Experimental Therapies and Ongoing Clinical Trials to Slow Down Progression of ADPKD

Abstract

The improvement of imaging techniques over the years has contributed to the understanding of the natural history of autosomal dominant polycystic kidney disease, and facilitated the observation of its structural progression. Advances in molecular biology and genetics have made possible a greater understanding of the genetics, molecular, and cellular pathophysiologic mechanisms responsible for its development and have laid the foundation for the development of potential new therapies. Therapies targeting genetic mechanisms in ADPKD have inherent limitations. As a result, most experimental therapies at the present time are aimed at delaying the growth of the cysts and associated interstitial inflammation and fibrosis by targeting tubular epithelial cell proliferation and fluid secretion by the cystic epithelium. Several interventions affecting many of the signaling pathways disrupted in ADPKD have been effective in animal models and some are currently being tested in clinical trials.

Renin-Angiotensin-Aldosterone System Antagonism and Polycystic Kidney Disease Progression

“…Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a multisystem disease characterised by the development of multiple bilateral renal cysts and extra-renal manifestations such as cardiovascular abnormalities [1]. ADPKD affects 1 in 500 to 1 in 1,000 people with a significant decline in glomerular filtration rate (GFR) and renal function usually occurring by the 4th decade of life [2].…”

“…ADPKD arises as a consequence of mutations in the PKD1 and PKD2 genes. Mutation of PKD1 causes cyst development to occur at an earlier age, resulting in worse survival and more severe disease progression compared to PKD2 mutation [1,3]. The proteins encoded by the PKD1 and PKD2 genes, polycystin-1 (PC1) and polycystin-2 (PC2), are both membrane-bound glycoproteins and constitute a subfamily of transient receptor potential (TRP) channels (TRPP1 and TRPP2, respectively) [2].…”

“…The proteins encoded by the PKD1 and PKD2 genes, polycystin-1 (PC1) and polycystin-2 (PC2), are both membrane-bound glycoproteins and constitute a subfamily of transient receptor potential (TRP) channels (TRPP1 and TRPP2, respectively) [2]. PC1 is found in plasma membranes at focal adhesions, desmosomes, and adherens junction sites contributing to epithelial integrity and extracellular matrix interactions [1]. Both PC1 and PC2 are also present in the plasma membranes of the primary cilia and form a complex that is sensitive to filtrate flow in the renal tubule [1].…”

“…PC1 is found in plasma membranes at focal adhesions, desmosomes, and adherens junction sites contributing to epithelial integrity and extracellular matrix interactions [1]. Both PC1 and PC2 are also present in the plasma membranes of the primary cilia and form a complex that is sensitive to filtrate flow in the renal tubule [1]. The development of ADPKD is characterised by enlarged kidneys, the formation of multiple fluid filled cysts and abnormal protein deposition [4].…”

“…PC2 is a smaller 110 kDa (968 aa) transmembrane protein that interacts with the carboxy-terminus of PC1 and other TRP channels, and also the ryanodine receptor-2. The carboxy-termini of PC1 and PC2 form a heterotrimeric G-protein-binding domain that can initiate intracellular signalling cascades [1]. PC1 and PC2 are both integrated into a complex network of signalling pathways that can be deregulated in ADPKD.…”