Is candesartan (angiotensin II receptor antagonist) nephrotoxic?

From the Guidelines

Candesartan, an angiotensin II receptor antagonist, is not considered nephrotoxic and is often used to protect kidney function in patients with hypertension, heart failure, or diabetic nephropathy. The most recent and highest quality study, published in 2018 1, suggests that angiotensin receptor blockers (ARBs) like candesartan are beneficial in improving renal outcomes in patients with chronic kidney disease (CKD), particularly those with albuminuria. While candesartan can cause changes in kidney function parameters, these effects are generally related to its therapeutic mechanism rather than direct toxicity to kidney tissues. Candesartan works by blocking the renin-angiotensin-aldosterone system (RAAS), which reduces efferent arteriolar constriction in the kidneys, potentially causing a temporary and modest reduction in glomerular filtration rate (GFR) and increases in serum creatinine levels, especially when therapy is initiated. This effect is typically hemodynamic rather than structural and often stabilizes with continued treatment.

Some key points to consider when using candesartan in patients with kidney disease include:

• Caution is warranted in certain populations, including patients with bilateral renal artery stenosis, severe volume depletion, or pre-existing significant kidney impairment.
• Combining candesartan with other RAAS inhibitors (like ACE inhibitors) or with NSAIDs can increase the risk of adverse renal effects.
• Regular monitoring of kidney function is recommended when starting candesartan therapy, particularly in high-risk patients.
• The target dose of candesartan for heart failure is typically higher than the dose used for hypertension, and physicians should be aware of the doses that have been shown to prolong survival in chronic heart failure 1.

Overall, the benefits of candesartan in protecting kidney function and reducing cardiovascular risk outweigh the potential risks, and it can be a valuable treatment option for patients with hypertension, heart failure, or diabetic nephropathy.

From the FDA Drug Label

Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia, or acute renal failure on candesartan cilexetil and hydrochlorothiazide tablets Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil and hydrochlorothiazide tablets.

Candesartan may be associated with a risk of nephrotoxicity, particularly in patients with pre-existing renal impairment or those who are at risk of volume depletion.

• Key factors that increase the risk of nephrotoxicity include:
  • Pre-existing renal artery stenosis
  • Chronic kidney disease
  • Severe heart failure
  • Volume depletion
• Monitoring of renal function is recommended in patients taking candesartan, especially in those with pre-existing renal impairment. 2

From the Research

Nephrotoxicity of Candesartan

• Candesartan is an angiotensin II receptor antagonist used to treat hypertension and protect the kidneys from damage in patients with diabetic nephropathy 3, 4, 5.
• Studies have shown that candesartan has a nephroprotective effect, reducing albuminuria and urinary protein excretion in patients with diabetic nephropathy 3, 4, 5.
• However, one study found that olmesartan was more effective than candesartan in reducing proteinuria in patients with chronic kidney disease other than diabetic nephropathy 6.
• The optimal dose of candesartan for renoprotection is 16 mg daily, as reflected by short-term reduction in albuminuria, in hypertensive type 2 diabetic patients with nephropathy 3.
• Candesartan has been shown to decrease glomerular filtration rate (GFR) by approximately 6 ml/min/1.73 m2, but this effect is not necessarily indicative of nephrotoxicity 3.

Comparison with Other Angiotensin Receptor Blockers

• Candesartan has been compared to other angiotensin receptor blockers, such as losartan, telmisartan, and valsartan, and has been found to have a similar or better tolerability profile and antihypertensive efficacy 7.
• However, the study that compared olmesartan to other ARBs, including candesartan, found that olmesartan was more effective in reducing urinary protein 6.

Mechanism of Action

• Candesartan works by blocking the actions of angiotensin II on the renin-angiotensin-aldosterone system, which plays a crucial role in volume homeostasis and blood pressure regulation 7, 4.
• The blockage of intrarenal angiotensin II type I (AT1) receptors by candesartan may contribute to its nephroprotective effects, which are not solely due to its blood pressure-lowering effect 4.