Is losartan (angiotensin II receptor antagonist) nephrotoxic?

Losartan is Not Nephrotoxic and Actually Provides Renal Protection

Far from being nephrotoxic, losartan actually provides significant renoprotection in patients with diabetes and kidney disease. 1 Losartan has been shown to slow the progression of kidney disease, particularly in patients with type 2 diabetes and proteinuria.

Renal Protective Effects of Losartan

Losartan demonstrates several beneficial effects on kidney function:

• Reduces progression to end-stage renal disease: In the RENAAL trial, losartan reduced the risk of end-stage renal disease by 28% compared to placebo (p=0.002) 2
• Prevents doubling of serum creatinine: Losartan reduced this risk by 25% (p=0.006) in patients with type 2 diabetes and nephropathy 2
• Decreases proteinuria: Treatment with losartan reduced proteinuria by 35% compared to placebo (p<0.001) 2
• Slows GFR decline: In diabetic nephropathy, losartan slows the decline in glomerular filtration rate compared to conventional antihypertensive treatment 1

Mechanism of Renoprotection

Losartan's renoprotective effects occur through:

1. Blockade of the renin-angiotensin system: By blocking angiotensin II AT1 receptors, losartan reduces intraglomerular pressure and proteinuria 1
2. Blood pressure-independent effects: Studies show that the renoprotective benefits exceed what would be expected from blood pressure reduction alone 2
3. Reduction in albuminuria: Losartan significantly reduces albuminuria, which is a marker of kidney damage and a risk factor for progression 3

Evidence from Clinical Trials

The strongest evidence comes from large randomized controlled trials:

• RENAAL Study: This landmark trial of 1,513 patients with type 2 diabetes and nephropathy demonstrated that losartan significantly reduced the composite endpoint of doubling serum creatinine, end-stage renal disease, or death by 16% compared to placebo (p=0.02) 2

• IDNT Trial: Showed that angiotensin receptor blockers like losartan are more effective than other antihypertensive drug classes in slowing GFR decline and preventing kidney failure in patients with type 2 diabetes and macroalbuminuria 1

Optimal Dosing for Renoprotection

• Start with losartan 50 mg daily and titrate to 100 mg daily for optimal renoprotection 4, 3
• A study in type 1 diabetic patients with nephropathy showed that losartan 100 mg provided significantly greater reduction in albuminuria (48%) compared to 50 mg (30%) 3
• The 100 mg dose appears to be optimal, as increasing to 150 mg did not provide additional benefit 3

Situations Requiring Caution

While losartan is generally renoprotective, caution is needed in specific situations:

• Bilateral renal artery stenosis: Losartan may cause acute renal failure in these patients 5
• Severe heart failure: Patients with severe volume depletion may experience reduced renal plasma flow 5
• Severe volume depletion: Monitor renal function closely in these patients 5

Monitoring Recommendations

When starting losartan:

1. Baseline assessment: Check serum creatinine and potassium before initiating therapy 4
2. Follow-up monitoring: Evaluate renal function and serum potassium 2-4 weeks after starting treatment 4
3. Dose titration: If blood pressure is controlled and there's no significant hyperkalemia (K+ <5.5 mEq/L) or increase in creatinine >30% from baseline, consider increasing to 100 mg daily 4
4. Post-titration monitoring: Re-evaluate renal function and serum potassium 2-4 weeks after dose increase 4

Conclusion

Losartan is not nephrotoxic but rather provides significant renoprotection, particularly in patients with diabetic nephropathy. The FDA has specifically approved losartan "for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension" 6. The evidence strongly supports its use for slowing kidney disease progression and reducing the risk of end-stage renal disease.