Kidney stones recur frequently, and they cause enormous healthcare expenditures and excess illness. The article discusses the mechanism of action, potential side effects, & shortcomings of earlier research when it comes to the use of thiazide diuretics for preventing kidney stone recurrence. 

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It is important to understand the etiopathology behind stone formation to understand the treatment and the basis for the use of thiazide diuretics.

Aetiology and pathophysiology of renal stone formation

Urolithiasis may occur due to the following:

• Anatomic features leading to urinary stasis
• Low urine volume
• Dietary factors (e.g., high oxalate or high sodium)
• Urinary tract infections
• Systemic acidosis
• Medications (e.g. Sulfonamides)
• Genetic factors such as cystinuria

The other four most common factors contributing to urinary stone formation are:

• Hypercalciuria
• Hyperoxaluria
• Hyperuricosuria
• Hypocitraturia

 

Pathophysiology 

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Types of renal stone

The four major types of renal calculi include:

1. Calcium stones (due to hyperparathyroidism, renal calcium leak, Hyperoxaluria, hypomagnesaemia, and Hypocitraturia).
2. Uric acid stones are associated with a pH of less than 5, a high intake of purine foods (fish, legumes, meat), or cancer. These stones may also be associated with gout.
3. Struvite stones (caused by gram-negative-urease positive organisms that breakdown urea into ammonia. Common organisms include pseudomonas, proteus, and Klebsiella. E coli is not associated with struvite stones).
4. Cystine stones are due to an intrinsic metabolic defect causing the failure of the renal tubules to reabsorb cystine, lysine, ornithine, and arginine.

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Hydrochlorothiazide

1. Mechanism of action

1. Thiazides are secreted in proximal tubules and act intraluminally by inhibiting Na/Cl symporter in Distal convoluted tubules.
2. They enhance Ca reabsorption in the distal convoluted tubule, by increasing Na/Ca exchange and thus reduce the urinary excretion of calcium.
3. Due to increased distal Na delivery, there is an increase in aldosterone-mediated K and H ions excretion causing lower urinary pH.

 

Mechanism of action

 

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2. The rationale for the use

Thiazide acts in two ways to reduce calcium oxalate stones:

1. Decreases Urinary ph and thus lowers calcium phosphate supersaturation.
2. Decreasing urinary calcium and thus reducing calcium oxalate supersaturation.

3. Potential adverse effects

• Hypokalemic metabolic alkalosis
• Hyponatremia
• Hyperuricemia
• Hyperglycemia
• Dyslipidemia

4. Trials and studies supporting its use

Many older studies in the last 5 decades have concluded that thiazide diuretics like hydrochlorothiazide help in reducing the recurrence of calcium stones.

• Limitations of older studies
• Inadequate concealment of treatment assignment
• A lack of double-blinding
• A lack of an intention-to-treat analysis
• The use of outdated dietary recommendation
• The use of imaging methods with low sensitivity and specificity.
• Also, only high doses of thiazides were studied; such dose levels are known to increase the risk of adverse effects

Thus, both the efficacy of thiazides in the prevention of the recurrence of kidney stones and the dose-response effect remain unclear

5. Recent trial

1. NOSTONE trial, a double-blind, randomised, placebo-controlled trial was conducted to evaluate a range of hydrochlorothiazide doses for the prevention of the recurrence of kidney stones.
2. A large trial of 416 patients followed over 2.9 years was conducted by Nasser A. Dhayat and colleagues which was published on 2nd March 2023 in The NEJM.
3. Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily.
4. There was a reduction in rates of radiologic stone recurrence in patients receiving higher doses of hydrochlorothiazide but was not statistically significant.
5. New-onset diabetes mellitus, hypokalemia, gout, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients in the hydrochlorothiazide groups than among those in the placebo group.

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Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Bhavin Mandowara is a practising nephrologist at Zydus Hospital, Ahmedabad.