Potential Therapeutic Interventions for Cardiovascular Disease in Autosomal Dominant Polycystic Kidney Disease

Abstract

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in autosomal dominant polycystic kidney disease (ADPKD). While the current interventions are appropriate, there is an urgent requirement for additional therapies due to ongoing burden of disease. The aim of this thesis is to evaluate the efficacy of preclinical and clinical interventions that target three separate pathogenic pathways in CVD in ADPKD. Interventions that are easily accessible, rapidly translatable, and sustainable for long-term therapy have been prioritised, leading to the selection of repurposed medications and non-pharmacological (lifestyle or dietary) interventions. The hypotheses investigated in this thesis are; (i) increased water intake reduces the progression of cardiorenal disease in experimental polycystic kidney disease, (ii) vitamin D receptor agonists reduces blood pressure and proteinuria in both early and late stages of experimental polycystic kidney disease, alone and in conjunction with ACE inhibitor therapy, and (iii) nitrate-containing beetroot juice lowers blood pressure compared with nitrate-depleted beetroot juice in hypertensive ADPKD. The novel findings were: (i) increased water intake reduced blood pressure, cardiac hypertrophy, cyst growth/area and renal fibrosis in the LPK rat, (ii) vitamin D receptor agonism reduced blood pressure and cardiac hypertrophy in late disease when used in conjunction with ACE inhibitors in the LPK rat, however it resulted in hypercalcaemia and weight loss, (iii) nitrate-replete beetroot juice did not lower blood pressure compared to nitrate-deplete beetroot juice in hypertensive patients with ADPKD, however both groups had a significant reduction in blood pressure over the course of the trial. Taken together, the findings of this thesis contribute to understanding of the underlying pathways that influence disease progression and suggest therapeutic directions that may attenuate CVD in ADPKD.