1/14/2014

New Data and New

Questions on
IgA Nephropathy

GERALD APPEL, MD
Professor of Clinical Medicine
Columbia University College of
Physicians and Surgeons
NY-Presbyterian Hospital
New York, New York

IgA Nephropathy
Defined by IgA deposition in glomerular
mesangium
Presents- Young gross hematuria
Adults Proteinuria + hematuria
Not benign hematuria ( Bergers Dis )
ESRD in 15-20% by 10 yrs from onset and 3040 % by 20 yrs.
Risk Factors for Progression.
Rx Not one therapy fits all.

DEMOGRAPHICS OF IgA NEPHROPATHY

IgA N is considered the most common
glomerulonephritis in the world.
In native kidney biopsies, IgA N accounts for:
U.S.A.
Asia
Europe

of all biopsies:
5%
30%
15%

of GN biopsies:
10%
40%
20%

Rare in African-Americans and common in

Native-Americans.

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In IgA N and HSP, serum IgA1 has reduced

terminal glycosylation in the hinge region

Reduced in
IgAN and
HSP

VH
VL
CL
Hinge Region

Ser/Thr-O-GalNAc
Ser/Thr-O-GalNAc--Galactose

IgA1

CH
3

Ser/Thr-O-GalNAc--Galactose-Sialic
Acid
Ser/Thr-O-GalNAc----Galactose-Sialic
Acid
Sialic
Acid
-

CH
2

CH
1

Pathogenesis: Gal-deficient IgA1

IgAN paents have circulang Gd-IgA1

Predisposed to immune complex formation
Makes up minority of circulating IgA, but
virtually all of the mesangial IgA
Recognized by naturally occurring Igs
Insufficient alone to cause disease
Normal

Galactose
deficient

Moldoveanu Z. et al., Kidney Int, 71: 1148-1154, 2007

Gharavi AG et al. J Am Soc Nephrol.

2008;19:1008-1014.

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Aberrant glycosylation of IgA1 is inherited in

both pediatric IgA nephropathy and HenochSchnlein purpura nephritis.
Kiryluk K, Moldoveanu Z, Sanders JT, Eison TM, Suzuki H, Julian BA,
Novak J, Gharavi AG, Wyatt RJ. Kidney Int. 2011;80:79-87

Genetics of IgAN

>90% cases sporadic, but rare familial cases exist

GWAS identified >5 genetic loci, explain at least 4-7% disease variance
Implicated genes: MHC, CFHR1, CFHR3, TNFSF13, DEFA
Elevated Gd-IgA1 also heritable

Gharavi, Kiryluk et al. Nature Genetics, March 2011

The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy
is associated with disease progression
Na Zhao, Ping Hou, Jicheng Lv, Zina Moldoveanu, Yifu Li, Krzysztof Kiryluk, Ali G
Gharavi, Jan Novak and Hong Zhang

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Glycan-specific IgG antibodies recognize

the aberrantly glycosylated IgA1 in IgA N

Suzuki H, et al.J Clin Invest. 2009;119:1668-77

Pathogenesis: multi-step model

Step 1: Generation of

aberrantly galactosylated
IgA1 (Gd-IgA1)
Mucosal antigens as trigger
Plasma cells (tonsils, marrow)
produce Gd-IgA1 (genetic risk)
Step 2: Autoantibodies form
against Gal-deficient hinge
region
Step 3: Circulating immune

complexes of polymeric GdIgA1 + autoantibodies, get

trapped in mesangium
Step 4: Glomerular Damage

Boyd & Barratt, Kidney Int, 2010

Box plots of serum levels of normalized IgG autoantibody (OD/0.5 g IgG) according to the
ARR evaluated at diagnosis, in both IgAN patients and in diseased (DC) and healthy (HC)
controls.

Berthoux F et al. JASN 2012;23:1579-1587

2012 by American Society of Nephrology

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KaplanMeier survival curves without dialysis/death event, with time zero set at diagnosis
and elevated serum levels of autoantibodies (IgG >1.33 OD and/or IgA >1.79 U/ml) at
diagnosis in IgAN patients.

Berthoux F et al. JASN 2012;23:1579-1587

2012 by American Society of Nephrology

Oxidative Stress and Galactose-Deficient IgA1 as

Markers of Progression in IgA Nephropathy
Sera from IgAN pts showed higher levels of Gd-IgA1, %
HAA, and AOPPS but lower levels of SH-Alb.
AOPPS correlated with serum Gd-IgA1 and %HAA.
Assessed in 62 pts long term AOPPs and % HAA
correlated with proteinuria at sampling and subsequent
proteinuria.
AOPPs corrleated with rate of decline in renla function
after sampling
Combination of high level of AOPPs and a high level of %
HAA was associated with decline in GFR.
Oxidative stress pathways are activated in IgA N and this
may modulate the nephrotoxicity of aberrantly
glycosylated IgA1.
Camilla R, Suzuki H, Dapra V,Gharavi A, Appel GB, Coppo R.
Clin J Am Soc Nephrol 6:1903-1911, 2011

Serum levels of galactose-deficient IgA1 and

markers of oxidative stress.

Camilla R, Suzuki H, Dapra V,Gharavi A, Appel GB, Coppo R.

Clin J Am Soc Nephrol 6:1903-1911, 2011

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Predictive value of the combination of AOPPs and

galactose-deficient IgA1 on eGFR loss.

Camilla R, Suzuki H, Dapra V,Gharavi A, Appel GB, Coppo R.

Clin J Am Soc Nephrol 6:1903-1911, 2011

Long-term Renal Survival and risk Factors

in IgAN 1126 Patients
Renal survival curve of 1126 IgAN Pts
83% , 74%, 64% at 10, 15, 20 ys.

Le W, Liang SS, Hu YL, Liu ZH Nephrol. Dial. Transplant. Sept 29 2011

Prediction of Progression in IgAN in 298 Pts

IgAN:
GFR Prediction
(-ml/min/year)
14
12
10
97mmHg
102mmHg
107mmHg
112mmHg

8
6
4
2
0
0.2g/d

0.5g/d

1g/d

2g/d

4g/d

6g/d

Bartosik, et al AJKD 38:728-735, 2001

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IgA Nephropathy:
Relative Risk of 2xScr after 5.6y
(Nishitani, et al KI 68:1078, 2005)

6
5
4

Male Sex
Age >60y
Scr
Upro
HTN

3
2
1
0
Clinical or Pathologic Features

Reduction of Proteinuria Improves

Prognosis in
IgAN
Regardless of peak proteinuria,
542 pts with IgAN from Toronto
.

registry
Followed for 78.1 59 mos
GFR declined at 4.56
ml/min/1.73 m2/yr
30% reached ESRD

attaining partial remission (<1 g/d)

leads to similarly good outcome s.
Group 1: 1-2 g/d peak
proteinuria Group 2: 2-3 g/d
peak proteinuria Group 3: >3
g/d peak proteinuria

Reich H N et al. JASN 2007;18:3177-3183

Reich H N et al. JASN 2007;18:3177-3183

R
.
Remission
of Proteinuria
Improves
e
Prognosis
m
in IgA Nephropathy
i
s
s
i
o
n
o
f

Reich H N et al. JASN 2007;18:3177-3183

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IgA

IgA Nephropathy

IgA nephropathy is
morphologically heterogeneous
(Roberts, et al ASN CNC. 2008)

MEST-Oxford Classification System

Mesangial Hypercellularity
0= <50%; 1=>50% glomeruli involved
Endocapillary proliferation
0= Absent; 1= Present
Segmental glomerulosclerosis
0= Absent; 1=Present
Tubulo-Interstitial Fibrosis
0= <25%; 1= 25-50%; 2= >50%
Preliminary Studies Show Good Correlation with Outcome

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Combinations of Glomerular Features

Impact on Deterioration in Renal Function
Criteria

Pt
(no.)

Slope
(mL/min/1.73

m2/yr)
Minimal mesangial hypercellularity
Without segmental sclerosis

M0, S0, E0

12

0.72.5

With segmental sclerosis

M0, S1, E0

22

-1.52.7

Without segmental sclerosis

M1, S0, E0

31

-2.24.3

With segmental sclerosis

M1, S1, E0

88

-4.77.6

Without segmental sclerosis

M0, S0, E1

21

With segmental sclerosis

M0/1, S1, E1 90

Mesangial hypercellularity

Endocapillary proliferation
1.21.2
-4.910.0

Kidney Int. 76:534-45, 2009

Clinical and Histopatholologic Prognostic Factors in IgA N

Huerta A, Bomback AS, Canetta PAppel GB WCN-ISN 2011

154 IgAN pts followed at Columbia U Med Ctr from 2005-2010 ( with clinical
data available from 1980 to 2010)
M/F - 64%:36% Age at Dx 32 yo NHW: 93 HW :17 AA:7 A:37
HBP 46% ; Pcreatinine 1.62 mg/dl eGFR 66 cc/min UVprot 3.7 g/d
Salb 3.7g/dl Scholesterol 322
Long-term Follow up Data (n=126) Mean time 5.8 years
Most received RAAS blockade and immunosuppresives

Predictors of CKD V-ESRD and halving of eGFR.

Baseline creatinine and eGFR
Proteinuria
African-American race
Male gender
Tubular atrophy/interstitial fibrosis and cumulative MEST score

Therapy of IgA Nephropathy

ACE inhibitors, ARBs, Combinations

Tonsillectomy
Glucocorticoids ( QD,QOD,Cyclic pulse )
Fish Oils ( n-3 PUFA )
Immunosuppressives
Corticosteroids
Azathioprine + steroids
Cyclophosphamide + steroids
Mycophenolate mofetil
Other ( Rituxan, ACTH )

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ACE Inhibitors in IgA Nephropathy:

A Controlled Trial
A RCT comparing ACEi or
ARB to non-ACEi therapy 60.00%
in IgA Nephropathy
50.00%
SCr<1.2mg/dl 24 hr urine
40.00%
Protein > 500mg / day
Follow-up=75 months

57%

RAAS block
PBO

30.00%

(Praga M, et al. JASN

14:1578, 2003)

20.00%
10.00% 13%
0.00%
50% increase in Scr

Survival without the combined end point of 30%

reduction of baseline CrCl and/or increase in
proteinuria up to >3.5 g/d/ 1.73 m2

Coppo, R. et al. J Am Soc Nephrol 2007;18:1880-1888

Therapy of IgA Nephropathy

ACE inhibitors, ARBs, Combinations

Tonsillectomy
Glucocorticoids ( QD,QOD,Cyclic pulse )
Fish Oils ( n-3 PUFA )
Immunosuppressives
Corticosteroids
Azathioprine + steroids
Cyclophosphamide + steroids
Mycophenolate mofetil
Other ( Rituxan, ACTH )

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1/14/2014

The efficacy of tonsillectomy on longterm survival in pts with IgAN

118 IgAN Bxed 1973-1980
48 s/p Tonsilx and 70 w/oTonsilx follow
192 mo.
No dif in age, gender, Uprot, Screat,
SIgA, BP, histology, Rx.
Renal survival 90% w Tonsx vs. 64%
w/o Tonsx at 240 mo. By MVA tonsilx
significant effect on outcome.
Tonsillectomy has a favorable effect on
long-term outcome IF performed early in
the course.
Xie Y, Nishi S, Ueno M et al. Kidney Int 63:1861-1867, 2003.

The efficacy of tonsillectomy on longterm survival in pts with IgAN

Xie Y, Nishi S, Ueno M et al. Kidney Int 63:1861-1867, 2003.

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Tonsillectomy

Retrospective review of 200 Japanese IgAN, 70 with tonsillectomy

Tonsillectomy group had more endocap hypercellularity, but also received
more treatment with steroids and RAS inhibitors
Clinical remission defined as normal dipstick examination of hematuria
and proteinuria on two consecutive visits at least 3 months apart.
GFR decline defined as >30% loss of eGFR from baseline

Maeda I et al. Nephrol. Dial. Transplant. 2012, Jul;27(7):2806-13

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IgA Nephropathy:Fish Oils (Omacor)

Donadio J, et al. Semin Nephrol, 2004

IgA Nephropathy:Fish Oils (Omacor)

(Donadio J, et al. Semin Nephrol, 2004)
90%
80%
70%
60%
50%
Fish Oil
Placebo

40%
30%
20%
10%
0%
Survival Free of
ESRD at 8 yrs

Survival Free of
2XScr at 8 yrs

Multicenter Controlled Trial of QOD

Pred.vs QD Omega 3 FA vs PBO in IgAN
Hogg RJ, LeeJ, Nardelli NA, et al. Clin JASN 2006

99 IgAN <40yo GFR > 50ml/min Up/Ucr >0.5

33 Pts Pred QOD x3mo
32 Pts OM-3 FA 4g/d
31 Pts PBO
End-Point at 2yrs
GFR < 60% baseline
All HBP Rx ACEi

8
7
6

5
4
3
2

steroids
Fish Oils
PBO

1
0
# Failed Therapy

Neither Rx group showed a benefit over PBO

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Therapy of IgA Nephropathy

ACE inhibitors, ARBs, Combinations

Tonsillectomy
Fish Oils ( n-3 PUFA )
Glucocorticoids ( QD,QOD,Cyclic pulse )
Immunosuppressives
Azathioprine + steroids
Cyclophosphamide + steroids
Mycophenolate mofetil

IgAN: Controlled Trial of Steroids

25
20
15
Doubled Scr
ESRD

10
5
0
Control

Steroids

Pozzi et al. JASN 15:157-163, 2004

Steroids plus ACEi versus ACEi alone in IgA Nephropathy

A Prospective Randomized Controlled Trial

N = 63
18 to 65 years old
Biopsy-proven IgAN within a one year period
Urine protein excretion of 1-5g/d
Estimated (eGFR) >30ml/min/1.73m2 according to a
Modified MDRD equation for a Chinese population.
Treated with Cilazapril or Combination of cilazapril +
prednisone: 0.8-1.0 mg/Kg/day X 8 weeks tapered

by

5-10mg every two weeks

Lv J et al. Am J Kidney Dis 2009; 53(1): 26-32

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NO 50% creatinine increase

1.0

0.8

Log Rank P=0.006

0.6

0.4

Combination

0.2

ACE inhibitor
0.0
10

20

30

40

50

Patient Not Reaching an End Point

Patient Not Reaching an End Point

Kidney survival estimated based on an increase up to

50% greater than baseline serum creatinine level and a
decrease of 25% in estimated glomerular filtration rate
(eGFR).
NO 25% eGFR decrease
1.0

Log Rank P<0.001

0.8

0.6

0.4

Combination
0.2

ACE inhibitor
0.0
10

20

30

40

50

Time (month)

Time (month)
# at risk
ACE-I

30

29

28

10

29

28

10

Combo

33

32

30

14

32

30

16

Lv J et al. Am J Kidney Dis 2009; 53(1): 26-32

PROSPECTIVE RANDOMISED CONTROLLED TRIAL

OF STEROIDS PLUS RAMIPRIL IN
PROTEINURIC IgA NEPHROPATHY
n = 97
Proteinuria > 1g/24h - GFR > 50 ml/min
ALL PATIENTS
Ramipril
dose titrated to achieve
BP < 120/80 Proteinuria < 1g/24h
RANDOMISATION
Prednisolone 1 mg/kg/d for 2 months
tapered by
0.2 mg/kg per month

Manno C et al. NDT 2009

PROSPECTIVE RANDOMISED CONTROLLED TRIAL

OF STEROIDS PLUS RAMIPRIL IN
PROTEINURIC IgA NEPHROPATHY
n = 97
Proteinuria > 1g/24h - GFR > 50 ml/min
RAMIPRIL mean dose 4.5 mg/day

STEROIDS
1/48

98%

CONTROL
ESRD

8 year renal survival

8/49

70%

P = 0.006

Manno C et al. NDT 2009 Epub 23 July

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Benefits of corticosteroids for IgAN

limited for patients with reduced GFR

25 IgAN pts CUMC. Screat 1.75 mg/dl eGRF 52ml/min ,

proteinuria 3.1g/day on RAAS blockade.
Alternate day prednisone, start 2 mg/kg for 1 month- tapering off
over 5-6 mo.
Primary outcome a sustained 25% increase in Screatinine
At > 32 months follow-up, 40% of pts (10/25) experienced a
sustained 25% increase in Screatinine.
By multivariate analysis only predictor of outcome was eGFR
<45 ml/min/1.73m2 (p<0.0001, HR 17.6).
Of 11 pts with eGFR <45 ml/min/1.73m2 , 9 reached the
outcome in an average of just 12.7 months, vs. only 1/14 pts
with higher eGFR.
Canetta PAppel GB WCN/ISN 5/ 2011

Steroids and Cytotoxic Agents

in Progressive IgA
Nephropathy
Oral Pred.+ oral Cyclophosphamide
(1.5mg/kg/d) for 3 mo then 2 years or more
of AZA(1.5mg/kg/d) improved renal
survival in progressive IgAN in RCT.
Treated = 72% 5 year renal survival
Untreated =5% 5 year renal survival
Ballardie, F & Roberts, I. JASN 13:142, 2002

Steroids and Immunosuppressive

Agents in Progressive IgA N

Ballardie, F Roberts, I. JASN 13:142, 2002

Pozzi C, Andrulli S, Pani A, et al.

JASN 21:1783, 2010.

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Therapy of IgA Nephropathy

ACE inhibitors, ARBs, Combinations
Tonsillectomy
Glucocorticoids ( QD,QOD,Cyclic pulse )
Fish Oils ( n-3 PUFA )
Azathioprine + steroids
Cyclophosphamide + steroids
Mycophenolate mofetil

Controlled Trial of MMF in IgAN

Maes BD et al. KI 65:1842-1849, 2004
33 pts - Pcreat 1.4 mg/dl 2
UV prot 1.6 g/d
1.8
1.6
Low Na+, ACEi
1.4
MMF 2g/day vs. placebo 1.2
for 2 yrs
1

MMF
Control

0.8

In IgA N at moderate risk

- no advantage to MMF

0.6
0.4
0.2
0
UpV Initial UpV 3 yr Scr initial Scr 3 yr

MMF in IgA N: A Controlled Trial

(Tang et al, KI 68:802, 2005)
70%
60%
50%
40%
MMF- % CR+PR
Control % CR+PR

30%
20%
10%
0%
2 months

6 months

12 months

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Mycophenolate Mofetil in IgA N:

Controlled Trials
Maes (n=34)

Tang (n=40)

MMF2.0g/d x 3yr
1.5-2.0g/d x 6mo
eGFR71ml/min (Cin)
72ml/min (Ccr)
Scr1.43mg/dl
1.59mg/dl
UpV1.6g/d
1.8gm/d
SBP128mmHg
121mmHg
ACEi/ARB- All
All
Histology- II-III (Churg/Sobin)
3.0 (Haas)
Ethnicity- N. European
Oriental
Courtesy of Dr. Richard Glassock

Mycophenolate Mofetil in IgA N:

A Controlled Trial
(Frisch G, et al NDT, 2005)

A randomized, controlled trial of MMF

2.0gm/d X one year or placebo in 40
patients* with severe, high-risk IgA N.
Average Scr at entry= 2.4mg/dl UpV >
1.0gm/d;
All received A-II inhibition
Follow-up 2 years

Mycophenolate Mofetil in IgA N:

Controlled Trial
(Frisch GAppel GB

et al NDT 2005)

30.00%
25.00%
20.00%
MMF
Control

15.00%
10.00%
5.00%
0.00%
50% increase in Scr

50% decrease in UpV

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Future developments in therapy

Rituximab in IgA N Trial open-label multicenter RCT ( still enrolling)

STOP-IgAN Study (Germany):
Randomized, multicenter, open-label study of immunosuppression for IgAN
148 patients, all get ACEI and statin x 6 mos, if proteinuria remains >0.75g/d,
randomized to immunosuppression or supportive care
If eGFR >60, prednisone QOD x 6mos + IV methylpred at mo 1,3,5
If eGFR 30-60, oral CYC/Pred x3 mos
AZA/Pred for 3yrs
Fully recruited, estimated study completion date: December 2013

TESTING study (China):

MMF vs. Glucocorticoids (Guangzhou, n=150), est. completion June-2013

Prednisone/CYC vs. Prednisone (Guangdong, n=200), est. completion 2015

New therapeutic targets being revealed by evolving genetic and

mechanistic research

RCT of oral methylprednisolone or placebo, goal enrollment N=1300! (2017)

Jerry Appels Therapy for IgAN in

2013
All pts ACEi or ARB or ACEi/ARB.
All pts strongly consider Rx w statin.
All pts consider low ( i.e NOT HIGH )protein
diet.
All pts BP <130/80.
Tonsillectomy for pts with frequent bad URI
and tonsillitis.
Fish Oils for those who want them Should not
replace other therapies.

J Appels Therapy for IgAN in 2013

Mild Disease- ( nl GFR, < 0.5g Uprot/d, good Bx)
No other Rx. Close Follow.

Moderate or SevereDis. ( Abnl GFR, or >

1gUprot/d, or Bx w risk of progression or
Crescentic GN)
- Steroids ( We use alternate day ) x 6months
- Consider Cyt +Stds or MMF if other therapy not
acceptable
- Consider ACTH, rituximab ( limitred data )

-High Pcreat. w Bx chronic damage GS-TIF no

immunosuppressives

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IgA N 2014 Refs G. Appel

Wyatt RJ, Julian BA. IgA Nephropathy. NEJM 368:24022414, 2013

Gharavi, Kiryluk et al. Genetics of IgAN Nature Genetics, March 2011
Kiryluk K, et al Aberrant glycosylation of IgA1 in both pediatric IgA
nephropathy and HSP nephritis. Kidney Int. 2011;80:79-87
Camilla R, ...Appel GB, Coppo R. Oxidative Stress and GalactoseDeficient IgA1 as Markers of Progression in IgAN CJASN 6:1903-1911,
2011
Le W Liu ZH Long-term Renal Survival and risk Factors in 1126 IgAN
Pts Nephrol. Dial. Txplant. 2011
Reich H N et al. Course and Prognosis of IgANJASN 2007;18:3177-3183
Hogg RJ, LeeJ, Nardelli NA, et al. Multicenter Controlled Trial of QOD
Pred.vs QD Omega 3 FA vs PBO in IgAN CJASN 2006.
Manno C et al. Prospective Randomized Controlled Trial of steroids plus
ramapril in proteinuric IgAN. NDT 2009 Epub 23 July
Frisch G, Lin J, Rosenstock J, Appel GB. MMF vs Placebo in pts with
IgAN- A double blind, randomized , controlled trial. Nephrol Dial
Transplant Oct 20 (10) :2139-2145, 2005
Pozzi C, Andrulli S, Pani A, et al. Steroids and Immunosuppressive Agents
in Progressive IgA N JASN 21:1783, 2010.

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