Polycystic Kidney Disease

Practice Essentials
Autosomal dominant polycystic kidney disease (ADPKD) is a multisystemic
and progressive disorder characterized by cyst formation and enlargement in
the kidney (see the image below) and other organs (eg, liver, pancreas,
spleen). Up to 50% of patients with ADPKD require renal replacement therapy
by 60 years of age.

Polycystic kidney.
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Signs and symptoms
Pain—in the abdomen, flank, or back—is the most common initial complaint,
and it is almost universally present in patients with ADPKD. Dull aching and
an uncomfortable sensation of heaviness may result from a large polycystic
liver.
The pain can be caused by any of the following:
 Enlargement of one or more cysts
 Bleeding: May be confined inside the cyst or lead to gross hematuria with
passage of clots or a perinephric hematoma
 UTI (eg, acute pyelonephritis, infected cysts, perinephric abscess)
 Nephrolithiasis and renal colic
 Rarely, a coincidental hypernephroma
See Presentation for more detail.
Diagnosis
Examination in patients with ADPKD may demonstrate the following:
 Hypertension: One of the most common early manifestations of
ADPKD, [1, 2] in which increased diastolic BP is the rule; clinical course in
ADPKD is usually more severe early on, then becomes less problematic
as the renal insufficiency progresses
 Palpable, bilateral flank masses: In advanced ADPKD
 Nodular hepatomegaly: In severe polycystic liver disease
 Rarely, symptoms related to renal failure (eg, pallor, uremic fetor, dry
skin, edema)
Testing
Routine laboratory studies include the following:
 Serum chemistry profile, including calcium and phosphorus
 CBC count from cysts
 Urinalysis
 Urine culture
 Uric acid determination
 Intact PTH assay
Genetic testing may be performed, in which the major indication is for genetic
screening in young adults with negative ultrasonographic findings who are
being considered as potential kidney donors. [3]
Staging
Staging of renal failure is by GFR, as follows:
 Stage 1: GFR above 90 mL/min
 Stage 2: GFR 60-90 mL/min
 Stage 3: GFR 30-60 mL/min
 Stage 4: GFR 15-30 mL/min
 Stage 5: GFR below 15 mL/min
Imaging studies
Radiologic studies used in the evaluation of ADPKD include the following:
 Ultrasonography: Technique of choice for patients with ADPKD and for
screening patients' family members; useful for exploring abdominal
extrarenal features of ADPKD (eg, liver cysts, pancreatic cysts)
 CT scanning: Not routine; useful in doubtful pediatric cases or in
complicated cases (eg, kidney stone, suspected tumor)
 MRI: Not routine; helpful in distinguishing renal cell carcinoma from
simple cysts; criterion standard to help determine renal volume for clinical
trials when testing drugs for ADPKD; best imaging tool for monitoring
kidney size after treatment, as an indication of disease progress.
  MRA: Not routine; preferred imaging technique for diagnosing ADPKD-
related intracranial aneurysms
Ultrasonographic diagnostic criteria for ADPKD1 are as follows [4] :
 At least 2 cysts in 1 kidney or 1 cyst in each kidney in an at-risk patient
younger than 30 years
 At least 2 cysts in each kidney in an at-risk patient aged 30-59 years
 At least 4 cysts in each kidney for an at-risk patient aged 60 years or
older
Ultrasonographic diagnostic criteria for ADPKD in patients with a family history
but unknown genotype are as follows [5] :
 Three or more (unilateral or bilateral) renal cysts in patients aged 15-39
years
 Two or more cysts in each kidney in patients aged 30-59 years
Fewer than 2 renal cysts in the findings provides a negative predictive value of
100% and can be considered sufficient for ruling out disease in at-risk
individuals older than 40 years.
Indications for MRA are as follows [6, 7] :
 Family history of stroke or intracranial aneurysms
 Development of symptoms suggesting an intracranial aneurysm
 Job or hobby in which a loss of consciousness may be lethal
 Past history of intracranial aneurysms
See Workup for more detail.
Management
Management of ADPKD includes the following:
 Control blood pressure: Drugs of choice are ACEIs (eg, captopril,
enalapril, lisinopril) or ARBs (eg, valsartan, telmisartan, losartan,
irbesartan, candesartan, olmesartan)
 Control abnormalities related to renal failure: Drugs to maintain electrolyte
levels (eg, calcium carbonate, calcium acetate, sevelamer, lanthanum
carbonate, calcitriol [possibly], diuretics, blood pressure medications)
 Treat UTIs
 Treat cyst infections: Gyrase inhibitors (eg, ciprofloxacin,
chloramphenicol, clindamycin, levofloxacin); dihydrofolic acid inhibitors
(TMX/SMP)
 Treat hematuria: Possibly analgesic plus copious oral hydration
 Reduce abdominal pain produced by enlarged kidneys
 Prevent cardiac valve infection in patients with intrinsic valve disease
 Reduce kidney function decline in adults at risk of rapidly progressive
ADPKD (tolvaptan [Jynarque])
Surgical intervention in ADPKD includes the following:
  Surgical drainage: Usually in conjunction with ultrasonographically guided
puncture; in cases of infected renal/hepatic cysts not responding to
conventional antibiotics
 Open or fiberoptic-guided surgery: For excision/drainage of the outer
walls of cysts to ablate symptoms
 Nephrectomy: Last resort for pain control in patients with inaccessible
cysts in the renal medullae; bilateral nephrectomy in patients with severe
hepatic involvement
 Partial hepatectomy: To manage massive hepatomegaly
 Liver transplantation: In cases of portal hypertension due to polycystic
liver or hepatomegaly with nonresectable areas
Patients with ADPKD who progress to end-stage renal disease may require
the following procedures:
 Hemodialysis
 Peritoneal dialysis
 Renal transplantation
See Treatment and Medication for more detail. For a discussion of ADPKD in
children, see Pediatric Polycystic Kidney Disease.

Background
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most
common inherited disorders in humans. It is the most frequent genetic cause
of renal failure in adults, accounting for 6-8% of patients on dialysis in the
United States.
ADPKD is a multisystemic and progressive disorder characterized by the
formation and enlargement of cysts in the kidney and other organs (eg, liver,
pancreas, spleen). Clinical features usually begin in the third to fourth decade
of life, but cysts may be detectable in childhood and in utero. [8]

Pathophysiology
The main feature of ADPKD is a bilateral progressive increase in the number
of cysts, which may lead to ESRD. Hepatic cysts, cerebral aneurysms, and
cardiac valvular abnormalities also may occur. [9, 10]
Although ADPKD is a systemic disease, it shows a focal expression because
less than 1% of nephrons become cystic. In ADPKD, each epithelial cell within
a renal tubule harbors a germ-line mutation, yet only a tiny fraction of the
tubules develop renal cysts.
It is currently held that the cells are protected by the allele inherited from the
parent without ADPKD. When this allele is inactivated by a somatic event
(mutation or otherwise) within a solitary renal tubule cell, the cell divides
repeatedly until a cyst develops, with an aberrant growth program causing
endless expansion. The severity of ADPKD is thought to be a direct
consequence of the number of times and the frequency with which this
cystogenic process occurs within the kidneys over the life of the patient.
However this hypothesis is hard to understand in neonatal cases.
The hyperplastic cells cause an out-pocketing of the tubule wall, with the
formation of a saccular cyst that fills with fluid derived from glomerular filtrate
that enters from the afferent tubule segment. Progressive expansion
eventually causes most of the emerging cysts to separate from the parent
tubule, leaving an isolated sac that fills with fluid by transepithelial secretion.
This isolated cyst expands relentlessly as a result of continued proliferation of
the mural epithelium together with the transepithelial secretion of sodium
chloride and water into the lumen.
The expanding fluid-filled tumor masses elicit secondary and tertiary changes
within the renal interstitium evinced by thickening and lamination of the tubule
basement membranes, infiltration of macrophages, and neovascularization.
Fibrosis within the interstitium begins early in the course of the disease.
Cellular proliferation and fluid secretion may be accelerated by cyclic
adenosine monophosphate (cAMP) and growth factors, such as epidermal
growth factor (EGF). In summary, cysts function as autonomous structures
and are responsible for progressive kidney enlargement in ADPKD.
Approximately 85-90% of patients with ADPKD have an abnormality on the
short arm of chromosome 16 (ie, ADPKD type 1 [ADPKD1]). A second defect,
termed ADPKD type 2 (ADPKD2), is responsible for 10-15% of ADPKD cases
and is found on the long arm of chromosome 4. A third candidate
gene, GANAB (Glucosidase II Alpha Subunit), accounting for a very low
number of ADPKD cases, has been recently described. [11]
PKD1 and PKD2 are expressed in most organs and tissues of the human
body. The proteins that are encoded by PKD1 and PKD2, polycystin 1 and
polycystin 2, seem to function together to regulate the morphologic
configuration of epithelial cells. The polycystins are expressed in development
as early as the blastocyst stage and are expressed in a broad array of
terminally differentiated tissues. The functions of the polycystins have been
scrutinized to the greatest extent in epithelial tissues of the kidneys and liver
and in vascular smooth muscle (see Etiology).
A decrease in urine-concentrating ability is an early manifestation of ADPKD.
The cause is not known. Plasma vasopressin levels are increased; this
increase may represent the body's attempt to compensate for the reduced
concentrating capacity of the kidneys and could contribute to the development
of renal cysts, hypertension, and renal insufficiency. [12]
Bleeding
Renal cysts in ADPKD are associated with excessive angiogenesis evinced
by fragile vessels stretched across their distended walls. When traumatized,
these vessels may leak blood into the cyst, causing it to expand rapidly,
resulting in excruciating pain. If bleeding continues, then the cyst may rupture
into the collecting system, causing gross hematuria. Alternatively, the cyst
may rupture into the subcapsular compartment and eventually dissect through
the renal capsule to fill the retroperitoneal space.

Etiology
ADPKD is a hereditary disorder. The pattern of inheritance is autosomal
dominant. Because the disorder occurs equally in males and females, each
offspring has a 50% chance of inheriting the responsible mutation and, hence,
the disease.
ADPKD is a genetically heterogeneous condition that involves at least 2
genes. PKD1 is located on 16p13.3 and accounts for most ADPKD
cases. PKD2 is located on 4q21-q22 and accounts for 15% of ADPKD cases.
Polycystin 1 and 2
PKD1 codes for a 4304–amino acid protein (polycystin 1). The function of
polycystin 1 is not yet fully defined, but this protein interacts with polycystin 2
and is involved in cell cycle regulation and intracellular calcium transport.
Polycystin 1 localizes in the primary cilia of renal epithelial cells, which
function as mechanosensors and chemosensors.
PKD2 codes for a 968–amino acid protein (polycystin 2) that is structurally
similar to polycystin 1 and co-localizes to the primary cilia of renal epithelial
cells. It is a member of the family of voltage-activated calcium channels.
Polycystin 1 and polycystin 2 are highly conserved ubiquitous transmembrane
proteins. In the kidney, they are located in the epithelial cells of the renal
tubules—in particular, in the primary cilia at the luminal side of the tubules, as
well as in other areas of the renal cell epithelium.
Polycystin 1 is a large protein with a long extracellular N-terminal region, 11
transmembrane domains, and a short intracellular C-terminal tail. Polycystin 2
is structurally related to the transient receptor potential (TRP) channel family,
and it is known to function as a nonselective cation channel permeable to
Ca2+.
Polycystin 1 and polycystin 2 form heteromeric complexes and colocalize in
the primary cilium of renal epithelial cells. The primary cilium is a long,
nonmotile tubular structure located in the apical surface of the epithelial cells
in the renal tubules. Its function was unknown for a long time. However,
studies now indicate that the primary cilium may be a mechanoreceptor that
senses changes in apical fluid flow and that transduces them into an
intracellular Ca2+ signaling response.
This model involves the participation of polycystin 1 as a mechanical sensor of
ciliary bending induced by luminal fluid flow. Bending of the cilium would
cause a conformational change in polycystin 1 that would, in turn, activate the
polycystin 2–associated Ca2+ channel, increasing the intracellular
Ca2+ concentration and triggering intracellular signaling pathways leading to
normal kidney development.[13]
There is a genotype-phenotype correlation for PKD1, with truncating
mutations causing a more severe phenotype than non-truncating ones. [14]
ADPKD1 is more severe than ADPKD2. The mean age of ESRD for patients
with ADPKD1 is 53 years. The mean age of ESRD for patients with ADPKD2
is 74 years.
The genetic heterogeneity of ADKPD, and the possible contribution of modifier
genes, may explain the wide clinical variability in this disease, both within and
between families. [15]

Epidemiology
Worldwide, ADPKD affects approximately 4 to 7 million individuals and
accounts for 7-15% of patients on renal replacement therapy. [16] In North
America and Europe, ADPKD is responsible for 6-10% of ESRD cases.
Approximately one per 800-1000 population carries a mutation for this
condition. Approximately 85-90% of patients with ADPKD have ADPKD1;
most of the remaining patients have ADPKD2. [17]
ADPKD is slightly more severe in males than in females, but the difference is
not statistically significant.
Symptoms generally increase with age. Children very rarely present with renal
failure from ADPKD.

Prognosis
The prognosis in patients with ADPKD covers a wide spectrum. Renal failure
has been reported in children; conversely, individuals with ADPKD may live a
normal lifespan without knowing that they have the disease. More typically,
however, ADPKD causes progressive renal dysfunction, resulting in grossly
enlarged kidneys and kidney failure by the fourth to sixth decade of life. There
is an inverse association between the size of polycystic kidneys and the level
of glomerular filtration. [18, 19]
An early study estimated that approximately 70% of patients with ADPKD
would develop renal insufficiency if they survived to age 65 years. Currently,
half of all patients with ADPKD require renal replacement therapy by age 60
years. Risk factors for progression include the following:
 PKD1 genotype
 Large kidneys
 Several episodes of gross hematuria [20]
 Severe and frequent kidney infections
 Hypertension
 Multiple pregnancies
 Black racial background [17]
 Male sex
The presence of more than one risk factor increases the risk of progression to
end-stage renal disease (ESRD).
Although the 2 forms of ADPKD, ADPKD1 and ADPKD2, share similar clinical
features, renal prognosis is strikingly different. [21, 22] ADPKD2 is a milder
disease, based on the age of onset of ESRD. The median age of renal
survival for individuals with ADPKD1 is 56 years, compared with 68 years in
those with ADPKD2. Although ADPKD2 is milder than ADPKD1, it has an
overall impact on survival and shortens life expectancy.
Cardiovascular pathology and infections account for approximately 90% of
deaths in patients treated with hemodialysis or peritoneal dialysis and after
renal transplantation. A rare cause of mortality is in ADPKD is subarachnoid
hemorrhage from intracranial aneurysms. [23]
In a retrospective, observational study of 88 patients with ADPKD who died
between 1981 and 1999, Rahman et al determined that almost half of the
patients died of cardiovascular problems. [24] The median age of death was
60.5 years. Causes of death included the following:
 Cardiovascular problems - 46.6% of patients
 Infection - 15.9% of patients, with 42% of these deaths resulting from
septicemia
 Central nervous system disorders - 11.36% of patients, with 60% of these
deaths caused by cerebrovascular events
 Uremia - 2.2% of patients
  Other, miscellaneous causes - 11.36%
The Mayo Clinic calculator for ADPKD is a useful tool for predicting disease
progression. Recommendations for assessing rapid progression of ADPKD
have been provided by European experts. [25]

Patient Education
Ensure that patients are aware that this disease is hereditary and that their
children have a 50% chance of acquiring the disease. Patients should also
understand that although several treatments are being tested, this disease
currently has no cure. Only interventions that slow the progression of renal
disease (eg, adequate blood pressure control) are of benefit. Hopefully,
effective specific therapy will be available in a few years.
Prenatal diagnosis is available through DNA linkage studies, if enough family
members cooperate, or through a mutation search. Suggest that family
members who are not screened for ADPKD have annual blood pressure
checks and urine screenings for hematuria.