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Renal Disease; Fluid and Electrolyte Disorders
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Adult PKD is usually caused by a dominant mutation in the PKD1 gene, which encodes the polycystin-1 protein. New mutations are common, so there may not be a family history. A minority of patients have mutations in the PKD2 gene, which encodes polycystin-2. Cysts develop and enlarge, compressing and destroying normal renal tissue, resulting in a progressive decline in renal function. The cysts may bleed (into the cyst or urinary tract) and become infected.
The kidneys
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
The two main groups of genetically determined renal disease of note are polycystic kidney disease and genetic abnormalities of the glomerular basement membrane. Polycystic kidney disease occurs in two main forms. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of cystic renal disease and one of the most common genetic diseases in the community, affecting approximately 1:500 to 1:1,000 individuals. It accounts for about 10% of patients requiring renal replacement therapy. The disease is genetically heterogeneous and is caused by germline mutation in one of three separate genes: the polycystin 1 gene, which is located on the short arm of chromosome 16 and accounts for 85% of cases; the polycystin 2 gene on the long arm of chromosome 4 (10%–14% of cases); and the third, recently described polycystic kidney disease gene 3 (PKD3) on chromosome 11 is responsible for a minority of cases. These genes regulate the action of the primary cilium and cell polarity. The cysts sometimes cause pain and haematuria but many of the patients with ADPKD remain asymptomatic until adult life. Then there may be a progressive deterioration in renal function, usually during the third or fourth decade, leading to established renal failure, particularly in those with untreated hypertension. The kidneys contain large numbers of cysts and may expand to weigh more than 1 kg (Figure 14.2). The cysts may be several centimetres in diameter and contain serous or blood-stained fluid. Cysts are present throughout the nephron (Figure 14.3).
SBA Answers and Explanations
Published in Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury, SBAs for the MRCS Part A, 2018
Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury
Adult polycystic kidney disease is one of the most common inherited disorders in humans, affecting approximately 1 in 1000 individuals and accounting for 10 per cent of cases of end-stage renal failure. It is inherited as an autosomal dominant condition with a late-onset mode of presentation. Eighty-five per cent of cases have been localized to a gene on the short arm of chromosome 16 (PKD1 gene). A second gene (PKD2), responsible for around 15 per cent of cases, has been localized to the long arm of chromosome 4. The corresponding gene products have been named polycystin-1 and polycystin-2, although their exact function is unknown.
Renal ciliopathies: promising drug targets and prospects for clinical trials
Published in Expert Opinion on Therapeutic Targets, 2023
Laura Devlin, Praveen Dhondurao Sudhindar, John A. Sayer
Heterozygous mutations in PKD1 and PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2) respectively, account for over 90% of ADPKD patients. PKD1 mutations account for 75–85% of identified mutations, and PKD2 mutations are less common, accounting for 15% of identified mutations and milder phenotypes with KF developing at a later age [41,47]. PC1 and PC2 are located in the primary cilium. PC1 acts as an ion channel and g-protein coupled receptor, and PC2 acts as an ion channel that forms a heteromeric complex with PC1 with fibrocystin, regulating PC1’s localization in kidney epithelia [48,49]. It has traditionally been proposed that the PC1/PC2 complex mediates Ca2+ signaling in the primary cilium, in response to fluid flow; however, more recently, this has been refuted, with the exact pathomechanism unclear [41,45,50,51]. Nevertheless, it is thought that loss or malfunction of PC1/PC2 has implications downstream for multiple pathways, including cAMP, mTOR, EGF, AMPK, and cMyc signaling, which effect orientated cell proliferation [52].
Analysis of urinary exosomes applications for rare kidney disorders
Published in Expert Review of Proteomics, 2020
Isabella Panfoli, Simona Granata, Giovanni Candiano, Alberto Verlato, Gianmarco Lombardi, Maurizio Bruschi, Gianluigi Zaza
Polycystic kidney disease (PKD) is a family of hereditary disorders characterized by a progressive growth and enlargement of numerous fluid-filled cysts, that disrupt the kidney parenchyma, leading to interstitial fibrosis, cellular infiltration, and the loss of functional nephrons. PKD includes autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). ADPKD has a prevalence of 0.1–0.25% [88] and is caused by mutations in the PKD1 or PKD2 gene, encoding for polycystin-1 (PC1) and polycystin-2 (PC2) proteins, respectively [89,90]. The main role of PC1 and PC2 is the formation of a protein complex that acts as a receptor-ion channel in primary cilia [91,92], minute membrane-encased microtubule-based structures that protrude from the apical surface of kidney tubule epithelial cells and that is used by cells as a sensory organelle for signal integration.
New insights into targeting hepatic cystogenesis in autosomal dominant polycystic liver and kidney disease
Published in Expert Opinion on Therapeutic Targets, 2020
Thijs R. M. Barten, Lucas H. P. Bernts, Joost P. H. Drenth, Tom J. G. Gevers
Mutations in PKD1 are generally associated with more severe disease than PKD2 [16,17]. PKD1 and PKD2 encode for the proteins polycystin 1 (PC1) and polycystin 2 (PC2) respectively, which act as a mechanosensor and calcium channel and are located in the primary cilium of cholangiocytes [6,7]. Additionally, PC2 is also located to the endoplasmic reticulum. Mutations in PKD1 and PKD2 genes result in inadequate formation of PC1 or PC2. Hepatic cystogenesis in ADPLD is caused by mutations in PRKCSH and SEC63 genes in approximately 35% of cases. Recently, GANAB, ALG8, and LRP5 have also been associated with ADPLD with large (>1 cm) hepatic cysts, while heterozygous mutations in PKHD1 and SEC61B were found in 10 and 2 PLD patients with numerous diffusely spread small hepatic cysts [18–20]. However, approximately 50% of causative genes in PLD still remain unresolved [19].