CYSTIC KIDNEY DISEASE ( BOOK)
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
(ADPKD)
 Autosomal dominant polycystic kidney disease
(ADPKD) is seen predominantly in adults
 Autosomal recessive polycystic kidney disease
(ARPKD) is mainly a disease of childhood.
Etiology and Pathogenesis
 ADPKD is a systemic disorder resulting from
mutations in either the PKD-1 or the PKD-2 gene.
- PKD-1-encoded protein, polycystin-1, is a large
receptor-like molecule
- PKD-2 gene product, polycystin-2, has features of
a calcium channel protein.
- Both are transmembrane proteins that are
present throughout all segments of the nephron.
- Localized to the luminal surface of tubular cells in
primary cilia, where they appear to serve as flow
sensors;
 On the basal surface in focal adhesion
complexes;
 On the lateral surface in adherens
junctions.
- The proteins are thought to function
independently, or as a complex, to regulate fetal
and adult epithelial cell gene transcription,
apoptosis, differentiation, and cell-matrix
interactions.
- Disruption of these processes leads to epithelial
dedifferentiation, unregulated proliferation and
apoptosis, altered cell polarity, disorganization of
surrounding extracellular matrix, excessive fluid
secretion, and abnormal expression of several
genes, including some that encode growth
factors.
 Vasopressin-mediated elevation of cyclic AMP levels
in cystepithelia plays a major role in cystogenesis by
stimulating cell proliferation and fluid secretion into
the cyst lumen through apical chloride and aquaporin
channels.
 Cyst formation begins in utero from any point along
the nephron, although <5% of total nephrons are
thought to be involved.
- As the cysts accumulate fluid, they enlarge,
separate entirely from the nephron, compress
the neighboring renal parenchyma, and
progressively compromise renal function.
Genetic Considerations
 Occurs in 1:400–1:1000 individuals worldwide and
accounts for ~4% of end-stage renal disease (ESRD) in
the United States.
 Equally prevalent in all ethnic and racial groups.
 Over 90% of cases are inherited as an autosomal
dominant trait, with the remainder probably
representing spontaneous mutations.
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NEPHROLOGY
 Mutations in the PKD-1 gene on chromosome 16
(ADPKD-1) account for 85% of cases, and mutations in
the PKD-2 gene on chromosome 4 (ADPKD-2)
accounts for the remainder. A few families appear to
have a defect at a site that is different from either of
these loci. Direct mutation analysis of isolated cysts
suggests that there is loss of heterozygosity, whereby
a somatic mutation in the normal allele of a small
number of tubular epithelial cells leads to
unregulated clonal proliferation of the cells that
ultimately form the cyst lining.
Clinical Features
 Phenotypic heterogeneity is a hallmark of ADPKD
 Affected individuals are often asymptomatic into the
fourth or fifth decade.
 Presenting symptoms and signs
Abdominal discomfort
Hematuria
urinary tract infection
incidental discovery of hypertension
abdominal masses
elevated serum creatinine,
cystic kidneys on imaging studies
 Diagnosis is made before the onset of symptoms,
when asymptomatic members in affected families
request screening.
 Renal function declines progressively over the course
of 10–20 years from the time of diagnosis, but not
everyone with ADPKD develops ESRD; it occurs in
about 60% of these patients by age 70.
 Those with ADPKD-2 tend to have later onset and
slower progression.
 Hypertension is common and often precedes renal
dysfunction, perhaps mediated by increased activity
of the renin-angiotensin system.
 There is only mild proteinuria, and impaired urinary
concentrating ability manifests early as polyuria and
nocturia.
 Risk factors for progressive kidney disease
- younger age at diagnosis
- black race
- male sex
- presence of polycystin-1 mutation
- hypertension
 There is a close correlation between the rate of
kidney expansion, as measured by magnetic
resonance imaging (MRI) scanning, and the rate of
decline in kidney function.
 Dull, persistent flank and abdominal pain and early
satiety are common due to the mass effect of the
enlarged kidneys or liver.
 Cyst rupture or hemorrhage into a cyst may produce
acute flank pain or symptoms and signs of localized
peritonitis.
2014 -2015
J.A. S.
 CYSTIC KIDNEY DISEASE ( BOOK)
 Gross hematuria may result from cyst rupture into the
collecting system or from uric acid or calcium oxalate
kidney stones.
 Nephrolithiasis occurs in about 20% of patients.
 Urinary tract infection, including acute pyelonephritis,
occurs with increased frequency in ADPKD.
 Infection in a kidney cyst is a particularly serious
complication. It is most often due to Gram-negative
bacteria and presents with flank pain, fever, and
chills.
 Blood cultures are frequently positive, but urine
culture may be negative because infected kidney
cysts do not communicate directly with the collecting
system. Distinguishing between infection and cyst
hemorrhage is often challenging, and the diagnosis
relies mainly on clinical and bacteriologic findings.
 Radiologic and nuclear imaging studies are generally
not helpful.
 Extrarenal manifestations of ADPKD highlight the
systemic nature of the disease.
- A twofold to fourfold increased risk of
subarachnoid or cerebral hemorrhage from a
ruptured intracranial aneurysm
Diagnosis and Screening
 Made from a positive family history and imaging
studies showing large kidneys with multiple bilateral
cysts and possibly liver cysts
 Criteria for the diagnosis of ADPKD by
ultrasonography in asymptomatic individuals account
for the later onset of ADPKD-2 and assume that the
genotype of the individual and family being tested is
unknown.
 Computed tomography (CT) scan and T2-weighted
MRI are more sensitive for detecting presymptomatic
disease in young patients.
 Genetic linkage analysis and mutational screening for
ADPKD-1 and ADPKD-2 is available for equivocal
cases, especially when a young adult from an affected
family is being considered as a potential kidney
donor.
 Genetic counseling is essential for those being
screened.
 Screening for asymptomatic intracranial aneurysms
should be restricted to patients with a personal or
family history of intracranial hemorrhage and those in
high-risk occupations.
 Intervention should be limited to aneurysms larger
than 10 mm.
Treatment: Autosomal Dominant Polycystic Kidney Disease
 No treatment has been proved to prevent cyst growth
or the decline in kidney function.
 Hypertension control with a target blood pressure of
130/80 mmHg or less is recommended according to
Joint National Committee (JNC) VII guidelines.
 Angiotensin-converting enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARBs) have a role in
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NEPHROLOGY
slowing growth of kidney volume and loss of
glomerular filtration rate (GFR).
 Lipid-soluble antimicrobials such as trimethoprim-
sulfamethoxazole and fluoroquinolones that have
good cyst penetration are the preferred therapy for
infected kidney and liver cysts.
 Pain management occasionally requires cyst drainage
by percutaneous aspiration, sclerotherapy with
alcohol, or, rarely, surgical drainage.
 Patients with ADPKD appear to have a survival
advantage on either peritoneal or hemodialysis
compared with patients with other causes of ESRD.
 Those undergoing kidney transplantation may require
bilateral nephrectomy if the kidney are massively
enlarged or have been the site of infected cysts.
AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE
GENETIC CONSIDERATIONS
 ARPKD is primarily a disease of infants and children
 The kidneys are enlarged with small cyst <5 mm
limited to the collecting tubules
 ARPKD gene on chromosome 6p21encoding
fibrocystin( polyductin) is primarily affected
 Mutations in PKHD1 have also been identified in
about 30% of children with congenital hepatic fibrosis
( caroli’s syndrome) without evident kidney
involvement
CLINICAL FEATURES
 50% of neonates die with pulmonary hypoplasia due
to olygohydramnios from severe intrauterine kidney
disease
 80% survived alive until 10 years but 1/3 of them
develop to ESRD
 Enlarged kidney ( bilateral abdominal mass) maybe
detected soon after birth
 Impaired urinary concentration ability
 Metabolic acidosis ensues
 Hypertension
 Complication:
- Portal HPN from periportal fibrosis
DIAGNOSIS
 UTZ reveals large echogenic kidneys
 Can be made in utero after 24 weeks AOG
TREATMENT
 NO SPECIFIC THERAPY
 Treat the symptoms
2014 -2015
J.A. S.