Distribution of different types of replacement fluids

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.

Figure 13.2 Relative effects of the addition of 1 L of: (a) water, (b) saline 0.9% and (c) a colloid solution.

Regulation of extracellular volume (Fig. 13.3)

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.

Figure 13.4 The nephron – electrolyte and water exchange: 180 L of water and 26 000 mmol of sodium/day enter the nephrons via the afferent arterioles to the kidneys. Removal or addition of electrolytes results in the excretion of approximately 1 L of water and 60–180 mmol of sodium/day.

Neurohumoral regulation of extracellular volume

This is mediated by volume receptors that sense changes in the EABV rather than alterations in the sodium concentration. These receptors are distributed in both the renal and cardiovascular tissues.

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.

Aldosterone and possibly ANP are responsible for day-to-day variations in Na⁺ excretion, by their respective ability to augment and diminish Na⁺ reabsorption in the collecting ducts.

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.

Volume regulation in oedematous conditions

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).

Mechanism of impaired escape from actions of aldosterone and resistance to ANP

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).

Regulation of water excretion

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 V_1A receptors induces vasoconstriction while V_1B 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.

The cortical collecting duct has two cell types (see also p. 597) with very different functions:

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.)

Plasma osmolality

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.

Two simple examples will illustrate the basic mechanisms of osmoregulation, which is so efficient that the plasma Na⁺ concentration is normally maintained within 1–2% of its baseline value.

Osmoregulation versus volume regulation

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).

The roles of these two pathways should be considered separately when evaluating patients.

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 V_1A (vasopressin) receptors distributed in the vascular smooth muscle cells.

Regulation of cell volume

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.

Clinical use of diuretics

Loop diuretics

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:

Urate retention causing gout

Hypokalaemia

Hypomagnesaemia

Decreased glucose tolerance

Allergic tubulointerstitial nephritis and other allergic reactions

Myalgia – especially with high-dose bumetanide

Ototoxicity (due to an action on sodium pump activity in the inner ear) – particularly with furosemide

Interference with excretion of lithium, resulting in toxicity.

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.

FURTHER READING

Bagshaw SM, Bellomo R, Kellum JA. Oliguria, volume overload, and loop diuretics. Crit Care Med 2008; 34(4 Suppl): S172–S178.

Thiazide diuretics (see p. 719)

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.

Resistance to diuretics

Resistance may occur as a result of:

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).

Effects on renal function

All diuretics may increase plasma urea concentrations by increasing urea reabsorption in the medulla. Thiazides may also promote protein breakdown. In certain situations diuretics also decrease GFR:

Haemorrhage

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 plasma

Loss of plasma, as occurs in burns or severe peritonitis, should be treated with human plasma or a plasma substitute (see p. 390).

Loss of water and electrolytes

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.

Loss of water alone

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.

If intravenous treatment is required, water is given as 5% glucose with K⁺, because pure water would lead to osmotic lysis of blood cells.

Causes

The most common causes of chronic hypokalaemia are diuretic treatment (particularly thiazides) and hyperaldosteronism. Acute hypokalaemia is often caused by intravenous fluids without potassium and redistribution into cells. The common causes are shown in Table 13.12.

Table 13.12 Causes of hypokalaemia

Bartter’s syndrome (clinically similar to loop diuretics)

This consists of metabolic alkalosis, hypokalaemia, hypercalciuria, occasionally hypomagnesaemia (see p. 657), normal blood pressure, and an elevated plasma renin and aldosterone. The primary defect in this disorder is an impairment in sodium and chloride reabsorption in the thick ascending limb of the loop of Henle (Fig. 13.6). Mutation in the genes encoding either the sodium-potassium-2-chloride cotransporter (NKCC2), the ATP-regulated renal outer medullary potassium channel (ROMK) or kidney-specific basolateral chloride channels (ClC-Kb) – Bartter types I, II and III, respectively – causes loss of function of these channels, with consequent impairment of sodium and chloride reabsorption. There is also an increased intrarenal production of prostaglandin E₂ which is secondary to sodium and volume depletion, hypokalaemia and the consequent neurohumoral response rather than a primary defect. PGE₂ causes vasodilatation and may explain why the blood pressure remains normal.

Barttin, a β-subunit for ClC-Ka and ClC-Kb chloride channels, is encoded by the BSND (Bartter’s syndrome with sensorineural deafness) gene. Loss of function mutations cause type IV Bartter’s syndrome associated with sensorineural deafness and renal failure. Barttin co-localizes with a subunit of the chloride channel in basolateral membranes of the renal tubule and inner ear epithelium. It appears to mediate chloride exit in the thick ascending limb (TAL) of the loop of Henle and chloride recycling in potassium-secreting strial marginal cells in the inner ear. A very rare variant of type IV is a disorder with an impairment of both chloride channels (ClC-Ka and ClC-Kb) producing the same phenotypic defects.

A gain of function mutation of the calcium sensing receptor (CaSR) which leads to autosomal dominant hypocalcaemia has also been recognized in Bartter’s syndrome. In the kidney, the CaSR is expressed mainly in the basolateral membrane of cortical TAL. Activation of CaSR by high calcium or magnesium or by gain of function mutation triggers intracellular signalling, including release of arachidonic acid and inhibition of adenylate cyclase. Both actions result in inhibition of ROMK activity, which in turn leads to reduction in the lumen-positive electrical potential and transcellular absorption of calcium. This effect of CaSR explains why patients with mutations in this receptor may present with both hypocalcaemia, hypercalciuria and renal wasting of NaCl, resulting in a Bartter-like syndrome.

In summary, these defects in sodium chloride transport are thought to initiate the following sequence, which is almost identical to that seen with chronic ingestion of a loop diuretic. The initial salt loss leads to mild volume depletion, resulting in activation of the renin-angiotensin-aldosterone system. The combination of hyperaldosteronism and increased distal flow (owing to the reabsorptive defect) enhances potassium and hydrogen secretion at the secretory sites in the collecting tubules, leading to hypokalaemia and metabolic alkalosis.

Diagnostic pointers include high urinary potassium and chloride despite low serum values as well as increased plasma renin (NB: in primary aldosteronism, renin levels are low). Hyperplasia of the juxtaglomerular apparatus is seen on renal biopsy (careful exclusion of diuretic abuse is necessary). Hypercalciuria is a common feature but magnesium wasting, though rare, also occurs.

Treatment is with combinations of potassium supplements, amiloride and indomethacin.

Gitelman’s syndrome (similar to thiazide diuretics)

Gitelman’s syndrome is a phenotype variant of Bartter’s syndrome characterized by hypokalaemia, metabolic alkalosis, hypocalciuria, hypomagnesaemia, normal blood pressure, and elevated plasma renin and aldosterone. There are striking similarities between the Gitelman’s syndrome and the biochemical abnormalities induced by chronic thiazide diuretic administration. Thiazides act in the distal convoluted tubule to inhibit the function of the apical sodium-chloride cotransporter (NCCT) (Fig. 13.7). Analysis of the gene encoding the NCCT has identified loss of function mutations in Gitelman’s syndrome.

Like Bartter’s syndrome, defective NCCT function leads to increased solute delivery to the collecting duct, with resultant solute wasting, volume contraction and an aldosterone-mediated increase in potassium and hydrogen secretion. Unlike Bartter’s syndrome, the degree of volume depletion and hypokalaemia is not sufficient to stimulate prostaglandin E₂ production. Impaired function of NCCT is predicted to cause hypocalciuria, as does thiazide administration. Impaired sodium reabsorption across the apical membrane, coupled with continued intracellular chloride efflux across the basolateral membrane, causes the cell to become hyperpolarized. This in turn stimulates calcium reabsorption via apical, voltage-activated calcium channels. Decreased intracellular sodium also facilitates calcium efflux via the basolateral sodium-calcium exchanger. The mechanism for urinary magnesium losses is described on page 656.

Treatment consists of potassium and magnesium supplementation (MgCl₂) and a potassium-sparing diuretic. Volume resuscitation is usually not necessary, because patients are not dehydrated. Elevated prostaglandin E₂ does not occur (see above) and, therefore, NSAIDs are not indicated in this disorder.

Liddle’s syndrome

This is characterized by potassium wasting, hypokalaemia and alkalosis, but is associated with low renin and aldosterone production, and high blood pressure. There is a mutation in the gene encoding for the amiloride-sensitive epithelial sodium channel in the distal tubule/collecting duct. This leads to constitutive activation of the epithelial sodium channel, resulting in excessive sodium reabsorption with coupled potassium and hydrogen secretion. Unregulated sodium reabsorption across the collecting tubule results in volume expansion, inhibition of renin and aldosterone secretion and development of low renin hypertension (Fig. 13.8).

Therapy consists of sodium restriction along with amiloride or triamterene administration. Both are potassium-sparing diuretics which directly close the sodium channels. The mineralocorticoid antagonist spironolactone is ineffective, since the increase in sodium-channel activity is not mediated by aldosterone.

Hypokalaemic periodic paralysis

This condition may be precipitated by carbohydrate intake, suggesting that insulin-mediated potassium influx into cells may be responsible. This syndrome also occurs in association with hyperthyroidism (thyrotoxic periodic paralysis) which occurs in Asians.

Excessive phosphatonins (FGF23)

This condition also occurs in patients with tumour-induced osteomalacia (TIO), X-linked dominant hypophosphataemic rickets (XLR), and autosomal-dominant hypophosphataemic rickets (ADHR). These syndromes have similar biochemical and osseous phenotypes. Patients have osteomalacia or rickets, reduced tubular phosphate reabsorption, hypophosphataemia, normal or low serum calcium, normal PTH and PTH-related protein concentrations, and normal or low 1,25-dihydroxyvitamin D₃. Urinary cyclic AMP levels are generally in the normal range.

In TIO, there is excessive production of phosphaturic agents (which are normally produced by osteoblasts and act as hormones by acting on kidneys and regulating phosphate absorption and vitamin D activation), e.g. fibroblast growth factor 23 (FGF23), matrix extracellular phosphoglycoprotein (MEPG) and frizzled related protein 4 (FRP-4). These cannot be degraded by normal concentrations of PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome). This results in net excess of inhibitors of the sodium-phosphate cotransporter in the proximal tubule, and phosphaturia.

In ADHR, FGF-23 is mutated so that it is resistant to PHEX proteolysis. In XLR, mutations in PHEX prevent binding to FGF23 and FRP-4, resulting in a net relative excess of phosphatonins.

Normal adaptive increases in 1,25-dihydroxyvitamin D₃ synthesis in response to low phosphate levels do not occur in TIO, ADHR and XLR, aggravating phosphaturia (Fig. 13.9).

Autosomal recessive hypophosphataemia with high FGF23 levels has been described in patients with mutations in the gene encoding dentin matrix protein 1 (DMP1), which is a transcription factor produced by dental cells, osteoblasts and osteocytes. It is also secreted and can modulate the formation of mineralized matrix.

Reduced NPT2a/NHERF1 activity

Mutations in NPT2a (sodium phosphate cotransporter 2a) and NHERF1 (sodium hydrogen regulator factor 1) have been identified in patients with low phosphate levels and reduced ratio of the maximum tubular reabsorption of phosphate (TmP) normalised for GFR (TmP/GFR ratio). Heterozygous loss of function mutation in NPT2a and NHERF1 in patients is characterized by hypophosphataemia, low TmP/GFR and normal PTH. Carriers of these mutations do not have hypercalcaemia, which means these mutation do not affect the action of PTH on bones.

Renal reabsorption of bicarbonate

The plasma [HCO₃⁻] is normally maintained at approximately 25 mmol/L. In individuals with a normal glomerular filtration rate (120 mL/min), about 4500 mmol of bicarbonate is filtered each day. If this filtered bicarbonate were not reabsorbed, the plasma [HCO₃⁻] would fall, along with blood pH. Thus, maintenance of normal plasma [HCO₃⁻] requires that essentially all of the bicarbonate in the glomerular filtrate be reabsorbed (Fig. 13.10).

Figure 13.10 Resorption of sodium bicarbonate in the renal (mainly proximal) tubule. Bicarbonate is reclaimed by the secretion of H⁺ in exchange for Na⁺ into the tubule. This results in the formation of H₂CO₃, which is then broken down to CO₂. This is reabsorbed and converted back to H₂CO₃, which now dissociates into H⁺ and HCO₃⁻. The net result is reabsorption of Na⁺ and HCO₃⁻. This process is dependent on carbonic anhydrase within the cells and on the luminal surface of the tubular cell.

The proximal convoluted tubule reclaims 85–90% of filtered bicarbonate; by contrast, the distal nephron reclaims very little. This difference is caused by the greater quantity of luminal (brush border) carbonic anhydrase in the proximal tubule than in the distal nephron. As a result of these quantitative differences, bicarbonate that escapes reabsorption in the proximal tubule is excreted in the urine.

Proximal tubular bicarbonate reabsorption is catalysed by the Na⁺/K⁺-ATPase pump located in the basolateral cell membrane. By exchanging peritubular potassium ions for intracellular sodium ions, the pump keeps the intracellular sodium concentration low, allowing sodium ions to enter the cell by moving down the sodium concentration gradient from the tubule lumen to the cell interior. Hydrogen ions are transported in the opposite direction (at the Na⁺-H⁺ antiporter), thereby maintaining electroneutrality. Before bicarbonate enters the proximal tubule, it combines with secreted hydrogen ions, forming carbonic acid. In the presence of luminal carbonic anhydrase (CA-IV) carbonic acid rapidly dissociates into carbon dioxide and water, which can then rapidly enter the proximal tubular cell. In the cell, carbon dioxide is hydrated by cytosolic carbonic anhydrase (CA-II), ultimately forming bicarbonate, which is then transported down an electrical gradient from the cell interior, across the membrane into the peritubular fluid, and into the blood. In this process, each hydrogen ion secreted into the proximal tubule lumen is reabsorbed and can be resecreted; there is no net loss of hydrogen ions or net gain of bicarbonate ions.

Renal excretion of [H⁺] (Fig. 13.11)

More acid is secreted into the proximal tubule (up to 4500 nmol of hydrogen ions each day) than into any other nephron segment. However, the hydrogen ions secreted into the proximal tubule are almost completely reabsorbed with bicarbonate; consequently, proximal tubular hydrogen ion secretion does not contribute significantly to hydrogen ion elimination from the body. The excretion of the daily acid load requires hydrogen ion secretion in more distal nephron segments.

Figure 13.11 Renal excretion of H⁺. Secretion of H⁺ from the cortical collecting ducts is indirectly linked to Na⁺ reabsorption. Intracellular potassium is exchanged for sodium in the principal cell. Aldosterone stimulates H⁺ secretion by entering the principal cell, where it opens Na⁺ channels in the luminal membrane and increases Na⁺/K⁺-ATPase activity. The movement of cationic Na⁺ into the principal cells then creates a negative charge within the tubule lumen. K⁺ moves from the electrochemical gradient and into the lumen. Aldosterone apparently also stimulates the H⁺-ATPase directly in the intercalated cell, further enhancing H⁺ secretion. When the urinary pH falls to 4.0–4.5, further H⁺ secretion by the α-intercalated cells ceases. The filtration of titratable acids (e.g. phosphoric acid, H₂PO₄) raises the intraluminal pH and permits this process to continue. Secreted H⁺ binds to the conjugate anion of a titratable acid (HPO₄²⁻ in this case) and is excreted in the urine. The H⁺ to be secreted arises from the reassociation of H₂O and CO₂ in the presence of carbonic anhydrase; thus, a bicarbonate molecule is regenerated each time an H⁺ is eliminated in the urine.

Most dietary hydrogen ions come from sulphur-containing amino acids that are metabolized to sulphuric acid (H₂SO₄), which then reacts with sodium bicarbonate as follows:

Excess sulphate is excreted in the urine, whereas excess hydrogen ions are buffered by bicarbonate and lower the plasma [HCO₃⁻]. This fall in plasma [HCO₃⁻] leads to a slight decrease in the blood pH, although a smaller decrease in the blood pH than would have occurred if buffer were unavailable. The subsequent excretion of hydrogen ions takes place primarily in the collecting duct and results in the regeneration of 1 mmol of bicarbonate for every mmol of hydrogen ions excreted in the urine.

The collecting duct has three types of cells:

Secretion of hydrogen ions from the cortical collecting duct is indirectly linked to sodium reabsorption. Aldosterone has several facilitating effects on hydrogen ion secretion. Aldosterone opens sodium channels in the luminal membrane of the principal cell and increases Na⁺/K⁺-ATPase activity. The subsequent movement of cationic sodium into the principal cell creates a negative charge within the tubule lumen. Potassium ions from the principal cells and hydrogen ions from the α-intercalated cells move out from the cells down the electrochemical gradient and into the lumen. Aldosterone also stimulates directly the H⁺-ATPase in the α-intercalated cell, further enhancing hydrogen ion secretion.

When hydrogen ions are secreted into the lumen of the collecting tubule, a tiny, but physiologically critical, fraction of these excess hydrogen ions remains in solution. Here, they increase the urinary [H⁺] and lower urinary pH below 4.0. Nevertheless, below this urine pH, inhibition of proton-secreting pumps such as H⁺-ATPase severely restricts kidney secretion of more hydrogen ions. Consequently, secretion of hydrogen ions depends on the presence of buffers in the urine that maintain the urine pH at a level higher than 4.0.

In the presence of alkali excess, the homeostatic needs are reversed. Although the kidney can excrete excess alkaline load by reducing reabsorption of filtered bicarbonate in the proximal and distal tubule, the collecting ducts also contribute by secreting bicarbonate brought about by switching to β-intercalated cells. This switch enables kidneys to secrete bicarbonate and conserve H⁺ ions.

Buffer systems in acid excretion

Two buffer systems are involved in acid excretion: the titratable acids such as phosphate, and the ammonia system. Each system is responsible for excreting about half of the daily acid load of 50–100 mmol under physiological conditions (Fig. 13.11).

Ammonium (NH₄⁺)

In the setting of metabolic acidosis, titratable acids cannot increase significantly because the availability of titratable acid is fixed by the plasma concentration of the buffer and by the GFR. The ammonia buffer system, by contrast, can increase several hundred-fold when necessary. Consequently, impaired renal excretion of hydrogen ions is always associated with a defect in ammonium excretion (Fig. 13.12).

Figure 13.12 The ammonia buffering system in the kidney. All ammonia used to buffer H⁺ in the collecting duct is synthesized in the proximal convoluted tubule, and glutamine is the main source of this ammonia. As glutamine is metabolized, α-ketoglutarate (α-KG) is formed, which ultimately breaks down to bicarbonate that is then secreted into the peritubular fluid at an Na⁺-HCO₃⁻ cotransporter.

All ammonia used to buffer urinary hydrogen ions in the collecting tubule is synthesized in the proximal convoluted tubule. Glutamine is the primary source of ammonia. It undergoes deamination catalysed by glutaminase, resulting in α-ketoglutaric acid (Fig. 13.12) and ammonia. Once formed, ammonia can diffuse into the proximal tubule lumen and become acidified, forming ammonium. Once in the proximal tubule lumen, ammonium flows along the tubule to the thick ascending limb of Henle’s loop. Here, it is transported out of the tubule into the medullary interstitium. Ammonium then dissociates to ammonia, leading to a high interstitial ammonia concentration. The notion that ammonia diffuses down its concentration gradient into the lumen of the collecting tubule has recently been challenged by the discovery of rhesus (Rh) associated glycoproteins acting as ammonia transport proteins also called RhCG/Rhcg which are expressed in the basolateral and apical surfaces of DCT, inner medullary collecting duct and type A intercalated cells. These proteins play a fundamental role in renal ammonia excretion under both basal and acidosis states. Once secreted, NH₃ reacts with the hydrogen ions secreted by the collecting tubular cells to form ammonium. Because ammonium (NH₄) is not lipid-soluble, it is trapped in the lumen and excreted in the urine as ammonium chloride. Two conditions predominantly promote ammonia synthesis by the proximal tubular cell: systemic acidosis and hypokalaemia.

Glutamine metabolism and ureagenesis in the liver were thought to play a role in acid–base homeostasis. The liver was believed to contribute to regulation of acid–base balance by controlling the rate of ureagenesis and therefore bicarbonate consumption in response to changes in plasma acidity. Studies in human volunteers have concluded that ureagenesis is a maladaptive process for acid–base regulation and that ureagenesis has no discernible homeostatic effect on acid–base equilibrium in humans.

FURTHER READING

Weiner ID, Verlander JW. Molecular physiology of the Rh ammonia transport proteins. Curr Opin Nephrol Hypertens 2010; 19(5):471–477.

Respiratory acidosis

This is caused by retention of CO₂. The P_aCO₂ and [H⁺] rise. Renal retention of bicarbonate may partly compensate, returning the [H⁺] towards normal (see p. 876).

Respiratory alkalosis

Increased removal of CO₂ is caused by hyperventilation, so there is a fall in P_aCO₂ and [H⁺] (see p. 876).

The anion gap

The first step is to identify whether the acidosis is due to retention of H⁺Cl⁻ or to another acid. This is achieved by calculation of the anion gap.

Because there are more unmeasured anions than cations, the normal anion gap is 10–18 mmol/L, although calculations with more sensitive methods place this at 6–12 mmol/L. Albumin normally makes up the largest portion of these unmeasured anions. As a result, a fall in the plasma albumin concentration from the normal value of about 40 g/L to 20 g/L may reduce the anion gap by as much as 6 mmol/L, because each 1 g/L of albumin has a negative charge of 0.2–0.28 mmol/L.

Type 4 renal tubular acidosis

Also called ‘hyporeninaemic hypoaldosteronism’, this is probably the most common of these disorders. The cardinal features are hyperkalaemia and acidosis occurring in a patient with mild chronic kidney disease, usually caused by tubulo-interstitial disease (e.g. reflux nephropathy) or diabetes. Gordon’s syndrome (see p. 655) shares biochemical abnormalities but differs in having normal GFR and hypertension. Plasma renin and aldosterone are found to be low, even after measures which would normally stimulate their secretion. The features for the diagnosis are shown in Table 13.22. An identical syndrome is caused by chronic ingestion of NSAIDs, which impair renin and aldosterone secretion. In the presence of acidosis, urine pH may be low. Treatment is with fludrocortisone, sodium bicarbonate, diuretics, or ion exchange resins to remove potassium, or a combination of these. Dietary potassium restriction alone is ineffective.

Table 13.22 Features of hyporeninaemic hypoaldosteronism (type 4 renal tubular acidosis)

Type 3 renal tubular acidosis (RTA)

This condition is vanishingly rare, and represents a combination of type 1 and type 2. Inherited type 3 RTA is caused by mutations resulting in carbonic anhydrase type II deficiency, which is characterized by osteopetrosis, RTA of mixed type, cerebral calcification, and mental retardation.

Type 2 (‘proximal’) renal tubular acidosis

This is very rare in adult practice. It is caused by failure of sodium bicarbonate reabsorption in the proximal tubule. The cardinal features are acidosis, hypokalaemia, an inability to lower the urine pH below 5.5 despite systemic acidosis, and the appearance of bicarbonate in the urine despite a subnormal plasma bicarbonate. This disorder normally occurs as part of a generalized tubular defect, together with other features such as glycosuria and amino-aciduria. Inherited forms of isolated type 2 RTA are described as both autosomal dominant and recessive patterns of inheritance, where putative mutations are in the Na⁺-H⁺ antiporter in the apical membrane and Na⁺-HCO₃⁻ cotransporter in the basolateral membrane of proximal tubular cells respectively (see Fig. 13.10). Treatment is with sodium bicarbonate: massive doses may be required to overcome the renal ‘leak’.

Type 1 (’distal’) renal tubular acidosis

This is due to a failure of H⁺ excretion in the distal tubule (Table 13.23). It consists of:

Table 13.23 Causes of distal renal tubular acidosis (type 1 RTA)

a May also cause proximal renal tubular acidosis.

These features may be present only in the face of increased acid production; hence the need for an acid load test in diagnosis (Practical Box 13.1). Other features include:

These abnormalities result in osteomalacia, renal stone formation and recurrent urinary infections. Osteomalacia is caused by buffering of H⁺ by Ca²⁺ in bone, resulting in depletion of calcium from bone. Renal stone formation is caused by hypercalciuria, hypocitraturia (citrate inhibits calcium phosphate precipitation), and alkaline urine (which favours precipitation of calcium phosphate). Recurrent urinary infections are caused by renal stones.

Both autosomal dominant and recessive inheritance patterns have been reported in primary distal RTA. In the autosomal recessive distal RTA, a substantial proportion of patients have sensorineural deafness, and this is associated with a loss of function mutation in the H⁺-ATPase at the apical surface of intercalated cells.

Treatment is with sodium bicarbonate, potassium supplements and citrate. Thiazide diuretics are useful by causing volume contraction and increased proximal sodium bicarbonate reabsorption.

Chloride-responsive metabolic alkalosis

Although replacement of the chloride deficit is essential in chloride depletion states, selection of the accompanying cation – sodium, potassium or proton – is dependent on the assessment of extracellular fluid volume status (see p. 646), the presence or absence of associated potassium depletion, and the degree and reversibility of any depression of GFR. If kidney function is normal, bicarbonate and base equivalents will be excreted with sodium or potassium, and metabolic alkalosis will be rapidly corrected as chloride is made available.

If chloride and extracellular depletion co-exist then isotonic saline solution is appropriate therapy.

In the clinical settings of fluid overload, saline is contraindicated. In such situations, intravenous use of hydrochloride acid or ammonium chloride can be given. If GFR is adequate, acetazolamide, which causes bicarbonate diuresis by inhibiting carbonic anhydrase, can also be used. When the kidney is incapable of responding to chloride repletion, dialysis is necessary.

Chloride-resistant metabolic alkalosis

Metabolic alkalosis due to potassium depletion is managed by the correction of the underlying cause (see hypokalaemia). Mild to moderate alkalosis requires oral potassium chloride administration. However, the presence of cardiac arrhythmia or generalized weakness requires intravenous potassium chloride.