treatment of iga nephropathy - jean hamburger · steroids in iga nephropathy 9 rct, 536 patients,...
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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 !
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