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ADPKD More than aKidney Disease
Dr Anand Saggar
PKD Information Day
Birmingham July 7 2007
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Hepatorenal Fibrocystic Diseases
Autosomal Dominant Polycystic Kidney Disease PKD1 (chromosome 16p13.3); polycystin-1 PKD2 (chromosome 4q21-23); polycystin-2
Autosomal Recessive Polycystic Kidney Disease
PKHD1 (chromosome 6p21-12); fibrocystin/polyductin
Autosomal Dominant Polycystic Liver Disease(without kidney cysts) 3 possible genes
Others including: Nephronophthisis Bardet-Biedl Syndrome
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What is a Cyst
Typically a fluid filled cavity
Common end result of insult
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Ultrasound showing cysts
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Autosomal Dominant Polycystic
Kidney Disease (ADPKD)
Autosomal dominant inheritance withvariable penetrance
Prevalence of 1 in 800
4-6% of ESRD population
Affects all ethnic groups worldwide
Genetically heterogeneous PKD1 (16p13.3)
PKD2 (4q21-23)
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Inheritance Patterns
Do you need a bit of revision!
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Autosomal DominantInheritance
Each child has50% chance ofinheriting the
mutation No skipped
generations
Equallytransmitted bymen andwomen
Affected
Normal
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Autosomal Dominant Inheritancewith Variable Penetrance
Penetrance is often incomplete
May appear to skip generations
Normal
Affected Carrier
Susceptible Carrier
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ADPKD is a focal disease in the Kidney
Baert, Kidney Int, 1978Jul 7 2007/ Slide 9
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Histology Slide showing a Cyst in Kidney Tissue
Cavity of the cyst in cross section
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ADPKD
Renal cysts increase insize and number with age
Enlarged kidneys
Cysts may also occur inliver, pancreas and rarely
other sites
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Diagnosis of Autosomal Dominant
Polycystic Kidney Disease
8 cysts both sides8 cysts in total>60 yr
5 cysts both sides4 cysts in total30-60 yr
5 cysts both sides2 cysts unilateral or bilateral
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Massive polycystic liver causing distention in ADPKD
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So, what else in ADPKD?
More than just a Kidney Disease
Multi-system Disorder
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Clinical features
Kidney pain
Hypertension
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A cause for the high blood
pressure?
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Clinical features
Haematuria (blood in urine)
Cyst rupture
Urinary tract infection Nephrolithiasis (kidney stones)
Renal failure
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Table to show frequency of renalmanifestations of ADPKD(adapted from Gabow [11])
Renal
Cysts 100%
Cyst calcification Common
Hypertension (adult) 60% (pre ESRF)
80% (post ESRF)
Hypertension (children) 30%
Haematuria 50%
Renal pain 60%
Urinary tract infection Common
Nephrolithiasis 30%
ESF 45% by age 60
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Extra renal features
Liver cysts 50% Pancreatic cysts 7% Cardiac valve disease 30% Left Ventricular Hypertrophy Common Abdominal herniae (in CAPD patients)
Diverticular disease (in ESF patients) 80% Thoracic aortic aneurysm 8% Arachnoid cysts 8%
But NOT PCOS
Intracranial aneurysm (ICA) 4-10% ICA rupture
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ICA - TYPES AND LOCATION
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Intracranial aneurysm inADPKD Occur in 4-10% of patients
Tends to run in families
May be worse with hypertension Most remain asymptomatic
Decision to operate depends on size,
location, age and hypertension Screen available for at risk families by
MRA
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Factors affecting progression toEnd Stage Renal Failure Hypertension
Recurrent Haematuria
UTI (in men)
Massive Liver cystic Disease (mostly women)
More than 3 pregnancies
Age at symptomatic diagnosis
Sickle Cell Trait
Genotype
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Survival in Type 1 and Type 2 PKD
Hateboer et al Lancet 353:103-7 (1999)
European Collaborative study with 333PKD1 and 291 PKD2 patients
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Survival data in ADPKDMedian PKD1 = 53yrs Median PKD2 = 69yrs
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Conclusions
Survival has improved by better treatment
Hypertension affects prognosis and earlydiagnosis and treatment of hypertensionmay further improve survival
Not all patients progress to ESRF even ifhave renal impairment
Genotype affects prognosis but is not yetwidely available
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Why are only a small number ofKidney Filter units (Nephrons)affected?
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ADPKD is a focal disease
Baert, Kidney Int, 1978Jul 7 2007/ Slide 28
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Why not cysts from every Nephron?
Marker1 2 1 2 1
Genotype: 1, 2 Genotype: 1, 2 Genotype: 1(Loss of
Heterozygosity)
PKD1
st
hit2
nd
hit
Normal Germline Cyst Cell
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Cysts can form by a two-hit mechanism
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Timeline of discovery in ADPKD
1500s Enlarged cystic kidneys first described by Eustachi
1880s Early clinical studies published in Europe
1957 Publication of first large scale epidemiological study
1985 Gene Locus identified to alpha globin gene on ch 16
1986 Second locus identified on chr 4
1992 TSC2 locus discovered at 16p13.3.
1993 PKD2 gene localised at chr 4q13-q23
1994 PKD1 gene isolated by the European PKD Consortium
1996 PKD2 gene cloned
1996 Two hit model for cystogenesis proposed
2002 Complete mutation screen of PKD1 and PKD2 by DHPLC
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