Renal potassium wasting from hydroxychloroquine at therapeutic doses: a case report

Abstract

Background

Hydroxychloroquine is a common disease-modifying treatment for systemic autoimmune disease and is usually well-tolerated. In acute hydroxychloroquine or chloroquine toxicity, hypokalemia typically reflects a transient intracellular potassium shift rather than true renal potassium losses. Persistent hypokalemia due to renal potassium wasting during therapeutic hydroxychloroquine use has not been well described.

Case Presentation

A 38-year-old woman with undifferentiated connective tissue disease developed recurrent symptomatic hypokalemia while receiving therapeutic hydroxychloroquine. She had normal renal function and blood pressure, and was not using diuretics or laxatives. Urine studies demonstrated inappropriate renal potassium loss during hypokalemia. Holding hydroxychloroquine for two weeks resulted in normalization of serum potassium levels, accompanied by symptom resolution. Rechallenge at a dose of 300 mg daily reproduced hypokalemia, which again resolved after drug discontinuation.

Discussion/Conclusion

The temporal relationship, objective urine indices, normalization after withdrawal, and recurrence with rechallenge suggest hydroxychloroquine-associated renal potassium wasting. The underlying mechanism remains uncertain and is hypothesized to involve tubular effects during chronic exposure. Clinicians should confirm the mechanism with urine studies when hypokalemia persists on hydroxychloroquine, consider a supervised medication hold when feasible, and pair potassium repletion with a potassium-sparing agent if the drug must continue.

Background

Hydroxychloroquine is a commonly used disease-modifying therapy for systemic autoimmune diseases, including systemic lupus erythematosus and related connective tissue disorders. It is generally well-tolerated at therapeutic doses up to 600 mg daily. Hydroxychloroquine is a lysosomotropic 4-aminoquinoline with a large apparent volume of distribution, a long terminal half-life, and measurable renal elimination of unchanged drug, which together provide sustained tubular exposure during chronic therapy [1, 2]. Patients with lupus and related autoimmune diseases are often treated with multiple medications, including corticosteroids, antihypertensives, and immunomodulatory agents, which can complicate attribution of electrolyte abnormalities.

In acute chloroquine or hydroxychloroquine toxicity, hypokalemia is well-described. It is typically attributed to a transient intracellular potassium shift rather than actual whole-body potassium depletion, with serum potassium levels often rebounding as the drug distribution normalizes [3, 4]. This pattern differs from chronic hypokalemia, which indicates an actual potassium deficit and poses significant neuromuscular and cardiac risks [5]. By contrast, persistent hypokalemia due to renal potassium wasting during therapeutic hydroxychloroquine use has not been well characterized and appears to be rare.

Chronic hypokalemia warrants evaluation for renal potassium loss, using urine potassium indices interpreted in conjunction with blood pressure and acid-base status. Failure to recognize renal potassium wasting may lead to recurrent symptoms such as muscle cramps, palpitations, and fatigue, which can overlap with manifestations of systemic autoimmune disease and be incorrectly attributed to disease activity. We report a patient with undifferentiated connective tissue disease treated with therapeutic hydroxychloroquine who developed chronic hypokalemia due to renal potassium wasting, demonstrated by objective urine studies and a clear medication withdrawal and rechallenge pattern.

Case presentation

This 38-year-old woman had a past medical history of undifferentiated connective tissue disease manifesting predominantly as arthralgia and fatigue. Serologies indicated antinuclear antibody positivity, anti -ribonucleoprotein positivity, and HLA B27 positivity. She was referred for persistent hypokalemia despite oral supplementation with potassium chloride. She was first evaluated for systemic symptoms of arthralgias and fatigue in 2017 and responded to short courses of corticosteroids. She subsequently began hydroxychloroquine in 2018 with improvement in fatigue, diffuse joint pain, and muscle twitching with potassium levels ranging from 3.1–3.4 mmol/L. During pregnancy in 2020 she discontinued hydroxychloroquine and reported remission of her arthralgias. At seven months of pregnancy, she restarted hydroxychloroquine to lower the risk of a postpartum flare and followed by her delivery in January 2021. She remained on therapy thereafter and continued rheumatology follow up.

In 2021, she presented to the emergency department with muscle cramps and fatigue after routine laboratories showed a serum potassium of 2.9 mmol/L. She denied any other symptoms, including vomiting, diarrhea, laxative use, or other gastrointestinal losses, and did not have symptoms suggestive of acid-base disturbance. Prior to that, her serum potassium levels ranged from 3.6–3.8 mmol/L. Her potassium was aggressively repleted with intravenous potassium chloride with an improvement to 4.1 mmol/L and she was discharged from the ER. Over the next two years, outpatient measurements showed serum potassium between 3.2 and 3.4 mmol/L, although with intermittent cramps and palpitations exacerbated with exercise. She remained normotensive at office visits, with blood pressure during visits being about 110 to 125 over 70 to 80 mmHg. Physical examination was unremarkable, with findings of normovolemia. Renal function remained normal with serum creatinine at 0.6 mg/dL with estimated glomerular filtration rate greater than 90 mL/min/1.73 m². Other electrolytes including serum sodium, chloride, and bicarbonate, were within reference ranges. She did not have hypomagnesemia with a serum magnesium level of 2.2 mg/dL. Table 1 depicts presenting lab values.

Table 1.

Presenting Lab Values

A Nephrology evaluation in 2023 included urine and endocrine testing. A spot urine potassium level was 114 mmol/L, with a urine creatinine level of 193 mg/dL. Using these values, the fractional excretion of potassium was high at 15% for ongoing hypokalemia [6, 7]. A 24-hour urine collection was ordered, which measured potassium excretion of 86 mmol/day for a serum potassium of 3.2 mmol/L. Other electrolytes for the same collection demonstrated the following: sodium: 176 mmol/day, chloride: 233 mmol/day, calcium: 117 mg/day, phosphorus: 530 mg/day, and a urine volume of 1.955 L in 24 hours. Plasma renin activity was normal at 1.87 ng/mL/h, with a normal serum aldosterone level of 8 ng/dL. Given the indications for renal potassium wasting, a 24-hour urine aldosterone was also measured by liquid chromatography tandem mass spectrometry, which was measured at 5.4. As discussed above, the patient remained normotensive. Total serum cortisol was 11.3 μg/dL drawn in the afternoon, which was within the laboratory’s reference interval for that time of day. Serum magnesium was normal at 2.2 mg/dL. TTKG was not calculated as urine osmolality measurements were unavailable. Table 2 demonstrates further urine studies. Figure 1 demonstrates potassium trends.

Table 2.

Urine Electrolyte Studies Obtained during Hypokalemia

Fig. 1.

Potassium Trend Over Time

A thorough review of her medications was performed, which demonstrated only hydroxychloroquine, vitamin D3, and potassium supplementation, which she took sporadically. Patient denied using any OTC supplements, diuretics, and especially indicated no ingestion of licorice, which is known to cause renal potassium wasting. She also denied any significant changes in her diet to induce weight loss. Given the propensity of hydroxychloroquine to cause potassium abnormalities at higher doses, we hypothesized that low doses of hydroxychloroquine may cause hypokalemia in some susceptible individuals.

We advised hydroxychloroquine to be temporarily put on hold for a trial of 2 weeks with serial sampling of serum electrolytes after the end of week 1 and 2. The patient was advised to continue oral potassium supplement KCl at 8 mEq daily. Serum potassium at the end of week 1 had improved to 3.4 mmol/L and by week 2 it had normalized to 4.1 mmol/L. She had improvement in her palpitations and muscle cramps with correction of her potassium levels being off hydroxychloroquine although her arthralgias recurred. To confirm that hypokalemia was indeed due to hydroxychloroquine, she was rechallenged with the same drug, but at a lower dose of 300 mg/day. Her serum potassium after hydroxychloroquine challenge was measured at 3.5 mmol/L, suggesting drug-induced hypokalemia. Adherence and tolerability were satisfactory with no adverse events. The patient exhibited no changes in her urine volume or bowel habits during this period.

Discussion

This case suggests chronic and persistent hypokalemia in a patient receiving therapeutic hydroxychloroquine, with urine studies demonstrating increased urinary potassium excretion. Although mild hypokalemia was intermittently present prior to hydroxychloroquine initiation, it was not persistent and was not associated with documented renal potassium wasting, in contrast to the recurrent hypokalemia with kaliuresis observed after hydroxychloroquine exposure. Hypokalemia at commonly used therapeutic doses of hydroxychloroquine has not been previously demonstrated. In acute chloroquine or hydroxychloroquine toxicity, hypokalemia typically results from a transient intracellular potassium shift and often normalizes as exposure wanes [3, 4]. The persistent hypokalemia observed in this patient, therefore, reflects true potassium depletion rather than redistribution.

Competing explanations were considered in light of the laboratory profile and clinical context. Primary hyperaldosteronism was unlikely given normal blood pressure and normal renin and aldosterone levels. Gitelman syndrome typically presents with hypomagnesemia and hypocalciuria, and Bartter syndrome is characterized by hypercalciuria and metabolic alkalosis, none of which were present. Autoimmune disease can cause acquired tubulopathies, including acquired Gitelman syndrome, and idiopathic hypokalemia has been described in lupus nephritis, but these reports are usually associated with hypomagnesemia, metabolic alkalosis, or hypocalciuria, features that were absent in this case [8–10]. Because this report did not involve experimental evaluation of tubular mechanisms, mechanistic considerations are presented only to establish biologic plausibility rather than causation.

Hydroxychloroquine pharmacokinetics make a kidney-mediated effect biologically plausible. The drug has a large apparent volume of distribution, a long terminal half-life, and measurable renal elimination of unchanged drug, resulting in sustained tubular exposure during chronic therapy [1, 2]. As an amphiphilic compound that accumulates in acidic intracellular compartments, hydroxychloroquine can alter lysosomal function, autophagy, and endolysosomal trafficking [11, 12]. Whether these effects directly influence potassium handling in the distal nephron, including renal outer medullary potassium channels, remains unknown. Laboratory findings in this case did not demonstrate renal tubular acidosis.

An alternative mechanism described in the literature involves cholestasis-associated accumulation of bile acids, which can inhibit renal 11β-hydroxysteroid dehydrogenase type 2, permitting endogenous cortisol to activate the mineralocorticoid receptor and promote kaliuresis [13, 14]. While this bile acid–mediated mechanism represents a biologically plausible pathway described in experimental and clinical models, it was not supported by patient-specific findings in this case, as liver function tests were normal and there was no evidence of cholestasis. Accordingly, this pathway remains a theoretical consideration rather than a demonstrated mechanism.

Hydroxychloroquine-associated renal phospholipidosis has been described predominantly as a podocytopathy with proteinuria, while direct tubular involvement has not been well established [11, 15, 16]. Phospholipidosis is therefore unlikely to represent the primary driver of renal potassium wasting in this case and is included only as a speculative consideration.

Although the serum bicarbonate was at the upper end of normal, there was no clinical evidence of gastrointestinal bicarbonate loss or vomiting, and the overall findings were not consistent with hypokalemia driven by extrarenal alkali losses. Although urinary chloride excretion was elevated, the temporal relationship to hydroxychloroquine exposure and reproducible dechallenge and rechallenge supported a primary renal potassium wasting process rather than chloride-driven kaliuresis. Hydroxychloroquine is administered as a sulfate rather than a chloride salt, further arguing against medication-related chloride delivery as the primary driver of the observed electrolyte abnormalities [1, 2].

Urinary potassium excretion remained inappropriately elevated during hypokalemia. Although the transtubular potassium gradient was not calculated due to unavailable urine osmolality, substantial urinary sodium excretion indicated preserved distal sodium delivery, supporting ongoing renal potassium secretion rather than extrarenal loss. The urine potassium-to-creatinine ratio was markedly elevated, further supporting inappropriate renal potassium wasting. Serum potassium normalized when hydroxychloroquine was withheld and declined again upon rechallenge, strengthening the causal association.

To our knowledge, symptomatic hypokalemia due to renal potassium wasting during therapeutic hydroxychloroquine use has not been previously reported. This presentation is distinct from acute hydroxychloroquine or chloroquine poisoning, in which hypokalemia reflects intracellular redistribution with rebound hyperkalemia during recovery [17, 18]. Recognition of true renal potassium loss is clinically important, as it represents whole-body potassium depletion with potential neuromuscular and cardiac consequences. When feasible, a supervised hydroxychloroquine hold serves both diagnostic and therapeutic purposes. If hydroxychloroquine must continue, potassium repletion may be paired with a potassium-sparing agent while alternative disease-modifying therapy is arranged in coordination with Rheumatology.

Conclusion

Hydroxychloroquine may be associated with chronic hypokalemia due to renal potassium wasting in susceptible individuals. Diagnosis requires confirmation with urine potassium levels and a careful review of medications. A medication withdrawal and rechallenge pattern can strengthen causality. Recognizing true renal potassium loss is essential because it reflects whole-body potassium depletion with important clinical implications.

Abbreviations

ER

Emergency room

HLA B27

Human leukocyte antigen B27

KCL

Potassium chloride

OTC

Over the counter

ROMK

Renal outer medullary potassium channel

Author contributions

JDT collected clinical data, prepared figures and tables, and drafted the manuscript. SK interpreted nephrology investigations, contributed to clinical management, and critically revised the manuscript. Both authors read and approved the final manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable, single patient case report with no experimental intervention beyond clinical care. The authors followed the CARE guidelines; the completed CARE checklist is provided.

Consent for publication

Written informed consent for publication of the case details and accompanying images was obtained from the patient.

Competing interests

The authors declare no competing interests.