Treatment of IgA nephropathy

Actualités Néphrologiques J. Hamburger,

Institut Pasteur, 29 Avril 2014

Dr Khalil El Karoui Service de Néphrologie adultes,

INSERM U1151 Hôpital Necker, Paris

« The most frequent primary glomerulonephritis »

IgA + C3+ Mesangial proliferation: Until 1,6% of pre-implantory biopsies in Japan

Introduction

Suzuki, KI, 2003

Evolution is highly variable

Blood pressure, proteinuria (1g ? 0,5g?), GFR dgn; obesity ?

Histological criteria ?

• Global Optical Score

• Oxford criteria: MEST

• Crescents if >50% glomeruli

Prognosis factors

Currently no consensual therapeutic strategy in IgAN !

Renal survival: 80% after 20 years ? Currently: 2003-2011: renal survival 91% after 45 months ? eGFR -3ml/mn/1,73m2/year ? Isolated hematuria: 14% spontaneous remission, only 30% evolutivity (HBP, Pu) 4% doubling sCreat (9 years)

Li, cJASN, 2014

Evolution

Berthoux, JASN, 2011

Gutierrez, JASN, 2013

KI, 2009

Katafuchi, cJASN, 2011

Berthoux, JASN, 2011 Reich, JASN, 2007

CKD progression is difficult to evaluate !

Serum creatinine ? 7,6% variability

Proteinuria is not a marker of kidney function !

Selvin, AJKD, 2013

ESRD rate needs very long-term follow-up in most patients

Poggio, JASN, 2005

Froissart, Actualités Néphrologiques, 2008

eGFR degradation is not well correlated with mGFR degradation (until 50% underestimation of degradation rate with MDRD formula ?)

Various clinical situations

Risk of evolutivity: Very Low / Very High

No proteinuria, No HBP, no severe histological lesions: No disease ? ESRD (10 y): 1%

Annual Follow-up

Berthoux, JASN, 2011

Very low risk

Rapidly progressive glomerulonephritis

>50%cellular+fibrocellular crescents

ESRD (1y): 43% !

IV steroids and cyclophosphamide (cf ANCA vasculitis)

Lv, JASN, 2013

Very high risk

KDIGO, 2012

Proteinuria, HBP, eGFR

Supportive therapy

Supportive therapy is systematic

Floege, JASN, 2011

Proteinuria: < 1g/d or < 0,5g/d ? Blood pressure: 130/80mmHg ?

Additive effect of Blood pressure and proteinuria control

ACE inhibition Enalapril vs placebo; 44 patients, Pu>0,5g/d, Creat<150µM; 7years

Renal survival (>50% sCreat): 92% (enalapril) vs 55% (other anti-HBP)

But: Similar effect of RAS inhibition on ESRD ?

Berthoux, JASN, 2011

Praga, JASN, 2003

Supportive therapy is systematic

Optimal supportive therapy

+ Persistent proteinuria or GFR degradation

(but >50mL/mn)

=

Steroids 6 months ? But which type/dosage of corticosteroids?

Proteinuria, HBP, eGFR

Floege, JASN, 2011

Steroids in IgA Nephropathy

Steroids: 3g IV M0 M2 M4+0,5mg/kg/d, 1d/2, 6months vs « supportive care »

Endpoint: 50% sCreat increase

86 adults patients, <70years, RCT; 1987-1995 Pu>1g/j, sCreat<133µM, no histological criteria (RBiopsy<1year) No systematic RAS inhibition; BP control ?

sCreat 50% increase (5 years) : 9/43 (steroids) vs 14/43 (supportive) ESRD (7y): 1/43 (steroids) vs 5/43 (supportive)

Pozzi, JASN, 2004

Cox regression analysis: sex, steroids, vascular sclerosis score

If « Pu reduction at 6 months »: no statistical effect of steroids

ACE inhibition: 14% at baseline, 42% during follow-up

No reduction of Pu in the control group

No adverse event ?

BUT…

97 adults, <70y, RCT, 2000-2004 Renal Biopsy<1year Pu>1g/d, eGFR>50ml/mn, Histological Grade2 (« moderate MEST »)

3 months run-in without RAS inhibition, then

Ramipril vs

Ramipril+Steroids 1mg/kg 2m, then 6 months

CreatX2 or ESRD

sCreatX2 or ESRD (5 years): 26.5% vs 4.2% ESRD: 7/49 (14%, ramipril alone ) vs 1/48 (2%, combination)

ESRD

BUT… Pu<1g/d: only 70%

ACE inhibition stop before starting the study (over-treatment ?) 98 exclusions for histological cause

63 adults, <65y, RCT, 2004-2006 Renal Biopsy<1year Pu>1g/j, eGFR>30ml/mn, no histological criteria

4 weeks run-in without RAS inhibition, then

cilazapril vs

Cilazapril+Steroids 0.8-1mg/kg 2m, then 6 months

Predictors of renal survival (multivariate analysis): combination therapy, time-average Pu

sCreat 50% increase (2.5 years): 7/29 (24%) vs 1/31 (3%) ESRD: 2/29 (cilazapril alone ) vs 0/31 (combination)

Steroids in IgA Nephropathy

9 RCT, 536 patients, Pu>1g/d, « normal renal function » 356 patients: sCreat < 130µM or eGFR >50ml/mn/1,73m2

8.6% « kidney failure » (doubling sCreat)

Overall: Steroids the risk of kidney failure (68%)

Dose effect: high dose, short term

Main Adverse effects: Cushingoid features

Meta-analysis

Steroids in IgA Nephropathy

For which patients ? Pu - eGFR

Control group ?

Evaluation of measured GFR ?

Reduction of ESRD risk ?

Remaining questions

Other therapies ?

No demonstrated benefit of MMF in caucasian patients (asian ?)

No benefit of cyclophosphamide in steroid-treated patients

No benefit of azathioprime in steroid-treated patients

Rituximab is under evaluation

Pozzi, JASN, 2010

Immunosuppressive therapy

NCT00498368

Fish oil : no statistically significant benefit

Amygdalectomy: recurrent tonsillitis and macrohematuria ?

Enteric steroids: reduce proteinuria ?

Dillon, JASN, 1997

Hogg, cJASN, 2006

Floege, JASN, 2011

Non-Immunosuppressive

Smerud, NDT, 2011

The next ?

STOP IgAN: results in 2014 ! Optimal supportive therapy

To improve supportive therapy

148 patients Optimal supportive therapy

Iry objective: 3 years: full remission or

15ml/mn eGFR loss

To improve Patient Selection

Impact of histological factors ?

Oxford Classification

Valiga Study: 1147 patients, 86% RAS inhibition, 48% steroids

MEST: no pejorative effect if steroids

Treatment according to histological factors ?

KI, 2014

KI, 2009

Retrospective studies

Prospective study ?

IgAN 90ml/mn>GFR>30ml/mn,

Pu>1g/g (ou 0,5g/g if RAS inhibition), HTA

Histological evaluation

Histological severity

No histological severity

Steroids 6 mois Nephroprotection

mGFR M0, M12, M24 ESRD

Nephroprotection 6-12 m

Steroids 6 m If disease progression

mGFR M0, M12, M24 ESRD

CONCLUSIONS

Various forms of the disease

Evaluation criteria of previous studies are questionable

But overall: Efficacy of steroids

The next: always steroids ?

Improve supportive therapy

Improve selection criteria

Thanks !