ASSESSMENT AND MANAGEMENT OF IgA NEPHROPATHY John Feehally

ASSESSMENT AND MANAGEMENT OFIgA NEPHROPATHY

John Feehally

IgA NEPHROPATHY

The commonest pattern of glomerulonephritis in the world

Histopathology Clinical Immune mechanisms

CLASSIFICATION OF GLOMERULONEPHRITIS



Patterns established on light microscopy

Membranous

Membranoproliferative

Focal segmental glomerulosclerosis

etc……



Patterns established on light microscopy

Membranous

Membranoproliferative

Focal segmental glomerulosclerosis

etc……‘Patterns’ not ‘diseases’

IgA1 depositionIn the glomerular

mesangium

IgA NEPHROPATHY


Is IgA nephropathy

a single ‘disease’ ?

IgA NEPHROPATHY

A pattern of glomerulonephritis

with many variations

Recurrent visible haematuria

Coincides with mucosal infection

Nephrotic syndrome

Asymptomatic

Haematuria / proteinuria

CKD

ProteinuriaHypertension

Renal impairment

HENOCH-SCHȌNLEIN NEPHRITIS

Henoch-Schőnlein purpuraHenoch-Schőnlein purpura

‘SECONDARY’ IgA NEPHROPATHY

COMMONLY REPORTED ASSOCIATIONS

Alcoholic liver diseaseCeliac disease

Ankylosing spondylitisReiter’s syndrome

UveitisDermatitis herpetiformis

RECURRENT IgA NEPHROPATHY


Recurrence

38-60%

Graft dysfunction due to recurrence

15%

Graft loss due to recurrence

7%

Pooled published data – 5 year follow up


Recurrence

38-60%

Graft dysfunction due to recurrence

15%

Graft loss due to recurrence

7%

Pooled published data – 5 year follow up

Why does IgA nephropathy

NOT always recur ?

4.7%

<5%

15-21%

Percentage of patients with

primary glomerular disease

4.7%

<5%

15-21%Male > Female

Male = Female

IgA NEPHROPATHY

Variations in:

Pathological pattern

Clinical pattern

Transplant recurrence

Epidemiological pattern

Pathogenesis

IgA NEPHROPATHY

No proof that IgAN is a single ‘disease’

No proof that IgAN is the same ‘disease’ in all parts of the world

Not expect

a single pathogenic mechanism

to lead tomesangial IgA deposition

and injury


Can you predict which patients with IgA nephropathy

will get kidney failure?




CLINICAL evidenceCLINICAL evidence

Rodicio 1982

PROGNOSIS IN IgA NEPHROPATHY

Rodicio 1982

PROGNOSIS IN IgA NEPHROPATHY

20% ESRD @ 20 years

Chacko B et al. Nephrology 2005; 10: 496

IgA NEPHROPATHY IN INDIA

CMC Vellore 1994-2003

Chacko B et al. Nephrology 2005; 10: 496

IgA NEPHROPATHY IN INDIA

CMC Vellore 1994-2003

478 adults

55% - Nephrotic syndrome at presentation

56% - Serum creatinine > 123 μmol/L at presentation

Beukhof 1983

MACROSCOPIC HAEMATURIA AND PROGNOSIS IN IgA NEPHROPATHY

LEAD TIME BIAS IN DIAGNOSIS OF IgA NEPHROPATHY

Geddes CC et al. NDT 2003; 18: 1541

ISOLATED NON-VISIBLE HAEMATURIA IN IgA NEPHROPATHY

How benign is it ?

Cohort study – Toronto – 286 patients

Non-visiblehaematuria plus

Proteinuria < 0.2 g/24hr

Normal BP

Bartosik et al. AJKD 2001; 38: 728

ISOLATED MICROSCOPIC HAEMATURIA IN IgA NEPHROPATHY

How benign is it ?

Cohort study – Toronto – 286 patients

Microscopic haematuria plus

Proteinuria < 0.2 g/24hr

Normal BP

10 year risk of deterioration in renal function

= ZERO

Bartosik et al. AJKD 2001; 38: 728

ISOLATED NON-VISIBLE HAEMATURIA IN IgA NEPHROPATHY

How benign is it ?

Cohort study – Hong Kong

Non-visible haematuria plus Proteinuria < 0.4 g/24hr

Szeto C et al Am J Med 2001; 110:434

During 7 years follow up, 44% had a ‘clinical event’

33% proteinuria

26% hypertension

7% renal impairment

OUTCOME AND AVERAGE FOLLOW-UP PROTEINURIA IN IgA NEPHROPATHY

REMISSION OF PROTEINURIA IMPROVES PROGNOSIS IN IgA NEPHROPATHY

Reich H et al. JASN 2007; 18: 3177

Time-average proteinuria1 - < 1g/24h2 – 1-2 g/24h3 – 2-3g/24h4 - >3g/24h




PATHOLOGICAL evidencePATHOLOGICAL evidence

A CLINICO-PATHOLOGICAL CLASSIFICATION FOR IgA NEPHROPATHY

Does pathology add prognostic information

.. to clinical data at time of biopsy ?

.. to clinical data during follow up ?

A CLINICO-PATHOLOGICAL CLASSIFICATION FOR IgA NEPHROPATHY

Does pathology add prognostic information

.. to clinical data at time of biopsy ?

.. to clinical data during follow up ?Perhaps the biopsy is only useful

to establish the diagnosis of IgAN ?

PATHOLOGICAL CLASSIFICATIONS IN RENAL DISEASE

Are usually based on expert opinion

... and pre-conceived ideas of what lesions are important

OXFORD CLASSIFICATION OF IgA NEPHROPATHY

A different way

Approach the problem with an open mind

With an international consensus group

• Study allall histological lesions

• Test reproducibility & independence

• Then test correlations with outcome

SCORING OF SELECTED PATHOLOGY FEATURES

Mesangial hypercellularity - in > or <50% of glomeruli M0 or M1

Endocapillary hypercellularity – present/absent E0 or E1

Segmental sclerosis/adhesions – present/absent S0 or S1

Tubular atrophy/interstitial fibrosis – 0-25%, 26-50%, >50% T0 or T1 or T2

Each can be scored easily in routine clinical practice

PREDICTIVE SIGNIFICANCE OF PATHOLOGY FEATURES IN IgA NEPHROPATHY

M E S T

Each adds predictive value to ….

Initial clinical features

Follow up clinical features

In all ages and races studied

VALIDATION STUDIES FOR THE OXFORD CLASSIFICATION OF IgAN

M E S T

Macedonia2010

98 + + + +

USA2011

54 + + - +

Japan2011

161 children + + - +

France2011

183 - + + +

USA, Canada2011

187 adults & children

+ + + +

China2011

410 - + + +

Japan 2011

702 - - + +

Sweden2012

99 + + - +

Korea2012

197 + - + +

6/10 7/10 6/10 10/10

WHAT NEXT ?

Validation studies

Work towards combining pathology and clinical elements

– to produce a single ‘risk score’

There is now the opportunity to design smaller, shorter RCTs


How good is the evidence to guide the treatment of

IgA nephropathy ?

KI Supplements 2012 2(2): 1-274

CLINICAL PRACTICE GUIDELINE FOR GLOMERULONEPHRITIS

Examples of Rating Guideline Recommendations

Level 1 We recommend….

Most patients should receive the recommended course of action

1A

Supported by evidence from high quality RCTs

Level 2 We suggest …

Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision appropriate for them

2D

No RCTsSupported by limited observational data

QUALITY of Supporting Evidence is shown as A, B, C or D

Examples of Rating Guideline Recommendations

Level 1 We recommend….

Most patients should receive the recommended course of action

1A

Supported by evidence from high quality RCTs

Level 2 We suggest …

Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision appropriate for them

2D

No RCTsSupported by limited observational data

QUALITY of Supporting Evidence is shown as A, B, C or D

Of 10 recommendations or suggestions in the IgA Nephropathy guideline

Only 2 (20%) are 1A or 1B

Clinical Practice Guideline for Glomerulonephritis

…. will not tell you what to do for every difficult patient in every situation


…. will not tell you what to do for every difficult patient in every situation

The Guideline is not there to give you expert advice about an individual problem case


…. will not tell us what to do for every difficult patient in every situation

….will remind us what we know


…. will not tell us what to do for every difficult patient in every situation

….will remind us what we know

….will remind us what we do not know


“Should I treattreat this patient with IgA nephropathy ?”

Non-visible haematuria

Visible haematuria

Nephrotic syndrome

Acute kidney injury

Proteinuria > 1g/day

Progressive fall in GFR

TREATMENT DECISIONS IN IgA NEPHROPATHY

Hypertension

Crescentic IgA nephropathy

Microscopic haematuria

Macroscopic haematuria

Nephrotic syndrome

Acute kidney injury




Hypertension


TREATMENT RECOMMENDATIONS FOR IgA NEPHROPATHY

Recurrent Macroscopic Haematuria

No role for antibiotics

No role for tonsillectomy



Nephrotic syndrome

Acute kidney injury


Progressive renal insufficiency


Hypertension


Macroscopic Haematuria with acute renal failure

Renal biopsy is mandatory if not improve in 2-3 days with supportive measures

AKI WITH VISIBLE HAEMATURIA IN IgA NEPHROPATHY

Moreno J et al. CJASN 2012; 7: 175

How common ?

AKI in 38% (4/11) of visible haematuria episodes (Praga 1985)Much less common in most other reports

How important are crescents ?Crescents often seen, but in <20% of glomeruli

and usually notnot the cause of AKI

9 published reports – 84 patients



Recovery of renal function ?

Most reports (29 patients) …

100% have complete recovery of renal function

Two reports (55 patients) – only 73% full recovery

9 published reports – 84 patients



Recovery of renal function ?

Full recovOne centre in Spain (52 patients)

Full recovery less likely:

Older ageDuration of visible haematuria (mean 15 vs 36 days)

Peak sCr (7.1 vs 309 mg/dL)

Tubular necrosisTubular red cell castsInterstitial; fibrosis


Acute Tubular Necrosis

Supportive measures only


Immunosuppression maymay be appropriate

Macroscopic Haematuria with acute renal failure

Renal biopsy is mandatory if not improve in 2-3 days with supportive measures



Nephrotic syndrome

Acute renal failure




Hypertension


Renal outcome with best known treatment

CRESCENTIC GLOMERULONEPHRITIS

Renal survival

1 year 5 years

Systemic vasculitis 80% 75%

Goodpasture’s 70% 50%

Crescentic IgA nephropathy 50% 20%

TREATMENT FOR CRESCENTIC IgA NEPHROPATHY

A number of recent optimistic reports -

Corticosteroids + Cyclophosphamide

Small : < 20 patients

Selection criteria variable

All are anecdotal


Definition?

More than just a few crescents

Rapidly progressive renal failure


Definition?

More than just a few crescents

Rapidly progressive renal failure

Which patients respond ?

Treat if crescents + other active glomerular damage

AND no chronic or irreversible changes


If immunosuppression is indicated…

INDUCTION: Prednisolone 0.5-1mg/kg/dayCyclophosphamide 2mg/kg/day

MAINTENANCE: Prednisolone in reducing dosageAzathioprine 2mg/kg/day

[plasma exchange unproven]


If immunosuppression is indicated…

INDUCTION: Prednisolone 0.5-1mg/kg/dayCyclophosphamide 2mg/kg/day

MAINTENANCE: Prednisolone in reducing dosageAzathioprine 2mg/kg/day

[plasma exchange unproven]

An RCT is badly needed

…. and will be difficult to achieve



Nephrotic syndrome

Acute renal failure




Hypertension


NEPHROTIC-RANGE PROTEINURIA IN IgA NEPHROPATHY

Chen M et al. NDT 2011; 26: 1247

IgAN and nephrotic range proteinuria

N = 233

More More likely to have normoalbuminaemia than minimal change, FSGS, or membranous

Nephrotic-range proteinuria and serum albumin > 35 g/l

95.8% specificity for IgAN

NEPHROTIC SYNDROME IN IgA NEPHROPATHY

Kim J-K et al. CJASN 2012; 7: 247

n = 100 – mean follow up 45 months

Complete remission 48%

Partial remission 32%

No remission 20%

Spontaneous remission 24%

PRIMARY END POINT - DOUBLE SERUM CREATININE

24%

More likely if partial or no remission



n = 100

Mean follow up 45 months

p<0.001



100

885

P<0.001

NEPHROTIC SYNDROME + MICROSCOPIC HAEMATURIA

NEPHROTIC SYNDROME + MICROSCOPIC HAEMATURIA

Corticosteroids: complete remission of nephrotic syndrome

Microscopic haematuria persists

Two common glomerular diseases coincide……

Minimal change nephrotic syndrome IgA nephropathy


Minimal change

Mesangial hypercellularity

Glomerulosclerosis


n = 34

Prednisolone for 4 months: 40-60 mg daily halved after 8 weeks

Follow up 38 months

Lai - Clin Neph 1986; 26:174

Response of proteinuria

only in those with minor histological changes

Randomised controlled trial


Minimal change

Mesangial hypercellularity

Glomerulosclerosis

The response to corticosteroids in minimal change

does not justify their use

in all IgAN with nephrotic syndrome



Nephrotic syndrome

Acute kidney injury




Hypertension


Non-visible haematuria

Visible haematuria

Nephrotic syndrome

Acute kidney injury




Hypertension


PUBLISHED TREATMENT TRIALS IN IgA NEPHROPATHY

Often underpowered

Often insufficient follow up for ‘hard’ endpoints

Most use clinical entry criteria

Some have patients beyond ‘the point of no return’

TREATMENT OPTIONS FOR PROGRESSIVE IgA NEPHROPATHY

Blood pressure control

Renin-angiotensin blockade

Corticosteroids

Other immunosuppressives




Corticosteroids

Other immunosuppression


Target Blood Pressure

Proteinuria < 1g/24hr 130/80

Proteinuria > 1g/24hr 125/75

RAS Blockade


Combination therapy ?

EFFECT OF ACE INHIBITOR PLUS ARB ON PROTEINURIA IN IgA NEPHROPATHY: META-ANALYSIS

Cheng J et al. Int J Clin Pract 2012; 66: 917

6 studies – 109 patients

EFFECT OF ACE INHIBITOR PLUS ARB ON PROTEINURIA IN IgA NEPHROPATHY: META-ANALYSIS

Cheng J et al. Int J Clin Pract 2012; 66: 917

NoNo effect on GFR

but

Study duration: 2-12 months

6 studies – 109 patients


Target Blood Pressure

Proteinuria < 1g/24hr 130/80


RAS Blockade


Combination therapy ?

SALT

RESTRICTION

DIETARY SODIUM RESTRICTION AMPLIFIES EFFECTS OF RAS BLOCKADE ON PROTEINURIA

Slagman M et al. BMJ 2011

Lisinopril 40mg/day

Valsartan 320mg/day

Sodium intake 50 or 200 mmol/day

DIETARY SODIUM RESTRICTION AMPLIFIES EFFECTS OF RAS BLOCKADE ON PROTEINURIA

Slagman M et al. BMJ 2011

Lisinopril 40mg/day

Valsartan 320mg/day

Sodium intake 50 or 200 mmol/day

Systolic BP

Diastolic BP


Proteinuria > 1g/day + hypertension

Only if

BP target achieved…

and proteinuria still >1g/24 hr

consider corticosteroids, immunosuppressive regimens …

What is the evidence these regimens are effective in these circumstances ?




Corticosteroids


CORTICOSTEROID TREATMENT FOR IgA NEPHROPATHY

Pozzi C et al Lancet 1999; 353; 883 - JASN 2004; 15: 157

Survival without end point - doubling of serum creatinine

Randomised controlled trial – serum creatinine < 130 µmol/L

n = 86

creatinine < 133 µmol/l - proteinuria 1-3.5g/24hr

Regimenmethylprednisolone 1g iv x3 at 1,3,5 months plusprednisolone 0.5 mg/kg/alt days for 6 months

No important side effects - no study ‘drop outs’

CORTICOSTEROID TREATMENT IN IgA NEPHROPATHY

Pozzi C et al Lancet 1999; 353; 883 - JASN 2004; 15: 157


n= 103

2 year treatment regimen

Prednisolone 20mg od reducing to 5mg by 6 months

CORTICOSTEROID TREATMENT IN IgA NEPHROPATHY

Katafuchi AJKD 2003; 41:972

Antiproteinuric effect but no effect on renal function


BLOOD PRESSURE CONTROL IN IgA NEPHROPATHY TRIALS

BP (mm Hg)

160

150

140

130

120

110

100

90

80

70

60

NKFRecommendation

125/75

Corticosteroids

Pozzi Katafuchi

CORTICOSTEROIDS PLUS ACE INHIBITOR IN PROTEINURIC IgA NEPHROPATHY

Lv J et al. 2009 AJKD; 53: 26Manno C et al. NDT 2009; 24: 3694

TWO SIMILAR STUDIESProteinuria > 1g/24h - GFR > 50 ml/min

Continuous ACE inhibitor

+ oral CORTICOSTEROIDS for 6-8 months

Follow up: 2 years (China), 5 years (Italy)

Well maintained BP


BP (mm Hg)

160

150

140

130

120

110

100

90

80

70

60

JNCRecommendation

125/75

Corticosteroids

Pozzi Katafuchi

Manno Lv


ESRD

STEROIDS CONTROL

ITALY 1/48 8/49

CHINA 1/30 7/33

Statisticallysignificant



STEROIDS CONTROL

ITALY 1/48 8/49

CHINA 1/30 7/33


But.. achieved ACE inhibitor dose rather low



STEROIDS CONTROL

ITALY 1/48 8/49

CHINA 1/30 7/33


But.. neither study had a ‘run-in‘ period





Corticosteroids


IMMUNOSUPPRESSIVE TREATMENT FOR PROGRESSIVE IgA NEPHROPATHY

NO ROLE FOR

Cyclophosphamide


BP (mm Hg)

160

150

140

130

120

110

100

90

80

70

60

JNCRecommendation

125/75

Ballardie

Corticosteroids+

Cyclophosphamide

Corticosteroids

Pozzi Katafuchi

Manno Lv

IMMUNOSUPPRESSIVE TREATMENT FOR PROGRESSIVE IgA NEPHROPATHY

NO ROLE FOR

Cyclophosphamide

What about Mycophenolate


BP (mm Hg)

160

150

140

130

120

110

100

90

80

70

60

JNCRecommendation

125/75

Ballardie

Corticosteroids+

Cyclophosphamide

Corticosteroids

Pozzi Katafuchi

Manno Lv

Mycophenolate

Maes

Tang

MYCOPHENOLATE IN IgA NEPHROPATHY

Benefit BP achieved ACE inhibitors[number of patients]

BELGIUM

Maes 2004 [34] None 125/73 100%salt restricted

HONG KONG

Tang 2005 [40] ESRD 122/71 100%reduced


• The role of corticosteroids and immunosuppressives after tight BP control and maximal RAS blockade ?

• The effect of ancestry on treatment responses

Uncertainty

Optimal supportive therapy for 6 months(ACEi, ARB, target BP < 125/75 mm Hg, Statin, etc.)

Optimal supportive

Responder

Non-Responder

Proteinuria >0.75 g/d

Run

-in P

hase

(6 M

onth

s)St

udy-

Phas

e(3

Yea

rs)

Optimal supportive + Immunosuppression

Drop-Out

RANDOMISATION

Study Design

0

50

100

150

200

250

300

350

400

Recruitment-Update STOP IgAN - Status 28.2.2011 -

Follow-up

IgA

N p

atie

nts

Study patientsn=356

Randomisedn=127


We are still short of evidence …..

So there is room for your own opinion …..

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ASSESSMENT AND MANAGEMENT OF IgA NEPHROPATHY John Feehally

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