cultural habits of seasoning food with salt. The impulse to add salt to prepared food appears to be automatic in many people, who do so even before tasting. Animal experiments have implicated an entirely separate, brain-based, renin–angiotensin–aldosterone system as a controlling influence on active salt-seeking behaviour.

There is a minimum obligatory loss of water by the kidneys each day that is dependent upon the maximum achievable urine concentration and the osmotic load for excretion. The maximum renal loss of water occurs when, for a given osmotic load, the minimum urine concentration is achieved.

In addition to osmoregulation, certain non-osmotic controls over the secretion of AVP exist, including ECF hypovolaemia, hypotension, nausea and an oropharyngeal response. The AVP response to hypovolaemia and hypotension is relatively insensitive when changes are proportionally small (5–10% reductions), but increases exponentially as further reductions occur. Thus, a reduction in ECF volume or blood pressure of 20% or more will result in a plasma AVP concentration far in excess of that observed during normal osmoregulation. The influence of baroreceptor or volume receptor afferent input appears to modulate the osmotic response but does not abolish it: modulation occurs by decreasing the threshold for AVP release and increasing the gain of the systems.

Nausea is the single most powerful stimulus to AVP secretion. It overrides osmoregulatory control, and plasma AVP concentrations may increase 100-fold or more. A short-lived oropharyngeal suppression of AVP can occur following oral ingestion of fluid and prior to any reduction in serum osmolality, thus direct studies of osmoregulation of AVP need to avoid any such stimulus.

The physiological stimulus to water intake is thirst. However, the act of drinking in human societies in temperate regions is predominantly a social or habitual act not dependent on thirst. The control of water balance under non-pathological conditions is thus, in many individuals and for much of the time, achieved by control of output.

Non-osmotic thirst occurs when extracellular fluid is lost without corresponding cellular dehydration, the osmotic pressure of the extracellular fluid remaining unchanged. In this respect, the overall control of thirst parallels the control of AVP, with both osmotic and hypovolaemic stimuli. There is good evidence from animal experiments of both neural and hormonal mediators controlling non-osmotic thirst. Angiotensin II is the most potent human thirst stimulant and may act directly upon the brain, but even when the effects of angiotensin II are blocked, significant hypovolaemia will still stimulate thirst.

Thirst following haemorrhage is a commonly reported clinical observation but, like the AVP responses to extracellular hypovolaemia, often a considerable degree of haemorrhage (15–20% of total blood volume) is necessary before the sensation becomes strong. Thus for day-to-day water balance, the primary physiological control of thirst is osmotic.

In health, plasma potassium concentrations range between 3.1 and 4.6 mmol/L, with values in serum approximately 0.3–0.4 mmol/L greater, owing to release of potassium during clot formation (mean serum concentration 4.0 mmol/L). The intracellular concentration of potassium is ~ 160 mmol/kg, and 98% of the total body potassium is present in the intracellular fluid. There are two aspects to the physiological control of potassium, namely, the total body content and its distribution between intra- and extracellular spaces.

The potassium content of cells is determined by the balance of activity between uptake of potassium due to membrane-bound Na⁺,K⁺-ATPase and the passive loss or leakage of potassium out of the cell. Many factors can influence the distribution of potassium, for example acid–base status, hormones (insulin, catecholamines), osmolality and the cellular content of potassium. The influence of acid–base status is widely recognized as an important contributor to potassium distribution, with an association between hypokalaemia and alkalosis and between hyperkalaemia and acidosis, particularly when the acidosis is induced by mineral rather than organic acids.

Insulin promotes active uptake of potassium by cells, probably by direct stimulation of Na⁺,K⁺-ATPase, and this activity appears to be independent of the effect of insulin on glucose uptake. The importance of the effects of insulin in controlling plasma potassium under physiological conditions is not understood, but its action has an important therapeutic role in the treatment of hyperkalaemia.

Catecholamines have an effect on potassium distribution, with β-adrenergic actions essentially promoting cellular uptake and α-adrenergic actions resulting in increases in plasma potassium concentration, but again the significance of these effects under physiological conditions is not understood. The net effect of catecholamines on cellular uptake of potassium probably explains the transient hypokalaemia frequently observed in acutely ill patients.

An acute increase in extracellular tonicity, such as occurs following hyperosmotic infusions of saline or mannitol, results in an increase in plasma potassium concentration. This results from leakage of potassium from cells, a phenomenon that is not related to extracellular acidosis, but may be linked to cellular dehydration, altered cell membrane function or altered cell metabolism. An increase in extracellular tonicity is also observed in patients with hyperglycaemia in the absence of insulin and has important therapeutic relevance in the provision of potassium replacement during the treatment of hyperglycaemia. The effects of tonicity under physiological conditions are probably of no significance.

Potassium depletion results in a greater loss of potassium from the ECF than the ICF, and potassium excess results in a greater proportional rise of ECF than of ICF potassium concentration. The controlling influences over these changes are not defined, but the result is a significant alteration in membrane potential: this is increased with potassium depletion and decreased with excess. The effects on neuromuscular function of either condition constitute the most important clinical complications of disorders of potassium metabolism.

The traditional understanding of potassium handling by the kidneys is that potassium is freely filtered by the glomeruli, but that up to 95% has been reabsorbed before the tubular fluid reaches the distal convoluted tubules. The predominant control of potassium excretion appears to reside in the control of distal tubular reabsorption and secretion.

Plasma potassium itself has a major effect on potassium secretion in the distal tubules, tending to correct any imbalance. Acute changes in sodium delivery to the distal tubules may also influence potassium excretion – restricted sodium delivery impairs potassium excretion, but a tendency to natriuresis is accompanied by a kaliuresis. However, chronic effects on potassium excretion as a result of changes in sodium intake are not seen because of the influence of the renin–angiotensin–aldosterone axis.

Potassium directly influences aldosterone secretion from the adrenal cortex. A high plasma potassium concentration stimulates aldosterone secretion and a low concentration suppresses secretion. In addition to its effects on sodium reabsorption by the principal cells, aldosterone stimulates hydrogen ion secretion by the α-intercalated cells of the distal tubules and collecting ducts. Acidosis is associated with reduced potassium secretion and alkalosis with enhanced secretion. The net effect of aldosterone is to stimulate exchange of potassium and hydrogen ions for sodium ions. Therefore, the relative proportions of potassium and hydrogen ions within the cells of the distal tubules, together with the ability to secrete hydrogen ions, will determine the effect of systemic acidosis or alkalosis on potassium excretion. Acting alone, an acidosis will promote potassium retention and an alkalosis will promote a kaliuresis.

Urine potassium concentration can vary between about 5 mmol/L and 150 mmol/L. Adaptation of urinary excretion to a variation in input tends to be slow, taking a few days to achieve a new balance. In this respect, urinary control of potassium is less sensitive than the control of sodium.

As sodium is predominantly an extracellular cation, the control of sodium balance will control the volume of the ECF. The tonicity of body fluids is under osmoregulatory control, therefore sodium deficit or sodium excess presents clinically with primary changes in ECF volume rather than changes in sodium concentration within the ECF. Hyponatraemic and hypernatraemic states are discussed in the section on water metabolism.

Sodium is always lost from the body in association with water. As the sodium concentration of all body fluids is equal to or less than plasma (except on occasions of high sodium intake, when urine sodium concentration may exceed plasma concentration), loss of any body fluid except plasma will generally result in an excess loss of water over sodium. Any loss of sodium, however, will result in a reduction of ECF volume, including a reduction in circulating plasma volume. Clinical presentation will depend on the severity of the decrease. When the changes are mild, patients are often described clinically as being dehydrated, a description that should be confined to pure water deficiency but, unfortunately, in general usage is not. Except in rare instances, truly dehydrated (water depleted) patients are extremely thirsty; patients with all but the most severe salt and water deficiency are not.

Reduced intravascular volume, when mild, will result in postural hypotension and a compensatory increase in pulse rate; central venous pressure is reduced and this can be assessed clinically by observation of neck vein filling or directly measured following insertion of a cannula into a central vein. When the volume reduction is more severe, hypotension and eventually shock will result in oliguria; the central venous pressure is further reduced. Reduction in interstitial fluid volume results in reduced skin turgor and transcellular fluid reductions result in dry mouth and reduced intraocular pressure.

Relief of urinary tract obstruction, most commonly seen in patients with prostatic enlargement, is often followed by a short period of diuresis and natriuresis. The exact mechanism of this is not fully understood, but is probably related to a urea-induced osmotic diuresis, together with elimination of excess sodium retained during the obstruction phase. The natriuresis in these cases is corrective and is not strictly a primary renal condition: it is unlikely to lead to sodium depletion. Normally, this phase of post-obstructive natriuresis and diuresis lasts between one and seven days, but occasionally a more prolonged natriuresis occurs, leading to sodium deficiency. This rare event is secondary to tubular damage occurring during obstruction. Salt wasting has been described in association with meticillin-induced acute interstitial nephritis. Full resolution of the condition may be delayed for several months, during which time minimum obligatory losses of sodium may exceed 100 mmol/24 h.

Chronic kidney disease is generally associated with a reduced capacity to excrete sodium. Considerable adaptation occurs to increase the natriuretic capacity of the remaining functioning nephrons, which paradoxically impairs the overall sodium conserving function. On a Western type diet, sodium intake normally exceeds minimum obligatory urine sodium loss, but if dietary salt is restricted or non-renal losses of sodium are increased, the obligatory loss may induce sodium deficiency. Minimum obligatory losses may be as little as 40 mmol/24 h and even lower if enough time is given for adaptation, but occasionally patients have minimum obligatory losses exceeding 150 mmol/24 h (3 mmol/kg body weight in children). The term salt-losing nephropathy is appropriate for this group of patients.

Salt-losing nephropathy is a clinical state, rather than a specific disease. It is normally associated with chronic kidney disease due to tubulointerstitial disease or to glomerulonephritis with significant interstitial abnormalities. A common example of a toxic nephropathy inducing a salt-losing state is analgesic abuse, in which there is typically also reduced concentrating ability and renal tubular acidosis.

No single laboratory finding is diagnostic of sodium deficiency, which, therefore, remains primarily a clinical diagnosis. There may be uraemia, particularly of a prerenal pattern (with urea concentration disproportionately elevated in relation to that of creatinine). Serum sodium concentration may be normal, decreased (usually in association with uraemia) or even increased when the sodium deficit is proportionately less than the water deficit. Serum sodium and urea concentrations cannot indicate accurately the degree of sodium depletion or reduction in ECF volume.

Hypoosmolal fluids may be used when sodium deficit is associated with a greater degree of water deficit, that is, sodium deficit in association with hypernatraemia.

Sodium excess is almost invariably associated with water excess (and is usually an iso-osmolal sodium excess). The clinical presentation will depend on the severity of the expansion of ECF volume and its relative distribution within the ECF volume compartments. In practice, the clinical presentation is with oedema (peripheral or pulmonary) or effusions (pleural, ascites) or with hypertension.

Peripheral oedema, due to sodium retention, is characteristically ‘pitting’ when digital pressure is applied to the affected part (lymphoedema, due to lymphatic obstruction, is characteristically non-pitting, while in myxoedema, the swelling is brawny in nature). Measurement or clinical observation of the central venous pressure may suggest an associated increase in intravascular volume, as may the demonstration of hepatic congestion or the presence of pulmonary crepitations.

Hypertension is a common clinical finding, but hypertension specifically due to chronic iso-osmolal sodium excess is rare. Causes of this form of hypertension are discussed later, but all are associated with an increased mineralocorticoid effect in the initial stages, promoting renal sodium conservation and renal loss of potassium. The association of muscle weakness (caused by hypokalaemia) with hypertension is an important clinical pointer to such a cause of sodium retention.

The nephrotic syndrome is characterized by severe glomerular proteinuria, hypoalbuminaemia and oedema. The classic hypothesis explained the oedema and secondary sodium retention, on the basis of reduced oncotic pressure owing to hypoalbuminaemia. However, the rare condition congenital analbuminaemia is not associated with significant oedema, and nephrotic patients infused with albumin do not consistently respond with a natriuresis and reduction of oedema. Sudden remission of minimal-change glomerulonephritis may result in clinical resolution prior to an increase in plasma albumin, and the presumed reduced circulating volume in nephrotic syndrome is less commonly found when sought than normal or increased circulating volume. These observations imply an intrarenal mechanism of sodium retention in the nephrotic syndrome. Sodium retention does not appear to be primarily driven by the renin–angiotensin–aldosterone system; moreover, ANP concentrations are moderately increased, not decreased, and the natriuretic effect of the hormone is maintained.

Chronic liver disease frequently results in a state of sodium retention leading to oedema and ascites. Again, the physiology of sodium retention is multifactorial, resulting from decreases in glomerular filtration, enhanced proximal tubular reabsorption and increased renin–angiotensin–aldosterone production, presumably from decreased ‘effective’ intravascular volume. As in CCF, the plasma ANP concentration is significantly increased, but again the natriuretic response is blunted. The concentration of AVP may also be significantly increased.

Pregnancy demands a retention of between 700 and 1000 mmol of sodium in order to expand the maternal plasma volume and interstitial space and to provide the fetus with sodium. Sodium retention occurs progressively during pregnancy, even though the glomerular filtration rate is greatly increased, so that the reabsorption of filtered sodium must be substantially increased above the non-pregnant level. The renin–angiotensin–aldosterone system is stimulated during pregnancy, a finding that supports the theory of renal sodium retention as a response to reduced ‘effective’ vascular volume (due to redistribution of ECF volume to the growing fetus and its maternal circulatory support). However, many studies have shown increased plasma ANP concentrations during pregnancy, a finding somewhat at odds with the presumed reduced ‘effective’ vascular volume. Thus, the kidneys may retain sodium in response to some other stimulus (such as the effect of oestrogens), and the increase in ANP may represent the response to the resultant increased atrial pressure from expanded vascular volume. However, these two apparently conflicting theories are not mutually exclusive and it seems likely that the resultant increase both in the activity of the renin–angiotensin–aldosterone system and the secretion of ANP forms the basis for an enhanced control over sodium balance. Enormous differences in daily sodium intake (from < 10 mmol to > 300 mmol) can be adequately accommodated during pregnancy.

Dependent leg oedema is extremely common during pregnancy, especially during the third trimester, and much of this is attributable to the mechanical pressure of the uterus upon the venous return from the lower limbs. However, there is a general tendency to an increased interstitial fluid content because of reduced oncotic pressure (as a result of reduced plasma protein concentration) and because of the effects of oestrogens, which enhance the hydration of the mucopolysaccharide ground substance of connective tissue. This general tendency to increased interstitial fluid content may also produce a more generalized oedema.

Excessive sodium retention occurs in pre-eclampsia. Total body sodium is increased, but plasma volume is usually decreased, with shifts of fluid to the interstitium. The reduced plasma volume is the result of intense vasoconstriction, which also results in hypertension. In pre-eclampsia, renin activity and aldosterone concentrations in plasma in the third trimester are less than those observed during normal pregnancy. Furthermore, ANP concentrations are significantly increased above those found in normal pregnancy, or indeed those found in pregnancy associated with essential hypertension. Atrial natriuretic peptide appears to be released into the maternal circulation in response to vasoconstriction and an increased volume load to the cardiac atria. Thus in pre-eclampsia, as compared with normal pregnancy, renin, aldosterone and ANP all act as if to promote natriuresis, but, for reasons which are not understood, natriuresis is impaired.

Despite intensive study over 50 years or so, the question of whether the normal menstrual cycle is associated with sodium retention remains unresolved. There is widespread belief that the majority of women retain sodium premenstrually, giving rise to premenstrual oedema in some. Plasma aldosterone and renin concentrations are elevated during the luteal phase of the ovulatory cycle, but this elevation is coupled with an increase in progesterone, which is thought to antagonize the renal actions of aldosterone. Studies have shown that plasma ANP concentrations remain the same during the follicular and luteal phases. It has also been demonstrated that, in healthy females, the ANP response to volume expansion is no different in the follicular and luteal phases of the menstrual cycle, and the proportional suppression of renin and aldosterone is also identical between the two phases of the cycle. When these findings are coupled with the observations that body weight, creatinine clearance and basal sodium excretion do not alter during the phases of the cycle, it is apparent that there is little evidence of renal sodium retention. This remains an area for further research, particularly as inappropriate treatment of perceived symptoms may lead to further complications of sodium balance (see below).

Idiopathic oedema, sometimes known as cyclical oedema, is a condition that occurs in females postpuberty. Oedema of the face, hands and legs can develop rapidly, and weight gains up to 4 kg in 24 h have been described. The aetiology of this condition is unknown, but one suggestion is that diuretics may be used to produce rapid weight loss and that cessation of this self-medication leads to rebound sodium retention. The diuretic is subsequently recommenced for cosmetic reasons to reduce oedema formation and weight gain. Thus, a vicious cycle of sodium depletion followed by sodium retention and oedema is set in place. However, in some patients prior diuretic use cannot be demonstrated.

Many patients with idiopathic oedema show exaggerated sodium retention on assuming an upright posture with a marked reduction in renal blood flow and GFR. Oestrogens do not appear to play an important role, as the condition has been demonstrated in a patient who had previously undergone bilateral oophorectomy. The role of renin–angiotensin–aldosterone is not fully understood, with a proportion of patients having increased plasma renin and aldosterone concentrations, particularly when in an upright posture, but with suppression of concentrations by a high salt diet. Limited studies of ANP have been performed, but no abnormalities have been demonstrated: normal basal values are found and are stimulated by volume expansion.

The investigation of sodium excess is confined almost exclusively to the investigation of oedema and of hypertension; hypernatraemia is not a feature of sodium excess except in rare instances of acute sodium loading, when the cause is usually clear from the clinical history.

In practice, the purpose of the investigation of oedema is primarily to differentiate reduced oncotic pressure from other causes, usually by the measurement of serum protein concentration and the confirmation of any route of protein loss, for example the measurement of urine protein excretion. The diagnosis of oedema secondary to CCF and liver disease is primarily clinical; detailed sodium balance studies are not normally justified or, indeed, practicable. Idiopathic oedema is also a condition that is initially diagnosed from the clinical history, although periods of continuous sodium loading with simultaneous sodium balance studies may reveal a propensity for sodium retention.

For those conditions associated with oedema, the management will be aimed primarily at ameliorating the primary cause. This primary treatment, when applicable, needs to be coupled with attempts to control sodium and water retention by the restriction of dietary sodium and, when appropriate, the use of diuretics. The laboratory’s role in management is to monitor the potential complications of diuretic treatment, notably hypokalaemia (especially with the use of loop diuretics), hyperkalaemia (with the use of potassium-sparing diuretics such as spironolactone) and hyponatraemia (when over-diuresis results in non-osmotic stimulation of AVP with secondary water retention). In addition, the laboratory’s function is to monitor the effects of natriuresis on renal function by monitoring serum urea or creatinine concentrations.

For conditions of sodium excess without oedema, the initial management is to increase renal sodium excretion, either by attention to iatrogenic causes (such as exogenous mineralocorticoid treatment) or by treatment with diuretics such as spironolactone. This treatment is combined, when appropriate, with antihypertensive therapy. The laboratory’s role in management is to monitor for possible complications, particularly with respect to potassium homoeostasis. For those patients with surgically correctable conditions, such as primary hyperaldosteronism due to an adrenal adenoma, the definitive treatment is surgery.

As water is distributed throughout all body spaces, the effects of pathological excess or deficiency will be reflected in the relative functional sensitivities of each space. For example, a 10% excess or reduction in total body water (TBW) is unlikely to result in clinical features of alterations in ECF volume. However, ICF volume changes may considerably impair cellular function; in particular, rapid changes may significantly impair brain cell function.

Disorders of water metabolism include three categories of conditions. First are conditions in which polyuria is the major feature. Polyuria is defined as a urine output in adults in excess of 50 mL/kg body weight/24 h. In polyuria, one aspect of water homoeostasis is defective but may be compensated by another: either a reduced ability to concentrate the urine is compensated by a secondary increase in thirst, or an excessive water intake is compensated with a secondary increase in urine output. In either case, patients are usually normonatraemic unless the compensatory mechanism is compromised.

Second are those of water deficiency in which homoeostasis is defective and normal body water content cannot be maintained: patients present with hypernatraemia (serum sodium above 145 mmol/L).

Third are conditions of primary water excess in which homoeostasis is defective: patients present with hyponatraemia (usually defined as a serum sodium < 130 mmol/L) or clinical features of water intoxication.

Polyuria is an early feature of diabetes mellitus as a result of the osmotic effects of an increased filtered load of glucose. Polyuria can also be a feature of renal failure due to the loss of medullary hypertonicity and the reduction in the production of AQP 2. Thus polyuria due to diabetes mellitus or renal failure should be differentiated at the outset. A primary inability to concentrate urine with secondary polydipsia is known as diabetes insipidus (DI), and may be due to either impaired release of AVP from the posterior pituitary (cranial diabetes insipidus, CDI) or to impaired renal response to AVP (nephrogenic diabetes insipidus, NDI).