Patofisiologi

Kista berkembang dari segmen tubulus ginjal dan sebagian besar terlepas dari tubulus
induk induk setelah tumbuh hingga beberapa millimeter. Perkembangan kista
umumnya dikaitkan dengan peningkatan proliferasi epitel tubular, kelainan pada tubular
silia dan sekresi cairan yang berlebihan.

Pathophysiology
Cysts develop from renal tubule segments and most detach from the parent
tubule after they grow to a few millimeters in size. Cyst development is
generally attributed to increased proliferation of tubular epithelium,
abnormalities in tubular cilia, and excessive fluid secretion.
Developmental cystic renal disease
MCDK represents abnormal development or formation of the kidney and may
involve part, or all of, one or both kidneys. This condition is thought to be
secondary to dysfunctional genetics, abnormal differentiation of the
metanephros or in utero ureteral obstruction. Patients are observed unless
complications arise directly from the kidney or its associated conditions.
Inherited cystic renal disease
ADPKD is due to mutations in the genes PKD1 and PKD2, which encode
polycystin proteins. Mutations in these genes can be inherited in autosomal
dominant or recessive forms, with varying levels of penetrance. The genetic
mechanism of cyst development requires a "second hit," a somatic mutation of
the normal PKD allele, which accounts for the onset of ADPKD, usually in
those aged 30-50 years.
Symptoms primarily include pain, hypertension and renal failure. The goal of
treatment is to control blood pressure and to slow the onset of renal failure.
ADPKD is associated with involvement of other organs, particularly
intracranial aneurysms, which have an asymptomatic prevalence of 8%
overall and 23% in patients 60-69 years old. [2]
ARPKD is due to mutations in PKHD1, a large gene that encodes
fibrocystin/polyductin, which plays critical roles in collecting-tubule and biliary
development. This disease carries a high neonatal mortality rate, and many
individuals who survive eventually require renal transplantation. Symptoms
include hypertension and liver disease. Diagnosis is often made in utero.
Treatment is supportive in severe cases but otherwise is similar to that for
ADPKD.
GCKD is often confused with ADPKD, as it is common in individuals with a
family history of ADPKD. This disease is distinguished histologically and
symptoms and treatment are similar to those in ADPKD.
JNPHP and medullary cystic disease are two diseases that some consider a
disease complex. [3] They share similar pathologic features but are due to
different genetic mutations and have different inheritance patterns. JNPHP is
inherited in an autosomal recessive manner and presents in childhood, while
MCKD is inherited autosomal dominantly and affects adults. Both diseases
present with symptoms of salt wasting and polyuria.
Systemic disease with associated renal cysts
TS is caused by mutations in the suppressor genes TSC1 and TSC2, which
encode hamartin and tuberin, respectively. Mutations of TSC2 are much
more frequent than mutations of TSC1 and are associated with more severe
disease. [4] Renal cysts and angiomyolipomas are part of a syndrome that
includes seizures and dermatologic findings.

VHLS is due to mutations in the VHL gene, which increases the risk for malignancy,
including RCC. Affected individuals develop cysts in multiple organs, including the
kidney, pancreas, liver, and epididymis.

Acquired cystic renal disease

The exact cause of this disease is not known. It occurs exclusively in patients on
dialysis. The severity of disease is directly related to the duration of therapy. Typically,
acquired cystic renal disease is asymptomatic but it is known to subsequently increase
the risk of RCC.

Etiologi

Etiologi dari kista renal yaitu :

- Perkembangan penyakit kista ginjal

- Penyakit kista ginjal yang diturunkan
- Penyakit sistemik yang terkait kista ginjal
- Penyakit kista ginjal yang didapat
- Penyakit ginjal kistik unilateral

Etiology
The etiology of renal cysts includes the following:
 Developmental cystic renal disease
 Inherited cystic renal disease
 Systemic disease with associated renal cysts
  Acquired cystic renal disease

 Unilateral renal cystic disease

Developmental cystic renal disease
Multicystic dysplastic kidney (MCDK) is thought to arise from abnormal
development of the metanephros. This may be a genetic effect or may reflect
a defect in the ampullary bud (inducer tissue) or the blastema (responder
tissue), with resultant poor nephron induction. [5] Additionally, in utero
obstruction has been identified as a possible cause, leading to urinary stasis
and cyst formation. Many patients, however, have normal renal development
despite obstruction.
Inherited cystic renal disease
See the list below:
Inherited cystic renal diseases include the following:
 Autosomal dominant polycystic kidney disease (ADPKD)
 Autosomal recessive polycystic kidney disease (ARPKD)
 Glomerulocystic kidney disease (GCKD)
 Juvenile nephronophthisis (JNPHP)
 Medullary cystic kidney disease
Currently, the exact mechanism of genetically induced cyst formation has not
been fully defined. Similarities between cystic diseases, however, reveal
common pathologic pathways. The vast majority of mutations affect the
primary cilia of the tubular epithelium, indicating that disruption of this
structure relates to disease development. [6] Additionally, dedifferentiation and
increased proliferation of tubular epithelium, along with abnormal fluid
secretion, appear to be common elements in cystic disease.
Autosomal dominant polycystic kidney disease
Inheritance of ADPKD is autosomal dominant, with close to 100%
penetrance. PKD1 (chromosome 16p13) encodes for the transmembrane
protein polycystin-1 (PC1), which is responsible for cell-to-cell and cell-to–
extracellular matrix binding. [6]Mutations in this gene are responsible for 85-
90% of cases. Mutations in polycystin-2 (PKD2, chromosome 4q21), a
calcium channel important for PC1 localization and function, account for the
remaining 10-15%. [7]
Interestingly, while ADPKD is a genetic disease that affects every cell in the
kidney, cysts involve only 1-2% of the nephrons or collecting ducts, supporting
the hypothesis that a "second hit," or mutation of the abnormal allele, must
occur. [3] Five to 8% of cases do not involve a family history and are the result
of spontaneous mutations.
Autosomal recessive polycystic kidney disease
All cases of ARPKD are caused by mutations in PKHD1, a large gene that
encodes fibrocystin/polyductin, which appears to be related to the polycystin
complex and controls epithelial proliferation, secretion, and structure and
development of the renal tubules and biliary ducts. [8] The genetic defect is
located on chromosome 6p21.1-p12.
In both ADPKD and ARPKD, epidermal growth factor (EGF) has been
identified as an important stimulus for proliferation of cystic epithelium. [7]
Glomerulocystic kidney disease
GCKD is a rare disease that is transmitted in an autosomal dominant manner.
The involved gene has not been identified, and both familial and sporadic
forms exist. [9]
Juvenile nephronophthisis
JNPHP is inherited in an autosomal recessive manner and is due to mutations
in the NPHP genes (NPHP1-NPHP5), which are located on multiple different
chromosomes and encode nephrocystins and inversin. All of the gene
products are found in the primary cilium. [10, 7, 11] Ten to 20% of cases are
associated with retinal disease and are termed Senior-Loken syndrome.
Genes involved in JNPHP are as follows:
 NPHP1 is located on chromosome 2q12-13 and encodes nephrocystin
 NPHP2 is found on chromosome 9q22-31 and encodes inversin
 NPHP3 is found on chromosome 3q21-22 and encodes nephrocystin-3
 NPHP4 is located at chromosome 1q36 and encodes nephrocystin-4
 NPHP5 (chromosome 3q13.33-21.2) encodes nephrocystin-5 and is
found only in cases associated with Senior-Loken syndrome
Medullary cystic kidney disease
MCKD is due to mutations in the MCKD1 (chromosome 1q21)
and MCKD2 (chromosome 16p12) genes. It is inherited in an autosomal
dominant manner. [7]
Systemic disease with associated renal cysts
Tuberous sclerosis (TS) is inherited in autosomal dominant fashion, with
variable penetrance. Sixty to 70% of cases are due to sporadic mutations.
Genetic markers have been identified at chromosome band 9q34
(TSC1, which encodes hamartin) and chromosome band 16p13 (TSC2, which
encodes tuberin). TSC2 accounts for two thirds of TS cases. [6, 3] While the
functions of these genes are not understood, TSC2 is adjacent to
the PKD1 gene, which is involved in the most common form of ADPKD. In
some cases, a contiguous gene syndrome has been described, involving
large deletions that affect both TSC2 and PKD1.
Inheritance of von Hippel-Lindau syndrome is autosomal dominant, with
variable penetrance. The genetic defect has been localized to chromosome
band 3p25.
Biochemical analyses [12, 13] have identified a protein (mammalian target of
rapamycin [mTOR]) that may be part of a common pathway in several of the
genetic forms of cystic disease. Activity of mTOR is related to cell growth,
proliferation, apoptosis, and differentiation. Increased levels of mTOR have
been found in cyst epithelium. Under normal conditions, PC1 (mutated in
ADPKD) and TSC2 (mutated in TS) suppress or inactivate mTOR. Mutations
in these genes, as well as in others that relate to the primary cilia, result in
dysregulation of mTOR activity, possibly allowing cyst formation.
Acquired cystic renal disease
The exact cause of cyst formation has not been identified. One theory
suggests that the development of cysts in acquired renal cystic disease
(ARCD) is secondary to obstruction of the tubules by fibrosis or oxalate
crystals. Another hypothesis invokes the accumulation of growth factors and
stimulatory chemicals (uremia), including EGF, which leads to the
development of cysts. [3] The disease occurs in patients on all types of dialysis
and appears to regress after transplantation.
Unilateral renal cystic disease
This is a rare disease characterized by multiple cysts with intervening normal
parenchyma in one kidney. It looks similar to ADPKD on both imaging and
pathologic examination. Patients may present with hematuria, pain, or a flank
mass. This is a benign entity and is not associated with cysts or malformations
in other organs. [14]
Imaging Studies
Developmental cystic renal disease (MCDK)
Prenatal sonography is the diagnostic tool of choice and can be used to
identify MCDK as early as 15 weeks' gestation. [16] Sonography demonstrates
multiple variably sized, noncommunicating cysts outlined by hyperechoic
intervening renal parenchyma. [30] The corresponding ureter and renal pelvis
are typically not visualized. See the image below.
After birth, serial (one within days of life and another 1 month later) high-quality
sonography should be performed to confirm the diagnosis and to evaluate the
contralateral kidney and the rest of the urinary tract. [20]
Intravenous pyelography (IVP) may show a nonfunctioning kidney or a deformed mass
with faint specks of contrast corresponding to small areas of functioning renal tissue. No
collecting system or ureter is identified. Shell-like calcifications outlining some of the
cysts may be noted.
Ureteral obstruction with collecting system dilatation may be difficult to differentiate from
MCDK. In these cases, nuclear medicine functional studies can be helpful and
demonstrate a rim of functional tissue in the obstructive cases. [16]
An association with contralateral ureteropelvic junction obstruction, as well as with renal
ectopia, exists. Previously, voiding cystourethrography (VCUG) was routinely performed
to rule out reflux into the contralateral kidney. More recent data suggest, however, that
VCUG is of little value if serial high-quality ultrasonography findings are consistent with
MCDK and demonstrate a normal bladder and contralateral kidney. [20]

Autosomal dominant polycystic kidney disease

Typically, cysts first are observed radiographically in the second to third decades of life.
With progression, the kidneys become enlarged with multiple spherical fluid-filled cysts
(1-3 cm) that are appreciated readily with computed tomography (CT), ultrasonography,
or magnetic resonance imaging (MRI). The Consortumium for Radiologic Imaging for
the Study of Polycycstic Kidney Disease has demonstrated a mean increase in renal
volume of 63.4 mL per year in an exponential fashion in their cohort of 200 patients. [31]
Sonographic criteria for ADPKD depend on patient age. Sonographic diagnosis in
individuals at 50% risk for the disease involves two unilateral or bilateral cysts in
patients younger than 30 years, two cysts in each kidney in individuals aged 30-59
years, and four cysts in each kidney in individuals 60 years or older. See the images
below.

Debris may produce heterogeneous cyst attenuation, and cysts may have fluid-fluid
levels from hemorrhage. Hemorrhagic cysts demonstrate unenhanced CT attenuation
values of 40-100 Hounsfield units (HU). Symptomatic episodes of gross hematuria
underestimate the true incidence of hemorrhage, as up to 90% of patients with ADPKD
have cysts that are hyperdense on CT. Calcification may be observed in the cyst walls
or in the parenchyma between cysts, and nephrocalcinosis or nephrolithiasis is
observed in as many as 50% of patients. Calcification likelihood increases with age and
is fairly common in patients older than 50 years.
Contrast enhancement of the renal parenchyma provides an indication of the amount of
functioning renal parenchyma that remains. The likelihood of hepatic cysts increases
with age; 40% of patients demonstrate liver cysts by the fourth decade of life, and nearly
90% of patients have them by the sixth decade of life.
When ADPKD presents in childhood, ultrasonography may reveal hyperechoic enlarged
cystic kidneys, a pattern that may be difficult to differentiate from ARPKD. In this
situation, family history and possible ultrasonography of the parents' or grandparents'
kidneys is recommended.
When malignancy or infected cysts are a concern, a contrast-enhanced CT scan can be
performed.
Recommendations do not exist for intracranial aneurysm screening but it is advised,
especially in patients with a positive family history. [16] The screening can be readily
accomplished noninvasively with magnetic resonance angiography (MRA).

Autosomal recessive polycystic kidney disease

Second-trimester ultrasound imaging of bilateral hyperechogenic kidneys with poor
corticomedullary differentiation suggests a diagnosis of ARPKD. Other features include
enlarged kidneys that maintain their reniform shape and have increased echogenicity.
Finding large echogenic kidneys with poor corticomedullary differentiation and
coexisting liver disease by ultrasound is sufficient for diagnosis. Genetic testing is
needed only in cases ambiguous by imaging. [32]
With severe renal disease, absence of urine in the bladder, oligohydramnios, pulmonary
hypoplasia, and a small thorax may be observed. At birth, neonates require assisted
ventilation, and pneumothorax is common.
In children, kidney size is typically at least two standard deviations greater than normal
and diffusely hyperechogenic. In 29% of cases, bilateral cysts of 5-7 mm are found at
presentation. [33] Loss of corticomedullary differentiation may be observed, and small
cysts oriented in a radial pattern in the distribution of the collecting ducts may be
evident. The cysts tend to enlarge over time.
If severe oligohydramnios is seen, fetal MRI should be used, as it better shows renal
anatomy. ARPKD is associated with signal void in a contracted bladder on a T2-
weighted sequence. [34] Furthermore, MRI can be used to predict nonsurvival. In one
series of 46 fetuses, a ratio of MRI-calculated lung volume to gestational age of 0.90 (in
fetuses with a gestational age of over 26 weeks) demonstrated a sensitivity and
specificity of 77.8% and 95%, respectively, for predicting mortality. [35]
Precontrast CT scan images show enlarged, smooth kidneys with low attenuation (likely
representing the large volume of fluid in the collecting tubules). Renal calcifications are
frequently noted. With contrast, poor opacification of the kidneys may be observed (with
severe renal failure), and the physician may appreciate radial streaks of contrast
extending from the cortical surface to the inner medulla. The classic radial streak
pattern is best appreciated with IVP.
Liver disease can be visualized with ultrasonography, which demonstrates
hepatomegaly with echogenic parenchyma (secondary to fibrosis), hepatic cysts, and
dilatation of the peripheral hepatic ducts with fibrous bridging. [16] Magnetic resonance
cholangiography is more sensitive in detecting dilated biliary ducts. Patients at the age
of 5 years should have abdominal ultrasound performed, with followup every 2-3
years. [32]
Once a diagnosis is made by imaging, serial assessment by ultrasound should be
performed every 2-3 weeks. Particular attention should be paid to the onset of
oligohydramnios, as it is a predictor for nonsurvival. In one series, oligohydramnios in
the presence of kidney size >4 standard deviations above the mean was associated
with 100% mortality in the perinatal period. [36]

Glomerulocystic kidney disease

The kidneys appear either hypoplastic or normal in size on sonography and maintain
their reniform shape. Cysts are small (9</ref>
On CT and MRI, glomerulocystic kidney disease (GCKD) appears as numerous small
cortical cysts. These do not enhance with gadolinium during MRI. [37]

Juvenile nephronophthisis and medullary cystic kidney disease

Sonography and CT scan reveal bilaterally shrunken kidneys. On sonography, cysts are
observed at the corticomedullary junction in a background of diffusely echogenic renal
parenchyma. [16]

Acquired cystic renal disease

Acquired renal cystic disease (ARCD) can be diagnosed if involvement is bilateral, with
at least four cysts per kidney. Once cysts are observed sonographically, further
evaluation with contrast-enhanced CT scan is indicated to rule out carcinoma. Contrast-
enhanced helical CT scanning has 96% sensitivity and 95% specificity in detecting
carcinoma. In patients who cannot tolerate ionic contrast, MRI may be useful to
evaluate for neoplasms. See the image below.

Medullary sponge kidney

In medullary sponge kidney (MSK), findings on plain radiographs may be normal, or
radiographs may reveal medullary nephrocalcinosis (represented by multiple discrete
calculi clustered in the renal pyramids). At least one renal calculus (typically < 5 mm) is
often observed.
IVP demonstrates a "bouquet of flowers" or "paintbrush" pattern. Ectatic tubules are
observed as dense streaks of contrast material radiating from the calyces, while
papillary cysts are observed as round opacifications in the papillae. The "brush" pattern
of the ectatic tubules must be differentiated from a dense papillary blush, which may be
observed in healthy patients; with low-osmolar contrast, papillary blush is observed in
as many as 13% of routine IVPs. A greater than 0.3-mm cylinder or streak diameter has
been recommended to help differentiate between pathologic tubular ectasia and normal
variant physiology. CT scan may show calcifications at the corticomedullary junction.
Simple cyst
The most clinically significant aspect of a simple cyst is differentiating it from carcinoma.
Simple-cyst walls occasionally calcify and, thus, radiographically mimic malignancy.
Sonographic features that support the diagnosis of simple cyst include an anechoic
round mass with a smooth and sharply demarcated wall and through-transmission with
strong posterior wall echo.
If the ultrasonography findings are suspicious or equivocal, a CT scan is warranted. CT
scan criteria for a benign cyst include (1) sharp demarcation cyst with a smooth thin
wall, (2) homogeneous fluid within the cyst (typically with density < 20 HU, although
higher measurements may be found with a benign proteinaceous cyst or if hemorrhage
is present in a benign cyst), and (3) no contrast enhancement. Enlargement of the cyst
can raise the concern of malignancy, although the natural history of benign renal cysts
does show progressive slow enlargement.

Computed tomography
CT remains the gold standard for investigation of renal cysts, as it has been able to
delineate malignancy and is the basis of the intitial Bosniak classification. Predictors of
malignancy include thickened irregular wall or septa, enchancing soft tissue, and
internal cyst heterogeneity. Of these factors, septal and nodular enchancements provide
a sensitivity of 100% and sensitivity of 86%. Furthermore, contrast enhancement of 42
Hounsfield units (HU) between the corticomedullary phase and the pre-contrast phase
is an independent predictor of malignancy. [38]
The use of CT is more difficult for small and intermediate lesions. New techniques to
better define these lesions have surfaced, including dual-energy CT, thinner slicing (3
mm), and delayed-contrast CT. [39] Dual-energy CT is better able to expose vascularity
which is a predictor for malignancy. Thinner slicing at 3 mm used in overlapping
sections improves detection of renal cysts < 5 mm. Finally, using delayed contrast
enhancement can better differentiate renal cell carcinomas from non-neoplastic
cysts. [40] These new techniques help address challenging cases of
psuedoenhancement.

Magnetic resonance imaging

MRI can be used for the classification of renal cysts as studies have confirmed that MRI
results correlate with histopathology. Where MRI gains favor over CT is in the
evaluation of cystic fluid; different compositions of fluid, such as blood or protein, have
higher predictors of malignancy. These factors can provide upgrading on Bosniak
criteria based on CT. [41]
New techniques focus on multiparametric MRI with focus on diffusion weighted imaging
(DWI). DWI measures the motion and diffusion of water, which will be different in
malignant and benign tissue. Further investigation of this technique is needed due to
lack of standardization and determination of the appropriate amount of weighting (b
value).

Bosniak classification
Bosniak has described a classification scheme for renal cysts based on CT scan
findings. The categories are as follows [42] :
 Category I (simple cyst) - Thin wall without septa, calcifications, or solid
components; measures water density (< 20 HU) and does not enhance (< 2%
chance of malignancy)
 Category II (minimally complex cyst) - Thin wall (< 1 mm) and no enhancement;
may contain 1 or 2 hairline-thin septa, fine calcification, or short segment of
slightly thickened calcification; includes high-attenuation lesions that are smaller
than 3 cm (Malignancy rates in series range from 0-14%. Series with higher
malignancy rates include IIF lesions.)
 Category IIF (indeterminate) - Minimal enhancement and/or thickening of a
hairline-thin smooth septum or wall; mildly thickened or nodular calcification; no
enhancing soft-tissue components; includes nonenhancing high-attenuation
lesions that are 3 cm or larger (approximately 20% likelihood of malignancy)
 Category III (suspicious indeterminate) - Multilocular lesion with multiple
enhancing septae, uniform wall thickening, nodularity, or thick or irregular
calcification (30-60% likelihood of malignancy)
 Category IV (malignant) - Contains enhancing (>10 HU) large nodules or clearly
solid components (>90% likelihood of malignancy)
Another option for patients with renal impairment or allergy to iodinated contrast is
contrast-enhanced ultrasound (CE-US). CE-US is a technique that has been shown to
be equivalent to CT, and in one experience CE-US was found to be better than CT in
the diagnosis of malignancy in Bosniak IIF and III renal cysts. [43]
A multi-institutional review of Bosniak IIF and III cystic lesions has been performed. The
malignancy rate of resected Bosniak IIF lesions was 25% (4/16) and that of Bosniak III
lesions was 54% (58/107). Thirteen percent of Bosniak IIF lesions progressed at follow-
up with half of them being malignant at resection. Risk factors for having malignancy
seen with a Bosniak III lesions were: history of primary renal malignancy, coexisting
Bosniak category IV lesion and/or solid renal mass, and multiplicity of Bosniak III
lesions. Importantly, all patients had localized disease with either Bosniak IIF or III
lesion. [44]
The Bosniak classification system greatly varies from observer to observer, particularly
in the differentiation of Bosniak category II from Bosniak category III lesions.
Additionally, a significant portion of Bosniak category II lesions may prove to be
malignant. In one series, 14% of lesions so categorized were found to be malignant.
Thus, adherence to classification standards and recommended follow-up care,
particularly for Bosniak category IIF, should be strictly followed.

Histologic Findings
Developmental cystic renal disease
In multicystic dysplastic kidney, cystic dysplasia is a subset of renal dysplasia.
In this form, typical renal configuration is lost. The disease is usually a
unilateral process, but it ranges from involving a portion of one kidney to
completely involving both kidneys.
Grossly, the kidney appears to be an enlarged mass of cysts among immature
primitive tissue, often with surrounding fibrosis and an atretic collecting
system. [20]The ureter is often stenotic or hypoplastic, and the renal artery is
often small or absent. [16]
Microscopy reveals small areas of otherwise normal-appearing glomeruli and
tubules interspersed with cysts lined with cuboidal epithelium and surrounded
by collars of spindle cells. The cysts are filled with proteinaceous or
sanguinous fluid. In addition, immature-appearing cartilage is often present in
the tissue. See the image below.

Inherited cystic renal disease

In autosomal dominant polycystic kidney disease, the kidneys are enlarged and
distorted by multiple renal cysts. Cystic kidneys can exceed 40 cm in length and weigh
as much as 5 kg. Cysts range in size from a few millimeters to several centimeters and
are distributed relatively uniformly through the medulla and cortex. Cyst fluid ranges
from clear to hemorrhagic.
Microscopic evaluation shows cystic dilatations in all segments of the nephron, with loss
of connection to the tubule. While all segments are involved, the cysts derived from the
collecting duct are the largest and most numerous. [46] The cysts are lined by a single
layer of flattened-to-cuboidal epithelium. The intervening parenchyma demonstrates
interstitial fibrosis, tubular atrophy, chronic inflammation, and vascular sclerosis. See
the images below.

External surface of a nephrectomy specimen from a patient with

autosomal dominant polycystic kidney disease (ADPKD).

Cut surface of the same nephrectomy specimen from a patient with

autosomal dominant polycystic kidney disease (ADPKD).
In autosomal recessive polycystic kidney disease, the kidneys are enlarged bilaterally,
but a reniform shape is preserved. With neonatal presentation, the kidneys may be 10-
20 times normal size. Radial cysts are typically smaller than 3 mm in diameter and
extend perpendicularly from the papillary tips to the surface of the cortex.
Microscopically, the cysts are lined by flattened (undifferentiated) epithelium and
represent fusiform dilation of collecting tubules that retain their connection to the
afferent and efferent tubules. The parenchyma adjacent to the cysts progressively
develops interstitial fibrosis and glomerulosclerosis.
The liver is grossly enlarged, and microscopic evaluation demonstrates bile duct
dilatation and periportal fibrosis. This histologic pattern is known as congenital hepatic
fibrosis (CHF) and is always present in ARPKD. However, CHF is not specific to this
disease.
GCKD is characterized by dilatation of Bowman space without involvement of the
related tubule. The dilated Bowman spaces are lined by a flattened epithelium and
contain rudimentary glomerular tufts. [9]
Juvenile nephronophthisis and medullary cystic kidney disease are characterized by
thickening and wrinkling of the tubular basement membrane, tubular atrophy, and
interstitial fibrosis, leading to bilaterally small kidneys with a pitted surface. [10]The renal
cortex is uniformly thinned, and cysts are located at the corticomedullary junction and
are derived from the collecting ducts and distal tubules. [7]
The number of cysts varies (5-50), and cysts measure from several millimeters to 1 cm.
However, 25% of cases do not involve grossly visible cysts. Microscopic evaluation
demonstrates that the cysts are lined by single layers of cuboidal epithelium.
Systemic disease with associated renal cysts
In tuberous sclerosis, renal cysts are uncommon and usually not extensive, but diffuse
cystic renal disease that involves both the cortex and the medulla is occasionally noted,
particularly in children. Cysts vary in size from several millimeters to 3 cm. Diffuse renal
cystic disease grossly resembles kidneys affected by ADPKD. Microscopically, the cysts
are lined by large eosinophilic cells with enlarged hyperchromatic nuclei. [3]
In von Hippel-Lindau syndrome (VHLS), multiple renal cysts develop bilaterally. Renal
cysts are lined with glycogen-rich, clear-appearing cells (similar to those observed with
grade I clear-cell renal cell carcinoma [RCC]). Atypia and epithelial hyperplasia are
common in the cysts.
Acquired cystic renal disease
In acquired renal cystic disease, gross evaluation of early disease reveals cortical cysts
filled with clear fluid. Cysts are usually smaller than 0.5 cm in diameter but may be as
large as 3 cm in diameter. With more advanced disease, medullary cysts are observed.
The disease may progress to numerous diffusely distributed cysts and resemble a small
kidney affected by ADPKD.
Microscopy reveals a flattened, hyperplastic tubular epithelial lining. Foci of epithelial
hyperplasia or renal adenomas are common. The remaining renal tissue exhibits
sclerotic glomeruli, atrophic tubules, and interstitial fibrosis. Oxalate crystals are
common in the walls of cysts.
In medullary sponge kidney, gross evaluation reveals normal-sized kidneys, which may
be unremarkable with the exception of at least one enlarged and pale renal pyramid.
The disease is bilateral in 70% of cases. Microscopic evaluation reveals dilated
collecting ducts lined by cuboidal or flattened epithelium. The cystlike cavities range in
size from 1-7.5 mm (usually 1-3 mm) and are present in the papillary portions of the
pyramids. Roughly half of the dilated channels contain calcifications. Inflammatory
infiltrate is found adjacent to the dilated tubules.
Simple cysts measure 1-5 cm in diameter and are filled with clear fluid. The cysts are
usually lined by a flattened layer of epithelium, although they may lack an epithelial
lining. See the image below.

Nephrectomy specimen from a patient with a large benign simple cyst.

Cut section of nephrectomy specimen demonstrating renal cell
carcinoma (RCC), with an adjacent simple cyst.

Close-up photograph of the cut surface of the same

nephrectomy specimen demonstrating a simple cyst adjacent to a
renal cell carcinoma (RCC).
Medical Care
Effective means of prevention or modulation of disease have not yet been
identified. Current treatment is aimed at symptom control. In general, therapy
is reserved for pain, hypertension, infection, renal salt wasting, and
nephrolithiasis.
Inherited cystic renal disease
Autosomal dominant polycystic kidney disease
Patients with autosomal dominant polycystic kidney disease (ADPKD) have
decreased ability to concentrate urine and should be encouraged to drink 1-2
L of water daily.
Generally, a blood pressure of 130/80 mm Hg is considered the treatment
goal for hypertension in this population. Moderate hypertension may be
treated with sodium restriction (ie, < 100 mEq/d), exercise, and weight control.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs) are effective in controlling hypertension in ADPKD. However,
ACE inhibitors have been associated with reversible renal failure in polycystic
kidney disease. Calcium channel blockers also are effective in managing
hypertension in ADPKD.
Hypertension appears to correlate with the size of the cyst, and aspiration of
renal cysts results in a reduction of blood pressure. [47]
Prevention of infection with appropriate precautions is important, particularly in
women. Avoid urinary tract instrumentation whenever possible.
Treatment of infection involving cystic kidneys requires a prolonged course of
antibiotics. Most cyst walls are permeable to polar antibiotics, including
cephalosporins, penicillin derivatives, and aminoglycosides. Occasionally,
cysts are relatively impermeable to these agents and require parenteral
lipophilic antibiotics, such as ciprofloxacin, erythromycin, chloramphenicol, or
a tetracycline. Clinical evaluation findings, including sterile urine, lack of fever,
and no renal pain on deep palpation, should guide the route and duration of
antibiotic therapy.
Autosomal recessive polycystic kidney disease
Infants with autosomal recessive polycystic kidney disease (ARPKD) should
be delivered at a facility with a neonatal intensive care unit of level IV. [48] The
newborn should be provided supportive therapy while the degree of
pulmonary insufficiency and the etiology is reviewed.
Pulmonary hypoplasia is common and is responsible for 30-40% of
mortality. [49]Pulmonary insufficiency can be treated with-high frequency
ventilation. Pulmonary hypertension can be reversed with inhaled nitric oxide.
Dialysis may be required for renal failure. In one case series, neonates with
ESRD before 28 days of age had 1-year survival of 52% and 5-year survival
of 48% with peritoneal dialysis. [50]
With less severe childhood disease, edema often is a problem and is
managed with sodium restriction and loop diuretics. Hypertension is controlled
with salt restriction and antihypertensives, with particular emphasis on the use
of ACE inhibitors and ARBs.
The ESCAPE trial (Endovascular Treatment for Small Core and Proximal
Occlusion Ischemic Stroke) demonstrated that maintaining a mean arterial
blood pressure below the 50th percentile for age, height, and sex in children
with stage 2-4 chronic kidney disease can increase the length of time before
patients progress to ESRD.[51] Currently, there are no specific guidelines for an
ideal target blood pressure. [32]
Hypersplenism and associated thrombocytopenia should not be treated with
splenectomy. Limitation from contact sports is recommended. Cholangitis
secondary to hypersplenism should be treated with a prolonged course of
intravenous antibiotics.
Juvenile nephronophthisis (JNPHP) and medullary cystic kidney disease
In patients with severe salt wasting, salt supplementation may improve renal
function and slow renal demise. ESRD necessitates dialysis or renal
transplantation.
Acquired cystic renal disease
In acquired renal cystic disease (ARCD), mild bleeding episodes may be
managed with bed rest and analgesics.
In medullary sponge kidney (MSK), encourage patients with nephrolithiasis to
produce 2 L of urine daily. Patients with hypercalciuria may benefit from oral
thiazide diuretics. Patients may develop urinary tract infections and should be
taught preventative measures.
In patients with simple cysts, a cyst infection usually requires a combination of
antimicrobial and surgical management. Pathogens encountered most
frequently in infected simple cysts include Enterobacteriaceae, staphylococci,
and Proteus species.
Investigational therapy
Research has identified biochemical targets that may allow disease-modifying
therapy for renal cystic disease, and several agents have been tested in
randomized clinical trials. Results with mammalian target of rapamycin
(mTOR) inhibitors were disappointing: In adults with ADPKD and early chronic
kidney disease, 18 months of treatment with sirolimus did not halt polycystic
kidney growth.[52] Studies of somatostatin analogues (octreotide, lanreotide,
pasireotide) have yielded more encouraging results, and additional drugs are
being tested. [53]
Vasopressin receptor activation results in increased levels of cyclic adenosine
monophosphate (cAMP), and cAMP has been shown to be cystogenic. This
provides the rationale for vasopressin receptor blockade. Tolvaptan is a
vasopressin receptor antagonist with high affinity in humans. In a 3-year
phase III clinical trial in patients with ADPKD, tolvaptan slowed the increase in
total kidney volume and the decline in kidney function, compared with
placebo, but was associated with a higher discontinuation rate, owing to
adverse events. [54]
New candidate drugs are currently being investigated in the preclinical phase.
Promising therapies include metformin, rosiglitazone, calcimimetics (R-568),
and roscovitine, all of which have shown efficacy in animal models. Metformin
and rosiglitazone both have mTOR-inhibiting effects but act on additional
pathways. R-568 combats defective Ca2+ intracellular regulation, which favors
proliferation, and has been shown to decrease renal fibrosis and late stage
cystic volume but has no effect on overall cystic burden. Roscovitine is a
cyclin-dependent kinase inhibitor that initiates cell cycle arrest and inhibits
cystic disease in mouse models. [55, 56]

Surgical Care
Surgical indications in renal cystic disease vary with the underlying disorder.
Multicystic dysplastic kidney (MCDK)
Previously, the involved kidney in patients with MCDK was routinely removed
to prevent the subsequent development of symptoms. Currently, however,
surgical excision is indicated only if the dysplastic kidney interferes with
respiratory or digestive function or if significant hypertension has developed.
Additionally, cyst rupture, which can occur spontaneously or secondary to
trauma, may require emergent surgical intervention.
Inherited cystic renal disease
In autosomal dominant polycystic kidney disease (ADPKD), significant chronic
pain may result from expansion of renal cysts. Needle aspiration is usually the
first-line approach to symptomatic cysts.
Initial resolution and then return of symptoms with reaccumulation of cyst fluid
increases the chance that a laparoscopic cyst decortication will eliminate the
patient's pain. [57] However, for the management of severe pain, hypertension,
hematuria, or infection, surgical excision may be preferred.
Complex cysts can be explored laparoscopically and treated appropriately
based on intraoperative frozen sections. Laparoscopic techniques have been
used with good results. Studies have reported good outcomes of laparoscopic
cyst decortication using a retroperitoneal approach especially for posterior or
lower pole lesions. [58, 59]
Percutaneous endocystolysis is another technique described for treatment of
symptomatic cysts. The technique involves obtaining percutaneous access,
dilating the tract, and then introducing a resectoscope with rollerball electrode
to cauterize the internal surface of the cyst. A 13-year experience with this
technique reported clinical improvement in 100% of the patients with minimal
complications. [60]
Nephrectomy may be performed simultaneously with renal transplantation to
create space for the transplanted kidney and to relieve symptoms associated
with the native polycystic kidney. The timing of performing the nephrectomy in
the transplant patient has been debated. Data suggest that open ipsilateral
nephrectomy at the time of transplantation with staged contralateral native
nephrectomy has fewer perioperative complications than performing a
laparoscopic bilateral nephrectomy. [61] In extreme cases of liver enlargement,
severe pain and wasting may result. Partial hepatectomy may alleviate these
symptoms.
In autosomal recessive polycystic kidney disease patients with severe portal
hypertension, sclerotherapy or portosystemic shunt placement may be
necessary to control bleeding. Splenectomy may be indicated for
splenomegaly with significant complications. Patients with ESRD can be
treated successfully with kidney transplantation. In combination with peritoneal
dialysis, kidney transplantation in one series was associated with a 5-year
survival of 83%. [50]
In juvenile nephronophthisis (JNPHP) and medullary cystic kidney disease
(MCKD), if transplantation is considered, selecting an older or unrelated donor
is advisable to minimize the risk of the transplanted kidney also being affected
with these diseases.
Acquired cystic renal disease
In acquired renal cystic disease, persistent or severe hemorrhage may
necessitate nephrectomy or renal embolization. If a 3-cm renal mass
suggestive of renal cell carcinoma (RCC) is noted, a partial or radical
nephrectomy is indicated.
Simple renal cysts rarely require surgical management to relieve pain or
obstruction. Treatment options include the following:
 Aspiration
 Sclerosis
  Open resection
 Endoscopic marsupialization and fulguration
 Percutaneous resection
 Laparoscopic resection
A randomized trial by Agarwal et al that compared percutaneous
sclerotherapy versus laparoscopic unroofing for symptomatic renal cysts
determined that both procedures were safe and had equal efficacy. These
investigators also concluded that cyst aspiration with sclerotherapy was
associated with lower morbidity and shorter hospital stay. [62]
Bosniak category III and IV renal cysts require surgical exploration.
Approximately 50% of Bosniak category III cystic renal lesions are malignant.
Management depends on the appearance of the lesion and varies from
exploration and biopsy to nephrectomy. The current standard approach is
open exploration with anticipated partial nephrectomy. However, as the
experience with laparoscopic exploration and nephrectomy grows, this
technique may prove equally reasonable.
Cystic clear cell renal cell carcinoma
Whether the patient has known pathologically diagnosed malignancy from
biopsy or suspected malignancy based on Bosniak classification, a urologist
can anticipate good surgical outcomes after resection. In a study of
laparoscopic nephrectomy for cystic clear cell RCC, all patients treated were
alive after 5 years and no patient had extrarenal disease at the time of
surgery. These data suggest that patients with cystic RCC should expect to be
cured after surgical resection, and furthermore should undergo nephron-
sparing surgery when possible. [63]

Laboratory Studies
Developmental cystic disease (MCDK)
In MCDK, because of the associated ureteral obstruction, the patient may
have pyelonephritis in spite of an unremarkable urine specimen. However,
blood cultures and clinical examination should readily suggest this diagnosis.
Autosomal dominant polycystic kidney disease (ADPKD)
Diagnosis is primarily clinical, but, in presymptomatic patients with a family
history, gene linkage analysis can be used in combination with sonography for
screening.[6] The combination of these two modalities can achieve a detection
sensitivity of 88.5% in patients younger than 30 years and 100% in patients
older than 30 years. Some authors suggest that until effective treatments
become available, the adverse effects from presymptomatic diagnosis in
children (psychological, educational, career, and insurability issues) outweigh
the benefits. [27]
Autosomal recessive polycystic kidney disease (ARPKD)
Genetic testing for mutations at PKHD1 is currently available, with 80-85%
detection rates in patients with strong clinical and/or histopathological
evidence. [8] Current guidelines do not recommend the use
of PKHD1 mutational analysis as a first-line diagnostic test, due to the large
number of similar disorders that involve mutations in other genes
(eg, HNF1B, which is responsible for disorders including hepatorenal
fibrocystic disease). [28] However, early prenatal diagnosis is feasible only by
single-gene testing. Additionally, genotype is currently not a predictor for
clinical course. Correlations are complicated by inheritance of different
mutations from each parent.
On prenatal ultrasound, Erger et al reported sonographically visible kidney
cysts in only 3% of ARPKD cases. Pulmonary hypoplasia, oligohydramnois or
anhydramnios, and kidney enlargement were associated with a significantly
worse neonatal prognosis. [29]
A neonate may have hyponatremia during the first few weeks of life. The
infant subsequently may demonstrate diminished urine osmolality (ie, < 500
mOsm/kg) secondary to reduced concentrating ability and metabolic acidosis
secondary to decreased urinary acidification capacity. The patient may also
have recurrent pyuria. Bilirubin and hepatic enzyme values may also be
elevated. Annual complete blood cell counts (CBCs) should be performed,
with attention to the platelet count, due to the risk of portal hypertension and
splenic dysfunction.
See also Imaging in Autosomal Recessive Polycystic Kidney Disease
Juvenile nephronophthisis (JNPHP) and medullary cystic kidney disease
(MCKD)
The urine has elevated sodium levels and low specific gravity with minimal
proteinuria and normal sediment. Renal tubular acidosis may result in alkalotic
urine and systemic acidosis. Genetic linkage analysis may be used to
establish the diagnosis.
Systemic disease with associated renal cysts
Prenatal screening is available for tuberous sclerosis (TS) if the diseased
allele can be identified in an affected family member. In the absence of this,
no reliable genetic marker for TS is known. Genetic screening techniques can
be used to identify likely disease-causing mutations in 58-68% of cases.
History
Presentation in patients with renal cysts varies with the underlying disease.
Developmental cystic renal disease
Multicystic dysplastic kidney (MCDK) is almost uniformly identified during
prenatal sonographic examination. The involved kidney partially or completely
improves with age in 40-90% of patients. [19] Bilateral renal involvement is not
compatible with life.
MCDK can exist independently or as part of syndromes such as the vertebral
defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and
radial and renal anomalies (VATER) association; Zellweger syndrome; or
BOR syndrome.[20]
Inherited cystic renal disease
Inherited cystic renal disease includes the following disorders:
 Autosomal dominant polycystic kidney disease (ADPKD)
 Autosomal recessive polycystic kidney disease (ARPKD)
 Glomerulocystic kidney disease (GCKD)
 Juvenile nephronophthisis (JNPHP)
 Medullary cystic kidney disease
Autosomal dominant polycystic kidney disease
Manifestations of ADPKD vary by patient age, as follows:
 Patients present in the fourth decade of life with flank pain or
intermittent hematuria
 Patients may also experience cyst hemorrhage, renal infection, or
nephrolithiasis
 Hypertension and chronic renal failure are noted in the fifth decade of
life
 Patients progress to end-stage renal disease (ESRD) in the sixth
decade of life
 Hypertension is seen in 50% of patients with ADPKD aged 20-34 years
The disease course varies considerably among affected individuals. While all
gene carriers are believed to exhibit symptoms by the end of their eighth
decade of life, only 50% of carriers actually progress to renal failure. Kidney
size (a direct reflection of cyst volume) increases exponentially over time and
appears symmetric in a given individual, with an equal growth rate in both
kidneys. [21]
All aspects of the disease appear to develop more significantly in patients with
the PKD1 genotype. Despite similar rates of cystic growth, these patients
develop more cysts at a younger age than patients with PKD2 mutations, and
subsequently develop hypertension and ESRD at a younger age; the onset of
ESRD in persons with the PKD1 genotype occurs at a mean age of 53 years,
while the onset of ESRD in persons with the PKD2 genotype occurs at a
mean age of 69 years. [7]
In addition, studies have suggested that the type of PDK1 mutation also
affects prognosis. In one series, patients with non-truncating mutations (about
20%) developed ESRD 12 years later than those with truncating mutations, at
67.9 versus 55.6 years of age, respectively. [22]
Hepatic cysts are the most common extrarenal manifestation of ADPKD.
These increase in number with age (20% in the third decade of life, 75% after
the sixth decade of life) and may cause chronic pain. However, even with
extensive cystic involvement, liver function is not compromised.
In a study of 558 patients with ADPKD, hepatomegaly was common even in
early-stage disease and was not accounted for by cysts alone. Compared with
the liver volumes of patients without ADPKD, parenchymal volumes were
larger, even in patients who did not have cysts. Polycystic liver disease
severity was associated with altered biochemical and hematologic laboratory
tests and a lower quality of life. [23]
Other clinical associations in ADPKD include the following:
 Cardiac valve disease (particularly mitral valve prolapse [25%])
 Diverticulosis
 Cerebral aneurysms (5-10%)
 Pancreatic cysts
 Seminal vesicle cysts [6]
Autosomal recessive polycystic kidney disease
ARPKD affects renal and hepatic development (dysgenesis of the portal triad).
However, the degree of organ involvement varies in relation to the age of
onset.
In the neonatal period, pulmonary disease, resulting from nephromegaly and
oligohydramnios, dominates the presentation. Typically, the neonate has
profound respiratory compromise, often exacerbated by pneumothorax or
pulmonary hypoplasia. This presentation may result in neonatal death.
Symptoms in infancy include hypertension (80%), diminished urine-
concentrating ability, renal insufficiency, and subsequent electrolyte
abnormalities. Most affected children develop hypertension within the first few
years of life. Growth retardation has been reported in one fourth of children.
Up to 26.5% develop significant hyponatremia. [24] Fifty percent of affected
individuals develop ESRD in the first decade of life, requiring dialysis or
transplantation.
In older children (4-8 y), the kidneys often are less severely affected, while
hepatic disease may predominate. Hepatic involvement usually presents with
symptoms secondary to portal hypertension, particularly varices and
splenomegaly. Twenty-three percent of children with ARPKD experience
variceal bleeding by a mean age of 12.5 years. Hepatic disease may also
result in acute bacterial cholangitis or thrombocytopenia secondary to
hypersplenism.
Glomerulocystic kidney disease
GCKD occurs in early (neonatal) and late (adult) forms. Neonates present with
hypertension, abdominal masses, and variable degrees of renal failure. Adults
typically present with flank pain, hematuria, and hypertension. Hepatic cysts
may also develop. [9]
Juvenile nephronophthisis
JNPHP has several different phenotypic expressions, depending on the gene
involved. Infantile (NPHP2), juvenile (NPHP1, NPHP4) and adolescent
(NPHP3) forms of the disease exist, but most symptoms appear during the
first decade of life. These include growth retardation, urine concentrating
defects (polyuria and polydipsia), skeletal dysplasia, anemia, and progressive
renal failure. Additionally, some degree of hepatic fibrosis and biliary duct
enlargement is usually present. [3]Cysts usually occur secondary to ESRD and
in the corticomedullary junction.
Medullary cystic kidney disease
This disorder is clinically milder than JNPHP, occurs later in life (third to fourth
decades), and has limited extrarenal manifestations. Individuals with this
disease due to mutations in the MCKD2 gene present with uremia sooner
than those with disease due to MCKD1 mutations and are more likely to
develop hyperuricemia and gout. [3]
Systemic disease with associated renal cysts
Clinical features of tuberous sclerosis (TS) include facial nevi, cardiac
rhabdomyomas, epilepsy, angiofibromas, and mental retardation.
Approximately one half of patients have multiple renal angiomyolipomas.
Twenty to 25% of patients have renal cysts, although diffuse renal cystic
disease, which may result in chronic renal failure, is rare.
Clinical features of von Hippel-Lindau syndrome (VHLS) include retinal and
cerebellar hemangioblastomas, pheochromocytomas, and cystic disease of
the kidneys, pancreas, and epididymis. Renal cysts are very common,
occurring in two thirds of patients. Renal cell carcinoma (RCC) develops in as
many as 40% of patients. [25]
Acquired cystic renal disease
Acquired renal cystic disease (ARCD) may be found in patients with all
etiologies of ESRD, particularly in those who are dialysis dependent. The
incidence, number, and size of cysts all increase in proportion to the duration
of dialysis. Most patients are asymptomatic, but symptoms may include gross
hematuria, flank pain, renal colic, or a palpable renal mass. Hemorrhagic
cysts occur in 50% of patients. [16]
Medullary sponge kidney (MSK) is usually detected on radiographic
evaluation of adults with nephrolithiasis. Fifteen to 20% of patients with
calcium oxalate and calcium phosphate renal calculi have MSK. Patients may
also have a history of hematuria or urinary tract infection (UTI). Most patients
with MSK, however, are asymptomatic. Approximately 10% of patients
develop recurrent nephrolithiasis, bacteriuria, and pyelonephritis. Involvement
is usually bilateral.
Simple cysts usually are clinically silent. Occasionally, however, they
hemorrhage and cause acute pain.
Physical Examination
In developmental cystic renal disease, MCDK may be palpable as a flank
mass in an otherwise healthy infant. MCDK is the most common cause of a
renal mass and the second most common cause of a palpable abdominal
mass in neonates. [26, 5]
Inherited cystic renal disease produces the following findings:
 ARPKD: Bilateral flank masses are palpable in 30% of neonates and
infants with this disease; older children may demonstrate signs of portal
hypertension
 ADPKD: The enlarged kidneys and liver may be palpable
In acquired cystic renal disease, simple cysts rarely become large enough to
be palpable.