Autosomal Recessive Polycystic Kidney Disease (ARPKD)

The disease with more than one face

Ihab ShaheenConsultant Paediatric Nephrologist

RHSC- Glasgow

Learning objectives:

• Epidemiology• Genetics• Clinical feature• 2 Cases• Differential diagnoses• Prognosis• Literature• To take home

Epidemiology:

• Inherited disorder – progressive enlargement of renal collecting ducts varying degrees of hepatic abnormality

• Rare 1:10,000 to 1:40,000

• Caucasians > other ethnic groups?

• M = F

Epidemiology...

• Estimated frequency of gene 1:70 in non isolated population

• Incidence in isolated population 1:8000 ( Finnish)• Exact incidence is unknown:1. Published studies vary in the cohort of cases

examined2. Some severely affected babies die perinatally

without definite diagnosis

Genetics:

• AR• Mutation in PKHD1, chromosome 6P21• To date all kindereds with typical features of ARPKD

have demonstrated linkage to this locus• Over 350 mutations have been recognized ( 2009)

Genetics...

• Among the largest disease genes characterized to date in human genome (470 kb)

• Encodes for polyductin/fibrocystin protein• This protein is localised in primary cilia mainly in the

kidney• To lesser extent in liver, pancrease and arterial wall.

Genetics...

• Genotype-phenotype correlation from type of mutation rather than the site of mutation

• Truncating mutation displays severe form

• Missense mutations are more frequent in less severe form

Clinical features:

• Flank masses• HTN• Urinary concentration defect• Hyponatraemia• Renal insufficiency• Pulmonary hypoplasia• HSM• Oesophageal varices• hypersplenism

Renal:

• Very rarely to be the cause of death in NN period• Usually improving following recovery from

respiratory problems• Hyponatraemia is usually transient and related to the

concentration defect• Fluid restriction could sort low Na but?

Hypertension

• Unknown mechanism• 80% of affected children• ACE inhibitors,Ca channel blockers and beta blockers• Normal renin and aldosterone peripheral activity• May be related to local RAAS activation• Needs more than one agent to be controlled

Case 1....

• 35+3 premature Caucasian male• NVD, breech • Birth weight:2.3 kg• Normal antenatal scan• Both parents are under 30• No F/H of renal diseases

Case 1...

• Apgar of 1,9 @1 &5 minutes• 48 hrs of IV Ab• Needed initially CPAP, severe RD• Ventilated with surfactant x 2• Right pneumothorax, needed chest drain

Case 1...

• Generalised oedema by D2• B/L large abdominal masses• Oliguria,low Na, high urea and creatinine• Urinalysis blood & protein +++• Abdominal US: B/L PKD, most likely ARPKD, coarse

liver.

Case 1...

• Issues1. Persistent HTN ( required 5 anti HTN& diuretics)2. Poor weight gain3. Renal failure4. Family counselling

Case 2...

• 8 year old female• Normal antenatal scan, no F/H of renal diseases• 38/40, NVD• RD, pneumothorax • Discovered to have ARPKD at the age of 4 months• Never needed dialysis

Case 2 ...

• Kept on conservative treatment• Hypertension ( controlled by 2 anti HTN)• No concern regarding liver• Has LRD renal Tx from dad

Case 2 ...

3 months post renal Tx• Frequent blood Tx• Recurrent sepsis• Poor graft function• Massive spleenomegally

Case 2 ...

Issues:1. Graft nephrectomy2. Haemodialysis3. Combined liver-kidney Tx4. Family disappointment

Diagnosis:

• Diagnostic criteria were proposed by Zerres etal:1. US features typical of ARPKD( enlarged,ecchogenic

kidneys with poor CMD and2. One or more of the following: a) absence of renal cysts in both parents

particularly if they are > 30 years old

Diagnosis...

b) clinical, lab or radiological evidence of hepatic fibrosis

c) hepatic pathology demonstrating ductal plate abnormality

d) previous affected sibling e) parental consanguinity suggestive of AR inheritance

Diagnosis...

• Genetic testing is typically not required for patient with classic ARPKD

• Prenatal diagnosis in a family with at least one affected child via mutation analysis

• With identification and cloning of PKHD1, molecular analysis is now available

Neonatal large kidneys

• Differential diagnosis includes- ARPKD- ADPKD- Glomerulocystic disease- Diffuse cystic dysplasia

• Think about syndromes,e.g. Tuberous sclerosis , Zellweger syndromeTrisomy 13 ,etc…

Large NN kidneys

• Other causes- RVT- Congenital NS- Contrast nephropathy

- Renal candidiasis - Glycogen storage disease

- Leukaemia

Clinical features of cystic diseases presenting in the newborn period

Disease Inheritanc USS Pathology Associated anomalies

ARPKD AR Large echogenic kidneys, microcysts, occasional macrocytes

Fusiform dilatation CDs

Hepatic fibrosis/ biliary dysgenesis

ADPKD AD Large echogenic kidneys, occasional macrocysts (infants), multiple macrocysts (older)

Cysts from any portion of nephron

MV prolapse, cerebral aneurysm, AV malformation, hepatic cysts, pancreatic cysts

GCKD AD/sporadic

Large echogenic kidneys, occasional macrocysts

Cystic dilatations of glomeruli

May be syndromicHepatic fibrosis 10%

Diffusecysticdysplasia

Sporadic Large echogenic kidneys, microcysts or macrocysts

Immature nephron development, dysplastic features

Usually syndromic

Clinical features suggesting ADPKD rather than ARPKD:• Positive F/H• Extrarenal cysts• Cerebral aneurysm• Asymptomatic presentation• Unilateral presentation• Haematuria• UTIs

Renal Cysts

Bilateral Disease Unilateral disease

Large

Kidney size Parenchyma small and echogenic

Yes

Simple cyst ,ADPK

D,GCKD

MCKD

Normal or small

No

IVP demonstrates Pyramidal Blush

Medullary Cysts

Cortical Cyst

ADPKD or GCKD

Parents has Cystic Kidney disease

Yes No

MCD NPH

Medullary sponge Kidney

Parents with ADPKD

Yes No

ADPKD Liver Disease

Yes No

ARPKD Consider ADPKD , NPH-type 2 and GCKD

Prognosis ARPKD• Improved with NNIC

- 30% severely affected † NN period- for those surviving

1 yr survival 75-90% 5 yr survival 70-88%• Progression ESRF

- > 50% - time variable• Common problems

- feeding and growth failure- UTI- hepatic fibrosis- complications of RRT

Prognosis ARPKD...

• Portal HT not uncommon• Significant risk for ascending bacterial cholangitis• Hepatic complications are the main reason of death

in a 14 year follow up study post renal Tx

Bergmann et al. (2005)

Guay –Woodford and Desmond (2003)

Capisonda et al. (2003)

Roy et al. (1997)

Zerres et al. (1996)

Gagnadoux et al. (1989)

Kaplan et al. (1989)

Patients 186 166 31 52 115 33 55

Age at diagnosis 23% prenatal 31% <1 mo16% 1-12 mo30% >1 yr

46% prenatal 27% <1 mo11% 1-12mo16% > 1yr

32% prenatal 23% < 1 mo19% 1-2 mo26% > 1 yr

85% < 1yr15% >1yr

10% prenatal 41% <1mo23% 1-12 mo26% >1yr

33% <1 mo55% 1-18 mo12% 6-11yr

42% < 1 mo42% 1-12 mo16% <1yr

Renal function variable

Median age CRF 4.0 yr 29% ESRD ( by 10 yr)

13% ESRD 51% GFR <8016% ESRD

33% ESRD ( by 15yr)

10% ESRD 42% GFR <80 ml/min/1.73m221% ESRD

58% SC >100µmol/ml

Hypertension (%on drug treatment )

76%53% during 1st month

65% 55% 60% (by 15 yr )

70% 76% 65%

Evidence ofPortal hypertension

44%38% spleenomegaly 15% eosphageal varices 2% Ascites

15% 37% 23% (8/35) 46% 39% 47%

Survival rate 1 yr : 85%5 yr : 84% 10 yr : 82 %

1 yr : 79%5yr : 75%

1yr :87% 9 yr:80%

NA 1 yr:89% 3 yr : 88%

1yr :91 % 1yr: 79% 10yr: 51 % 15 yr : 46%

Death rate In the first year of life

15% 8% 13% 26% 9% 9% 24%

To take home

• Significant phenotypic variability• Neonatal period

- respiratory - fluid balance and electrolytes

- hypertension• Prognosis improved with NNIC but progression to

ESRF in >50%

To take home

• Portal HTN can develop with normal synthetic liver function

• Every patient with recurrent unexplained sepsis should be treated for cholangitis ( gram neg organisms)

• Dietetic input is crucial • BP control could be a challenge