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2014; 15(6): 16-27
MedicineToday
PEER REVIEWED FEATURE
2 CPD POINTS
Management of
autosomal dominant
polycystic kidney
disease
Key points GOPALA K. RANGAN MB BS, PhD, FRACP
• Autosomal dominant BRIAN J. NANKIVELL MD, MB BS, PhD, FRACP
polycystic kidney disease
(ADPKD) is a genetic Autosomal dominant polycystic kidney disease is the fourth most
condition characterised by common cause of end-stage kidney disease in Australia. GPs play an
the formation of multiple
fluid-filled renal cysts and important role in all aspects of management, including initial diagnosis,
kidney enlargement. treatments to slow disease progression, monitoring for complications
• Complications of ADPKD and screening of at-risk family members.
include end-stage kidney
disease, early-onset hyper- utosomal dominant polycystic kidney monogenic cause of chronic kidney disease
tension, nephro lithiasis, disease (ADPKD) is a genetic condi- (CKD). In Australia, it is the fourth most com-
intracranial cerebral tion characterised by the formation of mon cause of end-stage kidney disease, after
aneurysm and polycystic A multiple fluid-filled renal cysts and diabetes, glomerulonephritis and hypertension,
liver disease. kidney enlargement. Potential complications and accounts for around 5% of this population.
• Symptoms typically do not of ADPKD include adult-onset end-stage Currently, approximately 2000 Australians with
appear until after early to kidney disease, early-onset hypertension and end-stage kidney disease caused by ADPKD
middle adulthood, and nephrolithiasis. ADPKD is also associated receive renal dialysis or have had kidney
individual lifetime risk of with systemic conditions including intracra- transplantation.
renal failure varies markedly. nial cerebral aneurysm and polycystic liver
• Renal ultrasound examination 1
remains the preferred imaging disease. CHARACTERISTICS OF ADPKD
modality for diagnosis and GPs play an important role in all aspects ADPKD is usually diagnosed in adults. The
family screening. of management of patients with ADPKD, hallmarks of ADPKD are:
• Management includes including initial diagnosis, referral, genetic • multiple renal cysts and kidney enlargement
referral to a nephrologist, counselling and e ducation, treatment of hyper- on ultrasound examination
genetic counselling, tension, prevention of kidney function decline, • a family history of ADPKD.
education, dietary and screening for s ystemic complications and In ADPKD, microscopic renal cysts form
lifestyle treat ments to slow screening at-risk family members. early in life (possibly in utero or in early child-
progression of kidney hood) and slowly grow by 10 to 20% per year,
disease, antihyper tensives HOW COMMON IS ADPKD? becoming detectable by renal ultrasound when
and monitoring for systemic ADPKD affects about one in every 500 to 1000 they reach 1 cm in diameter. In the early stage,
complications. people of all races, and is the most common the kidney is near-normal in size with a few cysts.
• Disease-modifying treatments Dr Rangan and Dr Nankivell are Senior Staff Specialists in the Department of Renal Medicine, Westmead Hospital,
to slow cyst growth (e.g.
Copyright _Layout 1 17/01/12 1:43 PM Page 4
tolvaptan) are in development. Sydney, and the Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal
Research, Westmead Millennium Institute, University of Sydney, Sydney, NSW.
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However, in established and late-stage ADPKD
(usually in mid-adult life), the kidney can become
markedly enlarged and abnormal in appearance,
containing thousands of cysts varying in diam-
eter from one to several centimetres and weighing
up to 3 to 5 kg (Figures 1a to c).
Kidney failure develops when a critical num-
ber of cysts (possibly exceeding 1000) have
enlarged sufficiently to disrupt the internal renal
architecture and function. Mechanical compres-
sion of adjacent microvasculature by cysts and
the release of proinflammatory molecules from
cystic epithelial cells lead to interstitial inflam-
mation and fibrosis, with loss of normal cortical
parenchyma. Expanding cysts can cause dis-
comfort owing to their size or pain if they bleed
or become infected.
Other important features of ADPKD
include:
• hypertension
• kidney stones
• cysts in other organs (mainly in the liver
but occasionally in the pancreas, lungs
and seminal vesicles)
• vascular abnormalities (e.g. intracranial
arterial aneurysms, thoracic aortic
dissection)
• rarely, colonic diverticulosis, hernias, © MARIE ROSSETTIE, CMI
mitral valve prolapse, bronchiectasis and
male infertility (related to seminal vesicle How do cysts form?
and ejaculatory duct cystic dilatation The PKD1 and PKD2 genes encode the proteins
causing azoospermia). polycystin-1 and polycystin-2, respectively,
which are essential for maintaining the normal
CAUSES OF ADPKD geometric structure of the distal nephron and
What is the genetic basis? renal collecting duct. Although all cells of a
ADPKD is a dominant single-gene disorder person with ADPKD carry the mutated allele,
with complete penetrance, which means that only a small proportion (about 1 to 2%) of the
only one copy of the mutation (heterozygosity) tubular epithelial cells lining the distal nephron
is required for disease manifestation. Hence, start to proliferate, possibly because of a second
each child of an affected parent has a 50% chance ‘somatic hit’ to the unaffected allele, with loss
of inheriting the disease. In 85% of patients, of genetic heterozygosity, and/or age-related
ADPKD is caused by mutations in the polycystic variations in gene dosage. Proliferation of these
kidney disease 1 (PKD1) gene, located on chro- cells begins in utero or during early life and
mosome region 16p13.3. The remaining 15% of results in the formation of diverticular-like
patients have a mutation in the PKD2 gene ‘pouches’ (Figures 2a and b). The segmental
located on chromosome region 4q21. Despite pouches expand and eventually grow to 100 µm
being a single-gene disorder, there is large inter- in diameter or more, when they lose their tubular
and intra-familial variability in disease pheno- connection and form encapsulated cysts within
type and risk of renal failure, suggesting that the renal interstitium (Figure 2c).
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unknown environmental factors also have a role The interstitial cysts continue to grow at
in disease progression. different rates, as the lining epithelial cells
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AutoSoMAl DoMinAnt PolyCyStiC KiDney DiSeASe CONTINUED
The PKD gene mutations also cause
abnormalities in connective tissue and the
basement membrane. These permit cyst
growth and are responsible for systemic
complications such as aneurysms, colonic
diverticula and hernias.
HOW DO PATIENTS WITH ADPKD
PRESENT?
ADPKD is clinically silent in about half of
affected people, and symptoms typically
do not appear until after early to middle
adulthood (age in the 30s to 60s). Rarely, it
presents in utero or early childhood. Com-
mon asymptomatic and symptomatic
presentations in adults are summarised in
Box 1.
Symptoms associated with ADPKD
include:
• macroscopic haematuria following
abdominal trauma (such as during
contact sports)
• spontaneous or provoked abdominal
Figures 1a to c. Typical appearance of the kidney in late-stage autosomal dominant or loin pain from cyst rupture
polycystic kidney disease, macroscopically (a and b, left) and on an abdominal CT • rarely, rupture of an intracranial
scan (c, right). The kidneys are enlarged and the normal renal parenchyma has been cerebral (berry) aneurysm.
almost completely replaced by hundreds of large renal cysts containing blood or Clinical signs of ADPKD include bilat-
urine-like fluid. By the time the kidneys have developed this appearance there would be eral kidney enlargement on abdominal
associated renal scarring, impaired renal function and hypertension. palpation or ballottement and hyper-
tension. Systemic features, such as cardio-
proliferate and secrete fluid (Figures 3a by a layer of flattened epithelial cells (sim- vascular disease (e.g. mitral valve prolapse),
and b). This leads over decades to late-stage ilar to simple renal cysts), and are filled intracranial cerebral aneurysms, inguinal
disease, with multiple cysts compressing with discoloured fluid, which may be yel- hernias and diverticular disease, occur in
the renal parenchyma within an enlarged low similar to urine, or chocolate- or red- up to 5% of people with ADPKD, as a result
and irregular kidney. The cysts are lined coloured from altered blood. of associated connective tissue defects.
a b c Figures 2a to c. Postulated
mechanism of formation of renal
cysts from the distal nephron and
collecting duct in autosomal
dominant polycystic kidney disease.
a (left). A small number of cells lining
the distal tubule of the nephron start
to proliferate (blue-coloured cell).
b (centre). This proliferation leads to
the formation of a diverticular ‘pouch’.
c (right). With continued growth, the
pouch detaches from the nephron
and forms a cyst in the renal
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AutoSoMAl DoMinAnt PolyCyStiC KiDney DiSeASe CONTINUED
Figures 3a and b. Light micrographs of early-stage renal cysts in a patient with autosomal dominant polycystic kidney disease
(haematoxylin and eosin stain). The epithelial cells lining the cyst are highly proliferative with evidence of hyperplasia (a, left),
micropolyp formation (b, right) and de-differentiation (not shown).
DIAGNOSIS OF ADPKD Renal ultrasound examination family history. When cyst numbers fail
The diagnosis of ADPKD is based on a remains the preferred imaging modality to meet the Pei-Ravine diagnostic criteria
typical appearance on imaging, generally for diagnosis of ADPKD and for family for ADPKD (designated ‘indeterminate’)
supported by a family history with an screening, as it is safe, reliable and inex- in an at-risk person with a positive family
autosomal dominant pattern of inher- pensive (Figure 4). The Pei-Ravine crite- history then repeating the renal ultra-
itance. Although the family history is ria for the diagnosis of ADPKD by renal sound examination in one to two years
2
usually positive (an affected relative with ultrasound are summarised in the Table. is suggested.
confirmed ADPKD) or suggestive These criteria define age-specific thresh-
(first-degree relatives with renal failure olds for cyst numbers and can distinguish 1. CliniCAl SCenARioS FoR tHe
resulting in dialysis or death), approxi- patients with ADPKD from those with PReSentAtion oF ADPKD
mately 5 to 10% of patients with typical multiple simple (Bosniak class 1) renal
ADPKD on imaging have no family his- cysts, which can develop with ageing in Asymptomatic
tory despite careful radiological screening normal individuals. ADPKD is charac- • Screening of individual with a family
of both parents. These cases likely arise terised by larger numbers of renal cysts, history of ADPKD
through spontaneous mutation or genetic kidney enlargement and earlier age of • Incidental finding on imaging
mosaicism. onset, often combined with a positive (ultrasound, CT or MRI) performed
for another indication
Figure 4. Ultrasound • Early-onset hypertension (in an
image of the right individual younger than 40 years)
kidney showing • Reduced renal function and eGFR
multiple cysts of Symptomatic
different sizes, • Macroscopic haematuria in an
typical of the individual younger than 40 years
appearance in • Abdominal or loin pain from cyst
autosomal dominant rupture
polycystic kidney • Rupture of an intracranial aneurysm
disease. Larger cysts (rare)
are labelled ‘C’.
ABBREVIATIONS: ADPKD = autosomal dominant
Copyright _Layout 1 17/01/12 1:43 PM Page 4 polycystic kidney disease; eGFR = estimated
glomerular filtration rate.
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