1. Rosanna Coppo
Torino
Clinical and histological risk factors
for primary IgA nephropathy

2. IgA nephropathy

3. 40
IgA nephropahy:
the commonest glomerulonephritis in the world
30
Adults
20
20%
Children
10
0
Highest frequencies
when active screening programs
Japan, South Korea, Taiwan
ASIA AUSTR EUR NORTH AMERICA

4. IgA1
CH1
Hinge
region
CH2
CH3
CH1
Pro
Ser
Thr *
Pro
Pro
Thr *
Pro
Ser *
Pro
Ser *
Pro
Thr
Pro
Thr *
Pro
Ser
Pro
Ser
CH2
Cosmc
C1GalT1
core
--O--- GalNAc-α 2,6
Neu5Ac
Β1,3-Gal
α 2,3
Neu5Ac
syalyl transferase
syalyl transferase
ST6GalNAcI
ST6GalNAcII

5. Aberrantly glycosylated IgA1 in IgA nephropathy

6. ROC analysis: AUC 0.92
Sensitivity 75% Specificity 90%
Sensitivity 50% Specificity 99%
Sensitivity 44% Specificity 100%%
A disease marker
for IgAN

7. Sequential measurements of de
Untreated IgAN
galactosylated IgA1 in
and in patients on ACE-I
IgACE trial
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
basale
TO
2°anno 3 years
3° anno 5 years
4°anno
1 1° anno 2 years
year
Andamento IgAHA
Levels not relatednei placebo (rosso) e ACE-I(verde)
to treatment or to outcome

8. Aberrant IgA1 glycosylation
in 45% of relatives of familial cases
and
in 25% of relatives of sporadic cases.
Since they are healthy,
additional co-factors should exist.
IgAN relatives

9. Hypothesis based on
several hits
for the development
of IgA nephropathy

10. a
b
Gd-IgA1
%HAA
1750
120
1500
100
1250
p<0.0001
Aberrantly
Glycosylated
igA1
p<0.0001
80
%
U/ml
1000
60
750
40
500
20
250
0
0
Healthy controls
IgAN
Healthy controls
c
d
SH-Alb
AOPPs
20
400
15
mol/l
p<0.0001
Arbitrary units
300
200
IgAN
p<0.0001
10
100
5
0
0
Oxidative
markers

11. eGFR slope
(ml/min/1.73m 2/year)
20
p for trend test = <0.01
10
0
-10
-20
-30
20
eGFR slope
(ml/min/1.73m 2/year)
a
AOPPs - SH-Alb -
b
AOPPs - SH-Alb +
AOPPs + SH-Alb -
AOPPs + SH-Alb +
AOPPs + %HAA -
AOPPs + %HAA +
p for trend test = <0.01
10
0
-10
-20
-30
AOPPs - %HAA -
AOPPs - %HAA +
aberrantly glycosylated IgA1
associated with oxidative stress
(increase in AOPP and decrease in albumin SH groups):
an early new risk factor for IgAN.

13. %
macroscopic
hematuria
Primary IgAN
++
Hb
Proteinuria
no
urinary
signs
Proteinuria
and
microscopic
hematuria
Normal
110
100
renal function
90
80
70
60
50
40
30
20
10
0
Dis pe rs . (XY) 2
Chronic
renal failure
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
years
The natural history of IgAN depends on the time of
performing renal biopsy

14. IgAN in children
Linné, Berg, Levy, Hattori, Yoshikawa, Hogg, Wyatt
Estimated survival at 10 years
in children:87- 93%
Severe clinical signs
develop after 5-15 years:
at long-term follow-up
IgAN in children is a
progressive disease

15. Factors affecting progression of IgAN in children
(R Hogg, 1995)
Age (< 9 years) at presentation
Sex (male)
Race (Black)
Gross hematuria
GFR reduced at biopsy
Proteinuria at biopsy
Hypertension at biopsy
proliferation with mesangial sclerosis
sclerosis in > 20% of glomeruli
Focal global sclerosis
Crescents/synechiae
Tubulointerstitial disease
Peripheral capillary wall deposits (EM)
Other GBM changes (EM)
n.s.
n.s.
<0.005
n.s.
n.s.
<0.0001
<0.003
<0.0001
<0.0001
<0.01
<0.03
<0.03
n.s.
n.s.

16. Risk factors for progression of IgAN
HYPERTENSION
PROTEINURIA
prot<1g/day
normotensive
prot 1-1.9
prot 2-2.9
prot >3
hypertensive
RENAL FUNCTION AT PRESENTATION
Cr <1.2 mg/dl
Cr 1.3-1.9 mg/dl
Cr 2.0-2.9 mg/dl
Cr >3 mg/dl

17. VALIGA:
VALidation of the Oxford classification for IgA Nephropathy
Coppo R, Troyanov S, Cattran D,
Feehally J, Cook T. Roberts I
on behalf of the Immunonephrology Working Group of
the ERA-EDTA.

18. Survival from the combined end point (50% reduction in e-GFR or ESRD)
by quartiles of proteinuria at renal biopsy
Log rank test:
1 quartile vs 2 quartile  p = 0.036
2 quartile vs 3 quartile  p = 0.039
3 quartile vs 4 quartile  p < 0.0001

19. In VALIGA cohort
proteinuria >0.5 < 1 g/day is a significant risk factor for progression

20. In minimal change disease
proteinuria
rapidly develops and
rapidly goes into remission
In IgAN the development of
proteinuria
takes 5-10 years

21. Proteinuria
PAF
glomerular basement membrane
Activation of mesangial cells
by
deposited IgA

22. Glomerulo-tubular
cross-talk via TNF-α, IL6
and Angio II
Mesangio-podocytes
cross talk
TNF-α
IgA1
PAF
Ang II
Apoptosis
Bcl-2
Bax
proteinuria
TNF-α
IL6
Tubular atrophy

23. International IgA Nephropathy Network
&
Renal Pathology Society

24. International Consensus on clinico-pathological
Classification of IgAN: Oxford Classification
4 histologic features with
high reproducibility
low colinearity are
risk factors for progression
independently from
clinical data at renal biopsy and follow-up
Mesangial hypercellularity
Endocapillary hypercellularity
Segmental glomerular sclerosis
Tubular atrophy/interstitial fibrosis

25. Introduction
Aim of the study
Methods
Results
Conclusion
Lesions predictive of renal function decline
Mesangial hypercellularity
Endocapillary hypercellularity
265 patients
209
Segmental glomerulosclerosis adults
Tubular atrophy / Interstitial fibrosis
59 children

26. Consensus Classification of
IgAN (265 cases)
206 adults 59 children

27. Age and Geographical Origin of Study Cohort
of 265 Cases of IgA Nephropathy
Adults
Children
Total
206
59
Asia
48
14
Europe
73
21
North and South America
85
24

29. RATE OF RENAL FUNCTION DECLINE
Kaplan-Meier
Children: -2.7 11 ml/min/1.73m2/y
Adults -3.7
Survival
7.6 ml/min/1.73m2/y Functions
ped Bx
1,0
0
1
0-censored
1-censored
children
0,8
Cum Survival
adults
0,6
0,4
0,2
0,0
0
50
100
150 200 250 300
Months
0,000000 50,000000 100,000000 150,000000 200,000000 250,000000 300,000000
Children tend less likely to experience
time_comb
a 50% decline in renal function or renal failure
(hazard ratio 0.48, 95% CI 0.20-1.13, p=0.09).

30. Histology findings according to different age groups

31. CHILDREN
ADULTS
6
4
4
2
2
M0 S1 E0
0
-2
Slope (ml/min/1.73m )
2
Slope (ml/min/1.73m )
6
M0 S0 E0
-4
-6
-8
2
-2
-6
-8
6
4
4
2
2
Slope (ml/min/1.73m )
2
Slope (ml/min/1.73m )
-10
6
M1 S0 E0
M1 S1 E0
0
-2
-4
-6
-8
2
M1 S0 E0
M1 S1 E0
0
-2
-4
-6
-8
-10
6
6
4
4
2
2
M0/1 S1 E1
0
-2
Slope (ml/min/1.73m )
-10
2
M0 S0 E0
-4
-10
Slope (ml/min/1.73m )
M0 S1 E0
0
M0/1 S0 E1
-4
-6
-8
-10
M0/1: mesangial proliferation
E0/1: endocapillary hypercellularity
2
M0/1 S1 E1
0
-2
M0/1 S0 E1
-4
-6
-8
-10
S0/1: segmental sclerosis/adhesion
T0/1/2: tubular atrophy/interstitial
fibrosis

32. International Consensus on clinico-pathological
Classification of IgAN: Oxford Classification
Children had significantly less segmental glomerulosclerosis,
tubular atrophy/interstitial fibrosis and vascular lesions
and significantly more endocapillary lesions .
These differences in prevalence of lesions
contributed to distinct prognosis between children and adults.
However, the predictive value of each pathology variable
on outcome had a similar meaning regardless of age.

33. Introduction
Aim of the study
Methods
Results
Conclusion
European validation study VALIGA
• European Validation Study of the Oxford classification of IgA
Nephropathy
• 55 nephrology centers in 13 European countries

34. Introduction
•
Aim of the study
Methods
Results
Focus on the pediatric population included in VALIGA:
Age at renal
biopsy
< 18 years
• 174 children with primary IgA nephropathy (IgAN)
• reported by 20 Nephrology centers
• from 11 European countries.
Conclusion

35. Introduction
Aim of the study
Methods
Results
Participating centers
N° children
Huddinge Hospital- Stockholm -Sweden
Karolinska University -Stockholm - Sweden
Upssala Uiveristy - Uppsala - Sweden
Western Infirmary - Renal Unit - Glasgow – Great Britain
University of Leicester - Leicester - Great Britain
Radboud University - Nijmegen -Netherlands
Silesian University School of Medicine – Katowice - Poland
Warsaw Transplantation Centre – Warsaw - Poland
Warsaw University – Varsavia - Poland
University Nemocnice 2 – Praga – Czech Republic
Aachen University – Aachen - Germany
Ospedale SS. Trinità – Borgomanero -Italy
Ospedale Infantile Regina Margherita – Torino - Italy
Ospedale S. Giovanni Bosco - Torino - Italy
Spedali Civili – Brescia - Italy
Ospedale Maggiore – Lodi - Italy
Ospedale Civile Maggiore – Verona - Italy
Ospedale Infantile Bambino Gesù – Roma - Italy
Ospedale Belcolle – Viterbo - Italy
Azienda Ospedaliero-Universitaria “O.O-R.R” – Foggia - Italy
Ospedale Brotzu – Cagliari - Italy
Fondacion Puigvert – Barcellona – Spain
Hospital 12 de Octubre – Madrid – Spain
Hacettepe University – Ankara – Turkey
Istanbul University – Istanbul – Turkey
Dubrava Unviersity Hospital – Zagreb – Croatia
Aristotle University – Salonicco - Greece
20
2
1
2
1
2
2
2
4
1
1
2
42
2
3
2
1
48
5
5
1
1
2
16
4
1
1
TOTAL
174
Conclusion

36. Introduction
Aim of the study
Methods
N of patients
Results
Conclusion
174
Gender (males/females)
Age at renal biopsy (years)
GFR at renal biopsy (ml/min/1.73m2)
Proteinuria at renal biopsy (g/day/1.73m2)
MAP at renal biopsy (mmHg)
125/49
(72/28%)
12.7 ± 3.7
105.2 ± 21.1
0.8 (0.3-2.2)
87.5 ± 11.4
Duration of follow-up (years)
4.7 (2.4-7.8)
CKD I
CKDI I
CKDII I
CKD IV

37. Introduction
Aim of the study
Methods
Results
Conclusion
End-points
children (5%)

38. Introduction
Aim of the study
Methods
Results
Conclusion
MEST score
Mesangial hyperellularity
Endocapillary proliferation
Segmental sclerosis
Tubular atrophy/ Interstitial fibrosis

39. Introduction
Aim of the study
Methods
Results
MEST score in children with IgAN (VALIGA)
GFR at renal biopsy
Proteinuria at renal biopsy
Conclusion

40. Introduction
Aim of the study
Methods
Results
MEST and follow-up data
Proteinuria during follow-up
eGFR during follow-up
Conclusion

41. Introduction
Aim of the study
Methods
Results
Survival from the combined end-point
50% decrease in eGFR and/or ESRD
Conclusion

42. Introduction
Aim of the study
Methods
Results
Conclusion
Treatment
RAS blockers yes
RAS blockers no
Steroid/immunosuppressors yes
Steroid/immunosuppressors no

43. VALIGA cohort:1147 IgAN patients
523 patients received steroids/immunosuppressive drugs
622 patients had no steroids/immunosuppressive drugs
42
506
481
116
Steroids/Immunosuppressors
Steroids/Is + RAS Blockers
No therapy
RAS blockers

44. Added value of pathology variables in predicting the rate of renal function decline in IgAN
Added value of pathology scores in predicting rate of GFR loss
in patients having medangial or not
(right panel). Pathology variables include the presence ofreceived proliferation (M1), of
steroids/immunosuppressive therapy
segmental sclerosis (S1), of tubulo-interstitial lesions (T1/T2). Clinical variables include eGFR at
onset, TA-MAP, TA-Proteinuria
(MST added on e-GFR, TA-MAP, TA-proteinuria)
patients who never received immunosuppression (left panel) and who received immunosuppression
R.Coppo
ERA-EDTA 2013

45. Introduction
Aim of the study
Methods
Results
Conclusion
Multivariate linear regression
Independent
variables
β coefficients
Proteinuria MAP
R2
P
Proteinuria + MAP at RB
0.092
-0.089
0.015
ns
Proteinuria + MAP at 6-12 mo
-1.862
-0.107
0.184
0.001
Proteinuria + MAP at 12-24 mo
-2.332
0.003
0.183
<0.001
Proteinuria + MAP entire follow-up
-1.762
-0.231
0.149
<0.001
Dependent variable: GFR slope over follow-up

46. Introduction
Aim of the study
Methods
Results
Performace of different models
months months
Conclusion

47. Introduction
Aim of the study
Methods
Results
VALIGA formula
months
GFR slope
= (-1.636 * proteinuria12-24mo)
+ (-0.041 * MAP12-24mo)
+ [-0.183*(GFRinitial - GFR12-24mo)] + 2.724
Conclusion

48. Introduction
Aim of the study
Methods
Results
Conclusion
Conclusion
• The Oxford classification of IgAN was well applicable to this pediatric
population,
with
segmental
glomerulosclerosis
and
tubularatrophy/interstitial fibrosis being more significantly associated with renal
outcome independently from therapy.
•The predictive value of mesangial proliferation and endocapillary
hypercellularity was
• A formula was developed that precisely estimates renal function decline
over the f-up based on proteinuria, MAP and eGFR loss after 1-2 years of
observation, which will need a validation on other cohorts.

49. Thank you
Grazie
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