4-3. Risk factors for IgAN. Rosanna Coppo (eng)

transcript

Rosanna CoppoTorino

Clinical and histological risk factors for primary IgA nephropathy

IgA nephropathy

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

Hingeregion

ProSerThr *ProProThr * Pro core

Ser * --O--- -- ProSer *Pro

Thr ProThr *ProSerProSer

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

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

Healthy controls IgAN

%AOPPs

SH-Alb

p<0.0001p<0.0001

AberrantlyGlycosylated

Oxidative markers

AOPPs - SH-Alb - AOPPs - SH-Alb + AOPPs + SH-Alb - AOPPs + SH-Alb +-30

AOPPs - %HAA - AOPPs - %HAA + AOPPs + %HAA - AOPPs + %HAA + -30

p for trend test = <0.01

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

TNF-α

Apoptosis Bcl-2 Bax

TNF-αIL6

Tubular atrophy

proteinuria

Glomerulo-tubular cross-talk via TNF-α, IL6

and Angio II

Ang II

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

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

M0 S0 E0

M0 S1 E0

2 )CHILDREN

M0 S0 E0

M0 S1 E0

ADULTS

M1 S0 E0 M1 S1 E0

M0/1 S0 E1

M0/1 S1 E1

M0/1 S0 E1

M0/1 S1 E1

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

• Focus on the pediatric population included in VALIGA:

• 174 children with primary IgA nephropathy (IgAN)• reported by 20 Nephrology centers • from 11 European countries.

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

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)

CKDI I

CKDII I

CKD IV

End-points

children (5%)

Mesangial hyperellularity

Segmental sclerosis

MEST scoreEndocapillary proliferation

Tubular atrophy/ Interstitial fibrosis

MEST score in children with IgAN (VALIGA)

GFR at renal biopsy

Proteinuria at renal biopsy

MEST and follow-up data

Proteinuria during follow-up

eGFR during follow-up

Survival from the combined end-point50% decrease in eGFR and/or ESRD

Treatment

RAS blockers yes

RAS blockers no

Steroid/immunosuppressors yes

Steroid/immunosuppressors no

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

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

Performace of different models

months months

VALIGA formula

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

Thank you Grazie

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4-3. Risk factors for IgAN. Rosanna Coppo (eng)

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