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

None

• None

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