Nephrol Dial Transplant (1997) 13: 2402–2406 Continuing Nephrological Education (CNE) Iatrogenic hyperkalaemia—points to consider in diagnosis and

Kostas C. Siamopoulos, Moses Elisaf and Kostas Katopodis Department of Internal Medicine, Division of Nephrology, University Hospital of Ioannina, Greece Introduction
6.1 mmol/l ) and renal impairment (serum creatinine160 mmol/l, creatinine clearance 60 ml/min). Labor-atory investigation established the diagnosis of hypo- Hyperkalaemia is a potentially life-threatening electro- reninaemic hypoaldosteronism secondary to chronic lyte abnormality. In normal subjects it is rare because interstitial nephritis of unknown origin. A low- the homeostatic mechanisms to maintain normokalae- potassium diet plus small doses of frusemide were mia are highly effective. In particular, the capacity of introduced and the patient was discharged. A few days renal potassium excretion is very high under normal later he developed a urinary tract infection due to E circumstances [1–4]. Consequently, hyperkalaemia is coli and co-trimoxazole in conventional doses (1600 mg practically always associated with impaired urinary of sulphamethoxazole+320 mg of trimethoprim) was potassium excretion [5], but in patients with acute or administered. Five days later the patient was referred chronic renal failure high potassium intake can to our hospital with profound muscle weakness, further contribute to the development of hyperkalae- nausea, and constipation. Laboratory investigation on the patient’s admission showed severe hyperkalaemia We describe three cases of iatrogenic hyperkalaemia (serum potassium 7.8 mmol/l ) with ECG changes secondary to drug therapy. The cases illustrate the (peaked narrow T waves and a shortened QT interval ).
wide spectrum of causes and preconditioning circum- Hyperkalaemia was accompanied by low potas- stances. Based on these cases we discuss the appropriate sium excretion (urine potassium 19 mmol/l, FEK+ 9%, clinical management of this problem.
TTKG 2.4). Additionally, a normal anion gap hyper-chloraemic metabolic acidosis with an arterial pH of Case report 1
7.29, a pCO2 of 32 mmHg, a serum chloride level of 112 mmol/l, a serum bicarbonate of 15 mmol/l, a urine A 71-year-old man was admitted to our hospital anion gap of 23 mmol/l, and a urine pH of 5.1 was for evaluation of hyperkalaemia (serum potassium found. There was also evidence of a low urea excretion( FE 7.2%) in the face of the serum urea levels Table 1. Causes of hyperkalaemia
(6.6 mmol/l ). Co-trimoxazole was discontinued andhyperkalaemia was appropriately treated. Serum 1. Increased (oral/intravenous) potassium intake potassium levels were then stabilized at 5.5–6 mmol/l.
2. Increased potassium release from cells Case report 2
Insulin deficiency, hyperglycaemia and hyperosmolalityb-Adrenergic blockers A 73-year-old woman with a history of hypertension, Increased tissue catabolismSevere exercise non-insulin-dependent diabetes mellitus and hyperlipi- daemia was admitted because of malaise, diffuse muscle Drugs: digitalis overdose, succinylcholine, arginine pain and marked weakness. She had been given quinap- 3. Reduced urinary potassium excretion ril, amlodipine, gliclazide, and long-acting bezafibrate.
On physical examination all muscle groups were extremely tender and she could not raise her limbs.
Selective impairment of potassium excretionHypoaldosteronism Laboratory investigation on patient’s admission wereas follows: haematocrit 34%, white blood cell count8000/ml, platelet count 200 000/ml, serum glucose Correspondence and offprint requests to: Kostas C. Siamopoulos MSc 19.9 mmol/l, creatinine 186 mmol/l, urea 42.5 mmol/l, MD FRSH, Professor of Medicine/Nephrology, Division of potassium 6.5 mmol/l, uric acid 512 mmol/l, sodium Nephrology, University Hospital of Ioannina, GR 455 50Ioannina, Greece.
140 mmol/l, chloride 100 mmol/l, SGOT 860 IU 1998 European Renal Association–European Dialysis and Transplant Association Iatrogenic hyperkalaemia—points to consider in diagnosis and management (normal values 5–40 IU/l ), SGPT 335 IU/l (normal increasing in recent years. In practically all patients values 5–40 IU/l ), CK 22 000 IU/l (normal values with sustained elevation of serum potassium concentra- 40–190 IU/l ), LDH 4280 IU (normal values 225–450 tion predisposing conditions can be found, which inter- IU/l ), and aldolase 730 IU (normal values 0–8 IU/l ).
fere with potassium homeostasis and especially with pCO2 renal potassium excretion. Examples include renal 34.5 mmHg, and bicarbonate 16 mmol/l. The serum insufficiency (even of mild degree) or hypoaldosteron- anion gap was 24 mmol/l. The patient’s urine was ism ( Table 2) and this is also illustrated by our patients brown, cloudy, and strongly positive for blood. The [6–8]. It is of interest that typically the patients were urinalysis contained scarce granular casts, 14–20 white elderly: In elderly subjects age-specific changes of renal cells and 15–20 red cells per high-power field. Fibrate function increase the risk of hyperkalaemia, particu- was discontinued, hyperkalaemia was properly treated, larly when other potassium-regulatory systems have and vigorous intravenous fluid therapy to correct the hypovolaemia was administered. Treatment was fol- The first case illustrates that conventional doses of lowed by a progressive decrease in serum creatinine, trimethoprim may cause hyperkalaemia when addi- potassium and muscle enzymes towards normal tional predisposing conditions are present, i.e. in this values. On the patient’s discharge 10 days later, case advanced age with hyporeninaemic hypoaldos- muscle enzymes were normal, serum potassium was teronism [13–16 ]. Trimethoprim inhibits amiloride- 4.5 mmol/l, serum creatinine 132 mmol/l, and creatinine sensitive sodium channels in the distal nephron and dose-dependently reduces the transepithelial voltagewhich facilitates potassium secretion [17,18]. It hasbeen reported that even low doses of trimethoprim can Case report 3
significantly decrease net transepithelial sodium trans-port and thus lower potassium excretion [18]. In so- A 74-year-old patient was referred to our hospital with called renal tubular acidosis type IV, associated with acute weakness, fatigue, flatulence and vomiting. He hyporeninaemic hypoaldosteronism and hyperkalae- was hypertensive and was receiving quinapril 20 mg mia, tubular pH is typically low. This increases the once daily and a combination of frusemide plus amilor- concentration of the charged protonated species of ide (40 mg+5 mg) once daily. A mild impairment in trimethoprim, which blocks epithelial sodium channels renal function had been diagnosed (serum creatinine most effectively. Thus, the antikaliuretic effect of trime- 160 mmol/l ) 3 years before, as well as osteoporosis for thoprim is further increased [19]. Finally, nausea, as which he was administered vitamin D and calcium.
in our patient, reduces protein intake; low urea excre- revealed urea 71.4 mmol/l, creatinine 336 mmol/l, to a low flow rate and delivery of tubular fluid to the glucose 9.2 mmol/l, sodium 130 mmol/l, potassium cortical collecting duct. This may have further contrib- uted to a lower rate of potassium excretion in our patient and may have further exacerbated the impact of trimethoprim-mediated blockage of sodium channels 12 mmol/l, arterial pH 7.30, and pCO Creatinine clearance was 20 ml/min. Urinalysis showed Table 2. Causes of hypoaldosteronism
that the urine sediment contained 18–20 red cells and5–6 white cells per high-power field. Urine pH was Associated with decreased activity of the renin–angiotensin system 5.5. There were ECG changes suggestive of hyperkalae- mia (peaked narrow T waves and a shortened QT Hyporeninaemic hypoaldosteronism (diabetes mellitus most interval ). Both kidneys were of small size with Non-steroidal anti-inflammatory drugs (with possible exception increased echogenicity by ultrasonic examination.
haemodialysis sessions were carried out and the hyperkalaemia was corrected. A progressive clinical and laboratory improvement was achieved and he was discharged 5 days later when laboratory evalua- (a) low cortisol levels: primary adrenal insufficiency, congenital tion revealed urea 24 mmol/l, creatinine 168 mmol/l, potassium 4.8 mmol/l, sodium 146 mmol/l, calcium (b) normal cortisol levels: heparin, post-removal of 2.37 mmol/l, and arterial pH 7.35. A calcium-channel blocker was then given for blood pressure control.
hypoaldosteronism (in cases of severe illness) Aldosterone resistance with normal or increased Discussion
Potassium-sparing diureticsTrimethoprimCyclosporin These cases illustrate the wide spectrum of causes and Pseudohypoaldosteronism (hereditary or acquired resistance to clinical manifestations of drug-induced hyperkalaemia.
The incidence of this electrolyte abnormality has been Table 3. Drug-induced rhabdomyolysis
angiotensin II in the circulation and perhaps also inthe adrenal zona glomerulosa [33], and decrease both angiotensin II and potassium-mediated aldosterone release [33,34]. In patients with normal renal function, serum potassium rarely increases by more than 0.5 mmol/l [35]. In patients with diminished renal function, as in our patient, the rise in potassium concentration may be more marked, since the incre- ment is inversely related to GFR [26 ], particularly in patients with hyporeninaemic hypoaldosteronism (e.g. in diabetic nephropathy), in patients on beta- adrenergic blockers or in patients with potassium- sparing diuretics, as in our case [6,26,27,36–38]. The combination of potassium-sparing diuretics and ACE inhibitors should be avoided and the effects of potas- sium supplements on serum potassium concentrations must be closely monitored in elderly patients on ACE Table 4 summarizes the great number of drugs with reports on drug-induced hyperkalaemia.
on potassium excretion [20]. As to the management of kalaemia following a potassium load, severe exercise, such patients, it should be mentioned, that the antikali- or in the presence of hypoaldosteronism or renal failure uretic effects of trimethoprim are minimized by raising [39–42]. They alter transcellular partitioning of potas- urine pH [19], as well as by manoeuvres that increase sium and reduce the activity of the renin–aldosterone distal delivery of sodium, e.g. administration of system [5,39]. Central adrenergic inhibitors, e.g. cloni- dine, or beta-1-selective blockers, e.g. atenolol, inter- Drug-induced hyperkalaemia can also be caused by fere less with potassium homeostasis [43–45]. Non- drug-induced rhabdomyolysis, as illustrated by the steroidal anti-inflammatory drugs lower plasma renin.
second patient. Table 3 summarizes that, especially in As a consequence, plasma potassium concentration the elderly patient [22,23], a number of drugs, alone rises moderately, by approximately 0.2 mmol/l in sub- or in combination, can cause muscle damage, deteriora- jects with normal renal function, but may rise by more tion of renal function, and hyperkalaemia. Under than 1 mmol/l when renal function is impaired or when normal circumstances, the renal tubular cell will potassium homeostasis is strained, e.g. administration respond to an increase in serum potassium concentra- of potassium-sparing diuretics or non-cardioselective tion by augmenting potassium secretion. If tissue beta blockers [46–48]. Prolonged heparin administra- destruction is intense, the ability of the kidney to tion may cause hyperkalaemia via inhibition of adrenal excrete the potassium may be overwhelmed, so that 18-hydroxylase [49–53]; the risk of hyperkalaemia is hyperkalaemia ensues [24,25]. The risk is further exacerbated by administration of ACE inhibitors or aggravated, if rhabdomyolysis-induced renal failure presence of long-standing diabetes mellitus [49,52–55].
occurs. In this circumstance, hyperkalaemia may An interesting condition, recently reported, is selective became life threatening. In our case, administration ofACE inhibitors and the resulting relative hypoaldos- Table 4. Mechanisms of drug-induced hyperkalaemia
teronism, may have also interfered with potassiumexcretion [26,27], illustrating that not infrequently 1. Increased potassium release from cells several predisposing factors can be found in such complex situations. Hypolipidaemic drugs, e.g. fibrates and statins, may cause myolysis [28–30], specifically Insulin antagonists (somatostatin, diazoxide)Arginine hydrochloride when long-acting bezafibrate preparations are adminis- tered to elderly patients with reduced renal function without appropriate modification of the dose of the 2. Decreased activity of the renin–angiotensin axis drug [24,29,31,32]. Our case illustrates the necessity, particularly in the elderly patient, of adjusting the dose b-Adrenergic blockersNon-steroidal anti-inflammatory drugs to the renal function and to monitor CK levels as the first sign of impending muscle damage [24].
3. Inhibition of potassium secretion The third case illustrates that simultaneous adminis- tration of drugs with known hyperkalaemic potential may cause a dangerous increase in serum potassium concentration, again particularly in elderly patients with even minor reduction in renal function [6–8].
ACE inhibitors reduce conversion of angiotensin I to Iatrogenic hyperkalaemia—points to consider in diagnosis and management hypoaldosteronism in critically hypoxic patients which aldosteronism. Kidney Int 1980; 17: 118–134 predisposes to heparin-induced hyperkalaemia [12,56 ].
16. Williams GH. Hyporeninemic hypoaldosteronism. N Engl J Hyperkalaemia may also occur with low-molecular- weight heparin preparations [57,58]. Severe hyperkala- 17. Choi MJ, Fernandez PC, Patnaik A et al. Trimethoprim-induced emia has been reported after prolonged use of pentami- hyperkalemia in a patient with AIDS. N Engl J Med 1993;328: 703–706 dine to treat HIV-associated Pneumocystis carinii. Like 18. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal trimethoprim, pentamidine acts in the cortical col- mechanism of trimethoprim-induced hyperkalemia. Ann Intern lecting tubule to decrease the electrochemical driving force for potassium and hydrogen secretion [59].
19. Schreiber M, Schlanger LE, Chen C-B et al. Antikaliuretic action of trimethoprim is minimized by raising urine pH. Kidney Patients with HIV or AIDS who receive pentamidine or high doses of trimethoprim are at particular risk of 20. Schreiber M, Halperin ML. Urea excretion rate as a contributor hyperkalaemia [12,17,59]. This risk is further aggrav- to trimethoprim-induced hyperkalemia. Ann Intern Med 1994; presumably of infectious origin, e.g. cytomegalovirus 21. Reiser IW, Chou S-Y, Brown MI, Porush JG. Reversal of trimethoprim-induced antikaliuresis. Kidney Int 1996; 50: or mycoplasma avium intracellulare [60].
Cyclosporin A may cause hyperkalaemia by inhibit- 22. Zager RA. Rhabdomyolysis and myohemoglobinuric acute renal ing Na+–K+–ATPase activity, leading to diminished failure. Kidney Int 1996; 49: 314–326 potassium accumulation and transepithelial potential 23. Prendergast BD, George CF. Drug-induced rhabdomyolysis in potassium-secreting tubular cells, thus diminishing mechanisms and management. Postgrad Med J 1993; 69: 333–336 24. Terrovitou CT, Milionis HJ, Elisaf MS. Acute rhabdomyolysis the driving force for potassium secretion [61]. A role after bezafibrate re-exposure. Nephron (in press) of vasoconstriction and reduced GFR on the one hand 25. Demedts W, Desager Z, Belpaire F, Rinqoir S, Lameire N. Life and mineralocorticoid resistance on the other has also threatening hyperkalemia associated with clofibrate-induced myopathy in a CAPD patient. Perit Dial Bull 1983; 3: 15–16 26. Textror SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic patients during angiotensin-converting enzyme ATPase. Toxic doses, e.g. ingested in a suicide attempt, inhibition and aldosterone reduction with captopril. Am J Med It is obvious from the above that the physician in 27. Doman K, Perlmutter JA, Muhammedi M et al. Life-threatening charge of a patient with hyperkalaemia has to assess hyperkalemia associated with captopril administration. SouthMed J 1993; 86: 1269–1272 renal function and drug history of the patient carefully.
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