Polycystic kidney disease pathophysiology
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The pathogenesis of ADPKD is related to the protein products of the PKD1 and PKD2 genes known collectively as polycystins. These proteins are primarily involved in ciliary function in the renal tubular cells and defects in their function leads to intracellular cAMP accumulation and mTOR overactivity causing cell proliferation, fluid secretion, and abnormal extracellular matrix and intercellular interactions the main processes that lead to cyst formation.
- The pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) stems from the mutations of PKD1 and PKD2 genes on chromosomes 16 and 4 respectively.
- Polycystin-1 and polycystin-2, the protein products of PKD1 and PKD2, are transmembrane proteins that have distinct functions but interact to form one functional complex explaining the similar phenotype with both mutations.
- Despite their location, the primary cilia are usually structurally normal in ADPKD. However, functional abnormalities in mechanosensation have been documented.
- In wildtype variants, the polycystin protein complex detects changes in tubular flow, with resultant changes in Ca²+ influx via the polycystin-2 channel. This mechanism is defective in patients with ADPKD.
- Even before polycystins were discovered, cyst formation was considered to be the result of 3 processes:
- With the relatively recent advances in the pathogenesis of ADPKD, polycystins were found to regulate all these processes. 
- With the alterations in calcium hemostasis within tubular cells, intracellular cAMP concentration increase causing apical cAMP-dependent Cl channels to increase cyst fluid secretion activate cellular proliferation via extracellular signaling.
- These findings have made intracellular cAMP concentrations the focal point for targeted therapy in ADPKD. 
- Another proposed mechanism of pathogenesis involved increased mTOR activity.
- Normally, polycystin-1 is involved in suppressing the activity of mTOR , explaining the abnormally increased activity seen in ADPKD.
- mTOR is heavily in involved cell growth and proliferation with suggested involvement in increased cellular proliferation and apoptosis seen in ADPKD. 
- Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of the disease and its characteristics include: 
- ARPKD is caused by a mutation in PKHD1 gene that codes for an integral membrane protein fibrocystin 
- It is suggested that fibrocystin may be involved in regulation of cellular adhesion and proliferation
- Malfunction in fibrocystin leads to cyst formation by forming an undifferentiated secretory epithelium
- This defect leads to polarization abnormalities and high rate of proliferation and apoptosis
- There is a subsequent increase in cAMP signaling, epidermal growth factor receptor axis mediated proliferation and excess fluid secretion
- ARPKD: 
- ADPKD is transmitted in a dominant pattern.
- Genes involved in the pathogenesis of ADPKD include PKD1 gene, PKD2 gene 
- Autosomal dominant polycystic kidney disease (ADPKD) is caused by a mutation in either the PKD1 gene or PKD2 gene 
- ADPKD is an inherited disorder with 2 possible etiologic mutations
- PKD1 mutations found on short arm of chromosome 16 (16p13.3) accounts for roughly 85% of cases 
- PKD2 mutations found on the long arm of chromosome 4 (4q21) account for 15% of the remaining cases 
- All cases of ADPKD are heterozygous for either PKD mutations or both
- Homozygous cases usually die in utero 
- Generally, PKD1 mutants have more severe renal disease with mean age at onset of ESRD around 50 years compared to 75 years in PKD2 mutants 
- Patients heterozygous for both mutations have the most severe renal manifestations
- Despite the monogenic nature of the disease, the phenotype and severity of the disease as well as the extrarenal manifestations have been known to vary even within the same family
- Several mechanisms have been proposed to explain this variability including: 
- ARPKD is transmitted in a recessive pattern.
- Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene 
Conditions associated with autosomal dominant polycystic kidney disease (ADPKD):
Conditions associated with autosomal recessive polycystic kidney disease (ARPKD):
- Congenital hepatic fibrosis 
- Hepatosplenomegaly 
- Pulmonary hypoplasia 
- Respiratory distress 
- On gross pathology, enlarged kidneys, deformed external surface of kidney, numerous spherical cortical and medullary cysts, cysts containing serous, hemorrhagic, fluid, reduced intervening parenchyma between cysts are characteristic findings of ADPKD.
- On gross pathology, enlarged kidneys, smooth external surface, sponge like appearance, numerous cysts, dilated nephron tubules, rounded cysts on liver parenchyma are characteristic findings of ARPKD.
- On microscopic histopathological analysis, interstitial fibrosis, tubular atrophy, thickening and lamellation of tubular basement membranes, microcysts and negative immunofluorescence for complement and immunoglobulin are characteristic findings of ADPKD.
- Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millán JL; et al. (1995). "The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains". Nat Genet. 10 (2): 151–60. doi:10.1038/ng0695-151. PMID 7663510.
- Hayashi T, Mochizuki T, Reynolds DM, Wu G, Cai Y, Somlo S (1997). "Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2)". Genomics. 44 (1): 131–6. doi:10.1006/geno.1997.4851. PMID 9286709.
- Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG (1997). "PKD1 interacts with PKD2 through a probable coiled-coil domain". Nat Genet. 16 (2): 179–83. doi:10.1038/ng0697-179. PMID 9171830.
- Chapman AB (2007). "Autosomal dominant polycystic kidney disease: time for a change?". J Am Soc Nephrol. 18 (5): 1399–407. doi:10.1681/ASN.2007020155. PMID 17429048.
- Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X; et al. (2003). "Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells". Nat Genet. 33 (2): 129–37. doi:10.1038/ng1076. PMID 12514735 Check
- Belibi FA, Reif G, Wallace DP, Yamaguchi T, Olsen L, Li H; et al. (2004). "Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells". Kidney Int. 66 (3): 964–73. doi:10.1111/j.1523-1755.2004.00843.x. PMID 15327388.
- Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N; et al. (2006). "The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease". Proc Natl Acad Sci U S A. 103 (14): 5466–71. doi:10.1073/pnas.0509694103. PMC 1459378. PMID 16567633 Check
- Ward CJ, Hogan MC, Rossetti S, Walker D, Sneddon T, Wang X, Kubly V, Cunningham JM, Bacallao R, Ishibashi M, Milliner DS, Torres VE, Harris PC (March 2002). "The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein". Nat. Genet. 30 (3): 259–69. doi:10.1038/ng833. PMID 11919560.
- Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, Bergmann C, Senderek J, Esquivel E, Zeltner R, Rudnik-Schöneborn S, Mrug M, Sweeney W, Avner ED, Zerres K, Guay-Woodford LM, Somlo S, Germino GG (May 2002). "PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats". Am. J. Hum. Genet. 70 (5): 1305–17. doi:10.1086/340448. PMC 447605. PMID 11898128.
- Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Sweeney WE, Avner ED. PMID 20301501. Vancouver style error: initials (help); Missing or empty
- Sweeney WE, Avner ED (December 2006). "Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD)". Cell Tissue Res. 326 (3): 671–85. doi:10.1007/s00441-006-0226-0. PMID 16767405.
- "The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium". Cell. 77 (6): 881–94. June 1994. PMID 8004675.
- Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S (May 1996). "PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein". Science. 272 (5266): 1339–42. PMID 8650545.
- "Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. The International Polycystic Kidney Disease Consortium". Cell. 81 (2): 289–98. 1995. PMID 7736581.
- Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ; et al. (1996). "PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein". Science. 272 (5266): 1339–42. PMID 8650545 Check
- Torra R, Badenas C, Darnell A, Nicolau C, Volpini V, Revert L; et al. (1998). "[Clinical, genetic and molecular studies on autosomal dominant polycystic kidney disease]". Med Clin (Barc). 110 (13): 481–7. PMID 9611728.
- Paterson AD, Wang KR, Lupea D, St George-Hyslop P, Pei Y (2002). "Recurrent fetal loss associated with bilineal inheritance of type 1 autosomal dominant polycystic kidney disease". Am J Kidney Dis. 40 (1): 16–20. doi:10.1053/ajkd.2002.33908. PMID 12087556.
- Hateboer N, v Dijk MA, Bogdanova N, Coto E, Saggar-Malik AK, San Millan JL; et al. (1999). "Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group". Lancet. 353 (9147): 103–7. PMID 10023895.
- Torres VE, Harris PC, Pirson Y (2007). "Autosomal dominant polycystic kidney disease". Lancet. 369 (9569): 1287–301. doi:10.1016/S0140-6736(07)60601-1. PMID 17434405.
- Belz MM, Hughes RL, Kaehny WD, Johnson AM, Fick-Brosnahan GM, Earnest MP, Gabow PA (October 2001). "Familial clustering of ruptured intracranial aneurysms in autosomal dominant polycystic kidney disease". Am. J. Kidney Dis. 38 (4): 770–6. doi:10.1053/ajkd.2001.27694. PMID 11576880.
- Ring T, Spiegelhalter D (December 2007). "Risk of intracranial aneurysm bleeding in autosomal-dominant polycystic kidney disease". Kidney Int. 72 (11): 1400–2. doi:10.1038/sj.ki.5002488. PMID 17882153.
- Hossack KF, Leddy CL, Johnson AM, Schrier RW, Gabow PA (October 1988). "Echocardiographic findings in autosomal dominant polycystic kidney disease". N. Engl. J. Med. 319 (14): 907–12. doi:10.1056/NEJM198810063191404. PMID 3419455.
- Ivy DD, Shaffer EM, Johnson AM, Kimberling WJ, Dobin A, Gabow PA (June 1995). "Cardiovascular abnormalities in children with autosomal dominant polycystic kidney disease". J. Am. Soc. Nephrol. 5 (12): 2032–6. PMID 7579051.
- Bae KT, Zhu F, Chapman AB, Torres VE, Grantham JJ, Guay-Woodford LM, Baumgarten DA, King BF, Wetzel LH, Kenney PJ, Brummer ME, Bennett WM, Klahr S, Meyers CM, Zhang X, Thompson PA, Miller JP (January 2006). "Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort". Clin J Am Soc Nephrol. 1 (1): 64–9. doi:10.2215/CJN.00080605. PMID 17699192.
- Gabow PA, Johnson AM, Kaehny WD, Manco-Johnson ML, Duley IT, Everson GT (June 1990). "Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease". Hepatology. 11 (6): 1033–7. PMID 2365280.
- Telega G, Cronin D, Avner ED (June 2013). "New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney-liver complications". Pediatr Transplant. 17 (4): 328–35. doi:10.1111/petr.12076. PMC 3663883. PMID 23593929.
- Gunay-Aygun M, Font-Montgomery E, Lukose L, Tuchman Gerstein M, Piwnica-Worms K, Choyke P, Daryanani KT, Turkbey B, Fischer R, Bernardini I, Sincan M, Zhao X, Sandler NG, Roque A, Douek DC, Graf J, Huizing M, Bryant JC, Mohan P, Gahl WA, Heller T (January 2013). "Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease". Gastroenterology. 144 (1): 112–121.e2. doi:10.1053/j.gastro.2012.09.056. PMC 4162098. PMID 23041322.
- Roy S, Dillon MJ, Trompeter RS, Barratt TM (June 1997). "Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors". Pediatr. Nephrol. 11 (3): 302–6. PMID 9203177.
- Jahnukainen T, Kirjavainen T, Luoto T, Ylinen E, Linkosalo L, Arikoski P, Pakarinen M, Jalanko H (October 2015). "Long-term pulmonary function in children with recessive polycystic kidney disease". Arch. Dis. Child. 100 (10): 944–7. doi:10.1136/archdischild-2015-308451. PMID 26163120.
- Sweeney WE, Avner ED (May 2011). "Diagnosis and management of childhood polycystic kidney disease". Pediatr. Nephrol. 26 (5): 675–92. doi:10.1007/s00467-010-1656-1. PMID 21046169.
- Halvorson CR, Bremmer MS, Jacobs SC (2010). "Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment". Int J Nephrol Renovasc Dis. 3: 69–83. PMC 3108786. PMID 21694932.
- Igarashi P, Somlo S (September 2002). "Genetics and pathogenesis of polycystic kidney disease". J. Am. Soc. Nephrol. 13 (9): 2384–98. PMID 12191984.
- Stavrou C, Koptides M, Tombazos C, Psara E, Patsias C, Zouvani I, Kyriacou K, Hildebrandt F, Christofides T, Pierides A, Deltas CC (October 2002). "Autosomal-dominant medullary cystic kidney disease type 1: clinical and molecular findings in six large Cypriot families". Kidney Int. 62 (4): 1385–94. doi:10.1111/j.1523-1755.2002.kid581.x. PMID 12234310.
- Bleyer AJ, Kmoch S, Antignac C, Robins V, Kidd K, Kelsoe JR, Hladik G, Klemmer P, Knohl SJ, Scheinman SJ, Vo N, Santi A, Harris A, Canaday O, Weller N, Hulick PJ, Vogel K, Rahbari-Oskoui FF, Tuazon J, Deltas C, Somers D, Megarbane A, Kimmel PL, Sperati CJ, Orr-Urtreger A, Ben-Shachar S, Waugh DA, McGinn S, Bleyer AJ, Hodanová K, Vylet'al P, Živná M, Hart TC, Hart PS (March 2014). "Variable clinical presentation of an MUC1 mutation causing medullary cystic kidney disease type 1". Clin J Am Soc Nephrol. 9 (3): 527–35. doi:10.2215/CJN.06380613. PMC 3944763. PMID 24509297.
- Faguer S, Decramer S, Chassaing N, Bellanné-Chantelot C, Calvas P, Beaufils S, Bessenay L, Lengelé JP, Dahan K, Ronco P, Devuyst O, Chauveau D (October 2011). "Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood". Kidney Int. 80 (7): 768–76. doi:10.1038/ki.2011.225. PMID 21775974.
- Heidet L, Decramer S, Pawtowski A, Morinière V, Bandin F, Knebelmann B, Lebre AS, Faguer S, Guigonis V, Antignac C, Salomon R (June 2010). "Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases". Clin J Am Soc Nephrol. 5 (6): 1079–90. doi:10.2215/CJN.06810909. PMC 2879303. PMID 20378641.