Exaggerated Elevation of Uric Acid With Hydrochlorothiazide and Indapamide

Authors:
Nisreen Abu Al Hommos, MD
Internal Medicine, Regional One Health, and Assistant Professor, University of Tennessee Health Science Center, Memphis, Tennessee

Gale L. Hamann, PharmD
Clinical Pharmacy Specialist, Ambulatory Care, Regional One Health, and Professor, University of Tennessee Health Science Center College of Pharmacy, Memphis, Tennessee

Citation:
Abu Al Hommos N, Hamann GL. Exaggerated elevation of uric acid with hydrochlorothiazide and indapamide [published online February 11, 2019]. Consultant360.

A 65-year-old African American woman had a medical history of seropositive rheumatoid arthritis, gout, osteoarthritis, hypertension, asthma, seasonal rhinitis, and vitamin D deficiency. Her medications included aspirin, 81 mg daily; lisinopril, 40 mg daily; spironolactone, 25 mg daily; carvedilol, 25 mg twice daily; atorvastatin, 80 mg daily; etanercept, 50 mg subcutaneously weekly; albuterol inhaler as needed; and nasal fluticasone as needed.

Years earlier, the patient had received a diagnosis of gout after presenting with symptoms of intermittent pain, tenderness, and swelling of the dorsal aspect of her feet. Testing for urate crystals was not performed at that time. The patient had been treated intermittently with allopurinol and colchicine, but both agents had been discontinued due to the development of abdominal pain. The patient’s gout and serum uric acid level had been well-controlled without uric acid–lowering medications, with levels ranging from 5.2 to 6.9 mg/dL.

When the patient initially presented for treatment, her uric acid level had been elevated at 9.4 mg/dL on hydrochlorothiazide (HCTZ), 25 mg daily, but decreased to 6.8 mg/dL after HCTZ was discontinued. Several years later, HCTZ, 25 mg daily, was again prescribed for uncontrolled hypertension, which resulted in a gout flare and an increase in her uric acid level from 5.8 mg/dL to 9.6 mg/dL after 1 month of therapy. HCTZ was again discontinued, resulting in significant reduction of her uric acid level to 6.2 mg/dL. At this point, indapamide, 1.25 mg daily, was initiated for additional blood pressure control; however, her uric acid level increased to 9.2 mg/dL 17 days later. Indapamide was discontinued, and her uric acid level decreased to her baseline of 6.7 mg/dL. Her serum creatinine level was stable at 0.9 to 1.1 mg/dL during this treatment period. Her creatinine clearance was 74 mL/min/1.73 m² based on her adjusted body weight. The patient denied any changes in her eating habits or medications, including over-the-counter and herbal medications, during this time.

Using the adverse drug reaction (ADR) probability scale¹ to assess the probability of an adverse reaction due to a single drug, an ADR probability score of 9 was calculated for HCTZ and 7 for indapamide. A score of 9 or greater indicates a definite ADR, and a score of 7 indicates a probable ADR. HCTZ received a higher score because an elevated uric acid level occurred on 2 separate occasions, whereas the uric acid level increased only once with indapamide.

DISCUSSION

Thiazide diuretics are one of the initial agents recommended in the treatment of hypertension by the American College of Cardiology and American Heart Association’s 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults.² Thiazide and loop diuretics, particularly HCTZ and furosemide, are well known to elevate uric acid levels but generally not to a clinically significant effect. Conflicting reports exist about the effect of indapamide on uric acid; initial reports described a relative absence of hyperuricemia with the treatment of hypertension.³

Urate secretion and reabsorption occur in the proximal tubules in the kidney, normally resulting in the reabsorption of most filtered urate. Thiazide diuretics decrease urate excretion in a dose-dependent manner by increasing urate reabsorption by the proximal tubules. Serum uric acid is a weak organic acid and is regulated by several transporters, such as organic anion transporter 1 (OAT1) and urate/anion exchanger 1 (URAT1).⁴ OAT1 moves organic acids, such as uric acid, into the proximal tubules from the blood, and URAT1 is responsible exchanging organic acids and moving uric acid intracellularly from the renal filtrate. HCTZ competes with uric acid in both of these transporters in the proximal tubules.⁴

Leonetti and colleagues⁵ studied 342 patients in Italy who received indapamide, 2.5 mg daily, after a 1-month placebo run-in period. A total of 248 patients were considered responders, defined as having a diastolic blood pressure reduction of 5 mm Hg or more, and were continued in the study. After 1 month, atenolol, 100 mg daily, was added for patients with a diastolic pressure greater than 95 mm Hg. A total of 186 patients were continued on indapamide monotherapy for 24 months. Uric acid was evaluated in the group receiving indapamide monotherapy at baseline and at 2, 6, 12, 18, and 24 months. Mean uric acid levels increased from a baseline of 4.9 ± 0.1 mg/dL to 6.4 ± 1.0 mg/dL at 2 months and then decreased to 5.3 ± 0.1 mg/dL at 24 months.

Hashida,⁶ in a double-blind study at 21 centers in Japan, evaluated 101 hypertensive patients administered indapamide, 1 mg or 2 mg daily, after a 4-week placebo run-in period. Uric acid levels were evaluated at baseline and at 2, 4, and 6 weeks. Indapamide, 1 mg, resulted in a mean increase in uric acid of 0.5 ± 0.0 mg/dL from a baseline of 5.5 ± 0.2 mg/dL, and indapamide, 2 mg, resulted in a mean increase of 0.5 ± 0.0 mg/dL from a baseline of 5.6 ± 0.3 mg/dL.

Nikas and colleagues⁷ evaluated 20 patients with hypertension who were treated with indapamide, 2.5 mg daily, for 8 weeks. Uric acid levels were evaluated before and after indapamide therapy. They then evaluated uric acid levels 8 weeks after the addition of losartan, 50 mg daily. Indapamide increased uric acid levels from a mean of 4.9 ± 1.6 mg/dL to 5.9 ± 1.2 mg/dL. The combination of indapamide and losartan resulted in a decrease in uric acid levels to 5.1 ± 1.1 mg/dL.

Athanassiadis and colleagues⁸ reported on 40 patients in each group taking either indapamide alone, indapamide and captopril, or indapamide and propranolol for 4 months. Results are shown in the accompanying Table. While uric acid was significantly increased after the addition of indapamide, the increase was relatively mild at 12.2%, 20.3%, and 7.3%, respectively.

Vandell and colleagues⁹ evaluated single-nucleotide polymorphisms (SNPs) associated with HCTZ-induced elevations of uric acid. Several gene regions were identified that were associated with elevated uric acid. LUC7L2, ANKRD17/COX18, FTO, PADI4, and PARD3B were associated with HCTZ-induced uric acid elevation in African American participants, and GRIN3A was associated with HCTZ-induced uric acid elevation with white participants.

Our patient, an African American woman, may belong to a subset of patients with an exaggerated increase in uric acid associated with HCTZ or indapamide use. While most patients only experience a modest elevation in uric acid with the addition of a thiazide or loop diuretic, this report illustrates that a more dramatic elevation in uric acid can occur, and that clinicians need to be mindful of the potential for such a reaction.