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Women and Alport Syndrome. Michelle Rheault, M.D. Assistant Professor Division of Pediatric Nephrology University of Minnesota, USA. Disclosures. None. Historical Perspective. “ The females have deafness and heamaturia and live to old age ” - (Alport AC: Br Med J 1:504-506, 1927)

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Women and alport syndrome

Women and Alport Syndrome

Michelle Rheault, M.D.

Assistant Professor

Division of Pediatric Nephrology

University of Minnesota, USA



Historical perspective
Historical Perspective

  • “The females have deafness and heamaturia and live to old age”- (Alport AC: Br Med J 1:504-506, 1927)

  • “Females usually remain well throughout life…and only rarely have women died of the disease.”(Perkoff GT: Annu Rev Med 15:115-24, 1964)


Carrier Natural History Study

  • 195 families with known COL4A5 mutations (349 women and girls)

  • Microscopic hematuria present in 95.5%

  • Proteinuria present in 75%

  • Hearing loss present in 28%

  • By age 40, 12% of carriers had reached ESRD

  • By age 60, 30-40% of carriers had reached ESRD

Jais, et al. JASN. 14:2603-2610, 2003


Probability of esrd in alport carriers
Probability of ESRD in Alport Carriers

Males

Females

Jais, et al. JASN. 14:2603-2610, 2003


Probability of Hearing Loss in Alport Carriers

Males

Females

Jais, et al. JASN. 14:2603-2610, 2003


Risk of esrd in alport carriers with hearing loss

The risk of ESRD is higher in female carriers with hearing loss (p=0.02)

Risk of ESRD in Alport Carriers with Hearing Loss

+ hearing loss

no hearing loss

Jais, et al. JASN. 14:2603-2610, 2003


Risk of ESRD in Alport Carriers with Proteinuria loss (p=0.02)

  • Risk of ESRD greater if proteinuria present (p<0.001)

Proteinuria

No Proteinuria

Jais, et al. JASN. 14:2603-2610, 2003


What determines disease severity in alport carriers
What determines disease severity in loss (p=0.02)Alport carriers?

  • Mutation

    • Unlike males, there is no correlation between type of mutation and rate of disease progression (Jais, et al. JASN. 14:2603-2610, 2003)

    • No correlation in disease severity between males and females within the same family

  • Modifier genes

  • X chromosome inactivation

  • ?


X-chromosome Inactivation loss (p=0.02)

www.synapses.co.uk/genetics/tsg12.html


Case reports
Case Reports loss (p=0.02)

  • 19 year old female presented with microscopic hematuria and nephrotic syndrome and reached ESRD by 30

    • Found to have 2 mutations in COL4A5 expressed in >90% of both kidney and white blood cellsa

  • 2 year old female with hematuria/proteinuria with hearing loss developing at age 14. Biopsy showed X-linked Alport syndrome

    • Found to have balanced translocation t(X;1)(q22.3;p36.32) with preferential inactivation of the normal X chromosomeb

aGuo, et al., JCI. 95:1832-1837, 1995

bIijima, et al., Pediatr Nephrol, DOI 10.1007/s00467-010-1514-1, 2010


X inactivation in mice with xlas
X-inactivation in mice with XLAS loss (p=0.02)

  • Hypothesis: The variability of renal outcome in carriers of XLAS is caused by random X-inactivation

  • We used genetic tools in a mouse model of XLAS to test this hypothesis

X

Alport carrier

Mouse strains that

skew X-inactivation

Group 1:

Express more

mutant COL4A5

Group 2:

Express more

wild type COL4A5

Rheault et. al., Nephrol Dial Transplant, 25:764-9, 2010


Preferential expression of wild type X-chromosome (group 2) in mice with COL4A5 mutation confers a survival advantage

Group 2

Group 1

P<0.001

Rheault et. al., unpublished observations


X inactivation and alport syndrome
X inactivation and Alport Syndrome in mice with COL4A5 mutation confers a survival advantage

  • When tested directly in controlled genetic backgrounds, favorable X-inactivation increases survival and improves clinical parameters in female carriers of XLAS in mice

  • X inactivation is not the only factor that influences disease severity

  • Further research is needed


New european registry data
New European Registry Data in mice with COL4A5 mutation confers a survival advantage

Temme, et al. Kidney international. 81:779-83, 2012


New european registry data1
New European Registry Data in mice with COL4A5 mutation confers a survival advantage

Temme, et al. Kidney international. 81:779-83, 2012


Raas blockade is associated with delayed renal failure in heterozygous alport patients
RAAS blockade is associated with delayed renal failure in heterozygous Alport patients

Temme, et al. Kidney international. 81:779-83, 2012


Treatment recommendations for heterozygous xlas alport females
Treatment recommendations for heterozygous XLAS Alport females

  • For females with proteinuria: start ACE inhibitor

  • For females with microalbuminuria: consider ACE inhibitor if family history of early kidney failure or severe mutation

Kashtan, et al. Pediatr Nephrol. DOI 10.1007/s00467-012-2138-4, 2012


Should Alport Carriers be Kidney Donors? females

  • We can’t predict which carriers are going to progress to ESRD

  • Difficult balance between risk to donor and benefits for recipient

  • Little long term data about outcomes in carriers after donation


Should alport carriers be kidney donors

3/6 donors developed hypertension females

2/6 donors developed proteinuria

Renal function declined significantly in 4/6 donors

-35% after 2 years

-25% after 3 years

-30% after 4 years

-60% after 14 years

Should Alport Carriers be Kidney Donors?

Gross et. al., Nephrol Dial Transplant, 24:1626-30, 2009


Should Alport Carriers be Kidney Donors? females

  • Alport carriers should be kidney donors of last resort

  • Alport carriers with proteinuria or hearing loss should be excluded as kidney donors

  • Alport carriers with only microscopic hematuria should be considered as donors only after careful counseling about risks and with close post-transplant monitoring

  • Renal protective strategies for donors are needed (ACE inhibitors?)

  • Future collaborative studies are needed


Alport syndrome and pregnancy
Alport syndrome and pregnancy females

  • Case reports have been published suggesting increased risk of preterm delivery, decline in renal function, and increased proteinuria during pregnancy

  • No good data exists on renal outcomes in Alport carriers after pregnancy

  • Recommendation: Pregnant Alport carriers should have kidney function, blood pressure, and proteinuria monitored closely


Conclusions
Conclusions females

  • Carriers of X-linked Alport syndrome are at risk for ESRD

    • Higher risk of ESRD if proteinuria or hearing loss present

  • In a mouse model of X-linked Alport Syndrome, favorable X-inactivation increases survival and improves clinical parameters in carriers

  • ACE inhibitors are associated with decreased risk of end stage kidney disease in Alport carriers


Acknowledgements

Alport Syndrome Foundation females

University of Minnesota

Yoav Segal

Cliff Kashtan

Stefan Kren

Will Thomas

Linda Hartich

Melanie Wall

Hector Mesa

Texas A & M University

George Lees

Pasteur Institute

Philip Avner

Acknowledgements


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