Glomerulonephritis with non-organized non-Randall monoclonal Ig deposits (PGNMID): French experience of 71 patients V. JAVAUGUE1,4, L. ECOTIERE1, P. JAMET1, S. BOUYER2, J.M. GOUJON3, S. BENDER4, J.P. FERMAND5, A. JACCARD6, G. TOUCHARD1, C. SIRAC4 and F. BRIDOUX1,4 1Nephrology, 2Cytomety
and 3Pathology, CHU Poitiers; 4CNRS UMR7276, Limoges; 5Hematology, Saint Louis; 6Hematology, CHU Limoges
Montreal, May 23, 2019
Disclosures
None
Previous studies
More than 20 case reports and small series
1985
2004
2009
2011
2015
2017
2018
Inclusion criteria • Patients with monotypic glomerular deposits (1993-2018) • Granular electron-dense deposits by EM, resembling immune complex GN • No clinical and biological evidence of cryoglobulinemia
71 patients Chemotherapy n=35
Symptomatic treatment n=21
Immunosuppressive therapy n=15
Detected B-cell clone n=15
Undetected B-cell clone n=20
Clinical characteristics at presentation • Mean age: 59 years (rang : 24-86 years) • Renal presentation : - Renal insufficiency: 73% (CKD stage 3 = 50%, stage 4 = 33%, stage 5 = 17%) - Proteinuria: 100% (mean = 4.8 g/24h) - Nephrotic syndrome: 59% - Hematuria: 85% - Hypertension: 79%
• Hypocomplementemia: 18% (low C3 +/- C4) • No extra-renal manifestation
Renal-limited disorder
Pathological findings (LM) 1
0
0
8
0
6
0
4
0
2
0
%
N G M
e
M
m
e
b
s
r
a
a
n
n
o
g
i
u
a
s
P
l
G
G
N
N
0
M
75%
14%
11%
Pathological findings (IF) IgG-PGNMID (n=55) 1
77%
0
0
83%
10%
%
6% 7%
8
0
6
0
4
0
2
0
13%
4%
0%
γ3
κ
4 I
g
G
3 G g I
g I
I
g
G
G
1
2
0
λ
Pathological findings (EM) D
a
t a
1
Subepithelial
Mesangial Subendothelial
0
0 2
0 4
0
0 6
0
8
0 1
Hematological characteristics at presentation P
G
N
M
I D
- I g
M
( n
=
7
)
P
IgM-PGNMID (n=7) IFE+FLC
G
N
M
I D
- C
L
( n
=
5
P
86%
G
N
M
I D
- I g
M
( n
=
7
)
IgA-PGNMID (n=4)
)
LC-PGNMID (n=5)
P
75%
80%
G
N
d
' u
M
I D
- I g
G
( n
=
5
5
)
m
o
n
IgG-PGNMID (n=55) 29%
IFE
t e
c
t i o
n
d
' u
n
c
o
m
p
o
a
n
t
m
o
n
o
c
l o
n
a
l
d
é
t e
c
t i o
n
d
' u
n
c
o
m
p
o
s
a
n
t
m
o
n
o
c
l o
n
a
l
d
é
t e
c
t i o
n
d
' u
n
c
o
m
p
Lymphoplasmacytic (n=4) MZL (n=3)
0
0
0 1
1
%
o
s
a
n
t
m
o
n
o
c
l o
n
a
l
d
é
t e
c
t i o
n
n
c
o
m
p
o
s
a
n
t
o
c
l o
n
a
B-cell clone?
B-cell clone?
100%
%
%
%
s
5
0
5
é
%
1
%
%
d
0
5
1
%
0
0
0
0
0
5
0
0
0
0
0
0
Abnormal FLC
80%
75%
Symptomatic MM (n=2) Indolent MM (n=2)
Symptomatic MM (n=1) Plasmacytic (n=2)
Unknown (n=1)
Unknown (n=1)
15% Plasmacytic (n=4) CLL (n=2) MZL(n=2)
Unknown (n=47) The detection rate and the nature of the B-cell clone differ according to the subtype of PGNMID
l
Treatment and outcome Whole cohort 1
0
Chemotherapy
C
0
h
i m
i o
t h
é
r a
p
i e
Renal survival
IS therapy r a
i t e
m
e
n
t
i m
m
u
n
o
s
u
p
p
a
t i q
r e
s
l e
T
a
Symptomatic r a
i t e
m
e
n
t
s
y
m
p
t o
m
i e
r é
n
T
e
e
u
r
0
r v
5
u
s
Clone detected with clone-directed therapy n=15 No clone detected with empirical therapy n=20 • CyBorD n=13 IgG-PGNMID • RTX-CYC-D n=4 IgG-PGNMID • RTX-BorD n=3 IgG-PGNMID
S
u
Rituximab n=4 IgG-PGNMID CYC +/- Pred n=4 (IgG-PGNMID, n=3; LC-PGNMID, n=1) MMF n=3 IgG-PGNMID Prednisone n=4 (IgG-PGNMID, n=3; IgA-PGNMID, n=1)
p=0,04 0
0
5
0
1
0
0
Months M
o
i s
Proven or suspected clone-directed approach seems effective
Clone-directed cohort 0
l o
n
e
+
C
l o
n
e
-
0
5
0
Clone detected n=15 C
l o
n
e
+
R
D
f r e
e
s
u
r v
i v
a
Renal survival
l
1
C
S
No clone detected n=20
E
C
p=0,09 0
0
5
0
1
0
0
l o
n
e
-
IgG3k-PGNMID n=18/20
IgG3k-PGNMID : clone detection? Only patients with negative immunofixation and normal FLC at baseline
Serum immunoblot (n=20)
IgG3k detectable in 11 cases
Immunoglobulin Repertoire Sequencing (n=12)
RepSeq analysis (1 patient) vidjil 2017.03
M-spike (IgGk) was detectable at one-year follow-up
Sensitivity of immunofixation?
RepSeq analysis (11 patients) vidjil 2017.03
Is it really monoclonal in all cases: oligoclonal ?
In progress…
Conclusion • Renal limited disorder with constant proteinuria • Nature and rate of detection of B-cell clone varying according to the subtype of PGNMID
• Clone-directed approach seems effective to improve renal outcome • Physiopathology of IgG3k-PGNMID is still unknown
RepSeq analysis (bone marrow) vs. Proteomic analysis (kidney)
Thank you • APHP : • Bichat – Pr VRTOVSNIK • Cergy Pontoise – Dr MONTSENY • Henri Mondor – Dr REMY, Dr STEHLE • Necker – Pr KNEBELMANN, Dr HUMMEL
Collaborators • CHRU Tours – Dr GATAULT • CH Aix en Provence – Dr COZETTE
• CHU Amiens – Pr CHOUKROUN, Dr LECAQUE
• CH Avignon – Dr GOBERT
• CHU Besançon – Dr BAMOULID
• CH Bourg en Bresse – Dr TOUSSAINT, Dr ORFEUVRE
• CHU Bordeaux – Dr RIGOTHIER • CHU Clermont-Ferrand – Dr TIPLE, Dr GARROUSTE
• CH Boulogne sur Mer – Dr MESBAH • CH Cambrai – Dr MORABITI • CH Chambéry – Dr FOURCADE
• CHU Dijon – Pr MOUSSON, Dr ZANETTA, Dr LEGENDRE
• CH Douai – Dr CARDON, Dr MOREL
• CHRU Lille – Pr HAZZAN, Dr PROVOT, Dr FRIMAT
• CH Dunkerque – Dr BEAUMONT
• CHU Lyon – Dr NOUVIER, Dr KARLIN, Dr CARDOZO
• CH Metz – Dr MAURIER, Dr MOUGENOT, Dr GUERARD
• CHU Rouen – Dr POUSSART, Dr KHUZAIE
• CH Montceau les mines – Dr MONARD
• CHU Toulouse – Dr RIBES, Dr MEHRENBERGER
• CH Périgueux – Dr QUERON • CH Roubaix – Dr LE MONIES • CH Tournai – Dr MADHOUN • CH Valenciennes – Dr VANHILLE, Dr ULRICH, Dr LEMOINE
