Cystic Diseases of the Kidney UGR 2007 - UBC - Urology · PDF fileLinkage Analysis Direct DNA...

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Cystic Diseases of the Cystic Diseases of the

KidneyKidney

Derek OttemDerek Ottem

UGR May 30UGR May 30thth 20072007

OverviewOverview

Classification of Renal Cystic DiseaseClassification of Renal Cystic Disease

Cyst HistologyCyst Histology

ADPKDADPKD

Acquired Renal Cystic DiseaseAcquired Renal Cystic Disease

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VHL

Tuberous sclerosis

Medullary cystic disease

Simple CystsJuvenile nephronophthesis

Multicystic dysplastic kidney / MCDKJuvenile nephronophthesis–medullary cystic

disease complex

Medullary sponge kidneyFamilial hypoplastic glomerulocystic disease

Calyceal diverticulum / Pyelogenic

cyst

Congenital nephrosis/Familial Nephrotic

Syndrome

Benign multilocular cyst / Cystic

nephroma

ARPKD (infantile)

Acquired renal cystic diseaseADPKD (adult)

Non-GeneticGenetic

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What is a cyst?What is a cyst?

Kidney most common organ to form cystsKidney most common organ to form cysts

Microscopic or macroscopic sacs lined Microscopic or macroscopic sacs lined

with epitheliumwith epithelium

Dilated duct reaches > 4 times itDilated duct reaches > 4 times it’’s normal s normal

diameter (Gardner 1988)diameter (Gardner 1988)

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ADPKDADPKD

EpidemiologyEpidemiology

Genetics and PathogenesisGenetics and Pathogenesis

Screening IssuesScreening Issues

DiagnosisDiagnosis

ManifestationsManifestations

Complications and ManagementComplications and Management

Transplant IssuesTransplant Issues

ADPKD: EpidemiologyADPKD: Epidemiology

1 in 5001 in 500--10001000

Most prevalent monogenic disorderMost prevalent monogenic disorder

Most identified clinically between age 30Most identified clinically between age 30--5050

Age at diagnosis decreasing as genetic testing Age at diagnosis decreasing as genetic testing

becomes more prevalentbecomes more prevalent

Slightly more progressive disease in menSlightly more progressive disease in men

Accounts for 3Accounts for 3--15% of pt15% of pt’’s on RRTs on RRT

Accounts for 3Accounts for 3--13% of renal transplants13% of renal transplants

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ADPKD: GeneticsADPKD: Genetics

PKD1PKD1

Short arm chromosome 16Short arm chromosome 16

16p13.316p13.3

85% of cases of ADPKD85% of cases of ADPKD

Earlier onset and faster progressionEarlier onset and faster progression

Polycystin1 glycoproteinPolycystin1 glycoprotein

Membrane protein receptorMembrane protein receptor

Located in primary ciliumLocated in primary cilium

Average life expectancy 53 yearsAverage life expectancy 53 years

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PKD2PKD2

Chromosome 4Chromosome 4

4q214q21

15% of cases15% of cases

Slower progression and later onsetSlower progression and later onset

Polycystin 2 glycoproteinPolycystin 2 glycoprotein

Membrane proteinMembrane protein

Primary cilium Ca channelPrimary cilium Ca channel

Average life expectancy 69 yearsAverage life expectancy 69 years

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ADPKD: Genetic ImprintingADPKD: Genetic Imprinting

Disease more severe and manifests Disease more severe and manifests

earlier when transmitted from motherearlier when transmitted from mother

ADPKD: Genetic AnticipationADPKD: Genetic Anticipation

Subsequent generations have earlier Subsequent generations have earlier

onset and severity of diseaseonset and severity of disease

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ADPKD: Inter and IntraADPKD: Inter and Intra--Familial Familial

VariabilityVariability

Variability in location of mutationVariability in location of mutation

2 hit phenomenon2 hit phenomenon

Genetic and environmental modifiersGenetic and environmental modifiers

ADPKD: HistologyADPKD: Histology

Cysts range from few mm to several cmCysts range from few mm to several cm

Diffusely throughout cortex and medullaDiffusely throughout cortex and medulla

May resemble portion of nephron from May resemble portion of nephron from

which derivedwhich derived

Epithelial hyperplasia is commonEpithelial hyperplasia is common

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ADPKD: Epithelial HyperplasiaADPKD: Epithelial Hyperplasia

No increased risk of RCCNo increased risk of RCC

Other conditions with epithelial Other conditions with epithelial

hyperplasiahyperplasia

1.1. ARCD (3ARCD (3--6 times population risk)6 times population risk)

2.2. VHL (40VHL (40--50% of VHL pt50% of VHL pt’’s)s)

3.3. TS (2% of TS ptTS (2% of TS pt’’s)s)

Screening for ADPKDScreening for ADPKD

ImagingImaging�� U/S 1U/S 1stst line testline test

Genetic testingGenetic testing�� Linkage AnalysisLinkage Analysis

�� Direct DNA sequencingDirect DNA sequencing

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Benefits of Testing for ADPKDBenefits of Testing for ADPKD

Identification of possible kidney donors Identification of possible kidney donors

Family planningFamily planning

Early detection of disease complicationsEarly detection of disease complications

Early treatment of disease complicationsEarly treatment of disease complications

Detriments of ScreeningDetriments of Screening

PsychologicalPsychological

Educational and career implicationsEducational and career implications

InsurabilityInsurability

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ScreeningScreening

Until effective treatments become Until effective treatments become

available the adverse effects from preavailable the adverse effects from pre--

symtomatic diagnosis in children symtomatic diagnosis in children

outweights the benefitsoutweights the benefits

Lancet April 2007: Torres et al

U/S Diagnosis For 50% At RiskU/S Diagnosis For 50% At Risk

4 cysts in each kidney4 cysts in each kidney>60>60

2 cysts in each kidney2 cysts in each kidney3030--6060

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

CriteriaCriteriaAge Age

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

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Normal U/S Values per AgeNormal U/S Values per Age

9%9%22.1%22.1%>70>70

4%4%11.5%11.5%5050--7070

1%1%1.7%1.7%3030--5050

<1%<1%<1%<1%1515--3030

Bilateral CystBilateral CystUnilateral CystUnilateral CystAgeAge

Am J Kidney Disease 1993: Ravine et al

Sensitivity of US for ADPKDSensitivity of US for ADPKD

100100100100100100SpecificitySpecificity

979790909898SensitivitySensitivity

Any AgeAny Age



>30>30



<30<30

ADPKDADPKDPKD2PKD2PKD1PKD1AgeAge

Radiology OCT 1999: Nicolau et al

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Diagnosis in Absence of Family Diagnosis in Absence of Family

HistoryHistory

Bilateral Renal Cysts And 2 or more of:Bilateral Renal Cysts And 2 or more of:

1.1. Bilateral renal enlargementBilateral renal enlargement

2.2. 3 or more hepatic cysts3 or more hepatic cysts

3.3. Cerebral artery aneurysmCerebral artery aneurysm

4.4. Arachnoid cystArachnoid cyst

5.5. Pineal gland cystPineal gland cyst

6.6. Pacreatic cystPacreatic cyst

7.7. Splenic cystSplenic cyst

Genetic Testing: LinkageGenetic Testing: Linkage

PKD1 and PKD2 genesPKD1 and PKD2 genes

Linkage analysisLinkage analysis

Blood samples from pt and at least 2 Blood samples from pt and at least 2

affected family members and 2 non affected family members and 2 non

affected family membersaffected family members

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Genetic Testing: Direct DNAGenetic Testing: Direct DNA

Athena DiagnosticsAthena Diagnostics

PKDxPKDx

i.i. Direct DNA test (not linkage Direct DNA test (not linkage –– no family no family

members required)members required)

ii.ii. Detects most PKD1 and PKD2 defectsDetects most PKD1 and PKD2 defects

Potential Indications for Genetic Potential Indications for Genetic

TestingTesting

1.1. Living donor evaluationLiving donor evaluation

2.2. Unclear clinical diagnosisUnclear clinical diagnosis

3.3. Typical presentation without family Typical presentation without family

historyhistory

4.4. Differentiate between PKD1 and PKD2Differentiate between PKD1 and PKD2

5.5. PrePre--natal diagnosisnatal diagnosis

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ADPKD: Renal ManifestationsADPKD: Renal Manifestations

HTNHTN

PainPain

ESRDESRD

Infected cystsInfected cysts

StonesStones

HematuriaHematuria

ADPKD: HTNADPKD: HTN

55--40% of children with ADPKD40% of children with ADPKD

50% of 2050% of 20--35 and normal RF35 and normal RF

100% of pt100% of pt’’s with ESRDs with ESRD

Principle form of presentationPrinciple form of presentation

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HTN: EtiologyHTN: Etiology

Association with renal sizeAssociation with renal size

Stretching of vesselsStretching of vessels

Distal ischemiaDistal ischemia

Activation of RASActivation of RAS

AtherosclerosisAtherosclerosis

PKD1 and 2 found in vessel wallsPKD1 and 2 found in vessel walls

Impaired NO mediated vasodilation in vascular Impaired NO mediated vasodilation in vascular smooth musclesmooth muscle

Insulin resistanceInsulin resistance

HTN: AssociationsHTN: Associations

Reduced renal BFReduced renal BF

Abnormal sodium handlingAbnormal sodium handling

Remodeling of renal vasculatureRemodeling of renal vasculature

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HTN: ComplicationsHTN: Complications

Left ventricular hypertrophyLeft ventricular hypertrophy

Diastolic dysfunctionDiastolic dysfunction

Worsening of MVPWorsening of MVP

Worsening of aneurysmsWorsening of aneurysms

HematuriaHematuria

Major risk factor for IHD / MIMajor risk factor for IHD / MI

Worsening of proteinuria / CRFWorsening of proteinuria / CRF

Increased risk of preIncreased risk of pre--eclampsia / fetal losseclampsia / fetal loss

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

Hypertensive Patients With Autosomal Dominant Polycystic Kidney Hypertensive Patients With Autosomal Dominant Polycystic Kidney DiseaseDisease

American Journal of Kidney DiseasesAmerican Journal of Kidney Diseases -- Volume 35, Issue 3 (March 2000) Volume 35, Issue 3 (March 2000) -- Copyright Copyright ©© 2000 W. 2000 W.

B. Saunders B. Saunders

RCT Comparing enalapril (ACEI) to RCT Comparing enalapril (ACEI) to

Amlodipine for BP control, Cr and Amlodipine for BP control, Cr and

ProteiuriaProteiuria

ADPKD with CCL <50cc/minADPKD with CCL <50cc/min

No difference in BP or CrNo difference in BP or Cr

ACEI had significantly lower proteinuria at ACEI had significantly lower proteinuria at

1 and 5 years1 and 5 years

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HTN: TreatmentHTN: Treatment

Early detection important Early detection important –– ambulatory BP ambulatory BP

monitoringmonitoring

ACEI better than CCB / HCTZ at reducing ACEI better than CCB / HCTZ at reducing

progression of proteiuria, but no effect on progression of proteiuria, but no effect on

CrCr

Optimal BP unclear, likely <130/80Optimal BP unclear, likely <130/80

HALTHALT--PKD trial PKD trial –– ACEI vs ACEI + ARBACEI vs ACEI + ARB

HALTHALT--PKD PKD –– is 110/75 better than 130/80is 110/75 better than 130/80


HTNHTN

PainPain

ESRDESRD


StonesStones

HematuriaHematuria

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Pain Pain

Most common symptomMost common symptom

Etiology:Etiology:

1.1. InfectionInfection

2.2. Stones / Renal coliStones / Renal coli

3.3. Bleeding into cystBleeding into cyst

4.4. Clot colicClot colic

5.5. Pressure on capsule / adjacent organsPressure on capsule / adjacent organs

6.6. GI (Heartburn)GI (Heartburn)

7.7. DiverticulitisDiverticulitis

8.8. PancreatitisPancreatitis

Pain:TreatmentPain:Treatment

•• Treat identifiable causes (calculi, infections)Treat identifiable causes (calculi, infections)

•• AnalgesicsAnalgesics

•• Percutaneous cyst aspiration and sclerosantPercutaneous cyst aspiration and sclerosant

•• Transcatheter arterial embolizationTranscatheter arterial embolization

•• MIS or Open Cyst UnMIS or Open Cyst Un--roofingroofing

•• MIS Denervation and NephropexyMIS Denervation and Nephropexy

•• MIS or Open NephrectomyMIS or Open Nephrectomy

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Pilot study of 15 pts over 1 year periodPilot study of 15 pts over 1 year period

Percutaneous cyst aspiration and injection of Percutaneous cyst aspiration and injection of

99% ETOH99% ETOH

Selected cysts were >5cm + pressure signs on Selected cysts were >5cm + pressure signs on

IVU or CECTIVU or CECT

Visual analog pain score, Cr and serial imagingVisual analog pain score, Cr and serial imaging

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ETOH Injection: ResultsETOH Injection: Results

Pain scores improved at 1 day and 1 Pain scores improved at 1 day and 1

monthmonth

Cr significantly increased at 1 year Cr significantly increased at 1 year

1.9mg/dL to 2.1mg/dL1.9mg/dL to 2.1mg/dL

Complications in 2 of 15 ptComplications in 2 of 15 pt’’ss

1 Pt developed nephrocutaneous fistula1 Pt developed nephrocutaneous fistula

1Pt developed UTI1Pt developed UTI

1.1. Absolute ETOHAbsolute ETOH

2.2. NN--ButylButyl--CyanoacrylateCyanoacrylate

3.3. EthanolamineEthanolamine

4.4. Povidone iodinePovidone iodine

5.5. Acetic acidAcetic acid

6.6. DextroseDextrose

7.7. Tetracycline, MinocyclineTetracycline, Minocycline

8.8. PhenolPhenol

9.9. BismuthBismuth

10.10. Fibrin glueFibrin glue

11.11. GlucoseGlucose

Sclerosing AgentsSclerosing Agents

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Cyst Unroofing:HistoricalCyst Unroofing:Historical

1911 1911 –– Rovsing unroofed cysts surgically Rovsing unroofed cysts surgically

in 3 patients to relieve painin 3 patients to relieve pain

Deteriorating renal function Deteriorating renal function -- procedure procedure

lost enthusiasmlost enthusiasm

1951 Goldstein (16 pts ) and Dalgaard 1951 Goldstein (16 pts ) and Dalgaard

(199 pts) (199 pts) -- significant pain reflief with cyst significant pain reflief with cyst

decorticationdecortication

Cyst Unroofing:HistoricalCyst Unroofing:Historical

1957 Bricker 1957 Bricker –– NEJM NEJM –– 2 patients had 2 patients had

worsening renal function after cyst worsening renal function after cyst

decortication for paindecortication for pain

Procedure discredited for 20Procedure discredited for 20--30 years30 years

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Prospective studyProspective study

30 patients total (14 pain, 4 renal insufficiency, 30 patients total (14 pain, 4 renal insufficiency, 12 both)12 both)

Unilateral or bilateral cyst reduction sxUnilateral or bilateral cyst reduction sx

Followed for 21 months for pain and Cr Followed for 21 months for pain and Cr

Objective: Pain relief + Effect on Renal FunctionObjective: Pain relief + Effect on Renal Function

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Pts with prePts with pre--operative renal dysfunction had operative renal dysfunction had

no change in declineno change in decline

Conclusions: PainConclusions: Pain

Effective pain relief in majority of ptEffective pain relief in majority of pt’’ss

80% at 1 year80% at 1 year

65% at 2 years65% at 2 years

In those who recurred, less intense than In those who recurred, less intense than

prepre--operativelyoperatively

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Conclusions: Renal FunctionConclusions: Renal Function

No deleterious effect on renal functionNo deleterious effect on renal function

No improvement in renal functionNo improvement in renal function

Does not change progression of renal Does not change progression of renal

decline in predecline in pre--existing CRFexisting CRF

In unilateral cases no change from In unilateral cases no change from

contralateral kidneycontralateral kidney

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15 patients15 patients

Unilateral 9Unilateral 9

Bilateral 6Bilateral 6

Followed BP, Cr, Analog Pain ScoresFollowed BP, Cr, Analog Pain Scores

Mean f/u 2.2 yearsMean f/u 2.2 years

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Results: PainResults: Pain

73% overall reported an improvement at 73% overall reported an improvement at

mean 2.2 yearsmean 2.2 years

In responders mean improvement 62%In responders mean improvement 62%

In failure ptIn failure pt’’s 2/15 had late failuress 2/15 had late failures

Bilateral had better result (83%) vs Bilateral had better result (83%) vs

unilateral (67%)unilateral (67%)

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Results: Cr and BPResults: Cr and BP

27% cured/improved HTN27% cured/improved HTN

33% worse HTN33% worse HTN

40% no change HTN40% no change HTN

No significant effect on CrNo significant effect on Cr

Results: ComplicationsResults: Complications

Urinoma in 3 Urinoma in 3 –– JJ stent for 4 weeksJJ stent for 4 weeks

Bilateral pleural effusion in 1 Bilateral pleural effusion in 1 –– treated treated

medicallymedically

Urine retention in 1 Urine retention in 1

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ConclusionsConclusions

Pain relief similar to large open series Pain relief similar to large open series (Barry and Elzinga 1992)(Barry and Elzinga 1992)

Better result with bilateral vs unilateralBetter result with bilateral vs unilateral

No worsening of renal functionNo worsening of renal function

No effect on BPNo effect on BP

Longer OR time than openLonger OR time than open

Decreased hospital stayDecreased hospital stay

Increased complicationsIncreased complications

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35 LCD procedures over 6 years (6 35 LCD procedures over 6 years (6

bilateral and 23 unilateral)bilateral and 23 unilateral)

Every cyst >2mm on / near surface txEvery cyst >2mm on / near surface tx

Followed pain analog scores, BP and CrFollowed pain analog scores, BP and Cr

Mean f/u 32 monthsMean f/u 32 months

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Results: PainResults: Pain

63%63%47%47%58%58%% %

reduction in reduction in

pain scorepain score

81%81%52%52%73%73%% pt% pt’’s with s with

pain relief pain relief

>50%>50%

36 months36 months24 months24 months12 months12 months

Results: Early ComplicationsResults: Early Complications

10 peri10 peri--operative complications (3 major 7 operative complications (3 major 7 minor)minor)

3 developed urinoma 3 developed urinoma –– stent for 4 weeksstent for 4 weeks

2 ileus2 ileus

1 atelectasis1 atelectasis

1 urine retention1 urine retention

1 pleural effusion treated medically1 pleural effusion treated medically

1 persistent pain1 persistent pain

1 spinal headache1 spinal headache

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Results: HTNResults: HTN

5/21 became normotensive5/21 became normotensive

9/21 had 49% reduction in ATI9/21 had 49% reduction in ATI

6/21 had worsening HTN6/21 had worsening HTN

Results: Renal functionResults: Renal function

No improvementNo improvement

In ptIn pt’’s with poor renal function or declining s with poor renal function or declining

function prefunction pre--operatively MIS decortication operatively MIS decortication

will not slow or stabilize itwill not slow or stabilize it

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Results: Late ComplicationsResults: Late Complications

1 pt developed abscess 6 months post1 pt developed abscess 6 months post--

operatively operatively –– nephrectomizednephrectomized

1 pt died of MI after bilateral 1 pt died of MI after bilateral

nephrectomies for recurrent / persistent nephrectomies for recurrent / persistent

painpain

4 pt4 pt’’s aged 15s aged 15--19 yrs19 yrs

Pain refractory to narcoticsPain refractory to narcotics

Mean f/u 11.5 monthsMean f/u 11.5 months

Bieri modified pain scaleBieri modified pain scale

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Results: Pain ScoresResults: Pain Scores

PrePre--Op pain scores 6Op pain scores 6--9 / 109 / 10

Score 0Score 0--1 / 10 at discharge1 / 10 at discharge

Score 0Score 0--1 / 10 at mean f/u 11.5 months1 / 10 at mean f/u 11.5 months

ComplicationsComplications

1 pt had renal pelvic urine leak requiring 1 pt had renal pelvic urine leak requiring

stenting for 6 weeksstenting for 6 weeks

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FeasibleFeasible

Good short term Good short term

resultsresults

Longer f/u and larger Longer f/u and larger

series required for series required for

definitive conclusionsdefinitive conclusions


HTNHTN

PainPain

ESRDESRD


StonesStones

HematuriaHematuria

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ESRDESRD

On average occurs between 4On average occurs between 4thth--66thth decadedecade

Later in PKD2 than PKD1Later in PKD2 than PKD1

Once begins, average decline 5ml/min / Once begins, average decline 5ml/min /

year in CrClyear in CrCl

50% develop renal failure by age 6050% develop renal failure by age 60

ESRD: EtiologyESRD: Etiology

Not completely understoodNot completely understood

Only about 1% of nephrons develop cystsOnly about 1% of nephrons develop cysts

Pressure atrophy?Pressure atrophy?

HTN?HTN?

Increased apoptosis in nephronsIncreased apoptosis in nephrons

Vascular remodelingVascular remodeling

Analgesic nephropathyAnalgesic nephropathy

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ESRD: Risk FactorsESRD: Risk Factors

1.1. PKD1 typePKD1 type

2.2. MaleMale

3.3. African AmericanAfrican American

4.4. Hematuria <30 yearsHematuria <30 years

5.5. HTN <35 yearsHTN <35 years

6.6. HyperlipidemiaHyperlipidemia

7.7. Low HDLLow HDL

8.8. Sickle cell traitSickle cell trait

9.9. SmokingSmoking

10.10. Rate of cyst growth / size of kidneysRate of cyst growth / size of kidneys

11.11. Multiple pregnanciesMultiple pregnancies

ESRD: PreventionESRD: Prevention

ACEI slow rate of proteinuria but no effect ACEI slow rate of proteinuria but no effect

on Cr compared to CCB, HCZTon Cr compared to CCB, HCZT

Cyst unroofing has no effect Cyst unroofing has no effect

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HTNHTN

PainPain

ESRDESRD


StonesStones

HematuriaHematuria

Infected CystsInfected Cysts

90% occur in women90% occur in women

Ascending infectionsAscending infections

E. coli, Klebsiella, Proteus and PseudomonasE. coli, Klebsiella, Proteus and Pseudomonas

Instrumentation a major risk factorInstrumentation a major risk factor

Poor antibiotic penetration Poor antibiotic penetration

R/O ObstructionR/O Obstruction

Lipophillic antibiotics (Flouroquinolones, Septra, Lipophillic antibiotics (Flouroquinolones, Septra, Chloramphenicol)Chloramphenicol)

Percutaenous cyst aspirationPercutaenous cyst aspiration

NephrectomyNephrectomy

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AUAUS Lesson 13 2001


HTNHTN

PainPain

ESRDESRD


StonesStones

HematuriaHematuria

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ADPKD: StonesADPKD: Stones

55--10 times the incidence of general 10 times the incidence of general

populationpopulation

30% of pt30% of pt’’s develop stoness develop stones

20% of pt20% of pt’’s are symptomatics are symptomatic

Contemporary endourological Contemporary endourological

managementmanagement


HTNHTN

PainPain

ESRDESRD


StonesStones

HematuriaHematuria

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Hematuria Hematuria

50% of ADPKD pt50% of ADPKD pt’’s s

Presenting symptom in 25%Presenting symptom in 25%

Hematuria a/w worsening CrHematuria a/w worsening Cr

Case reportCase report

Despite bed rest and 10 units blood transfusion Despite bed rest and 10 units blood transfusion

pt became unstablept became unstable

TXA 20mg/kg infused while awaiting ORTXA 20mg/kg infused while awaiting OR

Hematuria ceased Hematuria ceased

TXA continued for 2 monthsTXA continued for 2 months

No recurrence for 24 monthsNo recurrence for 24 months

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Transexamic AcidTransexamic Acid

Plasminogen inhibitor Plasminogen inhibitor –– antifibrinolytic antifibrinolytic

agentagent

Reversibly blocks lysine binding sites on Reversibly blocks lysine binding sites on

plasmin moleculeplasmin molecule

Used during orthopedic and cardiac Used during orthopedic and cardiac

surgerysurgery

Used for bleeding duodenal and gastric Used for bleeding duodenal and gastric

ulcersulcers

Transexamic AcidTransexamic Acid

Urokinase activity often high in cysts Urokinase activity often high in cysts ––

fibrinolysisfibrinolysis

APPKD ptAPPKD pt’’s with CRF likely have local and s with CRF likely have local and

systemic hyperfibrinolysissystemic hyperfibrinolysis

Consider using in cases of severe Consider using in cases of severe

hematuria in ADPKDhematuria in ADPKD

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ADPKD: Transplant IssuesADPKD: Transplant Issues

1.1. When to consider transplantationWhen to consider transplantation

2.2. When to consider native nephrectomyWhen to consider native nephrectomy

3.3. Timing of native nephrectomyTiming of native nephrectomy

4.4. Issues unique to ADPKD after RTIssues unique to ADPKD after RT

When to consider transplantWhen to consider transplant

1.1. GFR < 10cc/minGFR < 10cc/min

2.2. Cr > 800umol/lCr > 800umol/l

3.3. Symptomatic uremiaSymptomatic uremia

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Indications for Native Nephrectomy Indications for Native Nephrectomy

1.1. Chronic painChronic pain

2.2. HTNHTN

3.3. Cyst infectionsCyst infections

4.4. Renal massRenal mass

5.5. GI (Early satiety, constipation)GI (Early satiety, constipation)

6.6. No room for renal allograftNo room for renal allograft

7.7. Respiratory compromiseRespiratory compromise

8.8. Recurrent calculiRecurrent calculi

Native NephrectomyNative Nephrectomy

Rate of native nephrectomy for ADPKD Rate of native nephrectomy for ADPKD

decreased over last 3 decadesdecreased over last 3 decades

85% in 197085% in 1970’’ss

47% in 198047% in 1980’’ss

20% contemporary series20% contemporary series

Better conservative management Better conservative management

(improved abx, analgesics, MIS (improved abx, analgesics, MIS

techniques)techniques)

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Native NephrectomyNative Nephrectomy

Current consensus is to avoid native Current consensus is to avoid native

nephrectomy if possiblenephrectomy if possible

Less complications on dialysisLess complications on dialysis

Improved survival on dialysisImproved survival on dialysis

EPO productionEPO production

Risk of blood transfusion Risk of blood transfusion –– sensitizationsensitization

Timing of Native NephrectomyTiming of Native Nephrectomy

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Retrospective analysis Retrospective analysis

Matched ptMatched pt’’s with similar characteristicss with similar characteristics

Group 1: Concomitant RT and BL Nx (10)Group 1: Concomitant RT and BL Nx (10)

Group 2: RT only (9)Group 2: RT only (9)

Group 3: Staged BL Nx and RT (4 ptGroup 3: Staged BL Nx and RT (4 pt’’s, 3 s, 3

after and 1 before)after and 1 before)

PeriPeri--operative parameters and Croperative parameters and Cr

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Increased blood loss and transfusion in Increased blood loss and transfusion in

concomitantconcomitant

Lower complications in concomitantLower complications in concomitant

No difference in graft functionNo difference in graft function

No cases of DGF in concomitant groupNo cases of DGF in concomitant group

Increased pt satisfaction (non validated Increased pt satisfaction (non validated

questionnaire)questionnaire)

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Retrospective review of 32 ptRetrospective review of 32 pt’’s over 12 yrss over 12 yrs

Group 1: PreGroup 1: Pre--transplant = 7 pttransplant = 7 pt’’ss

Group 2: Concomitant = 16 ptGroup 2: Concomitant = 16 pt’’ss

Group 3: PostGroup 3: Post--transplant = 9 pttransplant = 9 pt’’ss

Materials and MethodsMaterials and Methods

25 of 32 underwent bilateral nephrectomy25 of 32 underwent bilateral nephrectomy

Examined periExamined peri--operative course, OR time, operative course, OR time,

EBL, and effect on CrEBL, and effect on Cr

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ResultsResults

No difference between 3 groups;No difference between 3 groups;

��ComplicationsComplications

��Blood lossBlood loss

��Hospital stayHospital stay


Concomitant native nephrectomy is safe Concomitant native nephrectomy is safe

and does not compromise graft and does not compromise graft

Similar periSimilar peri--operative morbidity compared operative morbidity compared

to pre or postto pre or post

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Timing of Native Nephrectomy: Timing of Native Nephrectomy:

SummarySummary

Best to avoid nephrectomy if possible Best to avoid nephrectomy if possible

(especially in pre(especially in pre--dialysis patients)dialysis patients)

Concomitant nephrectomy safeConcomitant nephrectomy safe

Concomitant nephrectomy avoids dialysis Concomitant nephrectomy avoids dialysis

in prein pre--dialysis living donor ptdialysis living donor pt’’ss

Concomitant nephrectomy in dialysis ptConcomitant nephrectomy in dialysis pt’’s s

avoids the increased morbidity of anephric avoids the increased morbidity of anephric

ptpt’’s on dialysiss on dialysis

Issues Unique to ADPKD Post RTIssues Unique to ADPKD Post RT

ADPKD have graft survival outcomes similar to ADPKD have graft survival outcomes similar to

RT population as a wholeRT population as a whole

The following were more prevalent;The following were more prevalent;

1.1. Diverticulitis +/Diverticulitis +/-- perforationperforation

2.2. Arachnoid hemorrhage (no CVAArachnoid hemorrhage (no CVA’’s overall)s overall)

3.3. Erythrocytosis with need for phlebotomyErythrocytosis with need for phlebotomy

No increased risk of cardiovascular diseaseNo increased risk of cardiovascular disease

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Acquired Renal Acquired Renal

Cystic DiseaseCystic Disease

Acquired Renal Cystic DiseaseAcquired Renal Cystic Disease

1.1. DescriptionDescription

2.2. EpidemiologyEpidemiology

3.3. DiagnosisDiagnosis

4.4. HistopathologyHistopathology

5.5. SymptomsSymptoms

6.6. TransplantTransplant

7.7. Association with RCCAssociation with RCC

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DescriptionDescription

Cysts forming in nonCysts forming in non--cystic failing or failed cystic failing or failed

kidneyskidneys

Originally thought to be HD onlyOriginally thought to be HD only

HD = PD > ESRD onlyHD = PD > ESRD only

Kidneys initially shrink after dialysis started Kidneys initially shrink after dialysis started

then increase after 3 years (Ishikawa then increase after 3 years (Ishikawa

1985)1985)

ARCD: EpidemiologyARCD: Epidemiology

8% at start of dialysis8% at start of dialysis

1010--20% 120% 1--3 years3 years

60% at 3 years of dialysis60% at 3 years of dialysis

90% between 590% between 5--10 years on dialysis10 years on dialysis

100% at 10 years dialysis100% at 10 years dialysis

ACRD 2.9:1 male to female ratioACRD 2.9:1 male to female ratio

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ARCD: Risk FactorsARCD: Risk Factors

1.1. Length of time on dialysis or with ESRDLength of time on dialysis or with ESRD

2.2. Male > FemaleMale > Female

3.3. NephrosclerosisNephrosclerosis

4.4. African Americans > CaucasiansAfrican Americans > Caucasians

DiagnosisDiagnosis

U/S U/S

CT CT

MRIMRI

>3cysts per kidney>3cysts per kidney

Macroscopic cystic structures comprising Macroscopic cystic structures comprising

>25% of parenchyma>25% of parenchyma

Pope Urology 1994

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HistolopathologyHistolopathology

Cysts size is mmCysts size is mm’’s to several cms to several cm’’ss

Pathogenesis unclearPathogenesis unclear

Blocked tubules (ischemia, sloughing, Blocked tubules (ischemia, sloughing,

crystals, fibrosis) ?crystals, fibrosis) ?

Uremic growth factors / cystogenic growth Uremic growth factors / cystogenic growth

factor not cleared by dialysis ?factor not cleared by dialysis ?

Symptoms / ComplicationsSymptoms / Complications

PainPain

HematuriaHematuria

InfectionsInfections

Malignancy riskMalignancy risk

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ARCD and TransplantARCD and Transplant

Early transplant may prevent developmentEarly transplant may prevent development

Cysts may regress following transplantCysts may regress following transplant

Cysts may still develop after transplantCysts may still develop after transplant

Risk of RCC falls after transplantation (still Risk of RCC falls after transplantation (still

0.50.5--3.9% at a mean of 6 years)3.9% at a mean of 6 years)

Allografts become susceptible to ACKD Allografts become susceptible to ACKD

with chronic rejectionwith chronic rejectionIshikawa Am J Nephrology 1983

Vaziri Nephron 1984

Faber Lancet 1984

Ishikawa Nephron 1991

ESKD: Association with RCCESKD: Association with RCC

Population incidence of RCC 0.04%Population incidence of RCC 0.04%

11--3% prevalence of RCC in dialysis population3% prevalence of RCC in dialysis population

Incidence of RCC in ESRD 20 times population Incidence of RCC in ESRD 20 times population

risk in Japanrisk in Japan

Incidence of RCC 3Incidence of RCC 3--6 times population risk in 6 times population risk in

USAUSA

Annual incidence increases per time on dialysisAnnual incidence increases per time on dialysis

Ishikawa Nephron 1991

Matson Medicine 1990

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ACKD: Association with RCCACKD: Association with RCC

2020--25% of ESRD with ARCD have 25% of ESRD with ARCD have

adenomasadenomas

When RCC develops in ESRD When RCC develops in ESRD –– a/w a/w

ARCD 80% of timeARCD 80% of time

Prevalence of RCC in setting of ESRD + Prevalence of RCC in setting of ESRD +

ARCD = 2ARCD = 2--7%7%

Mean time on dialysis is 8Mean time on dialysis is 8--9 years9 years

Biology of RCC in ESRDBiology of RCC in ESRD

Younger age of occurrence (5years)Younger age of occurrence (5years)

Male > Female by 7:1Male > Female by 7:1

Much higher incidence than general populationMuch higher incidence than general population

Smaller tumorsSmaller tumors

Less likely to have mets at diagnosis (15% vs Less likely to have mets at diagnosis (15% vs 2020--30%)30%)

Less aggressive course and better prognosisLess aggressive course and better prognosis

Papillary subtype more common (50% of cases)Papillary subtype more common (50% of cases)

More often multifocalMore often multifocal

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Pathogenesis of RCC in ARCDPathogenesis of RCC in ARCD

Loss of nephronsLoss of nephrons

��

Hypertrophic changes + Hypertrophic changes + ‘‘unknown uremiaunknown uremia--related growth factorsrelated growth factors’’

��

Undifferentiated tubular growthUndifferentiated tubular growth

��

��risk of mutationrisk of mutation

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Proliferative activity of RCC in ESRD with Proliferative activity of RCC in ESRD with

ARCD vs Typical RCCARCD vs Typical RCC

SS--Phase, Ploidy, Proliferating Cell Nuclear Phase, Ploidy, Proliferating Cell Nuclear

Antigen (PCNA) Antigen (PCNA)

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ResultsResults

100% RCC100% RCC--ACDK had diploidACDK had diploid

56% RCC56% RCC--T had diploid T had diploid –– 44% aneuploid44% aneuploid

RCCRCC--A group A group –– same fraction in each same fraction in each

mode of cell cycle as normal renal tissuemode of cell cycle as normal renal tissue

PCNA higher in RCCPCNA higher in RCC--Typical than RCCTypical than RCC--AA


Histological characteristics correlate with Histological characteristics correlate with

observation that RCC in ARCD less observation that RCC in ARCD less

aggressive than typical RCCaggressive than typical RCC

Potential flaw Potential flaw –– compared smaller RCCcompared smaller RCC’’s s

in ARCD to larger typical RCCin ARCD to larger typical RCC’’ss

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ARCD : ScreeningARCD : Screening

Controversy exists about screening the dialysis Controversy exists about screening the dialysis population for RCCpopulation for RCC

Does cost of screening outweight the potential Does cost of screening outweight the potential benefits?benefits?

Risk of dying from coRisk of dying from co--morbid conditions?morbid conditions?

What screening modality should be used?What screening modality should be used?

When to start screening?When to start screening?

What is the life expectancy of dialysis patients in What is the life expectancy of dialysis patients in that region?that region?

Are patients candidates for therapy?Are patients candidates for therapy?

Continue screening after transplant?Continue screening after transplant?

ScreeningScreening

Proponents start screening after 3 years Proponents start screening after 3 years

dialysis dialysis –– marked increase in ARCD after marked increase in ARCD after

this pointthis point

Then every other year with U/SThen every other year with U/S

CECT if suspicious findingsCECT if suspicious findings

The longer the pt is on dialysis the higher The longer the pt is on dialysis the higher

the PPV of screeningthe PPV of screening

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Screening: SummaryScreening: Summary

U/S most cost effectiveU/S most cost effective

U/S least morbid modalityU/S least morbid modality

Population to be screened and timeline not Population to be screened and timeline not

well definedwell defined

THE ENDTHE END

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