Editing Autosomal dominant polycystic kidney disease (section)

==Pathophysiology==

In many patients with ADPKD, kidney dysfunction is not clinically apparent until 30 or 40 years of life.<ref name="grantham"/> However, an increasing body of evidence suggests the formation of renal cysts starts ''in utero''.<ref name="TP-150518-E31">{{cite journal | vauthors = Paul BM, Vanden Heuvel GB | title = Kidney: polycystic kidney disease | journal = Wiley Interdisciplinary Reviews. Developmental Biology | volume = 3 | issue = 6 | pages = 465–487 | year = 2014 | pmid = 25186187 | pmc = 4423807 | doi = 10.1002/wdev.152 }}</ref> Cysts initially form as small dilations in renal tubules, which then expand to form fluid-filled cavities of different sizes.<ref name="TP-150518-E31" /> Factors suggested to lead to cystogenesis include a [[germline mutation]] in one of the polycystin gene alleles, a somatic second hit that leads to the loss of the normal allele, and a third hit, which can be a renal insult that triggers cell proliferation, and an injury response.<ref>{{cite journal | vauthors = Weimbs T | title = Third-hit signaling in renal cyst formation | journal = Journal of the American Society of Nephrology | volume = 22 | issue = 5 | pages = 793–795 | date = May 2011 | pmid = 21493772 | pmc = 5619655 | doi = 10.1681/ASN.2011030284 }}</ref> Due to numerous similarities between the pathophysiology of ADPKD and the pathophysiology of the renal response to injury, ADPKD has been described as a state of aberrant and persistent activation of renal injury response pathways.<ref>{{cite journal | vauthors = Weimbs T | title = Polycystic kidney disease and renal injury repair: common pathways, fluid flow, and the function of polycystin-1 | journal = American Journal of Physiology. Renal Physiology | volume = 293 | issue = 5 | pages = F1423–F1432 | date = November 2007 | pmid = 17715262 | doi = 10.1152/ajprenal.00275.2007 }}</ref> In the progression of the disease, continued dilation of the tubules through increased cell proliferation, fluid secretion, and separation from the parental tubule lead to the formation of cysts.<ref name="TP-150518-E32">{{cite journal | vauthors = Igarashi P, Somlo S | title = Genetics and pathogenesis of polycystic kidney disease | journal = Journal of the American Society of Nephrology | volume = 13 | issue = 9 | pages = 2384–2398 | date = September 2002 | pmid = 12191984 | doi = 10.1097/01.asn.0000028643.17901.42 | doi-access = free }}</ref><ref name="TP-150518-E37">{{cite journal | vauthors = Parnell SC, Magenheimer BS, Maser RL, Zien CA, Frischauf AM, Calvet JP | title = Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins | journal = The Journal of Biological Chemistry | volume = 277 | issue = 22 | pages = 19566–19572 | date = May 2002 | pmid = 11912216 | doi = 10.1074/jbc.M201875200 | doi-access = free }}</ref>

ADPKD, together with many other diseases that present with renal cysts, can be classified into a family of diseases known as [[ciliopathy|ciliopathies]].<ref name="TP-150518-E33">{{cite journal | vauthors = Berbari NF, O'Connor AK, Haycraft CJ, Yoder BK | title = The primary cilium as a complex signaling center | journal = Current Biology | volume = 19 | issue = 13 | pages = R526–R535 | date = July 2009 | pmid = 19602418 | pmc = 2814769 | doi = 10.1016/j.cub.2009.05.025 | bibcode = 2009CBio...19.R526B }}</ref> Epithelial cells of the renal tubules, including all the segments of the nephron and the collecting ducts (with the exception of intercalated cells) show the presence of a single primary apical cilium.<ref name="TP-150518-E34">{{cite journal | vauthors = Reed BY, McFann K, Bekheirnia MR, Reza Bekheirnia M, Nobakhthaghighi N, Nobkhthaghighi N, Masoumi A, Johnson AM, Shamshirsaz AA, Shamshiraz AA, Kelleher CL, Schrier RW | display-authors = 6 | title = Variation in age at ESRD in autosomal dominant polycystic kidney disease | journal = American Journal of Kidney Diseases | volume = 51 | issue = 2 | pages = 173–183 | date = February 2008 | pmid = 18215695 | pmc = 2747334 | doi = 10.1053/j.ajkd.2007.10.037 }}</ref> [[PKD1|Polycystin-1]], the protein encoded by the [[PKD1]] gene, is present on these cilia and is thought to sense the flow with its large extracellular domains, activating the calcium channels associated with [[PKD2|polycystin-2]], the product of gene [[PKD2]],<ref name="TP-150518-E35">{{cite journal | vauthors = Chapin HC, Caplan MJ | title = The cell biology of polycystic kidney disease | journal = The Journal of Cell Biology | volume = 191 | issue = 4 | pages = 701–710 | date = November 2010 | pmid = 21079243 | pmc = 2983067 | doi = 10.1083/jcb.201006173 }}</ref> as a result of the genetic setting of ADPKD as explained in the '''genetics''' sub-section above.

Epithelial cell proliferation and fluid secretion that lead to cystogenesis are two hallmark features in ADPKD.<ref name="TP-150518-E36">{{cite journal | vauthors = Belibi FA, Reif G, Wallace DP, Yamaguchi T, Olsen L, Li H, Helmkamp GM, Grantham JJ | display-authors = 6 | title = Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells | journal = Kidney International | volume = 66 | issue = 3 | pages = 964–973 | date = September 2004 | pmid = 15327388 | doi = 10.1111/j.1523-1755.2004.00843.x | doi-access = free }}</ref> During the early stages of cystogenesis, cysts are attached to their parental renal tubules and a derivative of the glomerular filtrate enters the cysts.<ref name="TP-150518-E31" /> Once these cysts expand to approximately 2 mm in diameter, the cyst closes off from its parental tubule and after that fluid can only enter the cysts through transepithelial secretion, which in turn is suggested to increase due to secondary effects from an increased intracellular concentration of [[cyclic AMP]] (cAMP).<ref name="TP-150518-E31" />

Clinically, the insidious increase in the number and size of renal cysts translates as a progressive increment in kidney volume.<ref name="TP-150518-E20" /><ref name="TP-150518-E31" /> Studies led by [[Mayo Clinic]] professionals established that the total kidney volume (TKV) in a large cohort of ADPKD patients was 1060 ± 642ml with a mean increase of 204ml over three years, or 5.27% per year in the natural course of the disease, among other important, novel findings that were extensively studied for the first time.<ref name="TP-150515-017">{{cite journal | vauthors = Torres VE | title = Treatment strategies and clinical trial design in ADPKD | journal = Advances in Chronic Kidney Disease | volume = 17 | issue = 2 | pages = 190–204 | date = March 2010 | pmid = 20219622 | pmc = 4127876 | doi = 10.1053/j.ackd.2010.01.006 }}</ref>

[[Image:PKD1PKD2 en.png|thumb|Illustration of PKD1 and PKD2 proteins at the cell membrane]]