The risk of esrd is higher in female carriers with hearing loss (p 02)


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

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



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



Mutation

  • 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

  • ?





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

  • 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


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

  • 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





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

  • 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









For females with proteinuria: start ACE inhibitor

  • For females with proteinuria: start ACE inhibitor

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



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

  • 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



3/6 donors developed hypertension

  • 3/6 donors developed hypertension

  • 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


Alport carriers should be kidney donors of last resort

  • 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



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

  • 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



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

  • 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



Alport Syndrome Foundation

  • Alport Syndrome Foundation

  • 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




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