Cotrimoxazole-induced hyperkalaemia in a patient with known hypoaldosteronism
- Annalisa Montebello and
- Mark Gruppetta
- Department of Diabetes and Endocrinology, Mater Dei Hospital, Msida, Malta
- Correspondence to Dr Annalisa Montebello; a.montebello@smd18.qmul.ac.uk
Abstract
A70-year-old man, with established hypoadrenalism due to a previous bilateral adrenalectomy, was admitted with recurrent episodes of postural dizziness and presyncope. He had been discharged from hospital 3 weeks earlier on a 1-month course of cotrimoxazole following a diagnosis of prostatitis. His electrolytes on admission showed new onset hyponatraemia and hyperkalaemia.
His usual glucocorticoid replacement dose was doubled in view of a presumed diagnosis of hypocortisolaemia. However, the hyperkalaemia persisted. On rereviewing his treatment, we suspected a possible diagnosis of cotrimoxazole-induced hyperkalaemia. Cotrimoxazole was stopped and ciprofloxacin started instead. His fludrocortisone replacement was doubled for 3 days after stopping treatment to decrease his postural symptoms. His postural symptoms improved, his serum potassium decreased to normal levels and he was safely discharged.
It is essential to remember that cotrimoxazole, a commonly used antibiotic, can induce a potentially fatal hyperkalaemia especially in patients with known hypoadrenalism.
Background
Cotrimoxazole is a frequently prescribed antibiotic made up of a combination of trimethoprim and sulfamethaxozole; which act synergistically in a bacteriostatic manner. It is effective against a wide variety of bacteria. It is generally well tolerated, and side effects occur in 6%–8% of patients.1
Trimethoprim inhibits the epithelial sodium channels located on the luminal membrane of the distal nephron segments preventing sodium reabsorption. The binding of aldosterone to mineralocorticoid receptors in the collecting duct leads to opening of the same epithelial sodium channels. Thus, trimethoprim is a competitive inhibitor for aldosterone.
Sodium reabsorption is vital as it generates an electrochemical gradient that drives the Na/K/ATPase pump on the basolateral membrane. This pump is required to reabsorb sodium and secrete potassium. In patients with known hypoaldosteronism, hyperkalaemia may develop with administration of cotrimoxazole.
Case presentation
A 70-year-old man was admitted to hospital with severe sepsis. He was diagnosed with acute prostatitis and started on a 1-month course of cotrimoxazole (trimethoprim–sulfamethoxazole). He was discharged only to be readmitted 3 weeks later due to recurrent episodes of postural dizziness and presyncope.
His medical history was significant for a left nephrectomy and bilateral adrenalectomy performed in view of left renal cell carcinoma invading the left adrenal gland with contralateral right adrenal metastases. In view of this, he was on long-term hydrocortisone and fludrocortisone replacement. His other medications were amlodipine, trifluoperazine and procyclidine.
His bloods on admission showed no evidence of an acute infective process (table 1). However, an acute development of renal injury, hyponatraemia and hyperkalaemia were noted. His electrolytes had been normal prior to discharge (table 1). Calcium resonium was initiated as initial measure to correct the hyperkalaemia. He was noted to have a significant postural drop from 144/94 mm Hg in the lying position to 89/64 mm Hg after 2 min standing. He had no resting hypotension.
Renal function and electrolytes at different time frames
| Test | Prior to starting cotrimoxazole 8 May 2020 | Result on admission 28 May 2020 | Post cotrimoxazole removal 15 July 2020 | Range | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| The above results show development of an acute renal injury with hyperkalaemia andhyponatraemia on admission. Resolution of electrolyte imbalances is seen after removing cotrimoxazole. An element of renal impairment remains. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Creatinine | 90 | 133 | 120 | 59–104 μmol/L | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sodium | 143 | 125 | 140 | 136–145 mmol/L | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Potassium | 3.8 | 5.96 | 4.78 | 3.5–5.1 mmol/L | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Chloride | 93.6 | 89.8 | 101.1 | 98–107 mmol/L | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Urea | 3.7 | 9.3 | 6.8 | 1.7–8.3 mmol/L | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Estimated glomerular filtration rate | 77 | 49 | 55 | Ml/min | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| WCC | 15.24 | 9.41 | 11.25 | 4.30–11.40×10ˆ9/L | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neutrophils | 10.33 | 4.09 | 6.49 | 2.10–7.20×10ˆ9/L | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CRP | 31.4 | 5 | 2 | 0–5 mg/L | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigations
A serum renin level taken while the patient was on cotrimoxazole was abnormally high. Serum renin levels are elevated in response to hyponatraemia and hypovolaemia,2 but may also be elevated in this case because despite being compliant to his usual dose of fludrocortisone, it was not being effective. A repeat renin level 3 weeks after stopping cotrimoxazole had decreased to 37.3 (table 2). The aldosterone level is undetectable as the patient had a previous bilateral adrenalectomy.
Renin, aldosterone and aldosterone renin ratio
| Test | On cotrimoxazole | Three weeks off cotrimoxazole | Range |
|---|---|---|---|
| Renin | 182++ | 37.3 | 2.6–28 ng/L |
| Aldosterone | <1.5 | <1.5 | 1.2–24 ng/dL |
| Aldosterone renin ratio | <0.1 | <0.4 | <19.0 |
Differential diagnosis
The differential diagnosis in this case was functional hypoaldosteronism versus hypocortisolism. These can both present in the same manner with postural dizziness.
In our case, the patients’ glucocorticoid dose was doubled considering the stressful nature of inpatient stay, despite there being no evidence of acute infection. The persistence of symptoms and lack of electrolyte correction prompted investigations for hypoaldosteronism.
On reviewing his treatment, it was clear that cotrimoxazole was causing functional hypoaldosteronism leading to hyponatraemia and hyperkalemia. His sodium corrected with intravenous fluids but his potassium failed to correct. Both the hyperkalaemia and his symptoms improved on stopping the drug suggesting that cotrimoxazole was the culprit.
Outcome and follow-up
Stopping the cotrimoxazole and changing to a different antibiotic resulted in correction of the electrolyte imbalance. Unfortunately, our patient still has mild renal impairment and his potassium is in the upper range of normal levels. An ultrasound of the kidneys performed soon after discharge shows that the right kidney is normal in size and corticomedullary differentiation.
Discussion
In patients with known adrenal insufficiency standard doses of trimethoprim may lead to development of hyperkalaemia. Trimethoprim is structurally similar to amiloride and reversibly inhibits the amiloride sensitive sodium channels located on the luminal surface of the proximal cells in the collecting duct. Normally, these channels reabsorb luminal sodium to create a lumen negative electrochemical gradient across the principal cells. This gradient is necessary to bring about sodium reabsorption and potassium excretion.3
Aldosterone binds to mineralocorticoid receptors in the distal nephron and likewise results in opening of these amiloride sensitive sodium channels. Trimethoprim may thus lead to a state of functional hypoaldosteronism as it competitively inhibits these same channels. This results in hyponatraemia and hyperkalaemia.4 Functional hypoaldosteronism produces a type 4 renal tubular acidosis with hyperkalaemia and a hyperchloraemic metabolic acidosis. The main driving factor for metabolic acidosis is lack of ammonia production in the distal nephron.
Our patient developed acute hyperkalaemia 3 weeks after starting cotrimoxazole. Cotrimoxazole usually causes hyperkalaemia on day 7–10 of treatment.5 The hyperkalaemia associated with trimethoprim is dose dependent. It is usually seen with administration of very high doses of trimethoprim in AIDS patients.6–8 However, trimethoprim can cause high potassium at the usual doses in older adults.9–13
Patients with renal insufficiency are at an increased risk of high potassium.10 Older patients on ACE inhibitors or angiotensin receptor blockers (ARBs) are at increased risk of hyperkalaemia on trimethoprim.14 A case control study of 371 patients 66 years or above who were on ACE inhibitors or ARBs developed high potassium within 14 days after starting the antibiotic. These patients may have also had underlying diabetic nephropathy or were receiving nephrotoxic drugs.14 In patients receiving spironolactone, ACE or ARBs with trimethoprim sudden death has been reported.15 16
Management involves stopping trimethoprim. If this cannot occur, intravenous fluids, loop diuretics and urine alkalinisation may be attempted. Intravenous saline expands the intracellular space and increases urine output. Loop diuretics increase the urinary flow of sodium available for the sodium channels. Sodium bicarbonate may be administered both orally or intravenously to increase urinary pH. Urine alkalinisation increases the production of the non-protonated form of trimethoprim which produces less inhibition of the sodium channels.17
Motayar and Trawick used a combination of fludrocortisone and a loop diuretic to correct septrin induced hyperkalaemia in an HIV patient with Pneumocystis jirovecii pneumonia. Fludrocortisone increases transcription of the amiloride sensitive sodium channels resulting in an overexpression of these channels to counteract the effect of cotrimoxazole. The loop diuretic helps in natriuresis, thus increasing the delivery of sodium to these channels.18
Learning points
-
Administration of cotrimoxazole may lead to a potentially lethal hyperkalaemia.
-
This side effect is more prominent with high doses of cotrimoxazole, in elderly patients, in patients with renal insufficiency or with coadministration of nephrotoxic drugs.
-
Trimethoprim is a competitive inhibitor for aldosterone. Thus, patients with known hypoaldosteronism are also at an increased risk for developing hyperkalaemia when administered this medication.
Footnotes
-
Contributors AM wrote up the case with constant reviews, supervision and guidance from MG.
-
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
-
Competing interests None declared.
-
Patient consent for publication Obtained.
-
Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
Use of this content is subject to our disclaimer