Polycystic kidney disease pathophysiology

Jump to navigation Jump to search
https://https://www.youtube.com/watch?v=JmFpL3WLTAM%7C350}}

Polycystic kidney disease Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Polycystic kidney disease from other Diseases

Epidemiology and Demographics

Risk Factor

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-Ray

CT

MRI

Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Interventions

Surgery

Primary Prevention

Secondary Prevention

Future or Investigational Therapies

Case Studies

Case #1

Polycystic kidney disease pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Polycystic kidney disease pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Polycystic kidney disease pathophysiology

CDC on Polycystic kidney disease pathophysiology

Polycystic kidney disease pathophysiology in the news

Blogs on Polycystic kidney disease pathophysiology

Directions to Hospitals Treating Polycystic kidney disease

Risk calculators and risk factors for Polycystic kidney disease pathophysiology

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]

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.

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).

Template:WH Template:WS