Hypokalaemia and Hyperkalaemia

Postgrad Med J 2001;77:759–764 759 Hypokalaemia and hyperkalaemia

A Rastergar, M Soleimani

Abstract compartments. Humans, as carnivorous ani- Disturbances in potassium homoeostasis mals, consume large amount of potassium presenting as low or high serum potas- intermittently. Dietary potassium, which is sium are common, especially among hos- rapidly absorbed by the gut, could increase pitalised patients. Given the fact that serum potassium dramatically. However, sev- untreated hypokalaemia or hyperkalae- eral physiological mechanisms quickly shift the mia is associated with high morbidity and potassium intracellularly, allowing slow excre- mortality, it is critical to recognise and tion of potassium by the kidney, and mainte- treat these disorders promptly. In this nance of normal potassium homoeostasis.1 article, normal potassium homoeostasis is Normal physiological regulators, insulin and reviewed initially and then a pathophysi- catecholamines, are stimulated by ingestion of ological approach to work-up and man- food containing glucose and potassium. These agement of hypokalaemia and hyper- hormones are essential in shift of potassium kalaemia is presented. Recent advances intracellularly, depositing it primarily in the liver 2 with respect to the role of kidney in and striated muscle cells. Catecholamines, by handling of the potassium, the regulation acting through diVerent receptors, have diVerent of renal ion transporters in hypokalaemia, eVect on potassium deposition. â2-stimulation and treatment of hypokalaemia and hy- results in a shift of potassium into the cell, while 3 perkalaemia will be discussed. á-stimulation has the opposite eVect. The eVect (Postgrad Med J 2001;77:759–764) of mineralocorticoids and parathyroid hormone in internal potassium homoeostasis is minimal at Keywords: hypokalaemia; hyperkalaemia; potassium best. In addition to these physiological regulators, internal potassium homoeostasis is also Potassium homoeostasis aVected by changes in acid-base and osmolarity. Potassium is the most abundant cation in the Sudden changes in osmolarity, by shifting the body. It is predominantly restricted to the water out of cell, creates a solvent drag phenom- intracellular space, such that only 2% is located enon, and helps push potassium out of the cell, extracellularly and the remaining 98% is in the resulting in a rise in serum potassium (table 1). intracellular compartment. The ratio of intra- The eVect of acid-base status is much more Department of cellular to extracellular potassium (Ki/Ke) is complicated and depends on the nature of the Internal Medicine, the major determinant of resting membrane disorder (box 1). Although, the rule of thumb Yale University School potential, and is regulated primarily by the has been that for each 0.1 unit change in pH, of Medicine, New sodium-potassium ATPase pump located on there is a 0.6 mmol/l change in serum potas- Haven, Connecticut the plasma membrane of most cells. Although sium, this is a very crude approximation and A Rastergar extracellular potassium accounts for only 2% varies greatly by the nature of acid-base Department of of total body potassium, it has a major eVect on disorders. For example organic acidosis as seen Internal Medicine, the ratio of Ki/Ke and through that on the rest- in diabetic ketoacidosis or lactic acidosis result University of ing membrane potential. As a result, serum in little or no change in serum potassium while Cincinnati, Cincinnati, potassium is normally regulated around the non-organic (mineral) acidosis, such as acidosis Ohio narrow range of 3.5–5.0 mmol/l. M Soleimani of renal failure, has the greatest eVect. Other The daily intake of potassium in the western acid-base disorders shift potassium minimally.45 Correspondence to: diet is between 80–120 mmol. The kidney is Dr M Soleimani, Division of the major route of potassium excretion, Nephrology and Hypertension, University of accounting for 90% of potassium loss daily. Cincinnati Medical Center, The remaining 10% is excreted through the Box 1: EVect of acid-base disorders on 231 Albert Sabin Way, MSB gastrointestinal tract. The kidney is, therefore, serum potassium 5502, Cincinnati, OH 45267–0585, USA responsible for long term potassium homoeos- x For any pH change the eVect of acidae- [email protected] tasis, as well as the serum potassium concentra- mia is greater than alkalaemia. tion. On short term basis, serum potassium is Submitted 8 September x Non-organic (mineral acidosis) results in 2000 also regulated by the shift of potassium a shift of 0.24–1.7 mmol/l per 0.1 unit pH Accepted 14 June 2001 between the intracellular and extracellular change. Table 1 Regulators of potassium distribution between intracellular and extracellular x Organic acidosis has little to no eVect on compartment potassium shift. x Respiratory and metabolic alkalosis and Regulators Mechanism of action Potassium shift into cells respiratory acidosis result in similar small Insulin Activation of sodium-potassium Increase shift of potassium into and out of cell ATPase respectively (0.1–0.4 mmol/l on average). Catecholamines Activation of â receptors Increase 2 x In chronic acid-base disorders the ﬁnal Activation of á receptors Decrease Mineralocorticoids Unknown Mild increase potassium reﬂects primarily the eVect on Parathormone Unknown Mild decrease renal handling of potassium and to lesser Acid-base changes Exchange of H+ for K+ See table 2 extent of transcellular shift. Hyperosmolality Solvent drags Shifts potassium extracellularly

www.postgradmedj.com 760 Rastergar, Soleimani

Renal handling of potassium The filtered potassium (around 700–800 Box 2: Classification of hyperkalaemia mmol/day) is largely reabsorbed by proximal (1) Spurious hyperkalaemia nephron segments, including proximal convo- x Due to high platelet and/or leucocyte luted tubules and thick limb of Henle. The count. potassium that is excreted is, therefore, a result x Due to muscular activity during of secretion by distal segments, predominantly venepuncture. distal convoluted tubule and the collecting duct. Transport studies in these latter tubule (2) Transcellular shift of potassium segments have demonstrated that potassium x Acidaemia (for example, acute renal fail- secretion is accomplished via apical potassium ure). channels. The secretion of potassium in these x Hyperosmolality (for example, severe nephron segments is indirectly but tightly cou- hyperglycaemia). -blockers (for example, propranolol). pled to sodium reabsorption via the amiloride- x â2 sensitive sodium channel; increased sodium x Insulin deficiency (for example, type I reabsorption increases whereas decreased so- diabetes mellitus). dium reabsorption decreases potassium secre- (3) Increase intake tion. It is this secretory ability of the potassium x Infusion of potassium containing solu- channels in the distal segments which regulates tions. the excretion of potassium. As a result, any x Increase potassium intake in patients with condition that decreases the activity of renal defect in potassium excretion. potassium channels results in hyperkalaemia (4) Decrease renal excretion (for example, amiloride intake or aldosterone x Mineralocorticoid deficiency: (a) Addi- deficiency) whereas their increased activity son’s disease, (b) isolated aldosterone results in hypokalaemia (for example, primary deficiency, (c) renin deficiency (for exam- aldosteronism or Liddle’s syndrome). ple, diabetic nephropathy), (d) angio- In summary, kidney is the major regulator of tensin II receptor blockers, (e) angio- long term potassium homoeostasis and serum tensin converting enzyme inhibitors, (f) potassium. However, on short term basis, insu- use of non-steroidal anti-inflammatory lin and catecholamines, among others, regulate drugs. serum potassium through changes in transcel- x Resistance to mineralocorticoids eVect: lular distribution of potassium. (a) tubulointerstitial disease, (b) high dose mineralocorticoids antagonists (for Hyperkalaemia example, spironolactone, trimethoprim). Hyperkalaemia is defined as serum potassium x Severe renal failure. greater than 5.0 mmol/l. True hyperkalaemia should however be distinguished from pseudo- hyperkalaemia, a rise in serum potassium secondary to release of intracellular potassium metabolic acidosis; however, a sudden rise in during phlebotomy or storage of blood sample. osmolality, especially in association with insu- During phlebotomy the combination of venous lin deficiency, could result in significant hyper- occlusions and hand clinching could result in kalaemia. â-blockers alone are rarely associated potassium release locally. If this is suspected, a with significant hyperkalaemia, however, they blood sample should be drawn from a free could play a contributory part. flowing vein without fist clinching. Potassium Given the renal ability to excrete large can also be released in test tube by haemolysis, amount of potassium, increase in intake could severe thrombocytosis (usually >900 × 1010/l result in hyperkalaemia, only if associated with platelets) or leucocytosis (leucocytes >70 × 109/ subtle or overt defect in potassium excretion. l). If this is suspected the measurement should Salt substitutes, which may contains as much be repeated using fresh heparinised blood drawn as 200 mmol of potassium per tablespoon, are carefully to prevent haemolysis. major hidden sources of ingested potassium. The incidence of hyperkalaemia in hospital- Hyperkalaemia can also occur by infusion of ised patients varies depending on the level of potassium containing solution at a rate that can potassium used from 1.4% to 10%. In the larg- not be handled by transcellular shift and/or est study in a single hospital overall incidence renal excretion (see below under treatment of of hyperkalaemia (defined as serum potassium hypokalaemia). The most important cause of >6.0 mmol/l) was 1.4%. Potassium supple- hyperkalaemia is, however, decrease in renal mentation and potassium-sparing diuretics potassium excretion. This is seen in many dis- account for about one third of the cases. Severe orders including mineralocorticoid deficiency, hyperkalaemia is more common in older such as Addison’s disease or resistance to the patients with underlying renal insuYciency eVect of aldosterone such as seen in patients on treated with potassium supplementation. Hy- aldosterone antagonist drugs (box 2). Tri- perkalaemia accounts for approximately methoprim, a commonly used antimicrobial 1:1000 deaths in hospitalised patients (re- drug, is an important cause of hyperkalaemia in viewed by Ponce et al6). patients with mild renal failure.7 Although this side eVect is more common on high dose intra- CLASSIFICATION OF HYPERKALAEMIA venous therapy, it does occur on regular oral Hyperkalaemia could be due to transcellular dose. Patients with renal failure can often shift, increase in intake, and/or decrease in out- maintain near normal serum potassium unless put (box 2). Transcellular shift is often due to glomerular filtration rate decreases below 15

www.postgradmedj.com Hypokalaemia and hyperkalaemia 761

ml/min. However, a significant number of without a low renin level. In these patients we patients with renal disease have low aldoster- commonly do not embark on a costly and one levels with or without low renin level, or detailed evaluation and focus on long term have resistance to aldosterone eVect. This treatment. However in patients with normal group presents with mild to moderate renal renal function, and especially in patients failure and hyperkalaemia, often in association suspected of primary adrenal failure, a com- with renal tubular acidosis (type IV).8 plete work-up including measurement of aldosterone and cortisol level is mandatory. CLINICAL PRESENTATION One of the more overlooked and less well Hyperkalaemia is often asymptomatic and is understood causes of hyperkalaemia is the use discovered on routine laboratory tests. Patients of prostaglandin inhibitors or non-steroidal with severe hyperkalaemia (potassium >6.5 anti-inflamatory drugs (NSAIDS). Studies mmol/l) may, however, present with general- have shown that the use of NSAIDS, specifi- ised weakness, paralysis, and cardiac arrhyth- cally in conditions associated with raised basal mia, including cardiac stand still and sudden renal prostaglandins such as liver cirrhosis or death. In general, the severity of clinical mild renal insuYciency, can cause hyperkalae- presentation does correlate with the severity of mia by causing hypoaldosteronism. Two inde- hyperkalaemia. Changes in the electrocardio- pendent mechanisms are responsible for this gram (ECG) also reflect the severity of hyper- hyperkalaemia; first is the direct inhibition of kalaemia. In mild to moderate hyperkalaemia, renin synthesis by prostaglandin inhibition.11 changes in the ECG are subtle and often The second mechanism is indirect and is via limited to peaking of the T-wave. If hyperkalae- enhanced reabsorption of sodium and chloride mia is more severe, prolongation of PR and in the thick ascending limb which can result in QRS interval followed by loss of P wave and volume expansion and as a result suppress marked widening of QRS is seen. In extreme renin and aldosterone.11 hyperkalaemia, the ECG shows sine wave, If renal response to hyperkalaemia is appro- often followed by ventricular fibrillation. Al- priate (TTKG >5), increase in potassium though some patients show a gradual progres- intake, or transcellular shift of potassium sion of ECG findings, many progress rapidly should be suspected. As indicated above, tran- without warning. Therefore, hyperkalaemia in scellular shift most commonly occurs in the association with ECG changes is a true medical setting of metabolic acidosis, hyperosmolality, emergency. and/or insulin deficiency. If transcellular shift is ruled out, hyperkalaemia is probably due to an WORK-UP OF HYPERKALAEMIA increase in potassium intake, which should be It is important to stress that in severe hyperka- established by a careful dietary (including food laemia diagnostic work-up should be post- supplements) and drug history. poned until hyperkalaemia is treated. In other patients, if the cause of hyperkalaemia is not evident from the initial work-up, a stepwise MANAGEMENT OF HYPERKALAEMIA approach is recommended. The first step The initial management should be dictated by should be to evaluate the adequacy of the renal the changes in ECG. In the presence of ECG response to hyperkalaemia. Potassium excre- changes, hyperkalaemia should be considered tion is primarily through potassium secretion an emergency and treatment should begin in the cortical collecting duct. Urinary potas- immediately with calcium gluconate infusion. sium concentration is however greatly aVected This should be followed by use of insulin and by the amount of water reabsorbed in the col- glucose or albuterol to help shift potassium into lecting duct. To evaluate adequacy of renal the cell before a more definitive treatment, response it is therefore important that urinary cation exchange resin (sodium or calcium potassium to serum potassium ratio be cor- polysteryene sulphone resin) and/or dialysis, is rected for urinary concentration. This is simply used to remove potassium from the body. Insu- done by dividing the ratio of urinary potassium lin and albuterol have an additive eVect in low- to serum potassium by the ratio of urinary ering serum potassium.12 Table 2 summarises osmolality to serum osmolality (urinary potas- emergency treatment for severe hyperkalaemia. sium:serum potassium/urinary osmolality:se- Although sodium bicarbonate use has fallen rum osmolality). This ratio, referred to as tran- out of favour in patients on dialysis, it should stubular potassium gradient or TTKG, is >5 be considered in patients with significant and often 7 in hyperkalaemia and <1 in acidaemia where it is expected that infusion of hypokalaemia.910 It is worth mentioning that bicarbonate would increase serum pH signifi- the cut oV values of >5 or <1 are indicative of a cantly.13 Cation exchange resin mixed with sorbi- non-renal cause for high or low potassium, tol should be used orally if hyperkalaemia is not respectively. This formula, however, can not be life threatening, however resin mixed with used if urine is more dilute than the serum or water (and not sorbitol) can be repeated hourly contains very little sodium.910 for rapid removal of potassium. It should be The next step is to establish if low urinary remembered that each gram of sodium polysty- potassium excretion is due to low aldosterone or rene resin (Kayexalate) removes 0.5–1.0 mmol to resistance to aldosterone eVect by measuring of potassium in exchange for 2–3 mmol of serum aldosterone level. In patients with sodium. Therefore Kayexalate use is associated underlying renal disease hyperkalaemic renal with significant sodium infusion and can result tubular acidosis is a very common finding and in volume overload. In addition several cases of is often due to hypoaldosteronism with or colonic perforation have been reported in

www.postgradmedj.com 762 Rastergar, Soleimani

Table 2 Treatment of hyperkalaemia

Mechanism of action Therapy Onset/duration Dose I. Membrane stabilisation Calcium 1–3 min/30–60 min Calcium gluconate 10% 10 ml iv II. Shift of potassium intracellularly Insulin 20 min/4–6 hours 10 U regular insulin iv with 50 ml 50% dextrose

â2-adrenergic agonist 20 min/2–4 hours Dose depending on the type of agonist used III. Removal of potassium Sodium or calcium polystyrene sulphone 1–2 hours/4–6 hours 15 g every six hours orally or 30–60 g by retention enema Dialysis Immediate/duration of dialysis 2–3 hours haemodialysis iv = intravenous. patients treated with Kayexalate mixed with loop diuretics) or in patients with gastro- sorbitol.14 intestinal diseases (diarrhoea). Thiazide and After the acute treatment of hyperkalaemia, a loop diuretics increase delivery of sodium to long term plan should be devised to prevent the collecting ducts, where it is reabsorbed via recurrence of hyperkalaemia. Initially the treat- the amiloride-sensitive sodium channel, there- ment should be directed toward correction of fore creating a favourable gradient for potas- the underlying cause of hyperkalaemia (such as sium secretion via potassium channels. In replacement therapy in patients with Addison’s addition, volume depletion that results from disease). If hyperkalaemia is due to use of drug these diuretics increases aldosterone (by activa- (such as aldosterone antagonists or potassium tion of renin-angiotensin-aldosterone path- supplements), these should be discontinued. If way), further increasing potassium secretion hyperkalaemia is due to tubular defect in via the secretory potassium channels in the potassium secretion in association with renal collecting ducts. Increased aldosterone, in failure, several therapeutic manoeuvres should addition, can cause metabolic alkalosis by be considered including: increasing hydrogen mediated bicarbonate rea- x Hydration and volume expansion to increase bsorption in the collecting duct. This latter urine flow rate and sodium delivery to phenomenon can worsen the diuretic-induced exchange site. hypokalaemia by increasing potssium shift into x Use of loop diuretics to increase sodium cells. The diuretic acetazolamide, which causes delivery and stimulate potassium excretion. metabolic acidosis by decreasing bicarbonate x Restriction of dietary potassium intake to reabsorption in the proximal tubule, increases approximately 60 mmol/day. potassium excretion by increasing the delivery x Use of oral mineralocorticoids such as of sodium and bicarbonate to the distal fludrocortisone in supraphysiological doses. nephrons. Hypokalaemia can also be due by Most patients can be managed without use increased loss in the stool in patients taking of fludrocortisone, however in some patients large doses of laxatives or having diarrhoea. use of this drug in doses of 0.4–1.0 mg Hypokalaemia due to potassium shift into cells is caused by medications, hormonal maybe needed. Hypertension and/or 34815 oedema formation maybe a limiting side dysregulation, or raised blood pH. These medications include -sympathomimetics eVects in use of this drug. â2 (that is brochodilators such as albuterol) or phosphodiesterase inhibitors (that is theophyl- Hypokalaemia Hypokalaemia is probably the most common line and caVeine), exogenous insulin and rarely electrolyte abnormality in hospitalised patients. calcium channel blockers. Decreased potas- It is usually defined as a serum potassium of sium intake (less than 1 g/day), while rare, can lead to hypokalaemia. This is due to obligatory less than 3.5 mmol/l. Patients with mild potassium loss of 10–15 mmol/day by the kid- hypokalaemia (serum potassium 3.0–3.5 ney despite a low potassium intake. mmol/l) usually have no symptoms. However, Among other disorders causing hypokalae- with more severe hypokalaemia (serum potas- mia magnesium depletion needs special em- sium of less than 2.5 mmol/l), generalised phasis.14 Magnesium depletion, which is weakness can occur. In addition, patients with caused by either decreased dietary intake or severe hypokalaemia can develop muscle increased loss, is a common electrolyte disor- necrosis (rhabdomyolysis) and paralysis. Both der in hospitalised patients. It can cause severe mild and severe hypokalaemia can increase the hypokalaemia by increasing renal potassium incidence of cardiac arrhythmias. loss. The exact mechanism is, however, re- mains unclear. Hypokalaemia is also a com- CLASSIFICATION OF HYPOKALAEMIA mon finding in patients with raised serum Hypokalaemia can result from increased loss, aldosterone either secondary to the activation transcellular shift, or decreased intake of of the renin-angiotensin system (Bartter’s syn- potassium.348 Increased potassium loss drome or Gitelman’s syndrome) or due to (through the kidney or gastrointestinal tract) is overproduction by aldosterone-producing tu- the most common cause of hypokalaemia. Less mours (primary aldosteronism). frequently, hypokalaemia can occur as a result of shift of potassium from the extracellular CLINICAL PRESENTATION OF HYPOKALAEMIA space into cells. Rarely, hypokalaemia can Similar to hyperkalaemia, hypokalaemia is result from decreased intake of potassium. often asymptomatic. This is specifically true in Increased potassium loss, which is the most patients with mild hypokalaemia (serum potas- common cause of hypokalaemia, occurs mostly sium 3.0–3.5 mmol/l). Patients with more in patients who are on diuretics (thiazide or severe hypokalaemia (serum potassium of less

www.postgradmedj.com Hypokalaemia and hyperkalaemia 763

than 2.5 mmol/l) usually present with general- caused by a potassium shift due to medication ised weakness and, in some cases, ascending or alkalaemia, however prolonged hypokalae- paralysis. In addition, severe hypokalaemia can mia is commonly due to renal or gastro- precipitate rhabdomyolysis which manifests as intestinal loss of potassium. The most common muscle tenderness and swelling. Cardiac ar- causes of hypokalaemia in clinical practice are rhythmias are common in hypokalaemia, spe- due to diuretics and gastrointestinal loss cifically in patients with underlying heart secondary to diarrhoea and/or vomiting. These disease or on digoxin. In moderate to severe aetiologies should therefore be considered first hypokalaemia changes in ECG are minimal before exhaustive and sophisticated work-up is and is often limited to the presence of a U initiated. In other patients the initial step is to wave. see if hypokalaemia is in association with systemic hypertension or not. In the former RENAL SYNDROMES ASSOCIATED WITH group hypokalaemia is associated with a high HYPOKALAEMIA mineralocorticoid eVect due to high aldoster- In addition to the above clinical symptoms, one (as in primary aldosteronoma or renal hypokalaemia can cause several distinct renal artery stenosis) or cortisol as in Cushing’s dis- syndromes as will be discussed below. ease or hyperactive sodium channel as in Liddle’s syndrome. Measurement of the renin, Nephrogenic diabetes insipidus aldosterone, and cortisol concentrations under Hypokalaemia can impair urinary concentrat- appropriate conditions would help in diVeren- ing mechanism and result in nephrogenic tiating among these aetiologies. In normoten- diabetes insipidus. Patients with nephrogenic sive patients, hypokalaemia could be secondary diabetes insipidus due to hypokalaemia present to overt or occult gastrointestinal loss or due to with polyuria and polydipsia. Molecular stud- renal potassium wasting. Although low urinary ies have demonstrated that potassium deple- potassium (less than 15 mmol/l) would favour tion causes downregulation of the water chan- gastrointestinal loss, high urinary potassium is nel aquaporin 2 in the collecting duct, seen in patients with vomiting or diarrhoea due therefore impairing the renal concentrating to secondary elevation in the aldosterone level mechanism and resulting in polyuria.16 and is therefore not very helpful. In normoten- sive patients with renal potassium wasting, a Metabolic alkalosis low serum bicarbonate would favour the diag- Hypokalaemia can contribute to the mainte- nosis of renal tubular acidosis, while a high nance of metabolic alkalosis in several disease serum bicarbonate is compatible with the high states (such as vomiting) by enhancing bicar- mineralocorticoid eVect seen in patients with bonate absorbing ability of renal tubules.17–20 Bartter’s or Gitelman’s syndromes. Magne- This in turn decreases the ability of the kidney sium deficiency can result in renal potassium to excrete the excess bicarbonate and as a result wasting and is often seen in alcoholics who are maintains the plasma bicarbonate at a raised also nutritionally depleted. Diuretic and/or level.17 Functional and molecular studies in laxative abuse often mimics these rare syn- luminal and basolateral membranes of kidney dromes and should be considered in any adult proximal tubules and in microperfused kidney patient with hypokalaemia of unknown aeti- nephrons have demonstrated that hypokalae- ology and ruled out by urinary test for specific mia upregulates the expression of bicarbonate diuretics and stool test for phenolphthalein. absorbing transporters in proximal tubules and 17–20 cortical and medullary collecting ducts. MANAGEMENT OF HYPOKALAEMIA There is also evidence in support of hypokalae- The management of hypokalaemia is almost mia being involved in the generation of always by potassium replacement, with the metabolic alkalosis in human by increasing amount of potassium supplement depending ammoniagenesis.17 on the severity of hypokalaemia (box 4). The potassium can be given orally (in mild to Enhanced renal chloride excretion moerate hypokalaemia) or intravenously (in Hypokalaemia increases urinary chloride ex- severe hypokalaemia). When given intrave- cretion.19 20 Functional and molecular studies nously, the rate of potassium administration in the kidney have demonstrated that renal should not exceed 20 mmol/hour. To calculate chloride wasting in hypokalaemia is due to the amount of potassium supplement, one suppression of the apical sodium-potassium- should have an estimate of the potassium defi- chloride cotransporter in the thick limb of cit. On average, a reduction of serum potas- Henle and the apical sodium-chloride cotrans- sium by 0.3 mmol/l suggests a total body defi- porter in the distal convoluted tubule.21 It is cit of 100 mmol. Based on this formula, a possible that by increasing renal chloride patient with a serum potassium of 2.6 mmol/l excretion, hypokalaemia can result in hypo- needs at least 300 mmol of potassium for the chloraemia, which in turn can contribute to the correction of the deficit. In calculating the total maintenance of metabolic alkalosis in patho- body potassium deficit one has to consider fac- physiological states.17 tors that can independently aVect serum potassium. A patient with a serum potassium of WORK-UP OF HYPOKALAEMIA 2.6 mmol/l has less total body deficit at blood In working up patients with hypokalaemia a pH of 7.5 than 7.3. The reason is that alkaline combination of common sense as well as serum pH (that is, 7.5) can independently pathophysiology should be used (box 3). Tran- lower the serum potassium by intracellular sient short term hypokalaemia is usually shift.

www.postgradmedj.com 764 Rastergar, Soleimani

potassium phosphate and potassium bicarbo- Box 3: Work-up of hypokalaemia nate can be used in certain conditions. Potas- (1) Acute hypokalaemia (less than 12 hours of sium phosphate can be used in patients with onset) combined potassium and phosphate depletion x Alkalosis (metabolic or respiratory). (for example in patients with liver cirrhosis or x Insulin therapy (for example, in severe diabetic ketoacidosis). Potassium bicarbonate hyperglycaemia). can be used in patients with potassium depletion

x â2-stimulant (for example, albuterol). and metabolic acidosis (for example in distal (2) Chronic hypokalaemia (more than 24 renal tubular acidosis). Aside from intravenous hours of onset) potassium chloride for severe hypokalaemia, x With normal blood pressure. mild or moderate hypokalaemia (see above) can (A) Increased potassium loss through be treated with oral potassium chloride. Usually, gastrointestinal tract: (i) diarrhoea, (ii) laxa- 50 to 100 mmol of potassium chloride is tives. required per day to maintain serum potassium (B) Increased potassium loss through kid- concentration within the normal range in ney: (i) diuretics, (ii) hypomagnesaemia, patients with increased potassium loss (that is, in (iii) renal tubular acidosis (proximal and patients receiving a diuretic). distal), (iv) genetic defects (for example, Bartter’s syndrome, Gitelman’s syndrome). With high blood pressure. 1 Rosa RM, Williams ME, Epstein FH. Extrarenal potassium x metabolism. In: Seldin DW, Giebisch G, eds. The kidney, (A) Increased aldosterone: (i) primary physiology and pathophysiology. New York: Raven, 1992: aldosteronism (low renin), (ii) renal artery 2165–90. 2 DeFronzo RA, Felig P, Ferrannini E, et al.EVect of graded stenosis (high renin), (iii) Cushing’s disease doses of insulin on splanchnic and peripheral potassium (high renin). metabolism in man. Am J Physiol 1980;238:E421–7. (B) Normal or low aldosterone: (i) hyperac- 3 Brown MJ, Brown DC, Murphy MB. Hypokalemia from beta-2 receptor stimulation by circulating epinephrine. N tive sodium channel (Liddle’s syndrome), Engl J Med 1983;309:1414–19. (ii) increased liquorice intake. 4 Androgue HJ, Madias NE. Changes in plasma potassium concentration during acute acid-base disturbances. Am J Med 1981;71:456–67. 5 Fulop M. Serum potassium in lactic and keto acidosis. N Engl J Med 1979; 300:1087–90. 6 Ponce SP, Jennings AE, Madias NE, et al. Drug-induced Box 4: Treatment of hypokalaemia hyperkalemia. Medicine 1985;64:357–70. 7 Velazquez H, Perazella MA, Wright FS, et al. Renal (1) Intravenous potassium (as potassium mechanism of trimethoprim-induced hyperkalemia. Ann chloride) Intern Med 1993;119:293–301. Usually reserved for severe hypokalaemia 8 Dubose TD Jr. Hyperkalemic hyperchloremic metabolic x acidosis: pathophysiologic insight. Kidney Int 1997;51:591– (serum potassium of <2.6 mmol/l). 602. x The rate of should not exceed 20 9 Ethier JH, Kamel KS, Magner PO, et al. The transtubular potassium concentration in patients with hypokalemia and mmol/hour. hyperkalemia. Am J Kidney Dis 1990;15:309–15. 10 Kamel KS, Quaggin S, Scheich A, et al. Disorders of potas- (2) Oral potassium sium homeostasis: an approach based on pathophysiology. x Potassium chloride: 40–100 mmol/day in Am J Kidney Dis 1994;24:597–613. divided doses. 11 Wright FS, Giebisch G. Regulation of potassium excretion. In: Seldin DW, Giebisch G, eds. The kidney: physiology and x Potassium phosphate (in patients with pathophysiology. 2nd Ed. New York: Raven Press, 1992: hypokalaemia and hypophsphataemia). 2209–48. x Potassium bicarbonate (in patients with 12 Allon M, Copkney C. Albuterol and insulin for treatment of hyperkalemia in hemodialysis patients. Kidney Int 1990;38: acidosis). 869–72. 13 Blumberg A, Weidman P, Shaw S, et al. EVect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure. Am J Med 1988; 85:507–12. Box 5: Selected bibliography 14 Rashid A, Hamilton SR. Necrosis of gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate x Rastegar A, DeFronzo RA. Disorders of (Kayexalate) in sorbitol: an underrecognized condition. Am J Surg Pathol 1997;21: 60–9. potassium and acid-base metabolism in 15 Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451–7. association with renal disease. In: Schrier 16 Amlal H, Krane CM, Chen QK, et al. Early polyuria and RW, Gottschalk CW, eds. urinary concentrating defect in potassium deprivation. Am J Diseases of the Physiol 2000;279:F655–63. kidney. 6th Ed. Boston: Little, Brown, 17 Alpern RJ, Emmett M, Seldin DW. Metabolic alkalosis. In: 1997: 2452–77. Seldin DW, Giebisch G, eds. The kidney: physiology and pathophysiology. 2nd Ed. New York: Raven Press, 1992: 2733–56. x Halperin M, Kamel KS. Potassium. Lan- 18 Soleimani M, Bergman JA, Hosford MA, et al. Potassium + = - cet 1998;352:135–40. depletion increases Na :CO3 :HCO3 cotransport in rat x Gennari FJ. Hypokalemia. renal cortex. J Clin Invest 1990;86:1076–83. N Engl J Med 19 Amlal H, Habo K, Soleimani M. Potassium depletion 1998; :451–7. + - 339 upregulates the expression of the renal basolateral Na :HCO3 cotransporter (NBC-1). Am J Physiol 2000;279:F532–43. 20 Silver R, Soleimani M. H+-K+-ATPases: regulation and role in pathophysiologic states. Am J Physiol 1999;276:F799–811. 21 Amlal H, Wang Z, Soleimani M. Potassium depletion In addition to potassium chloride, which is downregulates chloride-absorbing transporters in rat kid- commonly used in treating hypokalaemias, ney. J Clin Invest 1998;101:1045–54.