1. Alport Syndrome – Diagnosis and Treatment Christoph Licht The Hospital for Sick Children, Toronto, ON Alport Syndrome Family Conference 2012 Minneapolis, MN - 21.-22.7.2012

2. The challenge Specific Disease Progression with Age/Time BirthLate childhoodEarly adolescence Phase I Hematuria Phase II Proteinuria Hematuria Phase III ↓ Renal Fx Proteinuria Hematuria Phase IV ESRD Adulthood Alport syndrome: A disease progressing to ESKD

3. Copyright ©2006 American Society of Nephrology Abbate, M. et al. J Am Soc Nephrol 2006;17:2974-2984 Figure 1. Mechanisms underlying the activation of inflammatory and fibrogenic pathways in proximal tubular epithelial cells by ultrafiltered protein load

4. Alport Syndrome: Current therapeutic approaches in humans and animal models Gross and Kashtan, Kidney Int 2009

5. COL4  3 knockout mice COL4  3 knock out-mice From week 4Hematuria From week 6Proteinuria From week 7Nephrotic syndrome At about 10 weeksDeath from renal failure In vivo model for Alport syndrome In vivo model for chronic proteinuric CKD Cosgrove et al, Genes Dev 1996

6. Increased lifespan by ACE inhibitor treatment Gross et al, Kidney Int 2003 No treatment (Placebo) ACE-inhibitor treatment: - Late:from week 7 (proteinuria) - Early short:week 4-10 (hematuria) - Early long:from week 4 (hematuria) until death

7. AT1 receptor blockers: Less efficient than ACE inhibitors Gross et al, Nephrol Dial Transplant 2004 No treatment (Placebo) Treatment: o Ramipril (ACE- inhibitor) from week 4 o Candesartan (AT1- antagonist) from week 4

8. RAAS blockade in pediatric AS patients Webb NJ et al. NDT. 2011 Multicenter, randomized, double- blind study of losartan versus placebo or amlodipine 30 children, ℞ for 12 weeks Significant  in proteinuria No safety concerns, increase in creatinine or hyperkalemia Gross O et al. Kidney Int. 2012 European Alport Registry 283 patients (109 received no ℞ ) over 20 years 3 groups with respect to commencement of ACE ℞ : o Onset of microalbuminuria o Proteinuria >0.3 g/day or o CKD stage III and IV A Tale of Two Trials

9. Survival benefit with therapy Gross et al, Kidney Int 2012

10. Start therapy early In sibling pairs where the elder sibling had invariably been started on ℞ much later  Median age of starting renal replacement was 27 years, while it was delayed until a median age of 40 in the younger child. Gross et al, Kidney Int 2012

11. Time to ESKD delayed with therapy RRT delayed 3 years in CKD group & 18 years in proteinuric group Proteinuria reduced in all More sustained if ℞ started prior to CKD stage III-IV Gross et al, Kidney Int 2012

14. Initiation of ACE inhibitors and/or ARBs at the onset of overt proteinuria to prolong renal survival and delay the need for renal replacement therapy

15. ACE inhibition should be first-line

16. ARB or aldosterone inhibition second-line agents

17. Aldosterone inhibition Increasing evidence that aldosterone inhibition has a reliable blood pressure- independent, antiproteinuric effect in adult studies Remains to be proven to translate to an improvement in GFR Navaneethan et al, Clin J Am Soc Nephrol 2009

18. Aldosterone inhibition Spironolactone is known to be relatively safe in the pediatric setting May offer renoprotection in CKD patients, especially if exhibiting the phenomenon of ‘aldosterone breakthrough’ Escape trial - Proteinuria decreased by 50% but gradually rebounded Ku et al, Pediatr Nephrol 2009 Wühl et al, Kidney Int 2004

19. Aldosterone inhibition in Alport Syndrome Only pediatric study of aldosterone inhibition in kidney disease involved 5 Alport patients o persistent proteinuria despite ACE inhibition or ACE/ARB in combination Significant improvement in proteinuria achieved & maintained for at least 18 months eGFR remained unchanged, lower BP (no ill effect), tendency to hyperkalemia (never exceeded 5 mmol/L) Kaito et al, Pediatr Nephrol 2006

20. Aldosterone inhibition in Alport Syndrome Kaito et al, Pediatr Nephrol 2006

21. Telmisartan – ARB with benefits

22. Telmisartan Second generation ARB Renoprotective and antiproteinuric effects due to its agonistic effect on the PPAR  receptor Reduce oxidative stress and inflammation Improved endothelial & vascular function Meta-analysis of clinical trials involving 25,425 patients confirmed antiproteinuric effect and can delay progression of proteinuria Destro et al, Expert Opin Pharmacother 2011 Zhang et al, J Mol Endocrinol 2012 Kusunoki et al, Hypertension 2012

23. PPAR  Peroxisome-proliferator-activated-receptor  (PPAR  ) - nuclear receptor that regulates gene transcription Expressed & upregulated in injured podocytes Thiazolidinediones - ligands for PPAR  developed for the management of insulin resistance o Reduce proteinuria o Activate PPAR  & directly increase nephrin gene transcription thus restoring slit diaphragm integrity o Decrease apoptosis of podocytes Yang HC et al. Kidney Int 2006 Benigni A et al. J Am Soc Nephrol 2006

24. Summary and Perspectives RAAS inhibition via ACEIs and ARBs is safe and effective in children Early therapeutic intervention seems to be key for … - delaying (preventing?) ESKD - improving quality of life International registries and treatment trials in children are needed focusing on safety, efficacy and cost saving of early therapy