Diagnosis and Treatment - Alport Syndrome Foundation

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
Alport syndrome:
A disease progressing
Phase IV
Phase III
Phase II
Phase I
↓ Renal Fx
Specific Disease Progression with Age/Time
Late childhood
Early adolescence
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
COL4a3 knockout mice
• COL4a3 knock out-mice
• From week 4
From week 6
From week 7
At about 10 weeks
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
No treatment (Placebo)
ACE-inhibitor treatment:
- Late:
from week 7
- Early short:
week 4-10
- Early long:
from week 4
until death
Gross et al, Kidney Int 2003
AT1 receptor blockers:
Less efficient than ACE inhibitors
No treatment (Placebo)
o Ramipril (ACEinhibitor) from week 4
o Candesartan (AT1antagonist) 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, doubleblind 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
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
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
• 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
• 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
• 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
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

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