Renal Cysts and ADPKD

J. T. Bestoso
 Overview

•Cysts - simple and complex

•ADPKD Types 1&2
 5 things to remember about renal cysts
1. Develop from pre-existing renal tubule
segments
2. The cyst epithelium shows abnormal
differentiation and sustained proliferation
3. The epithelium transforms from absorptive to
secreting
4. The extracellular matrix is remodeled to
accommodate the growth
5. Endocrine, autocrine, paracrine factors
apparently modulate the process
 Simple cysts

Prevalence

• Mostly in patients > 50

• Twice as common in males.
• Bilateral rare under 50.
• In half of population by age 50.
(Clinical Radiology, 1983)
 Simple Cysts

Prevalence

•U/S survey in 729 patients (AJKD

1993)
Age Male Female
15-29 0 0
30-49 1.9 1.4
50-69 15 6.7
>70 32.3 14.6
 Simple Cysts

Characteristics
• Micro: lined with simple cuboidal
epithelium
• Fluid clear, homogeneous, similar to
urine
• Most 0.5-1.0 cm, commonly 3-4 cm,
occasionally much larger
• Not calcified
• Few or no thin septations
• 1-”a few” on each kidney - rarely
diffuse
Simple Cyst
Large Simple Cysts
Very
Large
Simple
Cyst
 Simple Cysts

Complications

• Generally clinically silent

• Rare high-renin hypertension (better
with drainage)
• Rare pain and hemorrhage
• Rare infection - generally must drain
Simple Cysts

Imaging - U/S

• Round, smooth wall, sharply demarcated.

• No internal echoes
• Strong posterior wall echo
Normal Renal Ultrasound
Simple Cyst
Simple Cyst
 Simple Cysts

Imaging - CT

• Sharply demarcated
• Smooth, thin wall
• Generally < 20 Hounsfield units
(occasionally higher)
• No enhancement with contrast
Simple Cyst Non-Contrast CT
Simple Cyst Contrast CT
no enhancement
Simple Cyst Contrast CT
no enhancement
MRI Simple Cyst - no
advantage over CT
 MR vs CT
•Bosniak study
•69 cysts imaged by CT, then MR within 1 year
•7 (10%) upgraded (worse) by MR for increased number or
thickness of septae or change in density

Radiology 2004;231:365-371
IVP
Simple
Cyst
 Complex cysts

Causes

• Hemorrhage
• Infection
• Tumor
• Idiopathic
 Malignant Potential

• Very rare to find tumor arising from a

simple cyst
• Suggestive of neoplasia:

 Thickened, irregular walls

 Thickened or enhanced septae
 Enhancement with contrast
 Multiloculation
 Internal echoes
 Calcification in wall
 Bosniak Cyst Grading

CT Classification

I. Thin wall (1 mm), no septations, no

calcifications, density 0-20, no
enhancement
II. Same, but with few septations and/or
few calcifications. IIf is slightly worse
III. Thick wall, septations, calcifications,
density 0-20, no enhancement
IV. Thick wall, thick septations, course
calcifications, density more than 20,
enhancement
 Bosniak Cyst Grading

What it means

I. We know it’s a cyst

II/IIf. We’re still pretty certain it’s just a
cyst
III. We don’t know what it is
IV. It’s probably cancer
 Bosniak Cyst Grading

What to do about it

I. Do nothing
II. Do nothing for 1 cyst, monitor with
serial scans if multiple
III. Surgical exploration/resection
IV. Surgical exploration/resection
 Bosniak Cyst Aspiration

Usually don’t aspirate III or IV

• If positive, it is true positive, but might seed track

• If negative, might still be positive

Consider aspiration

• To rule out infection

• If lymphoma of metastases strongly suspected
QuickTimeª and aTIFF (Uncompressed) decompressorare needed to se

Bosniak I
QuickTimeª and aTIFF (Uncompressed) decompressorare nee

Bosniak II
QuickTimeª and aTIFF (Uncompressed) decompresso

Another Bosniak II
Bosniak
Class III

Hyperdense
with irregular,
thickened wall
Bosniak III

Non-cancerous
Bosniak
Class III

Hyperdense
with
thickened
wall
Bosniak III

Non-
cancerous

Bosniak
himself called
this particular
image IIF
QuickTimeª and aTIFF (Uncompressed) decompressorare needed

Bosniak IV Cyst
QuickTimeª and aTIFF (Uncompressed) decompressorare needed to see this picture.

Bosniak IV in A,
Could mis-read as I or II in right
(lower) cut
Bosniak IV cysts

Associated with renal carcinoma

Questions about cysts?
Autosomal Dominant Polycystic Kidney Disease
 ADPKD

Incidence/Prevalence

• 1:400 - 1:1000 worldwide prevalence

• All races equally
• M=F
• US: 250,000-600,000 have the disease
• 4% of ESRD in US, more elsewhere
• Fourth most common cause of ESRD
 ADPKD
• 250,000-300,000 have disease in US
• As of 2007, 12,500-15,000 made more than
$200,000
• Their babies are as cute as buttons
• They don’t want those kids on dialysis
• They give lots of money to PKD research
 ADPKD
Genetics

• Autosomal dominant
• Nearly complete penetrance but
variable expression
• 85% ADPKD1 - chromosome 16 -
faster progression, worse prognosis
• 15% ADPKD2 - chromosome 4
 Further Heterogeneity
• ADPKD Mutation Database: pkdb.mayo.edu
• Substitutions, splices, deletions, frameshifts, nonsense, as of
2/22/10

– PKD1: 436 unique pathogenic mutations of chromosome 16

(16p13.3)
– PKD2: 115 unique pathogenic mutations of chromosome 4 (4q21-
q23)

• Plus apparent modifier genes

 ADPKD
Pathogenesis

• Gene products are transmembrane

proteins called polycystins
• Found in tissues throughout the body

∆ Polycystin-1
∆ Polycystin-2
QuickTimeª and aTIFF (Uncompressed) decompressorare needed to see this picture.
 Polycystin Functions
• Strongest evidence: associated with a cilium-
triggered calcium channel
• Good evidence for intercellular adhesion functions
• Possibly both or more – 2 hit models to create cysts
• Not clear if/how they are associated with cAMP
(appears to stimulate cyst proliferation)
• PC1 interacts with mTOR
 6 Possible
Polycystin
complex
action
sites

Nephron Exp Nephrol 2006;103:e149–e155

 ADPKD
Pathology

• Less than 1% of tubules affected

• Cysts throughout kidney
• Cyst characteristics vary with nephron part
• Cyst fluid accumulates at rates of 0.1-1.0
ml/day
• Both kidneys abnormal
• Renal architecture can be completely
distorted.
• Can weigh 4kg or more each, but generally
much less
 ADPKD
Natural History

• Begins in utero in most patients (Adult PKD is

a misnomer)
• Generally discovered in 30s or 40s.
• Rarely, symptomatic in childhood or not
discovered until autopsy .
• 40% can’t give family history - spontaneous
mutations vs variable expression
• 100% have evidence of disease by age 80, but
only half at ESRD
• Cannot predict when/whether renal failure will
develop in a patient.
 ADPKD

Diagnosis in established disease

• Most palpable
• 50% with increased abdominal girth
• Hypertension common
• Hematuria - macrohematuria
associated with more rapid decline
• Mild polyuria
• U/S - multiple echo-free areas in both
kidneys
• CT (preferred) - cysts readily
distinguished
 ADPKD

Early disease (children)

• 1 cyst suggestive with family

history
• 3 or more bilateral cysts
diagnostic
• DNA testing
• Wisdom of testing for an
untreatable disease is ethical
dilemma
 ADPKD
Risk factors for more rapid progression

• Younger age at diagnosis

• Race - Blacks > whites, more severe with sickle trait
• Gender - Male > female
• Genetic abnormality - PKD1 > PKD2
• Gross hematuria (cause vs effect)
• Hypertension
• Increased renal size
• Combined risk factors
 CRISP Study
Consortium for Radiologic Imaging Studies of
Polycystic Kidney Disease
• Followed 241 patients by sequential MRI
• Renal and cyst volumes correlated
– Inversely with the GFR,
– Directly with hypertension and urinary albumin
excretion
• Avg annual increase in kidney volume was 5.3%
• Cyst growth more aggressive with
– large kidneys
– young age at diagnosis
Kidney Int 2003;64:1035-45.
N Engl J Med 2006;354:2122-30.
 Mechanisms of Renal Failure
• Unclear
• Does not appear to be “compression of normal
structures”
• Path: vascular sclerosis and interstitial fibrosis
• No primary glomerular injury
• Possibly apoptosis of non-tubular cells
• Correlates with kidney volume
• Rise in creatinine is late finding
 Clinical Features - Renal
• Hypertension
• Concentrating defect
• Reduced renal blood flow
• Modest proteinuria
• Pain
• Kidney stones
• Infection
• Elevation of creatinine
 Clinical Feature - Extra-renal
• Liver cysts
• Abdominal wall weakness and herniations
• GERD
• Migraine
• Valve disease (MVP)
• Diverticulosis
• Intracranial aneurysms
• Aortic aneurysms?
 Hypertension
• Often precedes cyst formation, with LVH
• High-renin from cyst compression
of surrounding tissue
• ACE-I and ARB effective
– No glomerular benefit, but usual CV
benefit
• Salt restriction, weight control, exercise
all advised
ADPKD Gross Specimen
ADPKD Cut Specimen
ADPKD Cyst - Micro
ADPKD Cyst - Micro
 ADPKD

Liver Cysts

• Ultimately 75-90% affected

• Correlation with female sex and parity
• Liver dysfunction very rare
• Rare association with cholangiocarcinoma
QuickTimeª and aTIFF (Uncompressed) decompressorare needed to s

ADPKD Liver Disease

(nl transaminases)
ADPKD - Liver Cysts
ADPKD on Ultrasound
QuickTimeª and aTIFF (Uncompressed) decompressorare needed t

Liver and Kidney Cysts

ADPKD on CT
 ADPKD

Cerebral aneurysms - conflicting data

• 4-10% prevalence, increases with age

• 2-4% in general population
• Aneurysm rupture kills 7-13% of patients
• Familial clustering - ask FH of CNS bleed
• Chronic headaches do not correlate with
CNS aneurysms
• Do not screen routinely
 ADPKD
Cerebral aneurysms - why not screen?

• Expensive
• Absence of aneurysm does not preclude
later development
• Presence does not guarantee rupture
much more than in general population
• Therapy with significant M&M
 ADPKD
Cerebral aneurysms - prophylaxis

• Superior BP control
• Avoid tobacco
• Control lipids
• Take new headaches very seriously
 ADPKD
Cerebral aneurysms - who and how?

• Screen those with FH or high risk

occupation or previous rupture or anxiety
• Screen with MRA

- ≥ 10 mm - surgery
- 7-10 mm - annual screen
- < 7 mm - every 1-10 years (wide range
of recs)
Ruptured Berry Aneurysm
 ADPKD

Other CV anomalies

• Mitral valve anomalies in 30%

• Increased frequency of other
incompetence of other valves.
• Thoracic aortic aneurysms increased
up to 7-fold? Not holding up to
scrutiny.
 ADPKD

Infections

• Hard to diagnose
• Urine cultures rarely positive
• Infected cysts hard to find, harder
to drain
• Antibiotics must be able to enter
cysts - use sulfa, floroquinolones
• Avoid aminoglycosides and
penicillins
 ADPKD

Kidney stones

• About 20%
• CT best for detection
• Mostly CaOx or urate
• Treat as other stones
 Pain
• Acute
– With cyst rupture
– May require narcotics and sedation
• Chronic
– Can lead to narcotic dependence
• Avoid demerol
– Operative interventions - generally declined
• Drain dominant cysts
• Marsupialize
• Denervate
Laparoscopic denervation

J. Urol 175, 2274-2276, 2006

 ADPKD

Miscellaneous effects

• Increased diverticulosis
• Increased inguinal/abdominal hernia
• Increased migraine headache
• Incidental splenic and pancreatic cysts
 ADPKD

Therapy

• Avoid hypokalemia - seems to

increase cyst growth
• Avoid contact sports
• Acute pain/hemorrhage -
bedrest and analgesics, cyst
drainage
 Older, Unproven Options

•Assuming cyst enlargement causes renal

failure:

Amiloride reduces cyst growth in animals

by blocking Na transport KI 1989; 35:1379-89
Caffeine in vitro increases cAMP
production and tubule cell secretion JASN 2002;
13:2723-9
Neither studied in humans
 Polycystin Functions
• Strongest evidence: associated with a cilium-
triggered calcium channel
• Good evidence for intercellular adhesion functions
• Possibly both or more – 2 hit models to create cysts
• Not clear if/how they are associated with cAMP
(appears to stimulate cyst proliferation)
• PC1 interacts with mTOR
 6 Possible
Polycystin
complex
action
sites

Nephron Exp Nephrol 2006;103:e149–e155

Intracellular Pathways in ADPKD

Kidney International 76, 149–16, 2009

 Future Directions
Sirolimus
• Sirolimus = Rapamycin
• Anti-proliferative immunosuppressant
• ADPKD kidneys often continue to grow atfer
transplant
• NK regression noted in many pts with sirolimus;
also seen in rat models
• Abnormal Polycystin-1 may be a dysregulator of
mTOR (mammalian Target of Rapamycin)
• Blocking mTOR may block cyst development
ProcNatl AcadSci USA 103: 5466-712006

NDT2006Mar;21(3):598-604.
 mTOR
• Serine/threonine kinase
• Specifically and uniquely inhibited by
rapamycin (sirolimus)
• Component of 2 distinct signaling pathways
– mTORC1 stimulates cell growth and proliferation
– mTORC2 involved in cell polarity and cytoskeleton
• Rapamycin has no effect on mTORC2

J Am Soc Nep hrol 20 : 2 4 9Ð23 5 0, 22 0 0 9

 mTORC1 effects
• Involved in coordinating growth of cells
as they move through cell cycle
• Mitosis results in 2 equal daughter cells
of half original size
• mTORC1 seems to help stimulate and
regulate the growth process
 mTOR in ADPKD
• The cytoplasmic tail of polycystin 1 interacts
with and inhibits mTOR
• Less PC1 in ADPKD1 so …
• Marked increase in mTOR activity which …
• Leads to increased cellular proliferation in
renal tubular cyst cells
• Rapamycin seems to inhibit the process
• Unknown how or if polycystin 2 interacts with
mTOR
Shillingford et al, Proc Natl Acad Sci 103:5466–5471, 2006
 Clinical Observations
• Rapamycin slows cyst growth in native
kidneys of humans with kidney
transplants
• Works in rat and mouse models of PKD
• Pilot sudy showed promise
• Three major clinical trials ongoing
 Pilot Study of Sirolimus
Sirolimus Control
• 16 patients Age 40.4 41.1
– 8 with ARB M/F 7/1 6/2
– 8 with ARB
and sirolimus MRI kidney 2845 2667
1 mg/day volume pre
• 6 months MRI kidney 3221 3590
volume post
• Creat < 2
Change in size +13% +35%
P NS P< 0.05
Sirolimus level 4.6
 V2 receptor antagonists
• The polycystin complex has a role in intracellular
calcium homeostasis
• PC1 signals PC2 to form calcium channel
• Increased calcium leads to increased cAMP
production
• Vasopressin stimulation separately associated with
cAMP production
• cAMP part of cascade to insert AQP2 into tubule cell
membranes
• Increased AQP2 may lead to cyst growth
 V2 receptor antagonists
• Tolvaptan already approved for SIADH and CHF
• Major side effect so far is polyuria (4-5 liters/day)
Inhibits PKD in rat and mouse models
• PKD rats with vasopressin knockouts are protected,
but develop cysts with exogenous vasopressin
• TEMPO Trials (Tolvaptan Efficacy and Safety in
Management of PKD and Outcomes)
– Phase 3 ongoing with 1445 patients randomized in 133
centers
 Octreotide

• Somatostatin analogue
• Inhibits cAMP production
• Two small studies showed small decreases
kidney and liver volumes at 6 months
• GFR not improved
• Two more studies ongoing.
 ADPKD
ESRD

• 50% by age 60
• ADPKD patients tolerate dialysis better
than most
• Often need no (or less) EPO
• PD assumed complicated hernias, by lack
of space for fluid
• Transplantation may lead to need for
nephrectomy
∗ To make room
∗ To extirpate infection
∗ To avoid hemorrhage
 ADPKD
Counseling

• Tell parents about genetics/50%

inheritance
• Genetic testing not clinically relevant
• Diagnosis in child will lead to loss of
insurance
• Follow BP and physical exam in
children annually
• Everyone with ADPKD has obvious
cysts by age 30 - if none present,
disease not there
Questions about ADPKD?
 Autosomal Recessive
Polycystic Kidney Disease
(ARPKD)

Overview

• 1:6000-40,000 births
• 1:4 chance of inheriting
• Genetic defect on chromosome
6
• Affects liver and kidneys
inversely
 ARPKD

Natural history

• Considerable variation of expression

• 75% die within days of birth
(pulmonary hypoplasia/insufficiency)
• Remainder have 75% survival at age
15
 ARPKD

Pathology - severe form

• Kidneys symmetrically enlarged to

10X normal (300 gm vs 25 gm)
• 1-2 mm cortical cysts connect with
• 1-8 mm radial medullary cysts - 60-
90% of collecting ducts
• Glomeruli and proximal nephrons
spared but crowded
• Collecting system mostly normal
 ARPKD -
Autopsy
Specimen
ARPKD - Gross Specimen
ARPKD - Cut Specimen
ARPKD - Micro
 ARPKD

Pathology - milder forms (survivors)

• 10-25% of collecting ducts

• Cysts tend to be larger and
round
• Can be confused with medullary
sponge kidney or ADPKD
• Distinguish ADPKD from ARPKD
by U/S of parents
 ARPKD

Hepatic lesion

• Central portal bile ducts absent

or reduced in number
• Peripheral portal ducts increased
in number, but with bizarre
shapes/orientations
• Ultimately hepatic fibrosis and
portal hypertension at age 5-10
Hepatic Fibrosis in ARPKD
 Acquired Cystic Kidney Disease
• Caused by “azotemia” - not necessarily dialysis
• Diagnosis by CT
At least 3 simple cysts in each kidney
0.5-4 cm
In patient with renal failure
After exclusion of prior cystic process
 ACKD Complications
• RCC - but rarely aggressive
• Infection
• Hemorrhage/kidney rupture
• Erythrocytosis
• Stones
ACKD
ACKD Gross
ACKD Gross
 ACKD as
RCC
KI 2002

QuickTimeª and a
TIFF (LZW) decompressor
are needed to see this picture.
ACKD US
ACKD US
Clin Nephrol. 2003 Mar;59(3):153-9
Twenty-year follow-up of acquired renal cystic disease.
Ishikawa I, Saito Y, Asaka M, Tomosugi N, Yuri T, Watanabe M, Honda R.

• 36 HD patients followed 20 years (79-99)

• Renal size increased on average because of cysts - x3
males, x2 females. Stable after 15 years
• 1 death from spontaneous hemorrhage
• Rate of RCC was “high”
• No deaths from RCC - all detected early
• A transplanted cohort did not have higher volumes
 Medullary Sponge Kidney
Pathology

• Marked enlargement of the medullary

collecting ducts
• 70% are bilateral
• Ducts dilated to 1-3 mm commonly,
rarely 7 mm
• Ducts contain inspissated material or
stones
• Intra-renal obstruction and infection are
common
• Cortex generally OK
 Medullary Sponge Kidney
• Prevalence 1:5000-1:20000
• M:F = 1:2 (or 1:1)
• Congenital disorder - not inherited (?)
• Fully developed at birth
• Renal failure uncommon
• 25% with MSK have hemi-hypertrophy
of body (1:100,000 in general
population)
• 5-10% with hemi-hypertrophy have MSK
 Medullary Sponge Kidney
Natural history

• Clinically apparent in 30’s-40’s

• GFR often decreased
• ESRD rare
 Medullary Sponge
Kidney
Kidney stones

• Acidification defect
• Hypercalciuria
• Hyperuricosuria
• Hypocitraturia
• Sluggish urine flow
 Medullary Sponge Kidney
Signs/symptoms

• Micro/macrohematuria
• Infections (not more, but worse)
• Renal colic, loin pain, passage of gravel
• Type 1 RTA (low serum bicarb, urine pH > 5.5)
 Medullary Sponge Kidney
Diagnosis

• IVP shows characteristic pattern of radial,

linear striations
• Blush pattern, bunch of grapes, bouquet of
flowers
• CT and US usually not needed
Medullary Sponge QuickTimeª and aTIFF (Uncompressed) decompressora
Kidney - Schematic
of IVP Patterns
 Medullary
Sponge Kidney
QuickTimeª and aTIFF (Uncompressed) decompressorare needed to see this picture.
- Schematic of
Plain Film
Patterns
Medullary Sponge Kidney - IVP
Medullar
y
Sponge
Kidney -
IVP
 QuickTimeª and aTIFF (Uncompressed) decompresso

MSK - IVP
Medullary
Sponge QuickTimeª and aTIFF (Uncompressed) decompressorare needed to s
Kidney -
IVP
 Medullary
Sponge QuickTimeª and aTIFF (Uncompressed) decompresso

Kidney IVP -
Grapes
Medullary Sponge Kidney - US
 Medullary Sponge Kidney
Differential Diagnosis

• Renal TB
• Papillary necrosis - analgesic, DM, SSD
• Other nephrocalcinosis - Primary PTH,
hypercalcemia, distal RTA
 Medullary Sponge Kidney
Treatment

• Acidosis with K-citrate (citrate becomes bicarb)

• Stones with fluids (> 2 liters/day) and K-citrate
• Avoid sodium
• Consider thiazide diuretics
• Treat infection vigorously and completely