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