Polycystic Kidney Disease

Polycystic Kidney Disease (PKD) is a genetic disease of the kidney that is characterized by the gradual replacement of normal kidney parenchyma by fluid-filled cysts and fibrotic tissue. The majority of patients suffer from the disorder called Autosomal Dominant Polycystic Kidney Disease, or in short ADPKD. They comprise about 10% of all patients with end-stage renal disease. The clinical course of the disease is highly variable but typically the first cysts are observed by ultrasonography in the third decade of life. As the disease progresses, thousands of cysts grow from all segments of the nephron causing massively enlarged kidneys, pain, hematuria, and eventually renal failure at an age of around 60 years old. Another characteristic of ADPKD kidneys is progressive tubulo-interstitial fibrosis which is known to be a major contributor to the decline in renal function. Besides abnormalities in the kidneys of ADPKD patients, extra-renal manifestations such as hypertension, cardiovalvular abnormalities, cerebral aneurisms and cyst formation in liver and pancreas also frequently occur¹.

Currently, only the vasopressin V2 receptor antagonist tolvaptan (Jinarc®) is approved as treatment, in a number of countries, to slow disease progression in patients. Unfortunately, this drug is accompanied by side effects, including polyuria and liver toxicity, restricting its use to a subset of ADPKD patients. Importantly, these studies have changed the field towards an open attitude to set-up clinical trials².

Mutations in PKD1-gene are responsible for almost 80% of cases of ADPKD, whereas approximately 15% of ADPKD cases are attributed to mutations in PKD2-gene. The remaining 5% of ADPKD cases are genetically unresolved or are due to rare mutations in other loci³. In renal epithelial cells, the proteins encoded by the PKD-genes colocalize in multimeric complexes at distinct subcellular sites in epithelial cells. From these different subcellular locations they orchestrate a network of signaling pathways that establish and maintain a differentiated renal epithelium⁴
The difficulty in identifying drugs for ADPKD treatment can be partially attributed to the lack of understanding of the functions of the PKD1- and PKD2-proteins, and on how inactivation of these two trans-membrane proteins leads to cyst development. Therefore, treatments are largely focused on targeting the signaling network and signaling pathways downstream of the PKD- complex.

^{1 Gabow PA: Autosomal dominant polycystic kidney disease: More than a renal disease. Am J Kidney Dis 16:403-413, 1990
2 Torres VE et al. NEJM 367: 2407-2418, 2012; Torres VE et al. NEJM 377: 1930-1942, 2017.
3 Cornec- Le Gall, E., Torres, V. E. & Harris, P. C. . J. Am. Soc. Nephrol. 29, 13–23 (2018).
4 Dong K, Zhang C, Tian X, Coman D, Hyder F, Ma M, Somlo S.Nat Genet. 2021 Dec;53(12):1649-1663.}