quistes hepáticos y renales: ¿cuándo es poliquistosis?quistes hepáticos y renales: ¿cuándo es...
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Quistes hepáticos y renales: ¿Cuándo es poliquistosis?
Alberto OrtizNefrología, IIS-Fundacion Jimenez Diaz, Madrid, Spain
Universidad Autónoma de MadridCoordinador, REDINREN
Quiste renal y poliquistosisCavidad llena de líquido, rodeada de epitelio (tubular) renal,
no comunicada con la vía urinaria
Grantham, NEJM 2008
lQuistes simples: 60% de >60 años tienen > 1 quiste
lNefropatías quísticas: múltiples quistes renales bilateralesHereditarias: 8% de enf renal terminal
PQRAD: 1: 2.000 nacidos vivosPQRAR: 1: 20.000Nefronoptosis: 1: 60.000
Adquirida de la ERC
Hereditaria
Adquirida
Polycystic liver diseasea) most often ADPKD. Incidence of hepatic cysts increases with age from 10% at age <30 to >50% at age >60. Cysts from biliary epithelium.• PKD1• PKD2
Polycystic kidney disease: a ciliopathy
Praetorius. Am J Physiol 2015
Polycystic liver diseasea) most often ADPKD. Incidence of hepatic cysts increases with age from 10% at age <30 to >50% at age >60. Cysts from biliary epithelium.• PKD1• PKD2
b) AD polycystic liver diseaseNot associated with kidney cysts or cerebral aneurysms.• PRKCSH (hepatocystin, glucosidase 2 beta subunit)• SEC63 (component of the protein translocation machinery in the endoplasmic reticulum).• 80% no genetic defect found
Polycystic liver disease: a REpathy?
http://www.nature.com/nrm/journal/v3/n4/fig_tab/nrm780_F3.htmlhttp://introducingorganelles.weebly.com/rough-and-smooth-endoplasmic-reticulum.html
http://jcs.biologists.org/content/121/17/2814
Polycystic liver diseasea) most often ADPKD. Incidence of hepatic cysts increases with age from 10% at age <30 to >50% at age >60. Cysts from biliary epithelium.• PKD1• PKD2
b) AD polycystic liver diseaseNot associated with kidney cysts or cerebral aneurysms.• PRKCSH (hepatocystin, glucosidase 2 beta subunit)• SEC63 (component of the protein translocation machinery in the endoplasmic reticulum).• 80% no genetic defect found
b) AD polycystic liver and kidney diseaseAssociated with kidney cysts.• GANAB (glucosidase 2 alpha subunit)• LRP5 (low density lipoprotein receptor-related protein 5)
Am J Hum Genet. 2016
Primary cilium
andendoplasmic reticulum?
http://ajpcell.physiology.org/content/308/3/C198 Praetorius. Am J Physiol 2015
Harris, Torres. Annu Rev Med 2009
SSTR2
Patogenia molecular: PC1 and PC2 affect multiple signaling pathways
PQRAD - ADPKD
Chapman CJASN 2008
PQRAD: patocronia
2017Nefrólogo!!!!
HTA
Hematuria
Dolor
InfecciónLitiasis
2% formas neonatales
2025Pediatra
Momento de tratar?Normal renal function
DOES NOT exclude ADPKD
Chapman CJASN 2008
PQRAD: patocronia
Grantham, NEJM 2008
Total kidney volume (ml)
MenWomen
Grantham. Nat. Rev. Nephrol. 2011
Factor pronóstico
Patogenia de las nefropatías quísticas• Patogenia molecular común (hereditarias): disfunción del cilio primario
• Patogenia celular
• Patogenia tisular: aumento volumen quístico determina pronóstico
• Mutación de genes que codifican proteínas del cilio primario– PKD1 codifica poliquistina 1:– PKD2 codifica poliquistina 2:
Rodriguez-Osorio et al. Kidney Int
85% of cases PKD1ESRD: 55a 15% of cases PKD2
ESRD: 75a
Patogenia molecular: efecto de dosis
Pei et al Kidney International advance online publication, 26 October 2011
66 yo, mild PKD1 mutation
Whole exome sequencing 7374 patients: 5 % 2 pathogenic mutations
Non-Mendelian inheritance
Welcome to the new era of exome sequencing
Doctor… I got sequenced and….
the PKD1 haplotype, includingR2220WR3277Cand polymorphisms (Q739R and W1399R), segregate with the disease
Asintomáticos, no quistes a 34 y 41 años por eco
Patogenia molecular: efecto de dosisIncompletely Penetrant PKD1 Alleles Mimic ARPKD
(alelos hipomórficos)
Vujic et al. J Am Soc Nephrol 21: 1097–1102, 2010
echogenic kidneys and at birth (34 w)
oligohydramnios, pulmonary hypoplasia, and severe respiratory distress
hypertension with renal insufficiency
Patogenia celular
Fluid
Normal tubule
Cell proliferation
Grantham, J. J. et al. Nat. Rev. Nephrol. 7, 556–566 (2011);
Patogenia tisular: obstrucción e isquemia
Imaging in ADPKD
• Sonography: criteria for diagnosis
• Contrast CT scan‘intermediate’ renal volume (hypoenhanced) regions of fibrotic kidney tissue
• MRI: total kidney volume calculation and progression
Heyer et al . JASN 2016
Liver and kidney cysts in ADPKD PKD1
Liver cyst volume
Heyer et al . JASN 2016
Liver and kidney cysts in ADPKD PKD1
Liver cyst volume Liver cyst volume
Heyer et al . JASN 2016
Liver and kidney cysts in ADPKD PKD1
Kidney cyst volume Liver cyst volume
2015
Somatostatin analogs?Reduce liver cyst volume by 3-5%/year
Do not appear to change natural history, improve QOL
<30 años
30-59 años
≥60 años
or
When to suspect ADPKD in patient with liver cysts
Family history of dialysis is important!
2
4
8
Si riñón no cabe en la eco: al nefrólogo!
Se cuentan todos los quistes
Irazabal et al. JASN 2015
ADPKD: TKVpredicts GFR loss
Imaging in ADPKD
• Sonography: criteria for diagnosis
• Contrast CT scan‘intermediate’ renal volume (hypoenhanced) regions of fibrotic kidney tissue
• MRI: total kidney volume calculation and progression
• Fluorodeoxyglucose (FDG)-PET/TC: intracystic infection
Recent clinical trials
• Tolvaptan
• BP
November 2012- Advanced online publication.
Primary end point: annual rate of % change in TKV; 50% difference
Tolvaptan 2.8% per year ( 95% CI 2.5 to 3.1) vs placebo 5.5% (5.1 to 6.0)
Secondary end point: change in slope of kidney function as measured by the reciprocal of sCr: 30% difference−2.61 vs −3.81 mg/ml/year:
Potential for liver toxicity!
Just drink water!!
Did you try?
Not so easy!!Natremia increases on tolvaptan
My patient is already polyuric!!
ADH-resistance!!
Nephrogenic diabetes insipidus
ADHADH-dependent
intracellular signalling
Recent clinical trials
• Tolvaptan
• BPTarget 95/60 to 110/75 mmHg mejor que 120/70 to 130/80
GFR >60
Take home message
• Patient with liver and kidney cysts… suspect autosomal dominant polycystic kidney disease (ADPKD)
• ADPKD is a treatable disease
• Liver cysts plus enlarged cystic kidneys• Liver cysts plus some kidney cysts below age 40• Liver cysts plus family history of dialysis
• The disease spectrum is expanding to encompass milder forms of the disease
Nephrologist
evaluation