Is Hydrochlorothiazide (HCTZ) nephrotoxic?

From the Guidelines

Hydrochlorothiazide (HCTZ) is not typically considered nephrotoxic when used appropriately, though it can affect kidney function in certain circumstances. HCTZ is a thiazide diuretic commonly prescribed for hypertension at doses of 12.5-50 mg daily. Unlike certain antibiotics or NSAIDs that directly damage kidney structures, HCTZ works by inhibiting sodium and chloride reabsorption in the distal convoluted tubule, which is its intended mechanism of action rather than a toxic effect. However, HCTZ can cause pre-renal acute kidney injury in susceptible individuals through excessive diuresis leading to volume depletion, particularly in elderly patients or those with heart failure, cirrhosis, or pre-existing kidney disease, as noted in a study published in the British Journal of Pharmacology 1. It may also cause electrolyte abnormalities including hyponatremia, hypokalemia, and hypercalcemia.

Some key points to consider when prescribing HCTZ include:

• The greatest diuretic effect is seen with the first few doses, causing significant electrolyte shifts within the first 3 days of administration, which can lead to hypokalaemia, hyponatraemia and compensatory mechanisms for sodium retention, including aldosterone release, thus effectively counteracting the diuretic effect 1.
• Patients taking HCTZ should maintain adequate hydration, have their kidney function and electrolytes monitored periodically, and be cautious during illness that may cause dehydration.
• Dose adjustments may be necessary for patients with moderate to severe kidney impairment, and the medication should be temporarily discontinued during acute illness with significant fluid losses.
• The effects of HCTZ on renal function are well documented, and current guidelines emphasize the importance of renal function monitoring, suggesting no more than 2 weeks between initiation and first follow-up test, as seen in a study published in the same journal 1.

Overall, while HCTZ is not typically considered nephrotoxic, it can have significant effects on kidney function, particularly in susceptible individuals, and should be used with caution and careful monitoring.

From the FDA Drug Label

Metabolic toxicities associated with excessive electrolyte changes caused by hydrochlorothiazide have been shown to be dose-related... In patients with renal disease, plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged The FDA drug label does not directly answer the question of whether Hydrochlorothiazide (HCTZ) is nephrotoxic, but it does mention that renal disease can affect the drug's pharmacokinetics, suggesting a potential interaction between HCTZ and kidney function 2.

• Key points:
  • HCTZ is eliminated primarily by renal pathways
  • Plasma concentrations are increased in patients with renal disease
  • The elimination half-life is prolonged in patients with renal disease However, this information does not directly support the conclusion that HCTZ is nephrotoxic.

From the Research

Nephrotoxicity of Hydrochlorothiazide (HCTZ)

• The nephrotoxicity of HCTZ is a topic of debate, with some studies suggesting that it may cause renal injury, while others indicate that it can be used safely in patients with chronic kidney disease (CKD) 3, 4, 5.
• A study published in 2015 found that the combination of HCTZ and loop diuretics improved blood pressure levels and decreased proteinuria in patients with type 2 diabetic kidney disease, without negatively affecting the change in estimated glomerular filtration rate (eGFR) 3.
• Another study published in 1996 found that the addition of HCTZ to high-dose furosemide resulted in a significant increase in urine volume and sodium excretion, but also caused hypokalemia and a decrease in endogenous creatinine clearance 4.
• A study published in 2005 compared the efficacy of furosemide and HCTZ in patients with chronic renal failure and hypertension, and found that HCTZ increased the fractional excretion of sodium and chloride, and decreased mean arterial blood pressure, but did not cause significant renal injury 5.
• However, a study published in 2007 found that HCTZ caused subtle renal injury, including increased kidney weight, glomerular ischemia, and cortical oxidative stress, which was not observed in states of equivalent hypokalemia 6.
• A study published in 2008 found that HCTZ decreased urinary calcium excretion in patients with Dent disease, but also caused adverse reactions, including muscle cramps, hypovolemia, hypokalemia, and hyponatremia 7.

Key Findings

• HCTZ can be used safely in patients with CKD, but may cause renal injury in certain situations 3, 4, 5.
• The combination of HCTZ and loop diuretics can improve blood pressure levels and decrease proteinuria in patients with type 2 diabetic kidney disease 3.
• HCTZ can cause hypokalemia, hypovolemia, and other adverse reactions, particularly when used in high doses or in combination with other diuretics 4, 7.
• The nephrotoxicity of HCTZ may be related to factors such as chronic ischemia, hyperaldosteronism, and volume depletion 6.