Cerebral Aneurysms in PatientsCerebral Aneurysms in Patientswith autosomal dominantwith autosomal dominantPolycystic Kidney DiseasePolycystic Kidney Disease(ADPK(ADPKD)D)-- Optimal care & Management-- Optimal care & Management

Optimal care of autosomal dominant polycystic kidney NEPHROLOGY 2006; 11, 124–130

Management of Unruptured Cerebral Aneurysms in Patients with Polycystic Kidney Disease Surg Neurol 2004;62:538–45. Present by R2 Present by R2 洪培恩 洪培恩 2007-1-182007-1-18

IntroductionIntroduction

POLYCYSTIC CYSTIC KIDNEY DISEASEPOLYCYSTIC CYSTIC KIDNEY DISEASE

ADULT = Autosomal Dominant PKDADULT = Autosomal Dominant PKD

INFANTILE = Autosomal Recessive PKDINFANTILE = Autosomal Recessive PKD

EpidemiologyEpidemiology

Autosomal Dominant Polycystic Kidney Autosomal Dominant Polycystic Kidney DxDx Occurs in approx 1 in 400-1000 populationOccurs in approx 1 in 400-1000 population Only less than 50% of cases are estimated to bOnly less than 50% of cases are estimated to b

e diagnosede diagnosed One of the most common life-threatening, here

ditary disease,10% of all ESRF is ADPKD10% of all ESRF is ADPKD

Genetic and molecular eventsGenetic and molecular events

Linked to abnormalities on: Linked to abnormalities on: Chromosome 16Chromosome 16 – – PKD1PKD1 locus (~85%) -- locus (~85%) -- Pol

ycystin-1 protein(a purported receptor for cell–cell or cell-matrix adhesion)

Chromosome 4Chromosome 4 – – PKD2 PKD2 locus(~15%) -- locus(~15%) -- PPolycystin-2 protein(appears to be an ion channel, particularly for calcium transport)

Spontaneous Mutation rate 10%Spontaneous Mutation rate 10%

Structures of polycystin-1 and polycStructures of polycystin-1 and polycystin-2ystin-2

DiagnosisDiagnosis• Frequently asymptomatic

• History

– Positive family history

• Initial Symptoms & Signs

– HTN (50-70%; avg 30y/o; renin-angiotension sys)

– Flank pain (36%)

– Gross hematuria (36%)

– Renal infection (16%)

– Renal insufficiency

• Films

– Large kidneys with multiple cysts

– Hepatic, Pancreatic, and/or Splenic Cysts• (Hepatic cysts more common in women and pt over 40y/o)

Criteria on UltrasoundCriteria on Ultrasound

With positive family historyWith positive family history

AgeAge Criteria for DiagnosisCriteria for Diagnosis

<30 <30 >>2 cysts uni- or bilateral2 cysts uni- or bilateral 30-59 30-59 >>2 cysts in each kidney2 cysts in each kidney >>60 60 >>4 cysts in each kidney4 cysts in each kidney

(-) US cannot exclude disease until 30-35 y/o(-) US cannot exclude disease until 30-35 y/o

CT and MRI have higher sensitivityCT and MRI have higher sensitivity

Extra-renal Extra-renal ComplicationsComplications

Cerebral aneurysmsCerebral aneurysms (22%) (22%)Hepatic cysts Hepatic cysts (83% w/MRI)(83% w/MRI)Cardiac Valve disease Cardiac Valve disease (20-30%)(20-30%) MV prolapse; MV/AV regurgitationMV prolapse; MV/AV regurgitationColonic diverticula Colonic diverticula Abdominal wall & inguinal herniaAbdominal wall & inguinal herniaPregnancyPregnancy Increased risk of preeclampsia, prematurity aIncreased risk of preeclampsia, prematurity a

nd perinatal mortality, ectopic pregnancy with nd perinatal mortality, ectopic pregnancy with uncontrolled HTNuncontrolled HTN

Risk Factors for Progressive Risk Factors for Progressive Renal DiseaseRenal Disease

Younger age at diagnosisYounger age at diagnosis

Male sex(European & African-Americans)Male sex(European & African-Americans)

Genotype (PKD1 vs PKD2)Genotype (PKD1 vs PKD2) (mean age at death: PKD1 53; PKD2 69; control 78)(mean age at death: PKD1 53; PKD2 69; control 78)

Episode of gross hematuriaEpisode of gross hematuria

HTNHTN (/c (/c Left Ventricular HypertrophyLeft Ventricular Hypertrophy))

ProteinuriaProteinuria

Increased/increasing renal sizeIncreased/increasing renal size

UTI UTI

HTN in Male v.s Female with HTN in Male v.s Female with ADPKDADPKD

Survival data in ADPKDSurvival data in ADPKDMedian PKD1 = 53yrs Median PKD2 = 69yrsMedian PKD1 = 53yrs Median PKD2 = 69yrs

Relationship between glomerular filtratRelationship between glomerular filtration rate (GFR) and renal volumeion rate (GFR) and renal volume

Causes of DeathCauses of DeathSimilar to other causes of ESRDSimilar to other causes of ESRDHeart Disease Heart Disease (36%)(36%)Infection Infection (24%)(24%)Neurologic Event Neurologic Event (12%)(12%) Ruptured aneurysm (6%)Ruptured aneurysm (6%); HTN intracerebral h; HTN intracerebral h

emorrhage (5%)emorrhage (5%)

Renal Cancer Renal Cancer (0%)(0%)Found at Autopsy:Found at Autopsy: Cardiac Hypertrophy Cardiac Hypertrophy (89%)(89%) CAD (81%)CAD (81%)

Activation of the renin-angiotensin-aldosterone system (RAAS)

Increased (a) plasma renin activity (PRA) and (b) plasma aldosterone in autosomal dominant polycystic kidney disease patients (ADPKD) as compared with patients with essential hypertension

Multifactorial pathogenic role of angiotensin II iMultifactorial pathogenic role of angiotensin II in the hypertension and renal disease associaten the hypertension and renal disease associated with ADPKDd with ADPKD

TreatmentTreatment

Treatment of choiceTreatment of choice : : ACE InhibitorACE Inhibitor Note use with potential future pregnancyNote use with potential future pregnancy

Efficacy of Efficacy of ARB’sARB’s under investigation with under investigation with limited data available (used as second line)limited data available (used as second line)

Goal BP: <120/80Goal BP: <120/80

Screen for occult cerebral aneurysmScreen for occult cerebral aneurysm

S/P if cerebral aneurysm >7-10mmS/P if cerebral aneurysm >7-10mm

Correlation between mean arterial pressure and left ventricular mass index (LVMI) in ADPKD

OPTIMAL BLOOD PRESSURE OPTIMAL BLOOD PRESSURE CONTROL v.s LVMICONTROL v.s LVMI

(a)Effect of rigorous versus standard blood pressure control to decrease left ventricular mass index in autosomal dominant polycystic kidney disease (ADPKD) patients.(b) Effect of blood pressure control with amlodipine versus enalapril to decrease left ventricular mass index in ADPKD patients

TreatmentTreatment

Treatment of progression to ESRD:Treatment of progression to ESRD: TransplantationTransplantation

With/without nephrectomyWith/without nephrectomy HemodialysisHemodialysis

(5yr survival: 10-15%)(5yr survival: 10-15%)

Experimental animals with Experimental animals with ADPKDADPKD

--slow the progression of the diseaseantiproliferative agent,rapamycin

caspase inhibition

and V2 vasopressin antagonists, which decrease renal tissue cyclic adenosine monophosphate(AMP)

Intracranial aneurysmIntracranial aneurysm in ADPKD in ADPKD

Occur in Occur in 4-14-111%% of patients(general of patients(general1%)1%)

(a defect in the extracellular matrix of the vessels, resulting in a high incidence of cerebral aneurysms)

Tends to run in familiesTends to run in families

May be worse with hypertensionMay be worse with hypertension

Tend to suffer their subarachnoid hemorrhage at a younger age and smaller size

Intracranial aneurysmIntracranial aneurysm in ADPKD in ADPKD

Most remain asymptomaticMost remain asymptomatic

Decision to operate more depends on sDecision to operate more depends on size, location, age and hypertension, regize, location, age and hypertension, regardless the dialysis status ardless the dialysis status

Screen ‘at risk’ families with MRA, Screen ‘at risk’ families with MRA, F/U eF/U every 10 years if negativevery 10 years if negative

J Am Soc Nephrol 15: 1023–1028, 2004

Study for Treatment StrategyStudy for Treatment StrategyA retrospective review of the management of A retrospective review of the management of unruptured cerebral aneurysms in unruptured cerebral aneurysms in 1616 patient patients with PKDs with PKD

Considering the potential toxicity of cerebral Considering the potential toxicity of cerebral angiographyangiography

8 p’t maintaining chonic H/D and 8 p’t non-H/8 p’t maintaining chonic H/D and 8 p’t non-H/D at the time for treatmentD at the time for treatment

F/U period: 24 monthsF/U period: 24 months

Criteria of prophylactic hemodialysis for Nonhemodialysis patients

moderate to severely reduced renal function (for example, blood urea nitrogen> 80, creatinine> 6, or potassium> 5.5)

In non-H/D p’ts, prophylactic hemodialysis(4 hours)was routinely performed after cerebral angiographyto prevent deterioration of the pre-existing renal dysfunction

ResultResult

DiscussionDiscussion

A prophylactic hemodialysis of 3 to 4 hours can remove 80% of the contrast media

Use gebexate mesylate instead of heparin for post –op hemodialysis to prevent postoperative bleeding from the surgical wounds.

DiscussionDiscussion

Chronic hemodialysis entails specific problems,

-Increased intracranial pressure-Progressive brain edema as a result of ra

pid lowering of the serum osmolality (dialysis disequilibrium syndrome).

-Tendency to hemorrhage, in response to either systemic heparinization or insufficient dialysis

Conclusions

Genetic and molecular biology findings have stimulated a great deal of exciting basic research in ADPKD, therapies to decrease morbidity and mortality in ADPKD patients have yet to emerge from these findings

The early diagnosis and treatment of hypertension with inhibitors of the renin-angiotensin-aldosterone system have the potential to decrease or prevent left ventricular hypertrophy cardiac complications and slow the progression of the renal disease.

Conclusions

As patients with PKD live longer because of improved management of their renal dysfunction, the extrarenal manifestations, as exemplified by cerebral aneurysms, may become an even greater problemPKD patients with unruptured cerebral aneurysms can be safely treated with an appropriate treatment strategy including the use of prophylactic hemodialysis

Others commentary Others commentary

MRA maybe an excellent way to initially screen these patients, and will often provide sufficient anatomic detail to determine whether intervention is required. It is often possible to operate on the basis of a MRA, thereby obviating the need for a cerebral angiogram altogether. If endovascular treatment is subsequently selected, the issues become very important

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