Glomcon presentation on MVI

Microvascular inflammation (MVI)
of the kidney allograft
Maarten Naesens, MD PhD
KU Leuven, Belgium
Glomcon session March 6th 2023

Kidney transplantation - a quiet revolution
Coemans, Callemeyn, Naesens. N Engl J Med, 2022
First transplantation, recipient 48 years, deceased donor of 45 years, 2.48 HLA-mismatches, 6.1% PRA
N=108 887

Late graft failure is a multifaceted problem
Van Loon et al. Transplantation 2020
24/33 experienced a
prior rejection episode

Adapted from Naesens et al.
J Am Soc Nephrol 2016;27(1):281–292.
0.3-1.0 vs. <0.3 g/24h
1.0-3.0 vs. <0.3 g/24h
>3.0 vs. <0.3 g/24h
30-45 vs. >45 mL/min/m2
15-30 vs. >45 mL/min/m2
<15 vs. >45 mL/min/m2
g+ptc ≥2 vs. <2
Banff grade 1 vs. 0
Banff grade 2-3 vs. 0
Banff grade 1 vs. 0
Banff grade 2-3 vs. 0
Present vs. absent
Present vs. absent
0.1 1 10 100
Proteinuria
eGFR
IFTA
Transplant
glomerulopathy
GNF
PVAN
microcirc. inflammation
Hazard ratio (95% CI)
for kidney graft loss
Several prognostic markers are independent risk factors
for graft failure

Graft
Survival
Probability
0
0.0
0.2
0.4
0.6
0.8
1.0
39
iBox risk strata 1
35
iBox risk strata 2
24
iBox risk strata 3
9
iBox risk strata 4
N at Risk
N
Time Post iBox Risk Evaluation (Years)
Graft
Survival
Probability
0 1 2 3 4 5 6 7
0.0
0.2
0.4
0.6
0.8
1.0
883 852 776 652 514 398 320 223
iBox risk strata 1
589 558 491 400 304 228 179 124
iBox risk strata 2
371 325 260 196 142 98 64 48
iBox risk strata 3
165 128 99 77 60 37 24 16
iBox risk strata 4
iBox risk strata 1
iBox risk strata 2
iBox risk strata 3
iBox risk strata 4
N at Risk
Log−rank p<0.0001
C−index − 95% CI : 0.83 (0.79−0.86)
European validation cohort
Time Post iBox Risk Evalu
0 1 2 3 4
0.0
0.2
615 613 606 598 585
iBox risk strata 1
475 462 451 439 420
iBox risk strata 2
301 287 276 263 247
iBox risk strata 3
135 119 99 84 69
iBox risk strata 4
iBox risk strata 3 : score 2.51−3.22 or nomogr
iBox risk strata 4 : score ≥ 3.22 or nomogram
N at Risk
Log−rank p<0.0001
C−index − 95% CI : 0.80 (0.77−0.83)
C
B
iBox provides a multidimensional predictor of graft failure
Loupy, Aubert, Orandi, Naesens et al BMJ 2019

Today, rejection is diagnosed
in biopsies
(Banff classification as current ground truth)

Mission of Banff
Risk markers:
- HLA mismatches
- vPRA
- HLA-DSA
- Missing self
- Non-HLA
antibodies
- …
Non-invasive
diagnostics:
- Serum
creatinine/eGFR
- Proteinuria
- Blood markers
(dd-cfDNA,
mRNA)
- Urinary markers
- Polyomavirus PCR
- ...
Biopsy-based
diagnosis:
- Histological Banff
classification
- Biopsy-based
molecular
diagnostics
Disease stage:
- Active disease
- Chronic/active
disease
- Chronic disease
Disease
severity/extent
- Activity index?
- Chronicity index?
Outcome
prognostication:
- Single markers
(e.g., eGFR
evolution)
- Multidimensional
markers (iBox)
- Patient
comorbidities
Predictive markers:
- None available
Future disease
risk
Ongoing disease
probability
Disease
diagnosis
Disease
stage/severity
Prognostication Prediction of
therapy
response
Banff Classification

Banff = dichotomization of a complex histological picture
Callemeyn J, et al. Kidney Int. 2022

The spatial distribution of the inflammatory infiltrates, not the content, defines the histological diagnosis of rejection
Antibody-mediated rejection T cell-mediated rejection
Production of proinflammatory cytokines
& recruitment of immune cells
Migration of activated T cells to the graft
Activation and clonal expansion of T cells
B cells activation & plasma cells differentiation
Secretion of donor-specific antibodies
Antibody-dependent cell-mediated cytotoxicity
& complement activation
Damage to donor kidney endothelium

Dichotomization leads to loss of information
g 0 1 2 3
ptc 0 1 2 3
c4d 0 1 2 3
t 0 1 2 3
i 0 1 2 3
v 0 1 2 3
cg 0 1 2 3
i-IFTA 0 1 2 3
ci 0 1 2 3
ct 0 1 2 3
pvl 0 1 2 3
ABMR 0 1
Borderline 0 1
TCMR 0 1
PVAN 0 1

1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 2019 2022
1. Tissue injury
2. Antibody interaction
3. Serological evidence
Microvascular inflammation
Microvascular inflammation
C4d deposition
C4d deposition
HLA-DSA

16
Histologic lesions are not specific

17
Occurrence of microvascular inflammation in absence of detectable HLA-DSA
Callemeyn J, at al. J Am Soc Nephrol. 2021

18
Microvascular and tubulointerstitial inflammation often coexist

19
Microvascular and tubulointerstitial inflammation often coexist
Heterogeneity of the immune cells infiltrate irrespective to location

Calvani et al Am J Transplant 2020

Heterogeneity of immune cell infiltrate of rejection is
not reflected in the Banff classification
Calvani et al Am J Transplant 2020
TCMR (Case #6) TCMR (Case #20)
ABMR (Case #26) ABMR (Case #40)

Allograft rejection =
a complex interplay
of genetic mismatches,
immune cells,
soluble mediaters and
structural cells

N=935
No ABMRh (N=727; 78%)
ABMRh (N=208; 22%)
We observed a very high percentage
of patients with ABMRh without HLA-DSA
Primarily microcirculation inflammation
(97% g/ptc criteria for ABMR)
Senev et al. Am J Transplant 2019
q .
q .
q Ba

N=935
No ABMRh (N=727; 78%)
ABMRh (N=208; 22%)
HLA-DSA positive ABMRh
(N=85; 41%)
HLA-DSA negative ABMRh
N=123 (59%)
of patients with ABMRh without HLA-DSA
q .
q .
q Ba

Banff’01 Banff’13 Banff’17
Not considered as sABMR or ABMR in any Banff update
n=3171
Callemeyn, al. Am J Transplant 2021.
ABMR
n=74
sABMR
n=238

DSA+ C4d- MVI+
DSA- C4d- MVI+
DSA+/C4d+ v > 0
DSA+ C4d+ v > 0
ABMR
n=199
sABMR
n=292
n=3171
No ABMR
n=179
ABMR
n=74
sABMR
n=238
DSA- MVI+

n=3171
DSA+ C4d- MVI+
DSA- C4d- MVI+
DSA+/C4d+ v > 0
DSA+ C4d+ v > 0
ABMR
n=199
sABMR
n=292
ABMR
n=237
No ABMR
n=254
DSA- C4d+ 1st/MVI+
DSA- C4d- MVI+
DSA+ C4d- 1st+
Isolated ptc
Isolated ptc
ABMR
n=74
sABMR
n=238
No ABMR
n=179
DSA- MVI+

The “suspicious for ABMR” category associates with increased risk
of graft failure, intermediate between no ABMR and full ABMR

The “suspicious for ABMR” category associates with increased risk
of graft failure, intermediate between no ABMR and full ABMR
?

Clinical presentation Impact
Causes Diagnosis
MicroVascularInflammation
2
3 4
1

Causes Diagnosis
1

The paradigm of antibody-mediated rejection
Callemeyn et al. Manuscript in preparation
Microvascular
inflammation
=
MVI

N=935
No ABMRh (N=727; 78%)
ABMRh (N=208; 22%)
(N=85; 41%)
N=123 (59%)
of patients with MVI without HLA-DSA

Prevalence
A. Histological picture of antibody-mediated rejection
C. Transplant glomerulopathy
MVI is more prevalent in HLA-DSA positive patients
Coemans et al. Transplant Int 2021
Prevalence
A. Histological picture of antibody-mediated rejection
C. Transplant glomerulopathy N = 1000 transplants; 3594 posttransplant biopsies

Coemans et al. Transplant Int 2021
Absolute number of cases
B. Histological picture of antibody-mediated rejection
D. Transplant glomerulopathy N = 1000 transplants; 3594 posttransplant biopsies
There is a high number of cases with MVI
without HLA-DSA

DSAneg MVI differs from DSApos ABMR
(97% MVI)
HISTOLOGICAL PICTURE
OF ABMR
(Banff criteria 1 and 2)
N=208 patients
HLA-DSA positive
N=85
HLA-DSA negative
N=123
More
graft failure
(33%)
Less
graft failure
(15%)
Time after
transplantation
(< 1y)
Light
microscopic
appearance More
Repeated
(52%)
More
transient
(27% repeat)
More
C4d positivity
(55%)
Less
C4d positivity
(38%)
C4d
p<0.001
p<0.001
p<0.01
First clinical
presentation
Equal

Causes Diagnosis
2
1

DSAnegABMRh
DSAposABMRh
Outcome of HLA-DSA negative MVI is better than in

Outcome of HLA-DSA negative ABMRh is better than in
Bestard & Grinyo, Am J Transplant 2018 Koenig et al Nat Comm 2019

ABMRh -> transplant glomerulopathy: one entity!
Logit
(ABMR)
Time post-transplant
First occurrence cg
• Highly significant in entire cohort (HR 1.19, p<0.001)
• And even in the DSA negative group (HR 1.16, p<0.001)
à ABMRh/cg
‘Exposure to’ ABMRh
Joint
modeling
Coemans et al. Transplant Int., 2021

Association between time-dependent aABMRh, cg and aABMRh/cg and
death-censored graft failure
(N=837 HLA-DSA negative patients; 3140 biopsies)
Coemans et al. Transplant Int., 2021
Parameters in the survival sub-modela
# phenotype
occurrences
HR (95% CI) P-value
aABMRh 205 1.17 (0.97 – 1.43) 0.10
cg 79 1.25 (1.08 – 1.55) 0.004
aABMRh/cg 268 1.32 (1.07 – 1.61) 0.008

Causes Diagnosis
2
3
1

The paradigm of antibody-mediated rejection
Callemeyn et al. Kidney Int 2022

How can we explain DSA-negative MVI?
HLA-DSA
negative
MVI
Direct
NK cell
activation
Missed/
resolved
HLA-DSA
Non-HLA
DSA B-cell
memory
Other
mechanism

DSA negative MVI can be explained by missed HLA-DSA
Talk to the HLA lab!
Senev et al AJT 2020

Non-HLA Ab detection immunoassay (NHADIA)
to detect non-HLA DSA
Lamarthée et al JASN 2021

MICA is confirmed as minor histocompatibility antigen
in kidney transplantation leading to anti-MICA DSA and MVI
Carapito et al Nat Med 2022

The STAR guideline on non-HLA antibody testing
Tambur et al In Press
Non-HLA DSA testing not recommended (Score 3)
with low to very low (C-D) quality of evidence

NK cells are kept in balance by inhibitory and activating receptors
KIR

Tumoral
NK cells activate by “absence of self” (missing self)

NK cells activate by “absence of self” (missing self)

The concept of missing self requires NK cell education
Callemeyn et al. J Am Soc Nephrol 2021

Missing self, direct NK cell activation and ABMRh
Koenig et al. Nature Commun 2019
A B
C

Missing self – prevalence in kidney transplantation

Missing self associates with MVI
“high” missing self

Missing self independently increases the risk of MVI
Pretransplant HLA-DSA

Missing self specifically increases the risk of MVI
Correlation only with glomerulitis and arteritis, not with other Banff lesions

Independent predictor of
transplant glomerulopathy
No additional effect on
allograft outcome after MVI
Missing self synergizes with DSA-dependent NK cell
activation with worse transplant glomerulopathy

Missing self synergizes with DSA-dependent NK cell
activation with worse prognosis of C’ negative chronic AMR
Koenig et al. J Am Soc Nephrol 2021

Callemeyn et al. JASN 2021
Koenig et al. Nat Commun 2020
102/222 of MVI (46%) not yet explained
15/44 of MVI (34%) not yet explained
Not all MVI is explained by DSA or by missing self

There are many
pathways of
NK cell activation
Hamada et al. HLA 2021

N=935
No ABMRh (N=727; 78%)
ABMRh (N=208; 22%)
(N=85; 41%)
N=123 (59%)
CONCLUSION:
DSA-negative MVI is very common
and further research is needed

Recent research on DSA-negative MVI
Association with
NK missing self
- Koenig et al Nat Commun 2019
- Callemeyn et al JASN 2021
- Koenig et al JASN 2021
Relation to HLA
mismatches and TCMR
- Senev et al cJASN 2022
Phenotype, prevalence
and outcome
- Sablik Transplant Int 2018
- Senev et al. Am J Transplant 2019
- Bestard et al. Am J Transplant 2019
- Lubetzku et al Clin Transplant 2019
- Parajuli et al Transplantation 2019
- Coemans et al Transplant Int 2021
- Vaulet et al JASN 2021
- Crespo et al Front Immunol 2021
- Halloran et al Am J Transplant 2022
- Saba et al ATC 2022 meeting abstract #209
Phenotype in the
molecular microscope
- Lubetzky et al Clin Transplant 2019
- Halloran et al JASN 2022
- Rosales et al JASN in press
- Callemeyn et al under review (sparse models)
Relation with non-HLA
antibodies
- Reindl-Schwaighofer et al Lancet 2019
- Lefaucheur et al Kidney Int 2019
- Delville et al JASN 2019
- Lamarthée et al JASN 2021
- Senev et al Front Immunol 2022
- Carapito et al Nat Med 2022
- Asano et al Nat Comm 2021; Chong present.
Non-invasive biomarkers
- Van Loon et al Nephrol Dial Transplant 2020 - mRNA
- Halloran et al JASN 2022 TRIFECTA study - ddcfDNA
- Van Loon et al under review - urinary CXCL9/10

Phenotype, prevalence
and outcome
- Sablik Transplant Int 2018
- Senev et al. Am J Transplant 2019
- Bestard et al. Am J Transplant 2019
- Lubetzku et al Clin Transplant 2019
- Parajuli et al Transplantation 2019
- Coemans et al Transplant Int 2021
- Vaulet et al JASN 2021
- Halloran et al Am J Transplant 2022
- Saba et al ATC 2022 meeting abstract #209
Recent research on DSA-negative MVI, indicating a need for definition
Association with
NK missing self
- Koenig et al JASN 2021
Relation to HLA
mismatches and TCMR
- Senev et al cJASN 2022
Phenotype in the
molecular microscope
- Lubetzky et al Clin Transplant 2019
- Halloran et al JASN 2022
- Rosales et al JASN in press
- Callemeyn et al under review (sparse models)
Relation with non-HLA
antibodies
- Reindl-Schwaighofer et al Lancet 2019
- Lefaucheur et al Kidney Int 2019
- Delville et al JASN 2019
- Lamarthée et al JASN 2021
- Senev et al Front Immunol 2022
- Carapito et al Nat Med 2022
- Asano et al Nat Comm 2021
Non-invasive biomarkers
- Van Loon et al Nephrol Dial Transplant 2020 - mRNA
- Halloran et al JASN 2022 TRIFECTA study - ddcfDNA
- Van Loon et al under review - urinary CXCL9/10
All these studies use DIFFERENT DEFINITIONS
of the phenotype of DSA negative MVI,
complicating interpretation

How to integrate DSA-neg MVI in Banff?
HLA-DSA
positive
MVI = AMR

HLA-DSA
negative
MVI
Direct
NK cell
activation
Missed/
resolved
HLA-DSA
Non-HLA
DSA B-cell
memory
Other
mechanism
HLA-DSA
positive
MVI = AMR
How to integrate DSA-neg MVI in Banff?

Disease diagnosis
- Criterion 1
- Criterion 2
- Criterion 3
Disease subtype
- Active
- Chronic/active
- Chronic
Histological/molecular description
Causal diagnosis
Differential diagnosis
Causal marker
Disease stage
- Activity index
- Chronicity index

MVI
MVI, DSA+ = AMR
MVI, DSA- = cause
unknown
Histological
description
Causal diagnosis Disease stage
Active
Chronic
active
Chronic
A clinical reasoning system
MN

Consensus according to Banff’22 survey
“MVI, DSA-negative and C4d-negative”
• “MVI, HLA-DSA-negative and C4d-negative” should be clearly defined in the Banff’22 report, to instigate and
streamline research on this topic, using a consensus-based definition
(86% Agree; 6% Partially agree; 8% Disagree)
• Although there is uncertainty on the causes and treatment options for “MVI, DSA-negative and C4d-negative”,
this phenotype should be included in the Banff Classification Table, and thus also be reported on in clinical
practice (77% Agree; 11% Partially agree; 13% Disagree)
• MVI, DSA-negative and C4d-negative can be diagnosed in patients with normal or abnormal kidney function.
This is a descriptive diagnosis, and the cause remains unclear. Further research is needed to determine the
causes and best treatment for this phenotype. These cases may represent autoreactive or alloreactive non-
HLA antibodies; primary NK cell activation through missing self, viral infection, and other mechanisms of
innate immune activation; ischemia reperfusion injury; alloreactive T cell mediated responses, etc.

Consensus according to Banff’22 survey
“Possible AMR”
• Cases with histological features of AMR (criterion 1 positive, i.e., g, ptc, v, TMA, cg, ptcml etc) and HLA-DSA
positivity (criterion 3 positive), but not reaching the Banff thresholds for AMR [criterion 2 negative: C4d
negative and g+ptc<2] should be reported to the clinician as “possible AMR”
• In the context of circulating DSA or C4d deposition in peritubular capillaries, individual lesions of MVI below
the histological and/or molecular threshold for MVI possibly indicate antibody activity. This can be diagnosed
in patients with normal or abnormal kidney function. Depending on the clinical context, antibody-targeted
treatment could be considered.

AMR/MVI lesion(s) present
(g, ptc, v, TMA, cg, ptcml)
MVI threshold*
At least moderate MVI (g + ptc ≥ 2) in the absence
of recurrent or de novo glomerulonephritis.
If borderline (suspicious for) or acute TCMR, or infection are
present, ptc ≥ 2 is not sufficient and Banff lesion score g≥1 is
required

AMR/MVI lesion(s) present
(g, ptc, v, TMA, cg, ptcml)
MVI threshold*
Above MVI threshold*
Lesion(s) present but
below MVI threshold*
Evaluate C4d** in ptc
and DSA
Evaluate C4d** in
ptc and DSA
Both C4d-
and DSA-
Either C4d+
or DSA+
C4d+ (independent
of DSA status)
MVI, DSA
negative and
C4d negative
AMR
AMR
AMR No AMR
Suspicious for
AMR
Banff'13
Banff'19
Banff'22 AMR
AMR
(DSA+)
AMR
Both C4d-
and DSA-
C4d-
but DSA+
Possible
AMR
Suspicious for
AMR
No AMR
No AMR
No AMR
No AMR
Suspicious
for
AMR (DSA-)
Both C4d+
and DSA+
AMR
AMR
AMR

Glomcon presentation on MVI

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