ARPKD: The Basics
Lisa M. Guay-Woodford, MD
Hudson Professor of Pediatrics
The George Washington University
Director, Center for Translational Science
Director, Clinical and Translational Science Institute-Children’s National
Children’s National Medical Center
ARPKD Family Information Day
Birmingham, UK
Saturday, 30 June 2012
Objectives
Overview: normal kidney and liver
ARPKD: key issues
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Overview of clinical features
Data from clinical studies
Management issues
Diagnosis - radiologic; genetic
Recent research advances
Therapies of the future
Normal Kidney
The kidneys are a pair of reddish-brown
organs located on either side of the spine
just below the diaphragm, behind the liver
and stomach. They are bean-shaped and
about 4 inches long, 2 inches wide and 1
inch thick.
The primary function of the kidneys is to
remove waste from the body through the
production of urine. They also help to
regulate blood pressure, blood volume,
and the chemical (electrolyte)
composition of the blood.
How do your kidneys help maintain health?
•  remove wastes (e.g., urea) and excess fluid from your body through
the production of urine
•  continuously regulate the body’s fluids and chemical composition
(sodium, potassium, phosphorus and calcium)
•  remove drugs and toxins from your body
•  produce and release hormones into your blood
Ø  erythropoietin - stimulates the bone marrow to make red
blood cells
Ø  renin - regulates blood pressure
Ø  calcitriol (a form of Vitamin D) - helps the intestine to absorb
calcium from the diet, and thereby maintain healthy bones
Kidney handling of salt and water
filtered
excreted
1,500 grams
6 grams
filtered
salt
excreted
water
200 quarts
2 quarts
Normal Liver
The liver is one of the largest and most
complex organs in the body. It weighs ~1
pound and is made up of a spongy mass of
wedge-shaped lobes. The liver has many
functions that are necessary for life:
•  helps process carbohydrates, fats, and
proteins absorbed from food in the
intestines and turns them into materials that
the body needs for life.
•  secretes bile to help digest fats.
•  makes the factors needed for clotting.
•  stores vitamins.
•  breaks down toxic substances in the blood.
Objectives
Overview: normal kidney and liver
ARPKD: key issues
• 
• 
• 
• 
• 
• 
Overview of clinical features
Data from clinical studies
Management issues
Diagnosis - radiologic; genetic
Recent research advances
Therapies of the future
ARPKD: background
•  ARPKD occurs in about 1 in 20,000 newborn babies
•  ~30% affected babies die as newborns
•  The disease causes major problems in the kidney and liver, but
these problems can vary from child to child and even from
brother to sister.
•  Abnormalities in just one gene appear to cause >99% of all
ARPKD
•  Special mouse strains and other animal models have a disease
that closely mimics ARPKD
ARPKD: what goes wrong
ARPKD: what goes wrong
liver
kidney
PKD and the cilia
cilia
Satlin et al. Pediatric Nephrology 2:135, 1988
Proteins disrupted by mutations in the ADPKD and ARPKD genes are expressed (at least
in part) in the cilia. This observation has led to the hypothesis that PKD is due, at least in
part, to a defect in function of the cilia.
Objectives
Overview: normal kidney and liver
ARPKD: key issues
• 
• 
• 
• 
• 
• 
Overview of clinical features
Data from clinical studies
Management issues
Diagnosis - radiologic; genetic
Recent research advances
Therapies of the future
North American ARPKD Database
•  Database enrollment
o  Enrolled:
o  Sufficient data for analysis:
278 patients
209 patients
•  Of enrolled patients, 43 (20.6%) born before 1990
•  The median age
o  Patients born after 1990:
o  Patients born before 1990:
5.3 years
14.5 years
•  Comparative data
birth < 01/90
birth > 01/90
p
age diagnosis
72 d
1d
0.0004
age HTN
240 d
16 d
0.0003
age CRI
3.7 yr
13.5 d
0.0013
age portal HTN
8.2 yr
2.8 yr
0.0004
ARPKD Database: clinical variability
Characteristics
Age
Median (25th-75th %ile)
Diagnosis
1 day (1-61 d)
Hypertension
65%
16 days (5-165 d)
Chronic renal insufficiency
42%
13.5 days (1-394 d)
Renal transplantation
8%
4.4 years (1.5-6.9 yrs)
Portal hypertension
15%
2.8 years (0.9-4.7 yrs)
Liver transplantation
2%
8.2 years (5.4-10.0 yrs)
Death
10 days (1-93 d)
Guay-Woodford and Desmond (2003) Pediatrics 111: 1072-1080
ARPKD: comparative data
No. Am. Database
(N=166*)
Bergmann (2005)
(N=164)
Prenatal dx
46%
23%
Hyponatremia
26%
--
Hypertension
65%
76%
CRI
42%
86%
ESRD
13%
29%
Growth retardation
24%
16%
Chronic lung disease
12%
--
Portal hypertension
15%
44%
1-yr survival
92%
85%
ARPKD: clinical data by age of diagnosis
Adeva et al. Medicine. 85:1-21, 2006
Objectives
Overview: normal kidney and liver
ARPKD: key issues
• 
• 
• 
• 
• 
• 
Overview of clinical features
Data from clinical studies
Management issues
Diagnosis - radiologic; genetic
Recent research advances
Therapies of the future
ARPKD: clinical issues
•  Fetuses
•  Limited or no amniotic fluid (oligo/anhydramnios)
•  Newborns (neonates)
•  Prematurity
•  Poor lung development --> respiratory failure
•  Problems with salt and water balance
•  Poor kidney function (renal insufficiency)
ARPKD: clinical issues
•  Older children
•  High blood pressure (hypertension)
•  Poor kidney function
•  Urinary tract infection (UTI)
•  Poor growth
•  Increased blood pressure in the liver (portal hypertension)
•  Bleeding from distended blood vessels (variceal bleeding)
•  Infection in the bile ducts (cholangitis)
ARPKD management: fetus/newborn
•  Fetuses
•  Amniotic fluid replacement??
•  Newborns (neonates)
•  Poor lung development --> respiratory failure
•  “routine” ventilation
•  “high frequency” ventilation
•  ECMO
•  Nitric oxide
ARPKD Database: newborn management
Characteristics
ARPKD Patients
N (%)
Ventilation
No
Yes
conventional
High frequency
88 (60)
59 (40)
49
20
ARPKD management: fetus/newborn
•  Newborns (neonates)
•  Problems with salt and water balance
•  Poor kidney function (renal insufficiency)
•  Dialysis
•  through the abdomen (peritoneal dialysis)
•  through the blood (hemo-dialysis)
ARPKD management: blood pressure
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“Blood pressure” reflects the pressure of the blood against the walls of the
arteries.
Normal blood pressure for children increases with advancing age, but is
generally <120/80 mmHg.
High blood pressure, or hypertension, is a condition in which blood pressure
levels are above the normal range.
Hypertension in children is defined as average systolic (or diastolic) blood
pressure ≥95th percentile for gender, age, and height on 3 occasions.
High blood pressure increases the risk for:
heart attack, stroke, and kidney failure
Ø  developing fatty deposit in arteries (atherosclerosis)
Ø 
Ø 
heart failure, due to the increased workload that high blood pressure places on
the heart.
Definitions:
•  High blood pressure
(hypertension)
Pediatrics 114:555-576, 2004
What causes hypertension in ARPKD?
•  The etiology is unknown but the likely cause:
Ø  excessive salt absorption by cystic collecting ducts
(which causes water retention and an “overfilled”
circulatory system)
• 
Less likely cause:
Ø  overactive “renin-angiotensin-aldosterone” axis as in
ADPKD
Renal physiology 101
Highlight the basics of kidney function that will allow you to
understand why your child with ARPKD may have:
•  high blood pressure
•  abnormalities in salt (sodium) and water balance
Ø  hyponatremia (low blood concentrations of sodium)
Ø  an inability to concentrate the urine (polyuria) and
thus large volume daily urine output
•  high blood concentrations of potassium or low
concentrations of bicarbonate
Normal collecting duct
principal cell:
• absorbs salt (sodium) from the urine
through pores known as epithelial Na
channels (ENaC)
• secretes potassium into the urine through
other channels
• in the presence of vasopressin, absorbs
water from the urine through water
channels
intercalated cell:
• secretes acid or base (=bicarbonate) into
the urine
ENaC
vasopressin
Renin-angiotensin-aldosterone system
*
* target of ACE inhibitors
http://www.merck.com/mmhe/sec03/ch022/ch022a.html
Management of children with hypertension
•  medications
Ø  ACE inhibitors
Ø  angiotensin receptor blockers (ARBs)
Ø  labetalol
Ø  calcium channel blockers
Ø  minoxidil
Ø  many others
•  (limit salt intake)
ARPKD management: older children
•  Poor kidney function (renal insufficiency)
•  Medical treatment
•  Dialysis
•  through the abdomen (peritoneal dialysis)
•  through the blood (hemo-dialysis)
ARPKD management: older children
•  Poor growth
•  Nutrition
•  G-tube
•  Growth hormone
ARPKD management: older children
•  Liver complications
•  Increased blood pressure in the liver
(portal hypertension)
•  Bleeding from distended blood vessels
(variceal bleeding)
•  Infection in the bile ducts (cholangitis)
Objectives
Overview: normal kidney and liver
ARPKD: key issues
• 
• 
• 
• 
• 
• 
Overview of clinical features
Data from clinical studies
Management issues
Diagnosis - radiologic; genetic
Recent research advances
Therapies of the future
Hepato-Renal Fibrocystic Diseases