The influence of spironolactone on renal function and cardiovascular disease in polycystic kidney disease

Polycystic kidney disease (PKD) is a progressive genetic disorder ultimately leading to renal failure, associated with hypertension and heart disease. We have shown previously in the Lewis polycystic kidney (LPK) rodent model of autosomal-recessive PKD that aldosterone levels increase in association with deteriorating renal function. In addition to its direct effects on renal sodium reabsorption, aldosterone has been shown to cause renal and cardiovascular injury, and may therefore be a key factor contributing to disease progression. We have therefore examined the hypothesis that inhibition of aldosterone with Spironolactone will reduce the severity of cardiovascular disease and improve renal function in PKD. Spironolactone (20mg/kg/day p/o) was administered in water to LPK and the control Lewis strain from 4 –12 weeks of age. Animals were divided into 8 groups according to strain, gender and treatment (n=14 LPK, n=16 Lewis). Systolic blood pressure was measured fortnightly via tail-cuff method and urine was collected in a metabolic cage at age 12 weeks for urinary 24hr volume and protein:creatinine ratio analysis. At 12 weeks the animals were weighed and euthanized, trunk blood collected, and the heart dissected and weighed. In the LPK, blood pressure increased over the 6 –12 week time frame. Spironolactone had a significant effect in reducing blood pressure in the female LPK only (179±3 systolic vs 209±3 mm Hg, P=0.03). LPK untreated animals had a higher heart weight; body weight ratio (0.54±0.02) compared to the treated LPK group (0.52±0.03, P<0.047), both of whom had significantly larger hearts than the Lewis (P<0.001). The left ventricle/heart weight ratio indicated LVH in both LPK groups (P<0.001), which was not influenced by spironolactone treatment. Urine creatinine: protein ratio improved significantly in the LPK treated group, such that it was no longer different to Lewis animals. In summary, spironolactone had a beneficial effect on renal function in the LPK model but did not significantly impact cardiovascular status. Additional studies will examine the degree of cardiac fibrosis in the different treatment groups. The outcomes of this study will be of benefit to determining optimal treatment strategies for patients with PKD.