1. Women and Alport Syndrome Michelle Rheault, M.D. Assistant Professor Division of Pediatric Nephrology University of Minnesota, USA

2. Disclosures None

3. 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)

4. 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

5. Probability of ESRD in Alport Carriers Jais, et al. JASN. 14:2603-2610, 2003 Males Females

6. Probability of Hearing Loss in Alport Carriers Males Females Jais, et al. JASN. 14:2603-2610, 2003

7. Risk of ESRD in Alport Carriers with Hearing Loss The risk of ESRD is higher in female carriers with hearing loss (p=0.02) Jais, et al. JASN. 14:2603-2610, 2003 no hearing loss + hearing loss

8. Risk of ESRD greater if proteinuria present (p<0.001) Jais, et al. JASN. 14:2603-2610, 2003 Proteinuria No Proteinuria Risk of ESRD in Alport Carriers with Proteinuria

9. What determines disease severity in 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 ?

10. X-chromosome Inactivation www.synapses.co.uk/genetics/tsg12.html

11. Case Reports 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 cells a 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 chromosome b a Guo, et al., JCI. 95:1832-1837, 1995 b Iijima, et al., Pediatr Nephrol, DOI 10.1007/s00467-010-1514-1, 2010

12. 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-inactivation in mice with XLAS Group 2: Express more wild type COL4A5 Alport carrier X Group 1: Express more mutant COL4A5 Mouse strains that skew X-inactivation Rheault et. al., Nephrol Dial Transplant, 25:764-9, 2010

13. 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

14. X inactivation and Alport Syndrome 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

15. New European Registry Data Temme, et al. Kidney international. 81:779-83, 2012

16. New European Registry Data Temme, et al. Kidney international. 81:779-83, 2012

17. RAAS blockade is associated with delayed renal failure in heterozygous Alport patients Temme, et al. Kidney international. 81:779-83, 2012

18. 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

19. 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?

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

21. 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 Should Alport Carriers be Kidney Donors?

22. Alport syndrome and 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

23. Conclusions 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

24. Acknowledgements 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