Women and Alport Syndrome Michelle Rheault M D

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) • “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 COL 4 A 5 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 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) Jais, et al. JASN. 14: 2603 -2610, 2003 + hearing loss no hearing loss

Risk of ESRD in Alport Carriers with Proteinuria • 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? • 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 www. synapses. co. uk/genetics/tsg 12. html

Case Reports • 19 year old female presented with microscopic hematuria and nephrotic syndrome and reached ESRD by 30 – Found to have 2 mutations in COL 4 A 5 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)(q 22. 3; p 36. 32) with preferential inactivation of the normal X chromosomeb a. Guo, et al. , JCI. 95: 1832 -1837, 1995 b. Iijima, et al. , Pediatr Nephrol, DOI 10. 1007/s 00467 -010 -1514 -1, 2010

X-inactivation in mice with XLAS X Alport carrier Group 1: Express more mutant COL 4 A 5 Mouse strains that skew X-inactivation Group 2: Express more wild type COL 4 A 5 • 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 Rheault et. al. , Nephrol Dial Transplant, 25: 764 -9, 2010

Preferential expression of wild type Xchromosome (group 2) in mice with COL 4 A 5 mutation confers a survival advantage Group 2 Group 1 P<0. 001 Rheault et. al. , unpublished observations

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

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

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

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 • 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/s 00467 -012 -2138 -4, 2012

Should Alport Carriers be Kidney Donors? • 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 • 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

Should Alport Carriers be Kidney Donors? • 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 • 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 • 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 • 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