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
to ESKD
Phase IV
Phase III
Phase II
Phase I
Proteinuria
Hematuria
ESRD
↓ Renal Fx
Proteinuria
Hematuria
Hematuria
Specific Disease Progression with Age/Time
Birth
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
COL4a3 knockout mice
• COL4a3 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
(proteinuria)
- Early short:
week 4-10
(hematuria)
- Early long:
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 (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
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  (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