Organoprotective Effects of Spironolactone on Top of Ramipril Therapy in a Mouse Model for Alport Syndrome

Abstract

Angiotensin-converting enzyme inhibitors (ACEi) delay progression of the inherited renal disease Alport syndrome. However, the effect of ACEis weakens gradually due to an “aldosterone escape”. Here, we investigate if an aldosterone antagonist can counteract loss of ACEi-efficacy. COL4A3-/- mice were treated with ramipril (ACEi), starting at 4.5 weeks of age, and spironolactone was added at 7 weeks of age. Lifespan until renal failure, as well as kidney function parameters, were investigated. Dual therapy decreased proteinuria levels compared to ACEi monotherapy. Matrix accumulation, as well as tubulointerstitial and glomerular scar-tissue formation, were significantly reduced compared to untreated mice and ACEi-monotherapy at 75 and 100 days. Lifespan in dual treated mice was extended compared to untreated mice. However, lifespan was not superior to ACEi monotherapy–despite improved urea-nitrogen levels in the dual therapy group. In conclusion, adding the aldosterone-antagonist spironolactone to ACEi therapy further improved kidney function and reduced proteinuria and fibrosis. However, survival was not improved further, possibly due to premature death from side effects of dual therapy such as hyperkalemia. Thus, dual therapy could offer an effective therapy option for Alport syndrome patients with progressive proteinuria. However, the risks of adverse events require close monitoring.

Angiotensin-converting enzyme inhibitors (ACEi) delay progression of the inherited renal disease Alport syndrome. However, the effect of ACEis weakens gradually due to an “aldosterone escape”. Here, we investigate if an aldosterone antagonist can counteract loss of ACEi-efficacy. COL4A3-/- mice were treated with ramipril (ACEi), starting at 4.5 weeks of age, and spironolactone was added at 7 weeks of age. Lifespan until renal failure, as well as kidney function parameters, were investigated. Dual therapy decreased proteinuria levels compared to ACEi monotherapy. Matrix accumulation, as well as tubulointerstitial and glomerular scar-tissue formation, were significantly reduced compared to untreated mice and ACEi-monotherapy at 75 and 100 days. Lifespan in dual treated mice was extended compared to untreated mice. However, lifespan was not superior to ACEi monotherapy–despite improved urea-nitrogen levels in the dual therapy group. In conclusion, adding the aldosterone-antagonist spironolactone to ACEi therapy further improved kidney function and reduced proteinuria and fibrosis. However, survival was not improved further, possibly due to premature death from side effects of dual therapy such as hyperkalemia. Thus, dual therapy could offer an effective therapy option for Alport syndrome patients with progressive proteinuria. However, the risks of adverse events require close monitoring.