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 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

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

Males

Females

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

no hearing loss

+ hearing loss

• 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

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/tsg12.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 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, 1995bIijima, et al., Pediatr Nephrol, DOI 10.1007/s00467-010-1514-1, 2010

• 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 moremutant COL4A5

Mouse strains thatskew X-inactivation

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

• 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/s00467-012-2138-4, 2012

• 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?

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

• 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?

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