IgA nephropathy: unusual forms
Transcript of IgA nephropathy: unusual forms
IgA nephropathy: unusual forms
Khalil EL KAROUI Service de néphrologie et transplantation rénale,
INSERM U1151 Hôpital Henri Mondor, Créteil
Actualités Néphrologiques J. Hamburger 23 Avril 2018
« The most frequent primary glomerulonephritis »
IgA + C3+ Mesangial proliferation: Until 1,6% of pre-implantory biopsies in Japan
Introduction: IgA nephropathy
Suzuki, KI, 2003
Several unusual forms !
Clinical presentation
Rapidly progressive GN,
malignant hypertension/hypertensive emergency
Histology
Monotypic IgA deposits
Associated diseases
Inflammatory bowel diseases, Infections (staphylococcal)
Unusual IgAN or other glomerulopathy ?
Unusual clinical presentation: rapidly progressive GN
IgAN: 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% !
Lv, JASN, 2013
Very high risk of evolutivity
KDIGO, 2012
Crescents/Necrosis: up to 30% patients !
But usually low proportion of glomeruli
Crescents/Necrosis and prognosis
Katafuchi, cJASN 2011
Japanese Study, 702 patients deleterious role of crescents if inclusion of <30ml/mn or rapidly progressive
Cut off: 6,8%
Crescents N (%)
<10% 892 (92%)
10-25% 43 (4%)
25-50% 19 (2%)
>50% 10 (1%)
St Etienne + Necker Cohort
<10% 10-25% 25-50% >50% P<0,001
Alamartine, personnal data
Crescents/Necrosis and prognosis
Low rate
Haas, JASN 2016
3096 patients, 4 cohorts, « Cellular or fibrocellular »
Rapidly progressive GN
Lv, JASN, 2013
Few studies 113 chinese patients, 8 centers (Discovery + validation cohort) 66% crescent (cellular, fibrocellular, fibrous) Acute renal failure, proteinuria
Rapidly progressive GN: pathology
Lv, JASN, 2013
Severe pathology Acute/fibrous lesions Glomerular AND interstitial lesions
Lv, JASN, 2013
Follow-up 22m Treatment: steroids +/- immunosuppressive (mainly CYC) ESRD last FU 56%
Rapidly progressive GN: Treatment
Lv, JASN, 2013
Rapidly progressive GN: Prognosis
Similar prognosis than AASV ?
Unusual clinical presentation: hypertensive emergency
Malignant Hypertension/Hypertensive emergency
Malignant hypertension: Definition ?
( Malignant ? OPH examination ?)
Severe BP elevation (180/120mmHg)
with involvement of 3 targets organs
(eye, kidney, heart, brain, microangiopathy)
« Multi-organ damage »
« Hypertensive emergency »
Morbidity: 5y ESRD 25% (to 84% ?!)
Mortality: 5y: 15%
Biological thrombotic microangiopathy during HE: 30%
Shantsila, Am J Hypert, 2017
Cremer, J Hum Hypert, 2015
Amraoui, BMC nephrol, 2012
Gonzalez, NDT, 2010
Mancia, ESH/ESC guidelines, J Hypert, 2013
IgAN-Hypertensive emergency
45 chinese patients, 1995-2004, IgAN + MHT (BP and hypertensive retinopathy), 26 primary MHT, no IgAN control cohort 1,2% of IgAN Renal failure, Severe proteinuria, haematuria. Prognosis vs IgAN without MHT ?? ESRD: 12% (3y) (?)
Chen, KBPR, 2005
IgAN-Hypertensive emergency
No specific associated histological lesions
45 chinese patients, 1992-2007, IgAN + MHT (BP and hypertensive retinopathy), 41 non-MHT IgAN 19 primary MHT First manifestation of IgAN 62% Renal failure, Severe proteinuria, haematuria. Frequency ?? Prognosis ??
Jiang, NDT, 2008
IgAN-Hypertensive emergency
El Karoui, Hill.. Nochy, JASN, 2012
French cohort, 2002-2008, 128 IgAN patients, 18 MHT (14%) FU 44mths Low eGFR, and high proteinuria, biol thrombotic microangiopathy (27%) 99% RAS blockade, no steroids No C rare variant (n=11)
58% immediate RRT, 82% RRT/doubling sCreat last follow-up
IgAN-Hypertensive emergency: histology
El Karoui, Hill, Nochy, JASN, 2012
But unusual cohort !
El Karoui, Hill,.. Nochy, JASN, 2012
Prognosis
Prognostic effect: eGFR, biological TMA, +/- chronic histological lesions
No effect of BP per se
Histological TMA may precede hypertension development
No C rare variant in the french cohort (n=11)
DelCFHR3-1 associates with IgAN protection (GWAS)
Decreased Factor H activity and elevated FHR1/FH ratio in « progressive IgAN » ?
(but what is progressive IgAN? Large overlap )
malignant hypertension
? IgAN-TMA
IgAN-Hypertensive emergency: pathophysiology ?
Tortajada, Kidney Int, 2017
Medjerak-Thomas, Kidney Int, 2017
Unusual histology: monotypic IgA deposits
Boumedienne, NDT, 2011 Alexander, AJKD, 2011
Soares, AJKD, 2006 Setoguchi, Nephrology, 2014
Birchmore, Arth Rheum, 1996 Van Ginneken, Clin Nephrol, 1999
Dosa, Nephron, 1980
Very rare published cases
Mainly: heavy chain deposition disease (HCDD) alpha
IgA-proliferative GN with Monoclonal Ig Deposits (IgA-PGNMID)?
Monotypic IgA deposits
Monotypic IgA deposits: 6 of 65 IgAN cases (9%) ?
Lambda predominance in IgAN
No difference in presentation and prognosis vs IgAN ?
Nagae, Clin Exp Nephrol, 2016
Monoclonal gammathy of renal significance Monotypic Ig deposits
- Organized: fibrillar (amyloidosis++), microtubular (cryo, immunotactoid)
- Non-organized : LHCDD (atteinte tubulaire), PGNMID (IgG)
Nasr, JASN 2009 Guiard, cJASN 2011
Fermand, Blood 2013 Bridoux, KI 2015
Monotypic IgA deposits
19 patients, 1980-2013
4 french centers + National reference center
retrospective analysis
Vignon, Kidney Int 2017
Monotypic IgA deposits: Histology
mIgA-GN n=14 MembranoProliferative GN: n=6
Mesangial GN: n=7 Membranous Nephropathy: n=1
Alpha-HCDD: n=5
Histological classification
Kappa n=7 Lambda n=7
Truncated alpha chain: n=5 (HCDD)
Immunofluorescence
N=11 Non-organized deposits n=10; paracristalline deposits n=1 (cryo ?)
Electronic microscopy
Mesangial
lambda
kappa
alpha
Membrano proliferative
Histology: GN-mIgA
Vignon, Kidney Int 2017
Eclectron microscopy
IgA-PGNMID Alpha-HCDD
Vignon, Kidney Int 2017
n=1
n=4
n=9
Circulating mIg n = 4 - positive serum
immunofixation n=4/4 - Positive urine
immunofixation n=3/4 - Monoclonal component
0,5-8g/L - Normal serum FLC - BM infiltration < 10%
plasma cells
Multiple myeloma n=1 (IgA kappa n=1) - Anemia and bone lytic lesion - BM: 12% plasma cells - IgA kappa = 18g/L
Absence of monoclonal Ig n=9 - Negative serum and urine
immunofixation - Normal serum free light
chain - Normal BM exploration BUT - 2/2: positive immunoblot - 2/2: positive molecular
analysis on BM
Haematological explorations in patients with GN-mIgA (n=14)
Underlying clonal plasma cells
Vignon, Kidney Int 2017
IgAN polytypic vs monotypic IgA deposits
monotypic n=19 polytypic n=49 p
Age 59 36 <0.0001
Sex (H/F) 9/9 34/15 ns
HBP (%) 67 49 ns
eGFR (MDRD, ml/mn/1,73m2)
42 62 0.02
Proteinuria (g/g) 3.8 1.6 0.01
Gammaglobulin (g/l) Albumin (g/l)
Gamma/Albu (%)
5.1 32.5 15
8.0 38 21
0.001 0.0004
0.03
25% mIgA cases: Initial diagnosis: IgA nephropathy
RAS blockade n=14 No specific treatment n=4 ESRD n=1
Chemotherapy regimen
Steroid alone n = 3 Steroid + CYC n=3 Rituximab n=2
(2nd line)
Major renal response n =1 RF stabilization n =3 RF degradation* n=2 ESRD n=1 *recurrence on renal transplant n=1
RF degradation n=2, ESRD n=1
Alkylating based n=2 Bortezomib based n=3 (3rd line n=2) Imid based n=1
Major Renal Response** n =6 ** Disapearance of renal deposits on repeat kidney biopsy n=1/1
Immunomodulatory treatment
Haematological response not evaluable
Haematological response - VGPR n=4 - Not evaluable n=2
IgA-PGNMID: Treatment
Monotypic IgA deposits
This is not an IgAN ?
Older patients
Low eGFR, High Proteinuria, Hypogammaglobulinemia
Atypical histology
IgA Galactosylation abnormalities ?
But typical MGRS ! Plasma cell disease, low tumoral proliferation, with renal expression (MGRS)
Steroids, alkylating agents, bortezomib if evolutivity
Risk of haematological evolutivity (myeloma)
Alexander, AJKD, 2011 Setoguchi, Nephrology, 2014
Boumedienne, NDT, 2011
Vignon, Kidney Int 2017
Unusual association
IgAN-associated diseases
Cirrhosis
Spondylarthropathies
Inflammatory bowel diseases
IgAN: most frequent GN in IBD
« the gut-kidney axis » GWAS: loci associated both with IBD and IgAN
Role of pathogens in mice IgAN (BAFF, CD89)
LIGHT Tg mice: T cell mediated intestinal inflammation, seric pIgA elevation, IgA kidney deposits
Diet effect on IgAN/ enteric steroids effect (NEFIGAN)
Wang, JCI, 2004 Coppo, Pediatr nephrol, 2018 Fellstrom, Lancet, 2017
IBD-associated IgAN
Hematuria: 50% of 29 UC patients ? Wang, JCI, 2004
Ambrucz, cJASN, 2014
11 y, 33183 renal biopsies, 83 from IBD patients IgAN: 20/83 (24%), 4 IgA-vasculitis
IBD-associated IgAN: french cohort Preliminary results
23 patients, 15males, 37y
18 Crohn’s disease, 5 Ulcerative colitis
IgAN diagnosed after IBD diagnosis
Proteinuria 260mg/mmol
Hu 52%
eGFR 70ml/mn/1,73m2
18 patients: RAS blockade, 11 patients: steroids
Preliminary results
Comparison with primitive IgAN (124 patients)
IBD-associated IgAN: french cohort
Centralized histological evaluation: ongoing
MICI + (n = 23) MICI – (n = 124)
AGE 37,9 (13-73) 39 (17-76) p = 0,56 t-test
SEX 8 ♀ - 15 ♂ 35 ♀ - 99 ♂ p = 0,39 X2
HBP 43,5% 41,8% p = 1 X2
Initial eDFG 70,9 (17-123) 66,7 (8-125) p = 0,54 t-test
Proteinuria J0 (mg/mmol) 260 (12-900) 174 (0-940) p = 0,03 t-test
Histological severity (MEST >1) 30,4% 54,9% p = 0,03 X2
Steroids 47,8% 34,9% p = 0,26 X2
FU (months) 60 (2,4-264) 63 (0-156) p = 0,59 Mann-Withney
Final eDFG 62,3 (5-150) 63,7 (5-133) p = 0,85 t-test
Final Protéinuria (mg/mmol) 124 (0-637) 88,16 (0-550) p = 0,24 t-test
IBD-associated IgAN: french cohort Preliminary results: renal survival
0 2 0 4 0 6 0 8 0 1 0 0 1 2 0
0
2 5
5 0
7 5
1 0 0
M o n th s
Re
na
l s
urv
iva
l (%
)
Ig A N
Ig A N - IB D
No obvious difference in renal survival Propensity score: ongoing
Unusual association: IgA-dominant infection related GN
IgA-dominant infection related GN 5 diabetic patients, 4males, 65y
ONGOING staphylococcal infection (foot ulcer)
Acute renal failure, hematuria, Proteinuria, Low C3
4/5 RRT (Follow-up 9 months)
Histology
diabetic nephropathy
polynuclear neutrophils endocapillary proliferation,
IgA+C3 deposits (mesangial/cap wall/subepithelial: humps)
Nasr, Hum Pathol, 2003
IgA-dominant infection related GN 13 patients among 6334, 50y, 11 males, 5 diabetic, 4 RRT
6 staphyloccocal infection
ARF, proteinuria, hematuria, low C3 (n=4/10)
Histology
diabetic nephropathy (n=3)
polynuclear neutrophils endocapillary proliferation,
IgA+C3 deposits (mesangial/cap wall/subepithelial: humps)
One monotypic kappa ?!
Haas, Hum Pathol, 2008
Not only diabetic Not only staphylococcal infection
Infection related GN Among infection related GN in adult >65y Clinico pathologic definition (infection, low C3, histology)
109 patients, 73% males, Diabetes, malignancy 61%
Skin infection 28%, no infection 17% ! 48% staphyloccocal infection
17% IgA-dominant (16 patients, 11/16 diabetic, 9/16 Staphyloccocal infection)
Endocapillary++/mesangial proliferation (neutrophils)
Nasr, JASN, 2011
Frequent in older patients Specific histopathologic features
IgA-dominant infection related GN: Staphylococcal GN
Among Saphylococcal GN
Kidney biopsy + documented Staphylococcal infection
78 patients, 55y, 78% males, 41% Diabetes
ARF, proteinuria, hematuria, Low C3 30%
Skin infection (22%), endocarditis (21%)
Histology
IgA 75%, C3 86%, Crescents 35%; humps only 31% !
Endocapillary++/mesangial proliferation (neutrophils)
« pauci-immune pattern » 13%
Statoskar, cJASN, 2015
Diagnostic pitfall IgANephropathy/IgA vasculitis
Statoskar, cJASN, 2015
Staphylococcal GN vs IgAN
Age overlap
IgA-dominant infection related GN Infection-related is not post-infectious !
Humps are not specific of postinfectious diseases
No indication to immunosupressive therapy in ongoing staphylococcal infection !
Glassock, AJKD, 2015
Conclusion (s)
The most frequent GN,
but also multiple unusual forms
True IgAN with specific features, or other GN ?
Pathophysiological implications Hypertensive emergency/TMA, IBD-associated IgAN
Diagnostic pitfalls with therapeutic consequences monotypic IgA deposits, Infection-related GN
Thank you for your attention !