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

The challenge

Birth

Alport syndrome: A disease progressing to ESKD

Phase II Proteinuria Hematuria Phase III ↓ Renal Fx Proteinuria Hematuria Phase IV ESRD Phase I Hematuria

Specific Disease Progression with Age/Time

Late childhood Early adolescence Adulthood

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

Copyright ©2006 American Society of Nephrology

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

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

Increased lifespan by ACE inhibitor treatment No treatment (Placebo) ACE-inhibitor treatment: - Late: from week 7 - Early short: (proteinuria) week 4-10

- Early long:

(hematuria)

from week 4 (hematuria) until death

Gross et al, Kidney Int 2003

AT1 receptor blockers: Less efficient than ACE inhibitors No treatment (Placebo) Treatment: o

Ramipril (ACE inhibitor) from week 4

o Candesartan (AT1 antagonist) from week 4 Gross et al, Nephrol Dial Transplant 2004

RAAS blockade in pediatric AS patients

A Tale of Two Trials

•

Webb NJ et al. NDT. 2011

Multicenter, randomized, double blind study of losartan versus placebo or amlodipine •

Gross O et al. Kidney Int. 2012

European Alport Registry • 283 patients (109 received no ℞ ) over 20 years • 30 children, ℞ for 12 weeks • Significant  in proteinuria • No safety concerns, increase in creatinine or hyperkalemia • 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

Survival benefit with therapy Gross et al, Kidney Int 2012

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

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

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

ACE inhibition should be first-line

ARB or aldosterone inhibition second-line agents

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

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

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

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

Telmisartan – ARB with benefits

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

PPAR  • Peroxisome-proliferator-activated-receptor  that regulates gene transcription (PPAR  ) - nuclear receptor • Expressed & upregulated in injured podocytes • Thiazolidinediones - ligands for PPAR  insulin resistance developed for the management of o o Reduce proteinuria 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

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