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 !