0
Rosanna Coppo
Torino

Clinical and histological risk factors
for primary IgA nephropathy
IgA nephropathy
40

IgA nephropahy:
the commonest glomerulonephritis in the world

30

Adults

20

20%
Children

10
0

Highest frequencies...
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

CH...
Aberrantly glycosylated IgA1 in IgA nephropathy
ROC analysis: AUC 0.92
Sensitivity 75% Specificity 90%
Sensitivity 50% Specificity 99%
Sensitivity 44% Specificity 100%%

...
Sequential measurements of de
Untreated IgAN

galactosylated IgA1 in

and in patients on ACE-I

IgACE trial

1.1
1.0
0.9
0...
Aberrant IgA1 glycosylation

in 45% of relatives of familial cases
and
in 25% of relatives of sporadic cases.

Since they ...
Hypothesis based on
several hits
for the development
of IgA nephropathy
a

b

Gd-IgA1

%HAA

1750

120

1500

100

1250

p<0.0001

Aberrantly
Glycosylated
igA1

p<0.0001

80

%

U/ml

1000
60

7...
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
...
%

macroscopic
hematuria

Primary IgAN

++
Hb

Proteinuria

no
urinary
signs

Proteinuria
and
microscopic
hematuria

Norma...
IgAN in children
Linné, Berg, Levy, Hattori, Yoshikawa, Hogg, Wyatt

Estimated survival at 10 years
in children:87- 93%

S...
Factors affecting progression of IgAN in children
(R Hogg, 1995)
Age (< 9 years) at presentation
Sex (male)
Race (Black)
G...
Risk factors for progression of IgAN
HYPERTENSION

PROTEINURIA
prot<1g/day

normotensive
prot 1-1.9
prot 2-2.9
prot >3

hy...
VALIGA:
VALidation of the Oxford classification for IgA Nephropathy
Coppo R, Troyanov S, Cattran D,
Feehally J, Cook T. Ro...
Survival from the combined end point (50% reduction in e-GFR or ESRD)
by quartiles of proteinuria at renal biopsy

Log ran...
In VALIGA cohort
proteinuria >0.5 < 1 g/day is a significant risk factor for progression
In minimal change disease
proteinuria
rapidly develops and
rapidly goes into remission

In IgAN the development of
protein...
Proteinuria

PAF

glomerular basement membrane

Activation of mesangial cells
by
deposited IgA
Glomerulo-tubular
cross-talk via TNF-α, IL6
and Angio II

Mesangio-podocytes
cross talk
TNF-α

IgA1
PAF
Ang II
Apoptosis
B...
International IgA Nephropathy Network
&
Renal Pathology Society
International Consensus on clinico-pathological
Classification of IgAN: Oxford Classification
4 histologic features with
h...
Introduction

Aim of the study

Methods

Results

Conclusion

Lesions predictive of renal function decline
Mesangial hyper...
Consensus Classification of
IgAN (265 cases)
206 adults 59 children
Age and Geographical Origin of Study Cohort
of 265 Cases of IgA Nephropathy

Adults

Children

Total

206

59

Asia

48

1...
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 Fu...
Histology findings according to different age groups
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
...
International Consensus on clinico-pathological
Classification of IgAN: Oxford Classification

Children had significantly ...
Introduction

Aim of the study

Methods

Results

Conclusion

European validation study VALIGA
• European Validation Study...
Introduction

•

Aim of the study

Methods

Results

Focus on the pediatric population included in VALIGA:

Age at renal
b...
Introduction

Aim of the study

Methods

Results

Participating centers
N° children
Huddinge Hospital- Stockholm -Sweden
K...
Introduction

Aim of the study

Methods

N of patients

Results

Conclusion
174

Gender (males/females)
Age at renal biops...
Introduction

Aim of the study

Methods

Results

Conclusion

End-points
children (5%)
Introduction

Aim of the study

Methods

Results

Conclusion

MEST score
Mesangial hyperellularity

Endocapillary prolifer...
Introduction

Aim of the study

Methods

Results

MEST score in children with IgAN (VALIGA)
GFR at renal biopsy

Proteinur...
Introduction

Aim of the study

Methods

Results

MEST and follow-up data
Proteinuria during follow-up

eGFR during follow...
Introduction

Aim of the study

Methods

Results

Survival from the combined end-point
50% decrease in eGFR and/or ESRD

C...
Introduction

Aim of the study

Methods

Results

Conclusion

Treatment

RAS blockers yes
RAS blockers no

Steroid/immunos...
VALIGA cohort:1147 IgAN patients
523 patients received steroids/immunosuppressive drugs
622 patients had no steroids/immun...
Added value of pathology variables in predicting the rate of renal function decline in IgAN

Added value of pathology scor...
Introduction

Aim of the study

Methods

Results

Conclusion

Multivariate linear regression

Independent
variables

β coe...
Introduction

Aim of the study

Methods

Results

Performace of different models
months months

Conclusion
Introduction

Aim of the study

Methods

Results

VALIGA formula
months

GFR slope
= (-1.636 * proteinuria12-24mo)
+ (-0.0...
Introduction

Aim of the study

Methods

Results

Conclusion

Conclusion

• The Oxford classification of IgAN was well app...
Thank you
Grazie

СПАСИБО
4-3. Risk factors for IgAN. Rosanna Coppo (eng)
4-3. Risk factors for IgAN. Rosanna Coppo (eng)
Upcoming SlideShare
Loading in...5
×

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

440

Published on

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
440
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
5
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • - Sono stati definiti pediatrici i pazienti sottoposti alla biopsia renale in età inferiore a 18 anni.- Sono 20 i centri in tutta Europa che hanno fornito al VALIGA dati relativi ai 180 bambini inclusi nello studio. Il nostro ospedale ne ha raccolti 42.
  • Al momento della biopsia solo i bambini con con danno tubulare (score T1 o T2) mostravano un GFR significativamente ridotto rispetto agli altri (score T0). I pazienti con proliferazione mesangiale (M1), proliferazione endocapillare (E1) e danno tubulare (T1 o T2) presentavano livelli di proteinuria iniziali significativamente superiori rispetto agli altri. Non si sono osservate differenze significative della MAP nelle diverse classi istologiche, nè all’esordio...
  • Transcript of "4-3. Risk factors for IgAN. Rosanna Coppo (eng)"

    1. 1. Rosanna Coppo Torino Clinical and histological risk factors for primary IgA nephropathy
    2. 2. IgA nephropathy
    3. 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. 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. 5. Aberrantly glycosylated IgA1 in IgA nephropathy
    6. 6. ROC analysis: AUC 0.92 Sensitivity 75% Specificity 90% Sensitivity 50% Specificity 99% Sensitivity 44% Specificity 100%% A disease marker for IgAN
    7. 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. 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. 9. Hypothesis based on several hits for the development of IgA nephropathy
    10. 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. 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.
    12. 12. % 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
    13. 13. 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
    14. 14. 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.
    15. 15. 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
    16. 16. 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.
    17. 17. 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
    18. 18. In VALIGA cohort proteinuria >0.5 < 1 g/day is a significant risk factor for progression
    19. 19. In minimal change disease proteinuria rapidly develops and rapidly goes into remission In IgAN the development of proteinuria takes 5-10 years
    20. 20. Proteinuria PAF glomerular basement membrane Activation of mesangial cells by deposited IgA
    21. 21. 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
    22. 22. International IgA Nephropathy Network & Renal Pathology Society
    23. 23. 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
    24. 24. 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
    25. 25. Consensus Classification of IgAN (265 cases) 206 adults 59 children
    26. 26. 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
    27. 27. 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).
    28. 28. Histology findings according to different age groups
    29. 29. 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
    30. 30. 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.
    31. 31. 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
    32. 32. 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
    33. 33. 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
    34. 34. 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
    35. 35. Introduction Aim of the study Methods Results Conclusion End-points children (5%)
    36. 36. Introduction Aim of the study Methods Results Conclusion MEST score Mesangial hyperellularity Endocapillary proliferation Segmental sclerosis Tubular atrophy/ Interstitial fibrosis
    37. 37. Introduction Aim of the study Methods Results MEST score in children with IgAN (VALIGA) GFR at renal biopsy Proteinuria at renal biopsy Conclusion
    38. 38. Introduction Aim of the study Methods Results MEST and follow-up data Proteinuria during follow-up eGFR during follow-up Conclusion
    39. 39. Introduction Aim of the study Methods Results Survival from the combined end-point 50% decrease in eGFR and/or ESRD Conclusion
    40. 40. Introduction Aim of the study Methods Results Conclusion Treatment RAS blockers yes RAS blockers no Steroid/immunosuppressors yes Steroid/immunosuppressors no
    41. 41. 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
    42. 42. 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
    43. 43. 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
    44. 44. Introduction Aim of the study Methods Results Performace of different models months months Conclusion
    45. 45. 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
    46. 46. 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.
    47. 47. Thank you Grazie СПАСИБО
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×