Clinical Trials in Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease is the most common life-threatening genetic disease, affecting 1/400 to 1/1000 live births. It represents the 4th leading cause of end-stage kidney disease and accounts for 13% of kidney transplants in the United States. It is characterized by irreversible cyst growth leading to progressive parenchymal damage. Despite promising results, there is currently no Food and Drug Administration approved therapy to cure or slow the progression of the disease. The growing understanding of the pathophysiological mechanisms leading to cyst formation and growth has led to the development of several therapeutic agents, some with very promising results. In this chapter, we will review the past and ongoing clinical trials that explored these specific targets, focusing mainly on drugs targeting the cyclic adenosine 3’,5’-monophosphate pathway (vasopressin V2 receptor antagonists and somatostatin analogs), mammalian target of rapamycin (mTOR) inhibitors and renin-angiotensin blockade. We will discuss novel therapeutic targets currently being explored in pilot clinical studies, including high dose niacinamide, tyrosine kinase inhibitors and others. Given its slowly progressive nature and lack of early sensitive biomarkers, clinical trials are limited by the need for long follow-up periods to assess the beneficial effect on kidney function of any therapeutic intervention. There is a growing need of new biomarkers of PKD progression to help accelerate the progress of clinical trials in this field. We will finally explore the current accepted and candidate biomarkers in PKD and discuss current challenges to the development of clinical trials in PKD.