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*Normally, polycystin1 is involved in suppressing the activity of mTOR , explaining the abnormally increased activity seen in ADPKD.  
*Normally, polycystin1 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.<ref name="pmid16567633‎">{{cite journal| author=Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N et al.| title=The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. | journal=Proc Natl Acad Sci U S A | year= 2006 | volume= 103 | issue= 14 | pages= 5466-71 | pmid=16567633‎ | doi=10.1073/pnas.0509694103 | pmc=PMC1459378 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567633 }} </ref>
*mTOR is heavily in involved cell growth and proliferation with suggested involvement in increased cellular proliferation and apoptosis seen in ADPKD.<ref name="pmid16567633‎">{{cite journal| author=Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N et al.| title=The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. | journal=Proc Natl Acad Sci U S A | year= 2006 | volume= 103 | issue= 14 | pages= 5466-71 | pmid=16567633‎ | doi=10.1073/pnas.0509694103 | pmc=PMC1459378 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567633 }} </ref>
*Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of the disease and its characteristics include:<ref name="pmid11919560">{{cite journal |vauthors=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 |title=The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein |journal=Nat. Genet. |volume=30 |issue=3 |pages=259–69 |date=March 2002 |pmid=11919560 |doi=10.1038/ng833 |url=}}</ref><ref name="pmid11898128">{{cite journal |vauthors=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 |title=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 |journal=Am. J. Hum. Genet. |volume=70 |issue=5 |pages=1305–17 |date=May 2002 |pmid=11898128 |pmc=447605 |doi=10.1086/340448 |url=}}</ref>
*Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of the disease and its characteristics include:<ref name="pmid11919560">{{cite journal |vauthors=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 |title=The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein |journal=Nat. Genet. |volume=30 |issue=3 |pages=259–69 |date=March 2002 |pmid=11919560 |doi=10.1038/ng833 |url=}}</ref><ref name="pmid11898128">{{cite journal |vauthors=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 |title=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 |journal=Am. J. Hum. Genet. |volume=70 |issue=5 |pages=1305–17 |date=May 2002 |pmid=11898128 |pmc=447605 |doi=10.1086/340448 |url=}}</ref><ref name="pmid20301501">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Sweeney WE, Avner ED |title= |journal= |volume= |issue= |pages= |date= |pmid=20301501 |doi= |url=}}</ref>
**Primarily a disease affecting infants and children
**Primarily a disease affecting infants and children
**Dilation of collecting ducts
**Dilation of collecting ducts
Line 56: Line 56:
**Haploinsufficiency
**Haploinsufficiency
**Environmental factors modifying disease processes
**Environmental factors modifying disease processes
*Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene<ref name="pmid11898128">{{cite journal |vauthors=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 |title=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 |journal=Am. J. Hum. Genet. |volume=70 |issue=5 |pages=1305–17 |date=May 2002 |pmid=11898128 |pmc=447605 |doi=10.1086/340448 |url=}}</ref><ref name="pmid11919560">{{cite journal |vauthors=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 |title=The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein |journal=Nat. Genet. |volume=30 |issue=3 |pages=259–69 |date=March 2002 |pmid=11919560 |doi=10.1038/ng833 |url=}}</ref><ref name="pmid20301501">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Sweeney WE, Avner ED |title= |journal= |volume= |issue= |pages= |date= |pmid=20301501 |doi= |url=}}</ref>
*Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene<ref name="pmid11898128">{{cite journal |vauthors=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 |title=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 |journal=Am. J. Hum. Genet. |volume=70 |issue=5 |pages=1305–17 |date=May 2002 |pmid=11898128 |pmc=447605 |doi=10.1086/340448 |url=}}</ref><ref name="pmid11919560">{{cite journal |vauthors=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 |title=The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein |journal=Nat. Genet. |volume=30 |issue=3 |pages=259–69 |date=March 2002 |pmid=11919560 |doi=10.1038/ng833 |url=}}</ref>
**PKHD1 is a gene that shares structural similarities with the hepatocyte growth-factor receptor
**PKHD1 is a gene that shares structural similarities with the hepatocyte growth-factor receptor


Revision as of 16:58, 22 May 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul

Overview

The pathogenesis of ADPKD is related to the protein products of the PKD1 and PKD2 genes known collectively as polycystins. These proteins are mainly 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.

Pathophysiology

Pathogenesis

  • 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.[1][2][3]
    • Polycystin-1 is a ligand receptor
    • Polycystin-2 is a non-selective cation channel.
    • Both proteins are located in the primary cilium in the renal tubular epithelial cells, which is typical of many other proteins also implicated in cystic diseases of the kidneys.
  • Despite their location, the primary cilia are usually structurally normal in ADPKD. However, functional abnormalities in mechanosensation have been documented.[4]
  • 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.[5]
  • Even before polycystins were discovered, cyst formation was considered to be the result of 3 processes:
    • Cell proliferation
    • Fluid secretion
    • Abnormal extracellular matrix and intercellular interactions
  • With the relatively recent advances in the pathogenesis of ADPKD, polycystins were found to regulate all these processes.[4]
  • 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.[6]
  • These findings have made intracellular cAMP concentrations the focal point for targeted therapy in ADPKD.[4]
  • Another proposed mechanism of pathogenesis involved increased mTOR activity.
  • Normally, polycystin1 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.[7]
  • Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of the disease and its characteristics include:[8][9][10]
    • Primarily a disease affecting infants and children
    • Dilation of collecting ducts
    • Biliary dysgenesis
    • Enlarged kidneys
    • Congenital hepatic fibrosis
    • Renal and hepatic morbidity and mortality

Genetics

  • [Disease name] is transmitted in [mode of genetic transmission] pattern.
  • Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
  • The development of [disease name] is the result of multiple genetic mutations.
  • Autosomal dominant polycystic kidney disease (ADPKD) is caused by a mutation in either the PKD1 gene or PKD2 gene[11]
  • 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[12]
  • PKD2 mutations found on the long arm of chromosome 4 (4q21) account for 15% of the remaining cases[13]
  • All cases of ADPKD are heterozygous for either PKD mutations or both
  • Homozygous cases usually die in utero[14]
  • 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[15]
  • 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:[16]
    • A two-hit hypothesis involving loss of two PKD alleles in both germline and somatic cell lines
    • Haploinsufficiency
    • Environmental factors modifying disease processes
  • Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene[9][8]
    • PKHD1 is a gene that shares structural similarities with the hepatocyte growth-factor receptor

Associated Conditions

Conditions associated with autosomal dominant polycystic kidney disease (ADPKD):

  • Berry aneurysms
  • Mitral valve prolapse
  • Benign hepatic cysts

Conditions associated with autosomal recessive polycystic kidney disease (ARPKD):

  • Congenital hepatic fibrosis

Gross Pathology

  • On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

  • On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].


References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 4.0 4.1 4.2 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.
  5. ↑ 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 |pmid= value (help).
  6. ↑ 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.
  7. ↑ 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 |pmid= value (help).
  8. ↑ 8.0 8.1 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.
  9. ↑ 9.0 9.1 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.
  10. ↑ 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 |title= (help)
  11. ↑ "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.
  12. ↑ 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 |pmid= value (help).
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.

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