Cystic Diseases of the Kidney

Cystic Diseases
of the Kidney
Yves Pirson
Dominique Chauveau
Akidney cyst is a fluid-filled sac arising from a dilatation in any
part of the nephron or collecting duct. A sizable fraction of all
kidney diseases—perhaps 10% to 15%—are characterized by
cysts that are detectable by various imaging techniques. In some, cysts
are the prominent abnormality; thus, the descriptor cystic (or poly-
cystic). In others, kidney cysts are an accessory finding, or are only
sometimes present, so that some question whether they are properly
classified as cystic diseases of the kidney. In fact, the commonly
accepted complement of cystic kidney diseases encompasses a large
variety of disorders of different types, presentations, and courses.
Dividing cystic disorders into genetic and “nongenetic” conditions
makes sense, not only conceptually but clinically: in the former cystic
involvement of the kidney often leads to renal failure and is most often
associated with extrarenal manifestations of the inherited defect,
whereas in the latter cysts rarely jeopardize renal function and gener-
ally are not part of a systemic disease.
In the first section of this chapter we deal with nongenetic (ie,
acquired and developmental) cystic disorders, emphasizing the imaging
characteristics that enable correct identification of each entity. Some
common pitfalls are described. A large part of the section on genetic
disorders is devoted to the most common ones (eg, autosomal-domi-
nant polycystic kidney disease), focusing on genetics, clinical manifes-
tations, and diagnostic tools. Even in the era of molecular genetics, the
diagnosis of the less common inherited cystic nephropathies relies on
proper recognition of their specific renal and extrarenal manifestations.
C H A P T E R
Most of these features are illustrated in this chapter.
9

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9.2
Tubulointerstitial Disease
General Features
FIGURE 9-1
PRINCIPAL CYSTIC DISEASES OF THE KIDNEY
Principal cystic diseases of the kidney.
Classification of the renal cystic disorders,
with the most common ones printed in bold
type. (Adapted from Fick and Gabow [1];
Nongenetic
Genetic
Welling and Grantham [2]; Pirson, et al. [3].)
Acquired disorders
Autosomal-dominant
Simple renal cysts (solitary or multiple)
Autosomal-dominant polycystic kidney disease
Cysts of the renal sinus (or peripelvic lymphangiectasis)
Tuberous sclerosis complex
Acquired cystic kidney disease (in patients with
von Hippel-Lindau disease
chronic renal impairment)
Medullary cystic disease
Multilocular cyst (or multilocular cystic nephroma)
Glomerulocystic kidney disease
Hypokalemia-related cysts
Autosomal-recessive
Developmental disorders
Autosomal-recessive polycystic kidney disease
Medullary sponge kidney
Nephronophthisis
Multicystic dysplastic kidney
X-linked
Pyelocalyceal cysts
Orofaciodigital syndrome, type I
IMAGING CHARACTERISTICS OF THE MOST COMMON RENAL CYSTIC DISEASES
Disease
Kidney Size
Cyst Size
Cyst Location
Liver
Simple renal cysts
Normal
Variable (mm–10 cm)
All
Normal
Acquired renal cystic disease
Most often small, sometimes large
0.5–2 cm
All
Normal
Medullary sponge kidney
Normal or slightly enlarged
mm
Precalyceal
Normal (most often)
ADPKD
Enlarged
Variable (mm–10 cm)
All
Cysts (most often)
ARPKD
Enlarged
mm increase with age
All
CHF
NPH
Small
mm–2 cm (when present)
Medullary
Normal
FIGURE 9-2
Characteristics of the most common renal cystic diseases detectable
in the vast majority of patients. ADPKD—autosomal-dominant
by imaging techniques (ultrasonography, computed tomography,
polycystic kidney disease; ARPKD—autosomal-recessive polycystic
magnetic resonance). In the context of family history and clinical
kidney disease; CHF—congenital hepatic fibrosis; NPH—
findings, these allow the clinician to establish a definitive diagnosis
nephronophthisis.

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Cystic Diseases of the Kidney
9.3
Nongenetic Disorders
FIGURE 9-3
Solitary simple cyst. Large solitary cyst found incidentally at ultra-
sonography (longitudinal scan) in the lower pole of the right kid-
ney. Criteria for the diagnosis of simple cyst include absence of
internal echoes, rounded outline, sharply demarcated, smooth
walls, bright posterior wall echo (arrows). The latter occur because
less sound is absorbed during passage through cyst than through
the adjacent parenchyma. If these criteria are not satisfied, comput-
ed tomography can rule out complications and other diagnoses.
PREVALENCE OF SIMPLE RENAL CYSTS DETECTED BY ULTRASONOGRAPHY
Prevalence, %
?1 Cyst
?2 Cysts*
?3 Cysts*
?1 Cyst in Each Kidney
Age group, y
M
F
M
F
M
F
M
F
15–29
0
0
0
0
0
0
0
0
30–49
2
1
0
1
0
1
0
1
50–69
15
7
2
1
1
1
2
1
?70
32
15
17
8
6
3
9
3
*Unilateral or bilateral. M—male; F—Female.
FIGURE 9-4
Prevalence of simple renal cysts detected by ultrasonography
increases with age and is higher in males. Cyst size also increases
according to age in an Australian population of 729 persons
with age. Most simple cysts are located in the cortex. (From
prospectively screened by ultrasonography. The prevalence
Ravine et al. [4]; with permission.)

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9.4
Tubulointerstitial Disease
A
B
FIGURE 9-5
A and B, Multiple simple cysts (one 7 cm in diameter in the lower
Each cyst exhibits the typical features of an uncomplicated simple
pole of the left kidney and three 4 to 5 cm in diameter in the right
cyst on CT: 1) homogeneous low density, unchanged by contrast
kidney) detected by contrast-enhanced computed tomography (CT).
medium; 2) rounded outline; 3) very thin (most often indetectable)
Additional millimetric cysts might be suspected in both kidneys.
wall; 4) distinct delineation from adjacent parenchyma.
A
B
FIGURE 9-6
A, Contrast-enhanced computed tomography (CT) shows a
Ultrasonographic appearance mimicked hydronephrosis. Also
simple, 3-cm wide cyst of the renal sinus (arrows) found during
known as hilar lymphangiectasis or peripelvic (or parapelvic)
investigation of renal calculi. Note subcapsular hematoma
cysts, this acquired disorder consists of dilated hilar lymph
(arrowheads) detected after lithotripsy. B, Contrast-enhanced
channels. Its frequency is about 1% in autopsy series. Although
CT shows bilateral multiple cysts of the renal sinus, leading to
usually asymptomatic, cysts of the renal sinus can cause severe
chronic compression of the pelvis and subsequent renal atrophy.
urinary obstruction, B.

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Cystic Diseases of the Kidney
9.5
A
B
FIGURE 9-7
A, Acquired cystic kidney disease (ACKD) detected by contrast-
hemodialysis and peritoneal dialysis, respectively [5]. In the early
enhanced computed tomography (CT) in a 71-year-old man on
stage, kidneys are small or even shrunken and cysts are usually
hemodialysis for 4 years. A, Note the several intrarenal calcifica-
smaller than 0.5 cm. Cyst numbers and kidney volume increase
tions, which are not unusual in dialysis patients. ACKD is charac-
with time, as seen on this patient’s scan (B) repeated 8 years into
terized by the development of many cysts in the setting of chronic
dialysis. Advanced ACKD can mimic autosomal-dominant polycys-
uremia. It can occur at any age, including childhood, whatever the
tic disease. ACKD sometimes regresses after successful transplanta-
original nephropathy. The diagnosis is based on detection of at
tion; it can involve chronically rejected kidney grafts. Although
least three to five cysts in each kidney in a patient who has chronic
ACKD is usually asymptomatic it may be complicated by bleed-
renal failure but not hereditary cystic disease. The prevalence of
ing—confined to the cysts or extending to either the collecting sys-
ACKD averages 10% at onset of dialysis treatment and subse-
tem (causing hematuria) or the perinephric spaces—and associated
quently increases, to reach 60% and 90% at 5 and 10 years into
with renal cell carcinoma. (Courtesy of M. Jadoul.)
FIGURE 9-8
Age <55 and > 3 years No
Screening for acquired cystic kidney disease (ACKD) and renal neoplasms in patients receiv-
on RRT and good
No
ing renal replacement therapy (RRT). The major clinical concern with ACKD is the risk of
clinical condition?
screening
renal cell carcinoma, often the tubulopapillary type, associated with this disorder: the inci-
Yes
dence is 50-times greater than in the general population. Moreover, ACKD-associated renal
carcinoma is more often bilateral and multicentric; however, only a minority of them evolve
No
Echography:
into invasive carcinomas or cause metastases [5]. There is no doubt that imaging should be
ACKD?
performed when a dialysis patient has symptoms such as flank pain and hematuria, the
Yes
question of periodic screening for ACKD and neoplasms in asymptomatic dialysis patients
is still being debated. Using decision analysis incorporating morbidity and mortality associ-
No
Suspicion of
ated with nephrectomy in dialysis patients, Sarasin and coworkers [6] showed that only the
renal neoplasm?
Biennial echo
youngest patients at risk for ACKD benefit from periodic screening. On the basis of this
analysis, it has been proposed that screening be restricted to patients younger than 55 years,
Yes
who have been on dialysis at least 3 years and are in good general condition. Recognized
risk factors for renal cell carcinoma in ACKD are male gender, uremia of long standing,
Enhanced CT:
No
confirmed neoplasm?
large kidneys, and analgesic nephropathy.
Yes
Nephrectomy
and annual
follow-up of
contralateral kidney

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9.6
Tubulointerstitial Disease
FIGURE 9-9
Multilocular cyst (or multilocular cystic
nephroma) of the right kidney, detected by
ultrasonography (A) and contrast-enhanced
CT-scan (B). Both techniques show the
characteristic septa (arrow) dividing the
mass into multiple sonolucent locules. This
rare disorder is usually a benign tumor,
though some lesions have been found to
contain foci of nephroblastoma or renal
clear cell carcinoma. The imaging appear-
ance is actually indistinguishable from
those of the cystic forms of Wilms’ tumor
and renal clear cell carcinoma. (Courtesy
of A. Dardenne.)
A
B
A
B
FIGURE 9-10
A, contrast-enhanced computed tomography (CT) for evaluation
of a left renal stone in a 67-year-old man. A cystic mass was found
at the lower pole of the right kidney. Only careful examination
revealed that the walls of the mass (arrows) were too thick for a
simple cyst (see Fig. 9-5 for comparison). B, The echo pattern of
the mass was very heterogeneous (arrows), clearly different from
the echo-free appearance of a simple cyst (see Fig. 9-3 for compari-
son). C, Magnetic resonance imaging showed thick, irregular
walls and a hyperintense central area (arrows). At surgery, the
mass proved to be a largely necrotic renal cell carcinoma. Thus,
although renal carcinoma is not a true cystic disease, it occasional-
ly has a cystic appearance on CT and can mimic a simple cyst.
C
(Courtesy of A. Dardenne.)

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Cystic Diseases of the Kidney
9.7
FIGURE 9-11
Medullary sponge kidney (MSK) diagnosed by intravenous urography in 53-year-old
woman with a history of recurrent kidney stones. Pseudocystic collections of contrast medi-
um in the papillary areas (arrows) are the typical feature of MSK. They result from congen-
ital dilatation of collecting ducts (involving part or all of one or both kidneys), ranging
from mild ectasia (appearing on urography as linear striations in the papillae, or papillary
“blush”) to frank cystic pools, as in this case (giving a spongelike appearance on section of
the kidney). MSK has an estimated prevalence of 1 in 5000 [2]. It predisposes to stone for-
mation in the dilated ducts: on plain films, clustering of calcifications in the papillary areas
is very suggestive of the condition. MSK may be associated with a variety of other congeni-
tal and inherited disorders, including corporeal hemihypertrophy, Beckwith-Wiedemann
syndrome (macroglossia, omphalocele, visceromegaly, microcephaly, and mental retarda-
tion), polycystic kidney disease (about 3% of patients with autosomal-dominant polycystic
kidney disease have evidence of MSK), congenital hepatic fibrosis, and Caroli’s disease [7].
FIGURE 9-12
Multicystic dysplastic kidney (MCDK) found incidentally by
enhanced CT in a 34-year-old patient. The dysplastic kidney is
composed of cysts with mural calcifications (arrows). Note the
compensatory hypertrophy of the right kidney and the incidental
simple cysts in it. MCDK consists of a collection of cysts frequently
described as resembling a bunch of grapes and an atretic ureter. No
function can be demonstrated. Only unilateral involvement is com-
patible with life. Usually, the contralateral kidney is normal and
exhibits compensatory hypertrophy. In some 30% of cases, howev-
er, it is also affected by some congenital abnormalities such as dys-
plasia or pelviureterical junction obstruction. In fact, among the
many forms of renal dysplasia, MCDK is thought to represent a
cystic variety.
FIGURE 9-13
Intravenous urography demonstrates multiple calyceal diverticula
(arrows) in a 38-year-old woman who complained of intermittent
flank pain. Previously, the ultrasonographic appearance had sug-
gested the existence of polycystic kidney disease. Although usually
smaller than 1 cm in diameter, pyelocalyceal diverticula occasion-
ally are much larger, as in this case. They predispose to stone for-
mation. Since ultrasonography is the preferred screening tool for
cystic renal diseases, clinicians must be aware of both its pitfalls
(exemplified in this case and in the case of parapelvic cysts; see
Fig. 9-6) and its limited power to detect very small cysts.

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9.8
Tubulointerstitial Disease
Genetic disorders
FIGURE 9-14
GENETICS OF ADPKD
Genetics of autosomal-dominant polycystic kidney disease
(ADPKD). ADPKD is by far the most frequent inherited kidney dis-
ease. In white populations, its prevalence ranges from 1 in 400 to 1
in 1000. ADPKD is characterized by the development of multiple
Gene
Chromosome
Product
Patients with ADPKD, %
renal cysts that are variably associated with extrarenal (mainly
PKD1
16
Polycystin 1
80–90
hepatic and cardiovascular) abnormalities [1,2,3]. It is caused by
PKD2
4
Polycystin 2
10–20
mutations in at least three different genes. PKD1, the gene responsi-
PKD3
?
?
Very few
ble in approximately 85% of the patients, located on chromosome
16, was cloned in 1994 [8]. It encodes a predicted protein of 460
kD, called polycystin 1. The vast majority of the remaining cases
are accounted for by a mutation in PKD2, located on chromosome
4 and cloned in 1996 [9]. The PKD2 gene encodes a predicted pro-
tein of 110 kD called polycystin 2. Phenotypic differences between
the two main genetic forms are detailed in Figure 9-19. The exis-
tence of (at least) a third gene is suggested by recent reports.
FIGURE 9-15
NH2
Autosomal-dominant polycystic kidney disease: predicted structure
of polycystin 1 and polycystin 2 and their interaction. Polycystin 1
Cysteine-rich domain
is a 4302-amino acid protein, which anchors itself to cell mem-
Leucine-rich domain
branes by seven transmembrane domains [10]. The large extracel-
PKD1 domain
lular portion includes two leucine-rich repeats usually involved in
C
protein-protein interactions and a C-type lectin domain capable of
C
L
C-type lectin domain
binding carbohydrates. A part of the intracellular tail has the
L
B
B
capacity to form a coiled-coil motif, enabling either self-assembling
Lipoprotein A domain
or interaction with other proteins. Polycystin 2 is a 968-amino acid
R
protein with six transmembrane domains, resembling a subunit of
E
REJ domain
J
voltage-activated calcium channel. Like polycystin 1, the C-termi-
nal end of polycystin 2 comprises a coiled-coil domain and is able
to interact in vitro with PKD2 [11]. This C-terminal part of poly-
Transmembrane segment
cystin 2 also includes a calcium-binding domain. On these grounds,
it has been hypothesized that polycystin 1 acts like a receptor and
Alpha helix coiled-coil
signal transducer, communicating information from outside to
inside the cell through its interaction with polycystin 2. This coor-
R
E
dinated function could be crucial during late renal embryogenesis.
J
It is currently speculated that both polycystins play a role in the
Out
maturation of tubule epithelial cells. Mutation of polycystins could
thus impair the maturation process, maintaining some tubular cells
Membrane
in a state of underdevelopment. This could result in both sustained
cell proliferation and predominance of fluid secretion over absorp-
In
tion, leading to cyst formation (see Fig. 9-16 and references 12 and
NH2
13 for review). (From Hughes et al. [10] and Germino [12].)
HOOC
COOH
Polycystin 1
Polycystin 2

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Cystic Diseases of the Kidney
9.9
allele is required to trigger cyst formation
Thickened tubular
(ie, a mechanism similar to that demonstrat-
basement membrane
ed for tumor suppressor genes in tuberous
sclerosis complex and von Hippel-Lindau dis-
ease). The hypothesis is supported by both
the clonality of most cysts and the finding of
Fluid
loss of heterozygosity in some of them [12].
Accumulation
Cell immaturity resulting from mutated
polycystin would lead to uncontrolled
growth, elaboration of abnormal extracellu-
lar matrix, and accumulation of fluid.
Aberrant cell proliferation is demonstrated by
the existence of micropolyps, identification of
Normal tubule
Occurrence
Monoclonal
Isolated cyst
mitotic phases, and abnormal expression of
with germinal
of somatic
proliferation
disconnected from
proto-oncogenes. Abnormality of extracellu-
PKD1
mutation of the
leading to
its tubule of
lar matrix is evidenced by thickening and
mutation
normal PKD1
cyst formation
origin
lamination of the tubular basement mem-
in each cell
allele in one
brane; involvement of extracellular matrix
tubular cell
would explain the association of cerebral
(the "second hit")
artery aneurysms with ADPKD. As most
cysts are disconnected from their tubule of
FIGURE 9-16
origin, they can expand only through net
Hypothetical model for cyst formation in autosomal-dominant polycystic kidney disease
transepithelial fluid secretion, just the reverse
(ADPKD), relying on the “two-hit” mechanism as the primary event. The observation that
of the physiologic tubular cell function [13].
only a minority of nephrons develop cysts, despite the fact that every tubular cell harbors ger-
Figure 9-17 summarizes our current knowl-
minal PKD1 mutation, is best accounted for by the two-hit model. This model implies that, in
edge of the mechanisms that may be involved
addition to the germinal mutation, a somatic (acquired) mutation involving the normal PKD1
in intracystic fluid accumulation.
FIGURE 9-17
Autosomal-dominant polycystic kidney disease (ADPKD): mecha-
nisms of intracystic fluid accumulation [13,14]. The primary mech-
Basolateral
Adenylate cyclase
Apical
anism of intracystic fluid accumulation seems to be a net transfer
of chloride into the lumen. This secretion is mediated by a
(CFTR)
Na+
bumetanide-sensitive Na+-K+-2Cl- cotransporter on the basolateral
cAMP
ATP
K+
Cl–
side and cystic fibrosis transmembrane regulator (CFTR) chloride
2Cl–
channel on the apical side. The activity of the two transporters is
PKA
regulated by protein kinase A (PKA) under the control of cyclic
Bumetanide
DPC
adenosine monophosphate (AMP). The chloride secretion drives
2K+
ATP
movement of sodium and water into the cyst lumen through elec-
(Na+-K+-ATPase)
Lumen
trical and osmotic coupling, respectively. The pathway for transep-
3Na+
ADP + Pi
ithelial Na+ movement has been debated. In some experimental
H O
2
conditions, part of the Na+ could be secreted into the lumen via a
Ouabain
(AQP)
mispolarized apical Na+-K+-ATPase (“sodium pump”); however, it
H O
2
is currently admitted that most of the Na+ movement is paracellu-
Na+
lar and that the Na+-K+-ATPase is located at the basolateral side.
(AQP)
The movement of water is probably transcellular in the cells that
express aquaporins on both sides and paracellular in others [13,
14]. AQP—aquaporine; DPC—diphenylamine carboxylic acid.

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9.10
Tubulointerstitial Disease
ADPKD: CLINICAL MANIFESTATIONS
0.46
1.0
(0.22-0.98)
0.47
. PKD1
(0.28-0.81)
0.8
Manifestation
Prevalence, %
Reference
Renal
0.6
l) PKD2 vs
0.28
0.18
Hypertension
Increased with age
[15]
(0.16-0.48)
(0.07-0.47)
(80 at ESRD)
Pain (acute and chronic)
60
[3,16]
0.4
Gross hematuria
50
[3,16]
tio (95% C
Urinary tract infection
Men 20; women 60
[3]
s ra 0.2
Calculi
20
[17]
Odd
Renal failure
50 at 60 y
[18]
Hepatobiliary (see Fig. 9–23)
0.0
Cardiovascular
Hypertension Renal infection Subarachnoid
Abdominal
Cardiac valvular abnormality
20
[16]
history
hemorrhage
hernia
Intracranial arteries
Aneurysm
8
[3]
80
PKD2
74
75
Dolichoectasia
2
[19]
PKD1
70
? Ascending aorta dissection
Rare
70
? Coronary arteries aneurysm
Rare
61
60
Other
60
Pancreatic cysts
9
[20]
Arachnoid cysts
8
[21]
50
Hernia
Inguinal
13
[22]
e
, y
Ag 40
Umbilical
7
[22]
35
Spinal Meningeal Diverticula
0.2
[23]
30
20
FIGURE 9-18
10
Main clinical manifestations of autosomal-dominant polycystic kid-
ney disease (ADPKD). Renal involvement may be totally asympto-
0
matic at early stages. Arterial hypertension is the presenting clinical
Clinical
End-stage
Death
finding in about 20% of patients. Its frequency increases with age.
presentation
renal failure
Flank or abdominal pain is the presenting symptom in another
Median age
20%. The differential diagnosis of acute abdominal is detailed in
Figure 9-22. Gross hematuria is most often due to bleeding into a
cyst, and more rarely to stone. Renal infection, a frequent reason
FIGURE 9-19
for hospital admission, can involve the upper collecting system,
Autosomal-dominant polycystic kidney disease (ADPKD): pheno-
renal parenchyma or renal cyst. Diagnostic data are obtained by
type PKD2 versus PKD1. Families with a PKD2 mutation have a
ultrasonography, excretory urography and CT: use of CT in cyst
milder phenotype than those with a PKD1 mutation. In this study
infection is described in Figure 9-21. Frequently, stones are radiolu-
comparing 306 PKD2 patients (from 32 families) with 288 PKD1
cent or faintly opaque, because of their uric acid content. The main
patients (17 families), PKD2 patients were, for example, less likely
determinants of progression of renal failure are the genetic form of
to be hypertensive, to have a history of renal infection, to suffer a
the disease (see Fig. 9-19) and gender (more rapid progression in
subarachnoid hemorrhage, and to develop an abdominal hernia. As
males). Hepatobiliary and intracranial manifestations are detailed
a consequence of the slower development of clinical manifestations,
in Figures 9-23 to 9-26. Pancreatic and arachnoid cysts are most
PKD2 patients were, on average, 26 years older at clinical presen-
usually asymptomatic. Spinal meningeal diverticula can cause pos-
tation, 14 years older when they started dialysis, and 5 years older
tural headache. ESRD—end-stage renal disease.
when they died. Early-onset ADPKD leading to renal failure in
childhood has been reported only in the PKD1 variety. (Data from
Hateboer [24].)

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