Cystic Diseases of the

Kidney
Derek Ottem
UGR May 30th 2007

Overview
Classification of Renal Cystic Disease
Cyst Histology
ADPKD
Acquired Renal Cystic Disease

1
Genetic Non-Genetic
ADPKD (adult) Acquired renal cystic disease
ARPKD (infantile) Benign multilocular cyst / Cystic
nephroma
Congenital nephrosis/Familial Nephrotic Calyceal diverticulum / Pyelogenic
Syndrome cyst
Familial hypoplastic glomerulocystic disease Medullary sponge kidney
Juvenile nephronophthesismedullary cystic Multicystic dysplastic kidney / MCDK
disease complex
Juvenile nephronophthesis Simple Cysts
Medullary cystic disease

Tuberous sclerosis

VHL

2
 What is a cyst?
Kidney most common organ to form cysts
Microscopic or macroscopic sacs lined
with epithelium
Dilated duct reaches > 4 times its normal
diameter (Gardner 1988)

3
 ADPKD
Epidemiology
Genetics and Pathogenesis
Screening Issues
Diagnosis
Manifestations
Complications and Management
Transplant Issues

ADPKD: Epidemiology
1 in 500-
500-1000
Most prevalent monogenic disorder
Most identified clinically between age 30-
30-50
Age at diagnosis decreasing as genetic testing
becomes more prevalent
Slightly more progressive disease in men
Accounts for 3-
3-15% of pt
pts on RRT
Accounts for 3-
3-13% of renal transplants

4
 ADPKD: Genetics

PKD1
Short arm chromosome 16
16p13.3
85% of cases of ADPKD
Earlier onset and faster progression
Polycystin1 glycoprotein
Membrane protein receptor
Located in primary cilium
Average life expectancy 53 years

5
 PKD2
Chromosome 4
4q21
15% of cases
Slower progression and later onset
Polycystin 2 glycoprotein
Membrane protein
Primary cilium Ca channel
Average life expectancy 69 years

6
 ADPKD: Genetic Imprinting
Disease more severe and manifests
earlier when transmitted from mother

ADPKD: Genetic Anticipation

Subsequent generations have earlier
onset and severity of disease

7
ADPKD: Inter and Intra-Familial
Variability

Variability in location of mutation

2 hit phenomenon
Genetic and environmental modifiers

ADPKD: Histology
Cysts range from few mm to several cm
Diffusely throughout cortex and medulla
May resemble portion of nephron from
which derived
Epithelial hyperplasia is common

8
 ADPKD: Epithelial Hyperplasia
No increased risk of RCC
Other conditions with epithelial
hyperplasia
1. ARCD (3-6 times population risk)
2. VHL (40-50% of VHL pts)
3. TS (2% of TS pts)

Screening for ADPKD

Imaging

U/S 1st line test
Genetic testing

Linkage Analysis

Direct DNA sequencing

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Benefits of Testing for ADPKD
Identification of possible kidney donors
Family planning
Early detection of disease complications
Early treatment of disease complications

Detriments of Screening
Psychological
Educational and career implications
Insurability

10
 Screening
Until effective treatments become
available the adverse effects from pre-
symtomatic diagnosis in children
outweights the benefits

Lancet April 2007: Torres et al

U/S Diagnosis For 50% At Risk

Age Criteria

<30 2 unilateral cysts or bilateral cysts (1 cyst each kidney)

30-
30-60 2 cysts in each kidney

>60 4 cysts in each kidney

*Sensitivity 100% for PKD1 and 67% for PKD2 when <30

11
 Normal U/S Values per Age
Age Unilateral Cyst Bilateral Cyst

15-
15-30 <1% <1%

30-
30-50 1.7% 1%

50-
50-70 11.5% 4%

>70 22.1% 9%

Am J Kidney Disease 1993: Ravine et al

Sensitivity of US for ADPKD

Radiology OCT 1999: Nicolau et al

Age PKD1 PKD2 ADPKD

<30
Sensitivity 95 67 93
Specificity 100 100 100
>30
Sensitivity 100 100 100
Specificity 100 100 100
Any Age
Sensitivity 98 90 97
Specificity 100 100 100

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 Diagnosis in Absence of Family
History
Bilateral Renal Cysts And 2 or more of:
1. Bilateral renal enlargement
2. 3 or more hepatic cysts
3. Cerebral artery aneurysm
4. Arachnoid cyst
5. Pineal gland cyst
6. Pacreatic cyst
7. Splenic cyst

Genetic Testing: Linkage

PKD1 and PKD2 genes
Linkage analysis
Blood samples from pt and at least 2
affected family members and 2 non
affected family members

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 Genetic Testing: Direct DNA
Athena Diagnostics
PKDx
i. Direct DNA test (not linkage no family
members required)
ii. Detects most PKD1 and PKD2 defects

Potential Indications for Genetic

Testing
1. Living donor evaluation
2. Unclear clinical diagnosis
3. Typical presentation without family
history
4. Differentiate between PKD1 and PKD2
5. Pre-natal diagnosis

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ADPKD: Renal Manifestations
HTN
Pain
ESRD
Infected cysts
Stones
Hematuria

ADPKD: HTN
5-40% of children with ADPKD
50% of 20-35 and normal RF
100% of pts with ESRD
Principle form of presentation

15
 HTN: Etiology
Association with renal size
Stretching of vessels
Distal ischemia
Activation of RAS
Atherosclerosis
PKD1 and 2 found in vessel walls
Impaired NO mediated vasodilation in vascular
smooth muscle
Insulin resistance

HTN: Associations
Reduced renal BF
Abnormal sodium handling
Remodeling of renal vasculature

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 HTN: Complications
Left ventricular hypertrophy
Diastolic dysfunction
Worsening of MVP
Worsening of aneurysms
Hematuria
Major risk factor for IHD / MI
Worsening of proteinuria / CRF
Increased risk of pre-eclampsia / fetal loss

Effect of Antihypertensive Therapy on Renal Function and Urinary Albumin Excretion in

Hypertensive Patients With Autosomal Dominant Polycystic Kidney Disease
American Journal of Kidney Diseases - Volume 35, Issue 3 (March 2000) - Copyright 2000 W.
B. Saunders

RCT Comparing enalapril (ACEI) to

Amlodipine for BP control, Cr and
Proteiuria
ADPKD with CCL <50cc/min
No difference in BP or Cr
ACEI had significantly lower proteinuria at
1 and 5 years

17
 HTN: Treatment
Early detection important ambulatory BP
monitoring
ACEI better than CCB / HCTZ at reducing
progression of proteiuria, but no effect on
Cr
Optimal BP unclear, likely <130/80
HALT-PKD trial ACEI vs ACEI + ARB
HALT-PKD is 110/75 better than 130/80

ADPKD: Renal Manifestations

HTN
Pain
ESRD
Infected cysts
Stones
Hematuria

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 Pain
Most common symptom
Etiology:
1. Infection
2. Stones / Renal coli
3. Bleeding into cyst
4. Clot colic
5. Pressure on capsule / adjacent organs
6. GI (Heartburn)
7. Diverticulitis
8. Pancreatitis

Pain:Treatment
Treat identifiable causes (calculi, infections)
Analgesics
Percutaneous cyst aspiration and sclerosant
Transcatheter arterial embolization
MIS or Open Cyst Un-Un-roofing
MIS Denervation and Nephropexy
MIS or Open Nephrectomy

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Pilot study of 15 pts over 1 year period
Percutaneous cyst aspiration and injection of
99% ETOH
Selected cysts were >5cm + pressure signs on
IVU or CECT
Visual analog pain score, Cr and serial imaging

20
 ETOH Injection: Results
Pain scores improved at 1 day and 1
month
Cr significantly increased at 1 year
1.9mg/dL to 2.1mg/dL
Complications in 2 of 15 pts
1 Pt developed nephrocutaneous fistula
1Pt developed UTI

Sclerosing Agents
1. Absolute ETOH
2. N-Butyl-
Butyl-Cyanoacrylate
3. Ethanolamine
4. Povidone iodine
5. Acetic acid
6. Dextrose
7. Tetracycline, Minocycline
8. Phenol
9. Bismuth
10. Fibrin glue
11. Glucose

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 Cyst Unroofing:Historical
1911 Rovsing unroofed cysts surgically
in 3 patients to relieve pain
Deteriorating renal function - procedure
lost enthusiasm
1951 Goldstein (16 pts ) and Dalgaard
(199 pts) - significant pain reflief with cyst
decortication

Cyst Unroofing:Historical
1957 Bricker NEJM 2 patients had
worsening renal function after cyst
decortication for pain
Procedure discredited for 20-30 years

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23
Prospective study
30 patients total (14 pain, 4 renal insufficiency,
12 both)
Unilateral or bilateral cyst reduction sx
Followed for 21 months for pain and Cr
Objective: Pain relief + Effect on Renal Function

24
Pts with pre-operative renal dysfunction had
no change in decline

Conclusions: Pain
Effective pain relief in majority of pts
80% at 1 year
65% at 2 years
In those who recurred, less intense than
pre-operatively

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Conclusions: Renal Function
No deleterious effect on renal function
No improvement in renal function
Does not change progression of renal
decline in pre-existing CRF
In unilateral cases no change from
contralateral kidney

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15 patients
Unilateral 9
Bilateral 6
Followed BP, Cr, Analog Pain Scores
Mean f/u 2.2 years

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 Results: Pain
73% overall reported an improvement at
mean 2.2 years
In responders mean improvement 62%
In failure pts 2/15 had late failures
Bilateral had better result (83%) vs
unilateral (67%)

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 Results: Cr and BP
27% cured/improved HTN
33% worse HTN
40% no change HTN
No significant effect on Cr

Results: Complications
Urinoma in 3 JJ stent for 4 weeks
Bilateral pleural effusion in 1 treated
medically
Urine retention in 1

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 Conclusions
Pain relief similar to large open series
(Barry and Elzinga 1992)
Better result with bilateral vs unilateral
No worsening of renal function
No effect on BP
Longer OR time than open
Decreased hospital stay
Increased complications

31
35 LCD procedures over 6 years (6
bilateral and 23 unilateral)
Every cyst >2mm on / near surface tx
Followed pain analog scores, BP and Cr
Mean f/u 32 months

32
33
 Results: Pain
12 months 24 months 36 months

% pt
pts with 73% 52% 81%
pain relief
>50%

% 58% 47% 63%

reduction in
pain score

Results: Early Complications

10 peri-
peri-operative complications (3 major 7
minor)
3 developed urinoma stent for 4 weeks
2 ileus
1 atelectasis
1 urine retention
1 pleural effusion treated medically
1 persistent pain
1 spinal headache

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 Results: HTN
5/21 became normotensive
9/21 had 49% reduction in ATI
6/21 had worsening HTN

Results: Renal function

No improvement
In pts with poor renal function or declining
function pre-operatively MIS decortication
will not slow or stabilize it

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 Results: Late Complications
1 pt developed abscess 6 months post-
operatively nephrectomized
1 pt died of MI after bilateral
nephrectomies for recurrent / persistent
pain

4 pt
pts aged 15-
15-19 yrs
Pain refractory to narcotics
Mean f/u 11.5 months
Bieri modified pain scale

36
 Results: Pain Scores
Pre-Op pain scores 6-9 / 10
Score 0-1 / 10 at discharge
Score 0-1 / 10 at mean f/u 11.5 months

Complications
1 pt had renal pelvic urine leak requiring
stenting for 6 weeks

37
 Conclusions
Feasible
Good short term
results
Longer f/u and larger
series required for
definitive conclusions

ADPKD: Renal Manifestations

HTN
Pain
ESRD
Infected cysts
Stones
Hematuria

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 ESRD
On average occurs between 4th-6th decade
Later in PKD2 than PKD1
Once begins, average decline 5ml/min /
year in CrCl
50% develop renal failure by age 60

ESRD: Etiology
Not completely understood
Only about 1% of nephrons develop cysts
Pressure atrophy?
HTN?
Increased apoptosis in nephrons
Vascular remodeling
Analgesic nephropathy

39
 ESRD: Risk Factors
1. PKD1 type
2. Male
3. African American
4. Hematuria <30 years
5. HTN <35 years
6. Hyperlipidemia
7. Low HDL
8. Sickle cell trait
9. Smoking
10. Rate of cyst growth / size of kidneys
11. Multiple pregnancies

ESRD: Prevention
ACEI slow rate of proteinuria but no effect
on Cr compared to CCB, HCZT
Cyst unroofing has no effect

40
ADPKD: Renal Manifestations
HTN
Pain
ESRD
Infected cysts
Stones
Hematuria

Infected Cysts
90% occur in women
Ascending infections
E. coli, Klebsiella, Proteus and Pseudomonas
Instrumentation a major risk factor
Poor antibiotic penetration
R/O Obstruction
Lipophillic antibiotics (Flouroquinolones, Septra,
Chloramphenicol)
Percutaenous cyst aspiration
Nephrectomy

41
 AUAUS Lesson 13 2001

ADPKD: Renal Manifestations

HTN
Pain
ESRD
Infected cysts
Stones
Hematuria

42
 ADPKD: Stones
5-10 times the incidence of general
population
30% of pts develop stones
20% of pts are symptomatic
Contemporary endourological
management

ADPKD: Renal Manifestations

HTN
Pain
ESRD
Infected cysts
Stones
Hematuria

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 Hematuria
50% of ADPKD pts
Presenting symptom in 25%
Hematuria a/w worsening Cr

Case report
Despite bed rest and 10 units blood transfusion
pt became unstable
TXA 20mg/kg infused while awaiting OR
Hematuria ceased
TXA continued for 2 months
No recurrence for 24 months

44
 Transexamic Acid
Plasminogen inhibitor antifibrinolytic
agent
Reversibly blocks lysine binding sites on
plasmin molecule
Used during orthopedic and cardiac
surgery
Used for bleeding duodenal and gastric
ulcers

Transexamic Acid
Urokinase activity often high in cysts
fibrinolysis
APPKD pts with CRF likely have local and
systemic hyperfibrinolysis
Consider using in cases of severe
hematuria in ADPKD

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 ADPKD: Transplant Issues
1. When to consider transplantation
2. When to consider native nephrectomy
3. Timing of native nephrectomy
4. Issues unique to ADPKD after RT

When to consider transplant

1. GFR < 10cc/min
2. Cr > 800umol/l
3. Symptomatic uremia

46
Indications for Native Nephrectomy
1. Chronic pain
2. HTN
3. Cyst infections
4. Renal mass
5. GI (Early satiety, constipation)
6. No room for renal allograft
7. Respiratory compromise
8. Recurrent calculi

Native Nephrectomy
Rate of native nephrectomy for ADPKD
decreased over last 3 decades
85% in 1970s
47% in 1980s
20% contemporary series
Better conservative management
(improved abx, analgesics, MIS
techniques)

47
 Native Nephrectomy
Current consensus is to avoid native
nephrectomy if possible
Less complications on dialysis
Improved survival on dialysis
EPO production
Risk of blood transfusion sensitization

Timing of Native Nephrectomy

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Retrospective analysis
Matched pts with similar characteristics
Group 1: Concomitant RT and BL Nx (10)
Group 2: RT only (9)
Group 3: Staged BL Nx and RT (4 pts, 3
after and 1 before)
Peri-operative parameters and Cr

49
 Conclusions
Increased blood loss and transfusion in
concomitant
Lower complications in concomitant
No difference in graft function
No cases of DGF in concomitant group
Increased pt satisfaction (non validated
questionnaire)

50
Retrospective review of 32 pts over 12 yrs
Group 1: Pre-transplant = 7 pts
Group 2: Concomitant = 16 pts
Group 3: Post-transplant = 9 pts

Materials and Methods

25 of 32 underwent bilateral nephrectomy
Examined peri-operative course, OR time,
EBL, and effect on Cr

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52
 Results
No difference between 3 groups;

Complications

Blood loss

Hospital stay

Conclusions
Concomitant native nephrectomy is safe
and does not compromise graft
Similar peri-operative morbidity compared
to pre or post

53
 Timing of Native Nephrectomy:
Summary
Best to avoid nephrectomy if possible
(especially in pre-dialysis patients)
Concomitant nephrectomy safe
Concomitant nephrectomy avoids dialysis
in pre-dialysis living donor pts
Concomitant nephrectomy in dialysis pts
avoids the increased morbidity of anephric
pts on dialysis

Issues Unique to ADPKD Post RT

ADPKD have graft survival outcomes similar to
RT population as a whole
The following were more prevalent;
1. Diverticulitis +/-
+/- perforation
2. Arachnoid hemorrhage (no CVA CVAs overall)
3. Erythrocytosis with need for phlebotomy
No increased risk of cardiovascular disease

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 Acquired Renal
Cystic Disease

Acquired Renal Cystic Disease

1. Description
2. Epidemiology
3. Diagnosis
4. Histopathology
5. Symptoms
6. Transplant
7. Association with RCC

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 Description
Cysts forming in non-cystic failing or failed
kidneys
Originally thought to be HD only
HD = PD > ESRD only
Kidneys initially shrink after dialysis started
then increase after 3 years (Ishikawa
1985)

ARCD: Epidemiology
8% at start of dialysis
10-20% 1-3 years
60% at 3 years of dialysis
90% between 5-10 years on dialysis
100% at 10 years dialysis
ACRD 2.9:1 male to female ratio

56
 ARCD: Risk Factors
1. Length of time on dialysis or with ESRD
2. Male > Female
3. Nephrosclerosis
4. African Americans > Caucasians

Diagnosis
U/S
CT
MRI
>3cysts per kidney
Macroscopic cystic structures comprising
>25% of parenchyma

Pope Urology 1994

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 Histolopathology
Cysts size is mms to several cms
Pathogenesis unclear
Blocked tubules (ischemia, sloughing,
crystals, fibrosis) ?
Uremic growth factors / cystogenic growth
factor not cleared by dialysis ?

Symptoms / Complications
Pain
Hematuria
Infections
Malignancy risk

58
 ARCD and Transplant
Early transplant may prevent development
Cysts may regress following transplant
Cysts may still develop after transplant
Risk of RCC falls after transplantation (still
0.5-3.9% at a mean of 6 years)
Allografts become susceptible to ACKD
with chronic rejection
Ishikawa Am J Nephrology 1983
Vaziri Nephron 1984
Faber Lancet 1984
Ishikawa Nephron 1991

ESKD: Association with RCC

Population incidence of RCC 0.04%
1-3% prevalence of RCC in dialysis population
Incidence of RCC in ESRD 20 times population
risk in Japan
Incidence of RCC 3-
3-6 times population risk in
USA
Annual incidence increases per time on dialysis

Ishikawa Nephron 1991

Matson Medicine 1990

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ACKD: Association with RCC
20-25% of ESRD with ARCD have
adenomas
When RCC develops in ESRD a/w
ARCD 80% of time
Prevalence of RCC in setting of ESRD +
ARCD = 2-7%
Mean time on dialysis is 8-9 years

Biology of RCC in ESRD

Younger age of occurrence (5years)
Male > Female by 7:1
Much higher incidence than general population
Smaller tumors
Less likely to have mets at diagnosis (15% vs
20-
20-30%)
Less aggressive course and better prognosis
Papillary subtype more common (50% of cases)
More often multifocal

60
Pathogenesis of RCC in ARCD
Loss of nephrons


Hypertrophic changes + unknown uremia-
related growth factors


Undifferentiated tubular growth


risk of mutation

61
Proliferative activity of RCC in ESRD with
ARCD vs Typical RCC
S-Phase, Ploidy, Proliferating Cell Nuclear
Antigen (PCNA)

62
 Results
100% RCC-ACDK had diploid
56% RCC-T had diploid 44% aneuploid
RCC-A group same fraction in each
mode of cell cycle as normal renal tissue
PCNA higher in RCC-Typical than RCC-A

Conclusions
Histological characteristics correlate with
observation that RCC in ARCD less
aggressive than typical RCC
Potential flaw compared smaller RCCs
in ARCD to larger typical RCCs

63
 ARCD : Screening
Controversy exists about screening the dialysis
population for RCC
Does cost of screening outweight the potential
benefits?
Risk of dying from co-
co-morbid conditions?
What screening modality should be used?
When to start screening?
What is the life expectancy of dialysis patients in
that region?
Are patients candidates for therapy?
Continue screening after transplant?

Screening
Proponents start screening after 3 years
dialysis marked increase in ARCD after
this point
Then every other year with U/S
CECT if suspicious findings
The longer the pt is on dialysis the higher
the PPV of screening

64
 Screening: Summary
U/S most cost effective
U/S least morbid modality
Population to be screened and timeline not
well defined

THE END

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