A M R Abbreviations ( read twice please ): o AB : antibody o Ag: antigen o a HUS: atypical hemolytic ...
AMR
Abbreviations (read twice please):
o AB: antibody
o Ag: antigen
o aHUS: atypical
hemolytic uremic syndrome.
o AKI: acute
kidney injury
o ALm:
Alemtuzumab
o
AMR: Antibody-mediated
rejection
o ARB: angiotensin
II receptor blocker
o Belat: belatacept
o BM: bone
marrow
o Bortz: bortezomib
o BW: body
weight
o
C: complement
o
C1 INHs: C1
inhibitors
o CDC: C-dependent
cytotoxicity
o
Ch. AMR: Chronic AMR
o
CMV:
cytomegalovirus
o CMX: crossmatch
o CyA:
cyclosporine
o
DD KTR: deceased-donor
kidney transplant recipients
o Dgx: diagnosis
o
DSA:
donor-specific antibodies
o
Dsnz: Desensitization.
o DX: dialysis
o Ecz:
Eculizumab
o
eGFR: estimated
glomerular filtration rate
o ENDATs:
endothelial cell-associated transcripts
o EOD:
every
other day.
o Evrol:
everolimus
o FDA: Food and
Drug Administration
o FFP: fresh
frozen plasma
o Gcrtcd: glucocorticoids
o
HLA: human
leukocyte Ag.
o
IA: immunoadsorption
o iABO: incompatible
ABO
o
IF/TA:
interstitial fibrosis/tubular atrophy
o Ig: immunoglobulin
o
IL-6: interleukin-6
o im/m: immunosuppression
o IVIG:
intravenous immunoglobulin
o
KPD: kidney
paired donation
o
KTR: kidney
transplant recipients
o
KTx: kidney
transplantation
o MAC: membrane
attack complex.
o
MCS: median
channel shift
o
MFI: mean
fluorescence intensity
o
MM: multiple
myeloma
o
MMF:
Mycophenolate mofetil.
o
Mthyprd: Methylprednisolone
o
NFkB: nuclear
factor kappa-B
o
NK: natural
killer.
o PCP:
Pneumocystis pneumonia
o
PE: plasma
exchange
o
PMN: polymorphonuclear
neutrophils
o PNH:
paroxysmal nocturnal hemoglobinuria
o
Pph: plasmapheresis
o Pred:
Prednisone
o Prox: prophylaxis
o PT:
prothrombin time
o Ptc:
peritubular capillary score
o PTT: partial thromboplastin time
o rATG-T: rabbit
antithymocyte globulin-Thymoglobulin
o RCT: randomized,
controlled trials
o RITUX ERAH: Impact of
ttt With Rtx on the
Progression of Humoral Acute Rj After Renal Transplantation.
o Rj: rejection
o Rtx: Rituximab
o SCr:
serum
creatinine
o SE: side
effects
o
Snz: sensitized/sensitization
o
SRL: sirolimus
o Tac:
Tacrolimus
o
TCMR: T
cell-mediated (cellular) rejection
o
TG: transplant
glomerulopathy
o
TMA: thrombotic
microangiopathy
o
TR: Transplant recipients
o
ttt: treatment/treated
o
tttp: therapy
o
Tx: transplant/transplantation
o UNOS: United
Network for Organ Sharing
o
UO: Urine
output
AMR is the most
common cause of allograft loss after KTx. The
revised Banff
2017 has classified AMR into active (= acute) and ch. active AMR as states of
histologic
evidence of acute/ch.
injury + evidence
of current/recent AB interaction
with vascular
endothelium + serologic evidence of DSA to HLA or non-HLA Ags.
The cellular & molecular pathways
regulating AMR still to
be recognized. However, evidence showed that B cell &
plasma
cell activation
> DSAs
production that bind to HLA or non-HLA molecules found
on the endothelial lining within kidney allograft. In active AMR, AB bind the
graft endothelium with C-dependent & -independent activating mechanisms and
recruiting NK cells, PMN, platelet
cells, & macrophages contributing to the peritubular
capillaritis, glomerulitis, cellular necrosis, TMA, with rapid
loss in graft function.
On
the other hand, ch. AMR is a separate
pathophysiological subset resulting from repeated thrombotic
events with inflammatory alterations leading to endothelial injury with graft matrix remodeling. It is presented
histologically as TG with slow/progressive loss of allograft
function. Growing evidence suggesting that prevention & ttt of AB-mediated injury mandates combined regimen
to inhibit B cell evolution,
maturation, and activity. Despite the wide No. of observational reports, it’s still
unclear which combined tttp is the
safest & most efficacious.
OUTCOME PREDICTORS:
Active & ch. AMR are both
associated with poor longevity after KTx. Ptns
with active AMR are at higher risk for subsequent Rj, ch. AMR, & allograft
loss. Similarly, ptns with ch. AMR have an
increased risk for allograft loss and mortality. However, not all
TR with AMR express poor
outcome, and many ptns maintain stabilized graft function for ys after ttt
of the early episode of Rj.
Histologic features: Some histopathological criteria on allograft
biopsy at the time of Rj are predicting
worse survival, e.g., associated acute TCMR is an independent risk factor for allograft loss
in ptns with AMR. There’s also obvious
& independent link between microvascular
injury & C4d staining (including focal C4d
st. in post-reperfusion biopsy) with poor survival in active or ch.
AMR. Similarly, TG & the degree of ch. injury (with semi-quantitative
assessment via ch. interstitial, tubular, vascular & glomerular Banff scores) are linked to worse allograft
survival.
DSA: Certain criteria of DSAs have been
associated with poor outcome in AMR:
1]
DSA strength: Study:
402 DD
KTR, the risk for both AMR & allograft
loss directly correlating with peak pre-existing anti-HLA DSA strength via
MFI. Ptns
with a peaked anti-HLA
DSA MFI
of > 6000 had > 100-fold higher risk for AMR compared
with MFI of <465. Allograft
survival with a peak anti-HLA DSA MFI of >3000 was less than that with MFI of ≤ 3000. However, lack
of tissue-proven Rj & acute inflammation, HLA DSA may not be
complicated with higher risk of graft failure.
2]
DSA subclass: The Ig subclass
of DSA can
predict outcome. Study: 125 ptns with DSAs recognized
in the 1st y. post-tx, the IgG4 immunodominant DSA was
associated with:
1)
IF/TA.
2)
Late graft injury,
3)
Higher graft glomerulopathy, &
In
contrary, IgG3 immunodominant DSA was
associated with:
1)
Short time
to Rj,
2)
Greater microvascular damage,
3)
C4d capillary
deposition, & graft failure.
3]
C-binding
capacity: The ability of anti-HLA DSAs to bind C, (via C1q assay),
may recognize TR
at higher
risk for allograft loss. However, one study: C1q-binding capacity
of DSAs is largely
reflecting the difference in AB strength, denoting the biologic importance of C1q assay.
4]
DSA type: either (pre-existing or de novo) may be a
predictor of worse outcomes. De novo DSA, mostly related to non-adherence or under im/m, has been
linked to poorer outcome compared to preexisting DSA (i.e., pre-Snz ptns).
5]
DSA response
to ttt: A growing evidence that lowered DSA strength
after ttt
showed better
graft longevity, despite little data about the +ve DSA response.
Graft function: The magnitude of graft dysfunction during biopsy is directly correlated with poor outcome in TR with AMR. Retrosp. Analysis: 205 ptns with biopsy- approved AMR, eGFR of <30 mL/min per 1.73 m2 at Dgx & urine protein-to-Cr ratio of ≥ 0.30 g/g at the timing of biopsy were determined as independent factors of allograft loss. Another study: 123 ptns with ch. AMR, SCr of >3 mg/dL and urine protein-to-Cr ratio of >1 g/g at the timing of Dgx were independently correlated to allograft failure.
Other risk factors: The
finding of ENDATs & DSA-selective transcripts has been observed to
be a biomarker of active AB-mediated
injury predicting worse allograft outcome. These molecular assays
that’re not yet included in clinical practice, reflecting the alterations in
micro-endothelium not normally identified by routine histopathology and DSA testing
to upgrade risk stratification and prognosis.
Prediction model: Novel
prediction models have been introduced to anticipate long-term renal graft
failure, including post-Rj tttp. Cohort
study: 7557 KTR from 10 Tx centers from Europe/US,
32
prognostic factors for renal graft survival were evaluated: 8 functional, histological, & immunologic factors
were independently correlated with graft failure and combined
into a risk prediction score
(iBox) showing distinct calibration/discrimination.
The iBox score presents accuracy if used at several
times of evaluation post-Tx and was approved
in several clinical scenarios that include response to Rj tttp
suggesting that iBox risk
prediction score can help monitoring TR with
further improvement of designing & developing valid & early new
endpoint in clinical trials.
PREVENTION: A suggested
approach to prevent AMR development depends
on detecting DSA before (pre-existing
DSA) or after (de novo DSA)
Tx.
Pre-existing
DSA before
Tx: Ptns with pre-existing DSA before Tx have a higher risk for AMR with allograft
loss as compared to non-Snz ptns.
This risk is correlated to the strength of DSA as ptns with +ve CDC CMX
(1st) have increasing risk of AMR and allograft loss than TR with +ve flow CMX (2nd),
who’s in turn show increasing risk than ptns with +ve virtual CMX
(3rd). Despite avoiding Tx highly
Snz ptns
is usually considered to prevent AMR, this option makes ch. DX the only option, with
its sequalae on health and quality of life. Long-term outcome in KTR has been improved with Dsnz programs evolution that can be offered to
limit DSAs
levels before Tx. Moreover, ptns enrollment
in specific plans to optimize matching may be enrolled in a timely Tx with better outcome. A suggested approach to
prevent AMR
with preexisting DSA before Tx include:
●
TR with potential living donor, according to
the findings of the most recent CMX:
(1) TR with +ve CDC CMX or strongly +ve flow CMX
> use KPD program,
rather than Dsnz, given the higher risk of
AMR &
graft loss in these ptns. KPD
program (National Kidney Registry, the
Alliance for Paired Donation, & UNOS KPD Pilot Program) enables Snz
ptns with immunologically incompatible living donors to be Tx with high-quality
graft from other living donor
with similar setting and agreed to exchange organ. Despite cost could be a matter
for kidney exchange registry in the US, KPD could help assisting Tx centers avoiding a costly Dsnz protocol with better long-term outcome.
Mathematic modeling has anticipated that an optimum
matching algorithm with national KPD
program could improve allograft outcome and limit health care costs for highly Snz TR.
Some Tx centers may combine Dsnz & KPD.
(2)
In TR with +ve virtual CMX
or a mild/moderate flow CMX (i.e., MCS <250), we employ HLA
Dsnz program including ttt with Pph, rATG-T,
& Rtx.
o
TR without a
potential living donor, we admit HLA Dsnz plans.
o
All ptns with
a preexisting DSA before Tx undergoing
KTx > use
induction & maintenance im/m tttp suitable for high-risk TR developing acute Rj.
Post-Tx monitoring: Monitoring of graft function in TR with preexisting DSA prior to Tx is similar to non-Snz ptns. Moreover, routine monitoring of DSA level at mo 1, 3, 6, & 12 post-Tx, then yearly. In TR with significantly higher DSA or developing de novo DSA within the 1st 3 mo > allograft biopsy that’s largely consistent with the recommendations of the Consensus Guidelines on the Testing & Clinical Management Issues Associated with HLA and Non-HLA AB in Tx. Ptns with pre-Tx DSA should perform protocol biopsy at mo 3 & 12 post-Tx. Some experts perform a post-reperfusion kidney graft biopsy at the timing of Tx to determine TR at risk for AMR. In ptns having evidence of +ve C4d staining, Pph (2-3 sessions) + single dosing of Rtx 375 mg/m2 (after the last Pph session) could be included in the induction im/m.
Ptns
with de novo
DSA after Tx: KTR
developing de novo DSA after Tx
may present as late-onset
AMR. AMR with de novo DSA
has been complicated by poorer outcome as compared to AMR with
pre-existing DSA. The 2 most
common causes of AMR due to de novo DSA
are:
1]
Under im/m, &
2]
Non-adherence
to tttp.
The
former cause can be frequently linked to the advent of the minimizing strategies. Moreover, acute TCMR, malignancy,
& opportunistic infections (e.g.,
BK polyomavirus
& CMV) requiring reducing im/m may also impact the development of late-onset AMR.
Preventing AMR must focus on non-adherence &
under-im/m while balancing the safety
& efficacy of long-term im/m. TR mostly maintained on triple im/m tttp (Tac, MMF
& Pred) with whole blood Tac monthly monitoring in the 1st 3 ys post-Tx and
every 3 mo thereafter. TR not tolerating Tac
> switch to Belat, rather than SRL or Evrol. All ptns with de novo DSA should
be vulnerable for annual:
1)
DSA estimation&
2)
Kidney
allograft biopsy.
Analysis
of 2 RCT: converting CyA to Evrol
at 3-4.5 mo after Tx was complicated with significant increasing
rates of de novo DSA (10
vs 23 %) & AMR (3 vs 13 %). In
contrary, Belat, a selective co-stimulation blocker
targeting CD80,86,28 interaction preventing T cell activation, has a lowered rate of de novo DSA
over 7 ys of ttt in phase III trials suggesting that co-stimulation
blockade may be safer & effective in blocking de novo DSA
& late AMR. Gcrtcd withdrawal/avoidance also may not augment
the risk of de novo DSA if appropriate im/m is maintained. In a 5-y, longitudinal
study: 37 KTR randomly assigned
to ch. Gcrtcd tttp or early Gcrtcd withdrawal
at d. 7 post-Tx; all TR receiving rATG-T for
induction & Tac & MMF as maintenance im/m.
Only one ptn in the ch. Gcrtcd arm &
none in the Gcrtcd withdrawal arm have
developed de novo DSA.
ACTIVE AMR tttp
The
primary target of AMR ttt is to eliminate the existing DSAs + B cells/plasma
cells eradication that’s responsible for their production. Generally, ALL ptns
with evidence of active AMR on allograft biopsy should be treated. Despite some
centers may not routinely apply protocol biopsy, they would ttt ptns having subclinical AMR via surveillance biopsy. Moreover, they
may ttt ptns with C4d -ve AMR with the same approach applied in ptns with C4d +ve AMR. Optimal tttp
of active AMR
is not certain, as there’re no RCT
to compare the safety & efficacy of different regimens. The recommended ttt of AMR is mainly based on the available, low-quality evidence
that’re consistent with 2009 KDIGO clinical practice guidelines & 2019 Tx Society Working Group Expert Consensus.
Initial
tttp: TR with
active AMR
may be ttt as out ptns, but we prefer ptns hospitalization due to protocol
complexity. Suggested approach to initial ttt of
active AMR
depending on the timing of AMR Dgx alg.:
Active
AMR within
the 1st y post-Tx > combined Gcrtcd,
Pph +
IVIG, and, in some ptns, Rtx as follows:
• IV Mthyprd 300-500 mg daily for 3-5 ds,
followed by rapid oral Pred
tapered to
the last maintenance Pred dosing.
If there’re no fear of non-adherence, we may augment the maintenance Pred dosing, e.g.,
if Rj seen
while ptn on 5
mg/d, we may increase the maintenance Pred dosing to 7.5-10 mg/d.
• Pph is offered
daily or EOD
maximum 6 sessions
or until SCr is within
20-30
% of its baseline. Initial ttt is typically a one-and-one-half-volume exchange with albumin, followed
by a one-volume
exchange with
albumin. We prefer an EOD
Pph as albumin alone can be provided for replacement with
interval
recovery of the PT, PTT, & fibrinogen to an accepted
levels with no need to give FFP. This avoids the risk of Ag Snz development;
however, 1-2
units of FFP may be supplied
for replacement at the end of Pph if
indicated via pre-procedural lab values or in the clinical setting, e.g., same-d.
graft biopsy.
•We give IVIG 100 mg/kg after each Pph session>
usually 500
mg/kg/d for 1-2
ds after the last session of Pph > total cumulative target dose of 1000 mg/kg of IVIG. Certain
centers determine the IVIG dose according
ideal BW.
Sucrose-free IVIG that’re no
> 5 % are usually
preferred to limit the risk of AKI.
o
The
finding of Microvascular inflammation on biopsy
(i.e., Banff glomerulitis score (g) + (ptc) >0) > Rtx single dosing
200-375 mg/m2
after Pph & IVIG.
o
Augment
other members of maintenance im/m as required.
Active AMR after the 1st y post-Tx: Gcrtcd tttp with similar approach as above in AMR within the 1st y post-Tx. However, we do not provide Pph in such ptns due to lack of evidence supporting Pph safety & efficacy in late-onset AMR. We give IVIG at 200 mg/kg/2 wks/3 doses. In obese ptns, some clinicians provide the IVIG dose according to ptn’s ideal BW. Sucrose-free IVIG fluids not > 5 % are preferred to limit the risk of AKI. With microvascular inflammation on biopsy, we provide Rtx 375 mg/m2 single dose after IVIG and augment maintenance im/m. ALL TR ttt for active AMR, we resume antimicrobial & antiviral Prox in a regimen similar to that given in the immediate post-Tx period including Prox against PCP, CMV, & herpes simplex (with low CMV risk) for 3 mo. Moreover, we may provide antifungal Prox & Prox H2 blocker to prevent peptic ulceration. We do not routinely provide IA, Bortz, Toci, Ecz, or splenectomy in initial tttp AMR, rather we may provide them to TR not responding to initial ttt. There’s lack of high-quality RCT to guide the optimal tttp of PCP, CMV with active AMR. The best available data come from:
1) Systematic review: 5 RCT & 7 non-RCT assessed
the effects of different ttt
on graft
outcome among KTR with
active AMR. All about
PCP, CMV were small,
& mostly proceeded via outdated criteria for AMR. 4 RCT assessed
the benefit of Pph; one
study: benefit, one reported potential harm, and 2 reported no effect.
However, the Pph protocol
differed in dose, frequency, & ttt interval, & IVIG was not provided.
One RCT: a
benefit of using protein IA. The non-RCT: potential
benefit from tttp
with Rtx, Pph, & Bortz; however,
as some trials used combined tttp, the impact of individual agents couldn’t be specified.
2) Phase III, multicenter, RCT: RITUX ERAH examined
the impact of Rtx among 38 KTR with tissue-approved,
active AMR. Ptns randomly
assigned to Rtx (375 mg/m2) or
placebo at d 5 of ttt;
all ptns provided Pph, IVIG, & Gcrtcd > no
difference between 2 g.s in frequency
of the initial endpoint = composite measure of graft loss or lack
of improved graft function at d 12. Both gs showed: improved histologic features
of AMR & Banff score at one &
6 mo, with a trend favoring Rtx g. Despite both g.s showed declined DSA intensity
as early as d. 12, no difference between g.s at 12 mo.
3) The benefit of combined tttp of Pph, IVIG, & Rtx was given
by an observational study (France) compared the efficacy of Pph/IVIG/Rtx vs
high-dose IVIG alone in
the ttt
of AMR. Graft
survival at 36 mo was 92
% among ptns ttt with Pph/IVIG/Rtx vs 50 % with IVIG alone. At 3 mo post-ttt,
DSAs were
significantly lowered in Pph/IVIG/ Rtx g. Another study: confirmed that active
clinical/subclinical AMR in the 1st
y. post-Tx have
better outcome if ttt with combined regimen including Pph.
Response to tttp: A suggested approach for ptns monitoring during tttp of active AMR primarily depends on whether the ptn is admitted for ttt or as an out-ptns. Ptns can be ttt as an out ptn basis, but it’s typically preferred in-ptn admission considering the complexity of the tttp protocol. For out-ptn setting, we can monitor SCr, electrolytes, & CBC before each Pph session or wkly/4 wks if Pph is not provided. Ptns receiving Pph revised and assessed during Pph tttp and then in the OPD at 4 wks from the start of tttp; TR not receiving Pph perform wkly labs for one mo and monthly thereafter. All ptns are revised for follow-up in the clinic at 3 mo from the start of ttt, we assess DSA level and repeat graft biopsy if not performed before. Data concerned with reversal of AMR are scarce. Generally, one-y graft survival after ttt of clinical & subclinical AMR is almost 80 & 95 %, resp. TR are considered having successful reversal of AMR if they meet ALL of the following criteria within 3 mo of tttp:
1)
Decline in
SCr of 20-30 % of the basal
line
2)
Decline in
proteinuria to its baseline value
3)
Decline in
immunodominant DSA by > 50 %
4)
Corrected AMR-associated
alterations on repeated biopsy
Most
ptns with AMR
with a successful response to anti-Rj
tttp will be reflected on SCr decline within 7 ds of ttt. Next
steps are based on TR response to initial tttp:
v Ptns with SCr decline in response to ttt > augment
maintenance Tac
to get a
trough level 20-25 % above
the level at timing of Rj, then resuming the routine monitoring. Ptns taking immediate-release
formula of Tac and not
tolerating higher doses, the extended-release formula of Tac with its
fewer SE allowing higher/therapeutic
trough, can be provided. Maintenance im/m can be also augmented via increasing the daily dosing
of oral Pred.
v Ptns with no decline in SCr after 7 d of Rj ttt are
considered failed initial ttt. In these TR, ongoing Rj and/or another etiology of graft dysfunction should
be expected, repeated biopsy should be considered. Next approach depends according
to the histopathological/clinical findings. If biopsy findings reveal lack of acute,
reversible finding or
show
extensive fibrosis (= dead renal
tissue), > hold ttt
of acute Rj. If biopsy
shows evidence of persistently
active AMR, 2nd-line
agents for tttp
of AMR can be instituted
as rescue tttp. However,
the magnitude of added tttp with Pph and other medications
e.g., Bortz &
anti-C tttp should be
balanced with associated comorbidities and the risk of infections and malignant
sequalae.
2nd-line agents with failed initial tttp: TR with active AMR will be mostly responding to combined Gcrtcd, Pph, IVIG, & Rtx. However, ptns not responding to initial ttt with this formula, the following agents may be tried as rescue tttp.
Bortezomib: Bortz is a
potent, reversible proteasome inhibitor approved
by FDA as 1st
line tttp for MM since 2008. Bortz decreases
intracellular
protein degradation via inhibiting
proteasomal
activity leading to
apoptosis, primarily via inhibiting NFkB-induced
survival signals. It’s specifically efficacious against differentiated plasma cells owing to
their high rate of protein
synthesis. Multiple case reports/series have shown the efficacy
of Bortz in AMR tttp, reversing
acute Rj, and/or DSAs decline. One
study: 2 ptns ttt with Bortz for
active AMR showed a transient decline in BM plasma cells in vivo with constant changes
in allo-AB specifications.
Total IgG levels were not changed, suggesting proteasome activity is crucial for plasma cell survival and
its suppression may control AB production
in vivo. Another study: 2 ptns have Bortz-based tttp for
active AMR seen within 1st 2 wks post-Tx. Both ptns
showed proper reversal of AMR and removal of detectable DSA within 14 ds. On the other hand, a follow-up
study: 28 ptns with active AMR reported that Bortz tttp was
associated with better DSA and histological response with early (< 6 mo of Tx) Rj but not late AMR.
Bortz in
late AMR was
evaluated in a RCT of 44 KTR
with ≥6 mo post-Tx, had a +ve DSA, and histological evidence of active
or ch. AMR. Ptns were assigned to 2
cycles of Bortz (1.3 mg/m2 IV
on d: 1, 4, 8, & 11) or placebo; baseline im/m was designed according to a pre-existing protocol. At 24 mo post-ttt,
no clear difference between the g.s in eGFR/
y. (-4.7 vs -5.2 mL/min/1.73m2 /y. in Bortz-
& placebo-ttt groups, resp). Ptns/graft outcome were comparable, and there
were no differences in average GFR,
proteinuria, DSA values, or morphologic or molecular Rj phenotypes in 24-mo graft biopsies. On the
other hand, Bortz-ttt ptns showed frequent
GI & hematologic toxicities.
Eculizumab: Ecz is a fully humanized, monoclonal AB directed against the C5 fragment
of the C cascade & inhibiting the generation of MAC. It’s approved by FDA for PNH
& aHUS
tttp. In KTx, Ecz has been utilized to prevent AMR in
highly Snz TR who already undergone
Dsnz. There’re also reports of beneficial
use as a salvage tttp in refractory active AMR. Dosing has been similar to those given
for aHUS
tttp, and duration of dosing was
variable. Lack of RCT showing its
efficacy & safety has prohibited its use in KTR.
Moreover, AMR
has been observed in KTR receiving
Ecz for other indications e.g.,
receipt of +ve CMX
kidney or HUS. Ecz also has not been shown to be effective
for ttt of C4d -ve active & ch. AMR,
suggesting its efficacy may be confined to acute, C-mediated processes.
Special
cohorts
Mixed
acute Rj: Ptns with mixed acute Rj (i.e., histological evidence of both AMR + acute
TCMR [Banff 2A or more]) should be ttt for both AMR & TCMR. We ttt with combined Gcrtcd, Pph,
& IVIG, as above, with + rATG-T added
to the ttt plan. Here, we provide Pph & IVIG on an alternate-d. (e.g., Mon, Wed, Fri., & Sun.) for minimum 4 ttt. We provide
rATG-T
(1.5-3 mg/kg) on
an alternate-d. on the intervening days (e.g.,
Tues, Thur., and Sat.),
total 3
doses.
Subclinical Rj: = finding
of histologic
evidence of acute Rj on biopsy
without rise in SCr. This Dgx is
typically settled by a protocol/ surveillance biopsy in a protocol-designed after
Tx rather
than clinically indicated. With subclinical AMR, we admit
the same
regimen used in
clinical AMR. Retrosp.
Studies: ttt
of
subclinical AMR can be
associated with better graft outcome. One study: compared graft outcome
of 219 KTR with AMR (77
subclinical, 142 clinical) with matched controls with no AMR. One- &
5-y graft survival among ptns with subclinical AMR were 95.9 & 75.7
%, resp, compared with 96.8
& 88.4
% in controls. Risk of allograft loss with subclinical AMR was 2.15-fold >
that in matched controls. However, there was no significant difference in allograft
loss between ttt
subclinical
AMR & controls.
C4d -ve AMR: Some TR with histologic evidence of AMR & +ve DSA but have little or no C4d st. in the peritubular
capillaries (C4d -ve AMR). Such ptns ttt in similar approach as that for
C4d +ve.
TR with non-HLA DSA: AMR can also
occur in ptns with non-HLA DSAs, e.g.,
anti-angiotensin II type 1 (AT1) receptor AB & anti-endothelial
AB. The im/m ttt of AMR in such ptns
is generally the same as that with AMR and an
anti-HLA DSA. Ptns found
to have an anti-AT1 receptor AB should
receive, added to im/m tttp, an ARB that may
inhibit AT1-receptor AB-mediated impacts.
Less
frequent therapies
Immunoadsorption: with protein A (IA) has been
utilized to correct AMR. The
only controlled, open-label trial: 10 ptns with severe AMR were assigned
to IA or no IA (with rescue
IA after 3 wks). ALL
IA-ttt ptns responded
to tttp, while 4
controls remained DX dependent.
Rescue IA was not efficacious.
Whilst not available in the US, selective IA is an attractive alternate to the non-selective
combined Pph & IVIG. Given
the improved outcome in ttt AMR with Pph & IVIG, as
compared with controls, and with IA, compared to controls in this small trial, further
analysis would compare the 2 ttt plans in a larger cohort. Although both types of ttt are
expensive, selective modality of IA with no need for IVIG would be
preferable if similar outcome is evident. The relative role of IVIG or Pph in ttt AMR still
uncertain.
Splenectomy: not
offered routinely in AMR, considering
the lack of proper evidence as a safer/ efficacious procedure than current tttp. Some centers may consider splenectomy for
refractory AMR.
o
4 (2 iABO, one CMX +ve, one with clear risk factors) with AMR + failed
standard tttp (mean 11 d.) with steroid, Pph, IVIG, rATG-T, & Rtx (3 ptns) or ALm (one ptn)
were ttt with laparoscopic
splenectomy. UO improved immediately, & SCr declined
within 48 hs.
o
5 TR with
living-donor RTx
after Dsnz for a +ve CMX had an AMR. After
rescue trials with Pph & IVIG failed,
they underwent splenectomy followed by Pph + IVIG. Graft
function recovered within 48 hs after splenectomy.
Experimental
therapies:
C1
inhibitors: Activation of C pathway is crucial
step in the pathogenesis of AMR. Binding of anti-HLA DSAs to C fraction
C1q, the 1st
component in activation of the C cascade, has been associated with poor graft
outcome with severe phenotyping of AMR. These findings have provided the rationale for using
proximal C inhibition
via C1 INHs in ttt of AMR. C1 INHs have been
approved by the FDA
for ptns
with hereditary
angioedema. The admit of a plasma-derived C1 INH in ttt of active AMR was
evaluated in a phase IIb,
multicenter, RCT
of 18 KTR with
biopsy-approved, active AMR. Ptns were assigned to receive C1 INH 20,000 units or
placebo EOD for 2 wks
(total 7 doses) as
adjunctive tttp to
standard ttt
with Pph, IVIG, & Rtx.
Resolution of AMR was seen
in 78 & 67 % of ptns ttt with C1 INH & placebo, resp. There was no significant
difference between gs in post-ttt histopathology/graft survival on d. 20; however, a
trend to sustained
better graft function at d 90
was seen in C1 INH g.
Similar
findings were seen in a prospective pilot study: of 6 KTR with active AMR & graft dysfunction not responding to Pph, IVIG,
& Rtx. All ptns received C1 INHs Berinert (20 units/kg/d:
1, 2, & 3 & then twice wkly) + high-dose IVIG (2 g/kg/once per mo)
for 6
mo; maintenance im/m: MMF, Tac,
& Pred. At 6 mo, all ptns showed improved
eGFR compared to baseline. Kidney
allograft biopsy at 6 mo
revealed no significant change in histological features; however, C4d deposition was seen in only one of 6 ptns compared with 5 of 6 ptns at baseline. Moreover,
of the 6 ptns who were +ve for a C1q-binding
circulating DSA at initiation of the
study, only one had +ve DSA at 6 mo. Further studies are needed to recognize efficacy/safety
of proximal C inhibition in the ttt of active AMR.
TREATMENT
OF CH. AMR
ch. AMR, the most common cause of allograft
failure, is more difficult to tttp as compared with active AMR considering
the irreversible renal damage that already involved to the allograft.
Despite evidence suggesting that ttt of AB-mediated injury requires a combined regimens to impede
B cell evolution,
maturation, & activity, it’s not clear that combined tttp is safe/efficacious
in ch. AMR ptns. In
all ptns with ch. AMR we use combined
tttp of Gcrtcd & IVIG. Rtx could be
added to the regimen if there’s evidence of active microvascular inflammation on renal allograft
biopsy. Usually, we do not utilize Ecz or Bortz in ttt of ch. AMR. The suggested
approach in ch. AMR is simulating
that used in active AMR seen after
the 1st y. post-Tx. Like active AMR, there’s
no high-quality
evidence guiding
the optimal tttp
of ch. AMR, and the
suggested approach is mainly linked to the observational trials:
o
Large
observational study: 123 KTR with biopsy-approved, ch. AMR, 76 % of TR lost their
grafts with average survival of 1.9 ys after ch. AMR Dgx. Ttt with Gcrtcd & IVIG can be
linked to lowered risk of allograft loss. Ptns with surviving allografts
showed more decline in DSA suggesting the need for more clinical trials to assess DSA in ptns
with ch. AMR.
o
One study: 4 KTR with ch. AMR 1 & 27 ys post-Tx, ttt with a
combined Rtx/IVIG showed
better allograft function in all TR; DSA dropped in
2 of 4 ptns.
o
Retrosp. Review: 31 TR with ch. AMR, average allograft survival was higher
among ptns ttt with Rtx compared to
those ttt without Rtx.
One
RCT of 25 ptns with ch. AMR found no difference in
eGFR drop at one y between ptns ttt
with combined IVIG (500
mg/kg/4 doses) & Rtx
(375 mg/m2) and ptns ttt with placebo. However, the trial
achieving only one-½ of its enrolled ptns and was underpowered to recognize any
difference in its primary endpoint. Using Ecz
in ttt of ch. AMR was assessed
in a pilot, RCT: 15 TR with
+ve DSA, deranged graft function, + histological AMR
evidence. Ptns assigned in a 2:1
ratio to ttt with Ecz (10 ptns) or no Ecz
(5 ptns)/6 mo, followed by 6 mo follow up. At 12 mo,
no differences in allograft function or the expressed ENDATs, a molecular
signature predicting AMR development, between the groups.
Bortz
has NOT been shown to be efficacious in the tttp of
ch AMR.
Toci:
is a monoclonal AB that’s directed
against the IL-6 receptor has been admitted for rheumatoid arthritis
& juvenile idiopathic arthritis tttp. One study: evaluated Toci as
rescue tttp in 36 KTR with ch.
AMR failing
the standard-of-care ttt with IVIG & Rtx,
with/without PE. Toci was provided as 8 mg/kg monthly, maximum
800 mg/6-25 mo.
Graft/ptn-survival rate in Toci-ttt ptns
were 80 & 91
% at 6 ys post-ttt,
resp. Significant decline in DSAs levels with
stabilized graft function were reported at 2 ys. No significant SE/adverse events were reported. Toci is not
routinely utilized in ch AMR tttp but may be considered a potential alternate for
stabilizing allograft function.
COMMENTS