4-3. Risk factors for IgAN. Rosanna Coppo (eng)
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Transcript of 4-3. Risk factors for IgAN. Rosanna Coppo (eng)
Rosanna CoppoTorino
Clinical and histological risk factors for primary IgA nephropathy
IgA nephropathy
0
10
20
30
40 IgA nephropahy:
the commonest glomerulonephritis in the world
Adults
Children
ASIA AUSTR EUR NORTH AMERICA
Highest frequencies when active screening programs
Japan, South Korea, Taiwan
20%
CH1
CH2
CH3
Hingeregion
CH1
CH2
ProSerThr *ProProThr * Pro core
Ser * --O--- -- ProSer *Pro
Thr ProThr *ProSerProSer
IgA1
GalNAc Β1,3-Gal
α 2,6Neu5Ac
α 2,3Neu5Ac
C1GalT1 Cosmc
syalyl transferase
ST6GalNAcI syalyl transferase
ST6GalNAcII
ABERRANTLY GLYCOSYLATED IGA1 IN IGA NEPHROPATHY
ROC analysis: AUC 0.92
Sensitivity 75% Specificity 90%
Sensitivity 50% Specificity 99%
Sensitivity 44% Specificity 100%%
A disease marker for IgAN
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
Andamento IgAHA nei placebo (rosso) e ACE-I(verde)
Sequential measurements of de galactosylated IgA1 in
Untreated IgAN and in patients on ACE-I IgACE trial
basale 2°anno 3° anno 4°anno1° annoTO 1 year 2 years 3 years 5 yearsLevels not related to treatment or to outcome
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. IgANrelatives
Hypothesis based onseveral hits
for the development of IgA nephropathy
Gd-IgA1
0
250
500
750
1000
1250
1500
1750
Healthy controls IgAN
U/m
l
%HAA
0
20
40
60
80
100
120
Healthy controls IgAN
%AOPPs
0
100
200
300
400
Healthy controls IgAN
mo
l/l
SH-Alb
0
5
10
15
20
Healthy controls IgAN
Arb
itra
ry u
nit
s
p<0.0001p<0.0001
p<0.0001p<0.0001
a b
c d
AberrantlyGlycosylated
igA1
Oxidative markers
AOPPs - SH-Alb - AOPPs - SH-Alb + AOPPs + SH-Alb - AOPPs + SH-Alb +-30
-20
-10
0
10
20
eG
FR
slo
pe
(m
l/m
in/1
.73m
2/y
ear)
AOPPs - %HAA - AOPPs - %HAA + AOPPs + %HAA - AOPPs + %HAA + -30
-20
-10
0
10
20
eG
FR
slo
pe
(m
l/m
in/1
.73m
2/y
ear)
p for trend test = <0.01
p for trend test = <0.01
a
b
aberrantly glycosylated IgA1 associated with oxidative stress
(increase in AOPP and decrease in albumin SH groups):an early new risk factor for IgAN.
Primary IgAN ++Hb
macroscopic hematuria
Chronic renal failure
Proteinuria
Proteinuriaand
microscopic hematuria
The natural history of IgAN depends on the time ofperforming renal biopsy
nourinary signs
%
years0
102030405060708090
100110
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Dispers. (XY) 2
Normal renal function
IgAN in childrenLinné, Berg, Levy, Hattori, Yoshikawa, Hogg, Wyatt
Estimated survival at 10 yearsin children:87- 93%
Severe clinical signs develop after 5-15 years:
at long-term follow-upIgAN in children is aprogressive disease
Factors affecting progression of IgAN in children(R Hogg, 1995)
Age (< 9 years) at presentation n.s.Sex (male) n.s.Race (Black) <0.005Gross hematuria n.s.GFR reduced at biopsy n.s.Proteinuria at biopsy <0.0001Hypertension at biopsy <0.003proliferation with mesangial sclerosis <0.0001sclerosis in > 20% of glomeruli <0.0001Focal global sclerosis <0.01Crescents/synechiae <0.03Tubulointerstitial disease <0.03Peripheral capillary wall deposits (EM) n.s.
Other GBM changes (EM) n.s.
Risk factors for progression of IgAN
PROTEINURIA
RENAL FUNCTION AT PRESENTATION
HYPERTENSION
normotensive
hypertensive prot >3
prot 1-1.9
prot 2-2.9
prot<1g/day
Cr <1.2 mg/dl
Cr 1.3-1.9 mg/dl
Cr 2.0-2.9 mg/dl Cr >3 mg/dl
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.
Log rank test: 1° quartile vs 2° quartile p = 0.0362° quartile vs 3° quartile p = 0.0393° quartile vs 4° quartile p < 0.0001
Survival from the combined end point (50% reduction in e-GFR or ESRD)by quartiles of proteinuria at renal biopsy
In VALIGA cohort proteinuria >0.5 < 1 g/day is a significant risk factor for
progression
In IgAN the development of proteinuria
takes 5-10 years
In minimal change disease
proteinuriarapidly develops andrapidly goes into
remission
Activation of mesangial cells by
deposited IgA
glomerular basement membrane
Proteinuria
PAF
TNF-α
Apoptosis Bcl-2 Bax
TNF-αIL6
Tubular atrophy
proteinuria
Glomerulo-tubular cross-talk via TNF-α, IL6
and Angio II
IgA1
Ang II
PAF
Mesangio-podocytescross talk
International IgA Nephropathy Network &
Renal Pathology Society
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 hypercellularityEndocapillary hypercellularitySegmental glomerular sclerosisTubular atrophy/interstitial fibrosis
Mesangial hypercellularity
Segmental glomerulosclerosis
Endocapillary hypercellularity
Tubular atrophy / Interstitial fibrosis
Introduction Aim of the study Methods Results Conclusion
265 patients
209 adults 59 children
Lesions predictive of renal function decline
Consensus Classification of IgAN (265 cases)
206 adults 59 children
Age and Geographical Origin of Study Cohortof 265 Cases of IgA Nephropathy
Adults Children
Total 206 59
Asia 48 14
Europe 73 21
North and South America 85 24
Adults Children
Total 206 59
Asia 48 14
Europe 73 21
North and South America 85 24
time_comb300,000000250,000000200,000000150,000000100,00000050,0000000,000000
Cu
m S
urv
iva
l
1,0
0,8
0,6
0,4
0,2
0,0
1-censored0-censored10
ped Bx
Survival Functions
children
adults
0 50 100 150 200 250 300Months
Kaplan-MeierRATE OF RENAL FUNCTION DECLINE
Children: -2.7 ± 11 ml/min/1.73m2/y
Adults -3.7 ± 7.6 ml/min/1.73m2/y
Children tend less likely to experience a 50% decline in renal function or renal failure(hazard ratio 0.48, 95% CI 0.20-1.13, p=0.09).
Histology findings according to different age groups
-10
-8
-6
-4
-2
0
2
4
6
M0 S0 E0
M0 S1 E0
Slo
pe (
ml/m
in/1
.73m
2 )CHILDREN
-10
-8
-6
-4
-2
0
2
4
6
M0 S0 E0
M0 S1 E0
Slo
pe (
ml/m
in/1
.73m
2 )
ADULTS
-10
-8
-6
-4
-2
0
2
4
6
M1 S0 E0 M1 S1 E0
Slo
pe (
ml/m
in/1
.73m
2)
-10
-8
-6
-4
-2
0
2
4
6
M1 S0 E0 M1 S1 E0
Slo
pe (
ml/m
in/1
.73m
2)
-10
-8
-6
-4
-2
0
2
4
6
M0/1 S0 E1
M0/1 S1 E1
Slo
pe (
ml/m
in/1
.73m
2)
-10
-8
-6
-4
-2
0
2
4
6
M0/1 S0 E1
M0/1 S1 E1
Slo
pe (
ml/m
in/1
.73m
2)
M0/1: mesangial proliferation S0/1: segmental sclerosis/adhesion
E0/1: endocapillary hypercellularityT0/1/2: tubular atrophy/interstitial fibrosis
International Consensus on clinico-pathological Classification of IgAN: Oxford Classification
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.
Children had significantly less segmental glomerulosclerosis,tubular atrophy/interstitial fibrosis and vascular lesions and significantly more endocapillary lesions .
European validation study VALIGA• European Validation Study of the Oxford classification of IgA
Nephropathy• 55 nephrology centers in 13 European countries
Introduction Aim of the study Methods Results Conclusion
• Focus on the pediatric population included in VALIGA:
• 174 children with primary IgA nephropathy (IgAN)• reported by 20 Nephrology centers • from 11 European countries.
Introduction Aim of the study Methods Results Conclusion
Age at renal biopsy
< 18 years
Participating centersN° children
Huddinge Hospital- Stockholm -Sweden 20Karolinska University -Stockholm - Sweden 2Upssala Uiveristy - Uppsala - Sweden 1Western Infirmary - Renal Unit - Glasgow – Great Britain 2University of Leicester - Leicester - Great Britain 1Radboud University - Nijmegen -Netherlands 2Silesian University School of Medicine – Katowice - Poland 2Warsaw Transplantation Centre – Warsaw - Poland 2Warsaw University – Varsavia - Poland 4University Nemocnice 2 – Praga – Czech Republic 1Aachen University – Aachen - Germany 1Ospedale SS. Trinità – Borgomanero -Italy 2Ospedale Infantile Regina Margherita – Torino - Italy 42Ospedale S. Giovanni Bosco - Torino - Italy 2Spedali Civili – Brescia - Italy 3Ospedale Maggiore – Lodi - Italy 2Ospedale Civile Maggiore – Verona - Italy 1Ospedale Infantile Bambino Gesù – Roma - Italy 48Ospedale Belcolle – Viterbo - Italy 5Azienda Ospedaliero-Universitaria “O.O-R.R” – Foggia - Italy 5Ospedale Brotzu – Cagliari - Italy 1Fondacion Puigvert – Barcellona – Spain 1Hospital 12 de Octubre – Madrid – Spain 2Hacettepe University – Ankara – Turkey 16Istanbul University – Istanbul – Turkey 4Dubrava Unviersity Hospital – Zagreb – Croatia 1Aristotle University – Salonicco - Greece 1
TOTAL 174
Introduction Aim of the study Methods Results Conclusion
N of patients 174
Gender (males/females) 125/49 (72/28%)
Age at renal biopsy (years) 12.7 ± 3.7GFR at renal biopsy (ml/min/1.73m2) 105.2 ± 21.1Proteinuria at renal biopsy (g/day/1.73m2) 0.8 (0.3-2.2)MAP at renal biopsy (mmHg) 87.5 ± 11.4
Duration of follow-up (years) 4.7 (2.4-7.8)
Introduction Aim of the study Methods Results Conclusion
CKD I
CKDI I
CKDII I
CKD IV
End-points
Introduction Aim of the study Methods Results Conclusion
children (5%)
Mesangial hyperellularity
Segmental sclerosis
MEST scoreEndocapillary proliferation
Tubular atrophy/ Interstitial fibrosis
Introduction Aim of the study Methods Results Conclusion
MEST score in children with IgAN (VALIGA)
Introduction Aim of the study Methods Results Conclusion
GFR at renal biopsy
Proteinuria at renal biopsy
MEST and follow-up data
Introduction Aim of the study Methods Results Conclusion
Proteinuria during follow-up
eGFR during follow-up
Survival from the combined end-point50% decrease in eGFR and/or ESRD
Introduction Aim of the study Methods Results Conclusion
Treatment
Introduction Aim of the study Methods Results Conclusion
RAS blockers yes
RAS blockers no
Steroid/immunosuppressors yes
Steroid/immunosuppressors no
42
481
116
506
Steroids/Immunosuppressors
Steroids/Is + RAS Blockers
No therapy
RAS blockers
VALIGA cohort:1147 IgAN patients
523 patients received steroids/immunosuppressive drugs
622 patients had no steroids/immunosuppressive drugs
Added value of pathology variables in predicting the rate of renal function decline in IgAN
patients who never received immunosuppression (left panel) and who received immunosuppression
(right panel). Pathology variables include the presence of medangial proliferation (M1), of
segmental sclerosis (S1), of tubulo-interstitial lesions (T1/T2). Clinical variables include eGFR at
onset, TA-MAP, TA-Proteinuria
Added value of pathology scores in predicting rate of GFR lossin patients having received or not
steroids/immunosuppressive therapy(MST added on e-GFR, TA-MAP, TA-proteinuria)
R.CoppoERA-EDTA 2013
Multivariate linear regression
Independent variables
β coefficientsProteinuria 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
Introduction Aim of the study Methods Results Conclusion
Dependent variable: GFR slope over follow-up
Performace of different models
Introduction Aim of the study Methods Results Conclusion
months months
VALIGA formula
Introduction Aim of the study Methods Results Conclusion
GFR slope = (-1.636 * proteinuria12-24mo)+ (-0.041 * MAP12-24mo)+ [-0.183*(GFRinitial - GFR12-24mo)] + 2.724
months
• The Oxford classification of IgAN was well applicable to this pediatric population, with segmental glomerulosclerosis and tubular-atrophy/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.
Conclusion
Introduction Aim of the study Methods Results Conclusion
Thank you Grazie
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