Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic disease (ADPKD) is the most common monogenic disease in humans and is among the leading causes of kidney failure. Dominantly inherited germline mutations in 2 genes, PKD1 and PKD2 followed by a second somatic hit that annuls or reduces the function of the remaining normal allele lead to loss of tube diameter control, cyst formation and eventual kidney failure. The respective gene products, polycystin-1 and polycystin-2 form a receptor–ion channel complex that transduces mechanical and/or chemical signals into a calcium entry signal that regulates cell polarity, proliferation and movement. Localisation of this complex in the primary cilium has linked this sensory organelle to the regulation of tube size. Here we review the recent advances made in elucidating pathogenesis, diagnosis and management of this disease and the experimental therapies targeting the implicated signalling pathways. Key Concepts: ADPKD presents with tubular dilatations/cysts mainly affecting the kidney, liver and cardiovascular system, reflecting a defect in tube diameter control. Arterial hypertension is common and occurs early. Current therapy is largely conservative. ADPKD is caused by commonly inactivating germline mutations in PKD1 or PKD2 combined with a second somatic hit that abolishes or reduces function of the remaining normal allele, an event enhanced by the genomic instability associated with the haploid state. Wide variations in onset and progression of the disease are caused by the type of the impaired gene, hypomorphic alleles, mosaicism, combining an inactivating germline mutation with an acquired hypomorphic allele, stochastic fluctuations in expression level of the remaining normal allele and the genetic background. Cerebral aneurysms are more common in ADPKD patients, occur at an earlier age and tend to rupture at a smaller size when compared to the general population. Progressive loss of renal function occurs before standard markers of renal function are abnormal. Measurement of kidney volume in patients with normal renal function using MR imaging (MRI), CT, or ultrasonography is a more sensitive approach for following disease progression at any age. DNA-based diagnostics are useful when imaging studies are equivocal, in individuals with a negative family history, in the selection of a young transplant donor from an ADPKD family or to facilitate pre-implantation genetic diagnosis. The gene products of PKD1 and PKD2, polyctytsin-1 (PC1) and polycystin-2 (PC2), respectively, localise to primary cilia as well as to other membrane compartments. Defects in primary cilium structure causes cysts, as are mutations in several other ciliogenic genes supporting a critical role of the primary cilium in tube formation and maintenance. PC1 and PC2 form a receptor-ion channel complex that triggers calcium entry, which normally activates the planar polarity pathway and represses mitogenic pathways thus regulating tube diameter. The abnormal mitogenesis and fluid secretion pathways that contribute to cyst growth are being targeted therapeutically. Keywords: PKD1; PKD2; primary cilium; TRP channels; tube size; cyst formation; calcium signalling; Wnt pathway; kidney failure; cardiovascular disease