Despite the great rise in the rate of annual LDAs Tx, many potential TR with suitable donors have been derived out to the ever-expanding DD W/L
HLA desensitization
By: Fedaey Abbas (MD)
Abbreviations (to facilitate your
reading, read twice please):
o
- ve: Negative
o
+ve: Positive
o
AB: Antibody (s)
o
Ac Rj: acute rejection
o
Aceta:
Acetaminophen
o
Ag (s): antigen(s).
o
aHUS: atypical hemolytic
uremic syndrome
o
ALm: alemtuzumab
o
AMR: Antibody-mediated
rejection.
o
ATG: Antithymocyte
globulin
o
Bort: Bortezomib
o
C: Complement
o
Carf: Carfilzomib
o
CDC: complement-dependent
cytotoxicity
o
CMV: cytomegalovirus
o
CMX: Crossmatch
o
CNI: calcineurin
inhibitor
o
cPRA: Calculated
panel reactive antibody
o
CTS: Collaborative
Transplant Study
o
DD: deceased-donor
o
DDA: Decreased-donor
allograft
o
Diphen:
Diphenhydramine
o
DSAs: donor-specific
antibodies
o
Dsnz: Desensitization/desensitized
o
DX: dialysis
o
Ecz: Eculizumab
o
EMA: European Medicines
Agency
o
Fc: flow cytometry
o
FcRn: Neonatal Fc receptor
o
FDA: Food and Drug
Administration
o
HAR: Hyperacute rejection
o
HF: heart failure
o
HLA: Human
leukocyte antigen antibodies.
o
iABO:
ABO-incompatible
o
ID: immunodominant
o
iHLA: incompatible HLA
o
IL: the interleukin
o
Im/m: immunosuppression
o
Imli: Imlifidase
o
IVIG: intravenous immune
globulins
o
KAS: kidney allocation
system
o
KPD: kidney paired
donation
o
KTR: kidney transplant
recipients
o
KTx: kidney transplant/transplantation
o
LD: living donor
o
LDAs: Living-donor
allografts
o
mAB: monoclonal antibody
o
MCS: median channel
shift
o
MFI: mean
fluorescence intensity
o
MMF: Mycophenolate
mofetil
o
Mthyprd:
Methylprednisolone
o
Obinu: Obinutuzumab
o
OPTN: The Organ Procurement and Transplantation Network
o
PCP: Pneumocystis pneumonia,
o
PE: plasmapheresis
o
PNH: paroxysmal
nocturnal hemoglobinuria
o
PRAs: panel
reactive antibody
o
Pred: prednisone
o
Preetx: Preemptive
transplantation
o
rATG: Rabbit anti-thymocyte
globulin.
o
RCT: randomized
controlled trials
o
RIS: Relative intensity
score
o
Rtx: Rituximab
o
SAB: Single antigen
bead.
o
Snz: Sensitization/sensitized.
o
Tac: Tacrolimus
o
TG: transplant
glomerulopathy
o
Tocil: tocilizumab
o
TR: Transplant recipients
o
Tx: transplant/transplantation
o
Un-Ag: "unacceptable antigens"
o
UNOS: United Network for
Organ Sharing
o
W/L: waiting list
Despite the great rise
in the rate of annual LDAs Tx, many potential TR with suitable donors have been derived out to the
ever-expanding DD W/L due to the pre-formed HLA AB that
can be acquired through pregnancy, transfusion, and/or previous Tx. The finding of these
anti-HLA AB
in a potential TR's serum
is called = HLA sensitization (Snz). If not properly suppressed, the finding
of these AB is probably inducing AMR with early allograft failure.
AMR was identified early in the
history of Tx
as HAR induced by the finding
of preformed AB, mostly seen as AB to donor HLAs.
The advent of the pre-Tx CMX technology
has originally eliminating the HAR. W/L timing may
exceed several years up to decades with disproportionate prolonged waiting for ptns
with blood group B or O. The prolonged timing spent on W/L for the
proper DDA to whom HLA AB not present
has a significantly harmful impact on both quality/quantity of ptn life. Preetx (Tx before DX is
required) may provide better ptn and graft outcome in comparison
with outcome of ptns on maintenance DX
for a prolonged period before Tx.
Considering 2020 database from the OPTN,
almost 12 % of ptns on the DDA W/L
are highly pre-sensitized to HLA
(determined as ≥80
% cPRA). Consequently, these ptns are
less likely
to be prone for Tx and may
spend a prolonged period on the W/L,
pending an offer of the appropriate donor. Several ptns having a
potential LD may be excluded with no
further workup considering the results of the initial +ve CMX with a potential TR candidate that reflecting the finding of the
pre-formed HLA AB.
The increasing risk of HA AMR with
followed graft failure if transplanted against prior finding of HLA AB has developed
a general prohibited attitude to this policy. However, recent reports about
successfully performed Tx across an HLA
barrier via several Dsnz
regimens tailored to limit the magnitude of the pre-existing ABs to an extent permitting a successful engraftment
have triggered more interest in utilizing an immunologic incompatible
graft in KTx. Willing ptns but
with iHLA donor may expect DD organ or receiving a LD organ via
Dsnz, KPD,
or combining both. Choosing Dsnz
or KPD for an individual TR relied
primarily upon the availability of a suitable matching via KPD and their
chance of successful Dsnz regimen. Several
approaches have been utilized in KTR to by-pass the HLA Snz barrier:
NEED FOR DSNZ
The magnitude of HLA
Snz of a candidate TR is 1st
identified at the timing of initial Tx
assessment via testing ptn serum against solubilized
HLA Ags
attaching solid beads. We 1st
perform a multiple-Ag Fc bead testing to screen for the finding of
anti-HLA AB;
if +ve, a SAB assay (Luminex)
is proceeded to recognize the specific HLA
Ags to
which the candidate TR has formed ABs. At certain centers, Ags
with an MFI of ≥15,000 are classified as Un-Ag and
introduced into UNet, the computerizing system guided by the UNOS.
If an Un-Ag for certain
ptn is listed in UNet, kidney grafts from
donors having this Ag will NOT be offered to
this ptn. Of note, MFI values may differ by about 20-25 % between various HLA labs
and MFI threshold
values used for designing an Un-Ag are
not universal along Tx centers. Computing cPRA
is basically depending on ptn's Un-Ag;
and currently reflecting both the widths and depth of the ptns' Snz. All ptns assessed with a cPRA ≥30 % or proceeding to a re-Tx are dealt as sensitized and
potentially eligible for Dsnz plans. Once
the magnitude of ptn Snz has been assessed,
the requirement for Dsnz regimen
before Tx
can be tailored. The suggested therapeutic options varies according to
whether or not the TR has a potential LD.
Potential LD: In a sensitized
ptn (i.e., cPRA ≥30 % or willing re-Tx) having one or more potential LD, we 1st prepare a virtual CMX
to identify if the TR has DSAs or not. A T/B cell CDC
CMX and T/B cell Fc CMX
are currently performed if the donor is determined. These data can be utilized
to determine the potential risks of AMR
occurrence and tailor a Dsnz program,
if appropriate, or to disagree against Tx with certain donor. Moreover, all Snz ptns with a potential LD can be listed on a DD Tx lists.
A suggested approach that is currently based on the findings of the CDC &
flow CMX:
o
+ve CDC CMX: A +ve CDC CMX
is dealt as a contraindication for Tx for certain
donor, despite considered in certain centers. Large, multicenter
study: 22 Tx US centers
performing iHLA KTx, incidence of all-cause allograft loss
at 1 & 5 ys: 19 & 40 %, resp, with +ve cytotoxic
CMX. This higher risk of AMR & allograft loss with +ve CDC CMX,
these ptns should not Dsnz. Rather assess
other potential LD or be enrolled in
a KPD regimen.
o
-ve CDC CMX & +ve
Fc CMX: For these ptns we
should assess the strength of the flow CMX via MCS
assessment:
·
MCS is ≤250: HLA Dsnz
can be offer according to the total specificity & strength of DSAs. We calculate RIS, with 10
points for each DSA in the strong-binding level (MFI ≥10,000), 5 points for each moderately intense DSA (MFI
5000-9999),
& 2 points for every weak DSA
(MFI <5000). If RIS is < 17 points -> proceed to standardized Dsnz
plan & Tx.
·
Rarely, MCS ≤250 with RIS >17 points (most ptns
with RIS >17
having MCS >250), NO Dsnz
advised and consider other potential donor(s) or KPD.
·
MCS >250, NO Dsnz
and consider KPD OR other potential donor(s).
o
-ve CDC CMX & -ve
Fc CMX: These ptns can be DSA-ve, CMX -ve or DSA +ve,
CMX -ve. Ptns in either classes
still at risk
of acute/chronic AMR
development, so -> Dsnz + Tx can be proceeded.
Ptns with no potential LD: Ptns Snz (cPRA ≥30 %) and not having a potential LD, should be listed for DD Tx with a pre-Tx Dsnz regimen offered once the ptn became within an accepted range for the offered DD kidney Tx. This can be recognized according to the number of ys on W/L and the quantity of points allotted via the KAS for the magnitude of allo-Snz.
HLA Dsnz
Overview of Dsnz: HLA-mismatched
KTx can be complicated by a greater rejection
rates with lowered allograft longevity in comparison with
HLA-matched Tx. HLA Snz is also associated with lowered allograft
longevity, and ptns with higher PRAs are commonly characterizing as being of greater immunological
risk. However, some reports suggest that this description may be confined
to TR with pre-existing
DSAs, as Snz TR with NO DSAs show
outcomes that are simulating those of non-sensitized TR.
A higher degree of HLA
Snz may lead to an increased possibility
of a +ve CMX to a potential DD kidney allograft that usually not accepted as
Tx with
an iHLA donor can be complicated with:
1)
An increased rate of
rejection,
2)
An increased rate of
post-Tx re-hospitalization, &
3)
An increased rate of
post-Tx allograft
loss & death.
However, it seems to be of a survival benefit with Tx from an iHLA donor as compared to ptns still remaining on the Tx W/L, and many Snz ptns either incurring a more timing on DX while on W/L or became unlikely to be offered a compatible donor.
The overall target of HLA
Dsnz is 2 folds:
o
To abort AMR evolution in these ptns after Tx
o
To augment the
chance of a successful KTR in TR with
broad HLA
AB Snz
Dsnz may be proceeded in
ptns awaiting either LD or DD Tx.
Goals of Dsnz are similar in both settings
with approach of therapy is little different considering the unpredicted timing
of DD Tx
in relation to the given Dsnz plans. The
offered HLA
Dsnz protocols are not universal, however, the most commonly applied
regimens are employing a combination of the following approaches:
o
Immunomodulation of the TR immune
system, ideally via IVIG
o
Removing the
circulating anti-HLA AB, via extracorporeal techniques e.g., PE
o
Depleting B cell, the source of anti-HLA AB, mostly via Rtx
(anti-CD20 agent).
HLA Dsnz protocols: HLA Dsnz
regimens are variable at various Tx centers
according to the current experience and ptns preference. Unfortunately, there is no RCT comparing
the current Dsnz regimens, and the
optimal therapeutic approach still uncertain. Pre-Tx HLA Dsnz via a combined IVIG (high-dose)
+ Rtx has been
suggested for most ptns. Dsnz
with this regimen will offer:
1)
Reducing the mean PRAs,
2)
Decreasing Fc CMX MCS,
&
3)
Shortened timing to Tx, allowing Tx in 75-80 % of ptns.
LD Tx: Ptns offered potential LD who’re mostly qualified for Dsnz, we can perform pre-Tx Dsnz with high-dose IVIG + Rtx. Dsnz protocol for LD Tx can be proceeded as follows:
o
Rtx 375 mg/m2 on days 0 & 14 with
pre-medication for every Rtx dose
with IV Mthyprd 40 mg, oral Aceta 650 mg, and oral Diphen 50 mg.
o
IVIG 2 g/kg (max 140 g/dose) on d.
28 & 42 with
same pre-medicating
With completed Dsnz
regimen, a donor-specific CDC
T/B
cell CMX & Fc T/B
cell CMX can be currently
repeated. The Fc CMX is usually proceeded
after pronase digestion,
so that removing CD20 from B cells and non-HLA Ags from T/B
cells that enables more distinct identification of HLA-specific
AB and eliminating the impact of Rtx. Dsnz
regimen can be considered successful if the ptn shows an
accepted CMX that is defined
as:
o
-ve CDC CMX in ≥1:2 diluted serum,
o
-ve Fc CMX, or
o
+ve Fc CMX + MCS
≤ 250.
If the findings of the CMX are accepted, Tx surgery can be proceeded within one wk. If the findings of the CMX are NOT accepted, we either:
o
Consider alternate
Dsnz plan or
o
TR enrolled in a KPD program.
Combining high-dose (2 g/kg/dose) IVIG + Rtx has been shown to be safe and efficacious in limiting the anti-HLA AB
values and enhancing the rates of Tx among highly
sensitized TR offered
either a LD
or DD Tx.
Open-label study: 20 highly
sensitized KTR receiving IVIG (2 g/kg on ds 0 & 30) + Rtx (1 g on ds 7
& 22)à ptns can be
eligible for KTx from either a LD or DD. This approach enables 16 of 20 ptns to
receive a KTx. Treating with IVIG & Rtx diminished the mean PRA levels
from 77 %
before therapy to 44
% after treating the ptns, lowering the mean timing to Tx from 144 to 5 mo. The Ac Rj rate was 50 %;
however, they were mostly reversible,
and, at one y., the mean SCr = 1.5 mg/dL (133 micromol/L), with ptn &
graft survival were 100 & 94
%, resp.
Follow-up study: 76 highly sensitized ptns
(75 %
with PRA ≥80 %),
Dsnz with the same regimen decreased class I
& II Fc
PRA
levels & Fc CMX MCS,
allowing Tx
in ALL candidates. Adding Rtx to
IVIG seems
to be superior to high-dose IVIG alone
for the Dsnz of highly sensitized TR.
The following reports showed the range of results:
One RCT: comparing IVIG + Rtx with IVIG + placebo
for Dsnz among highly sensitized KTR awaiting DD Tx.
Ptns were randomly receiving IVIG 2 g/kg (maximum 140 g)
on d. 1 & 20 with either Rtx (1 g) or placebo on d. 15. The study was enrolling
90 ptns but held early after only 15 ptns were
enrolled because of 3 serious untoward events, (3
episodes of AMR). Of the 15 enrolled ptns,
13 received Tx (6 in the IVIG + Rtx & 7 in the IVIG + placebo arms). With un-blinding, it was evident that all AMR episodes were observed among ptns receiving IVIG +
placebo; with No DSA rebounding was observed in those receiving IVIG + Rtx.
Moreover, there were 2 cases of allograft failure in the IVIG +
placebo arm in comparison with NILL in the IVIG + Rtx
arm.
Study: 54 DD
kidney TR with preformed DSA during Tx, 36 received IVIG 2 g/kg on the day of Tx
and on d. 21, 42, & 63
post-Tx, and 18 received similar IVIG dose
schedule conjugated with one dose of Rtx
on d. 4 post-Tx + PE 3 times/wk/1st
3 wks
post- Tx. Despite absence of
difference in AMR incidence between the 2 g.s, ptns treated with IVIG/Rtx/PE showed
greater GFR; 54
vs 43 mL/min/1.73 m2) with less
proteinuria (0.1 vs 0.5 g/L) at one y. post-Tx
as compared to those received IVIG alone.
Protocol biopsy: at one y. showed
few subclinical AMR and TG with
lowered degree of peritubular capillaritis among ptns received IVIG/Rtx/PE.
Moreover, fewer ptns treated with IVIG/Rtx/PE remained +ve
for DSA at
one y. (29 vs 75 %).
DD Tx: Ptns on W/L for a DD
Tx and qualifying for Dsnz plan, the target of Dsnz is similar to those waiting for a LD, but with little difference due to unpredicted timing
of DD Tx
in relation to the administrated Dsnz
regimen. As the date of Tx is not precisely
distinct, Dsnz protocol may be
offered to the ptn if a DD graft can
be likely offered within
one y. This consideration is based on the ptn's kidney allocation
points, recognized by the magnitude of waiting time as well as the allocation priority given
by the ptn's cPRA. With a DD organ is NOT likely expected within
one y., ptn can be kept on the DD
W/L with
NO specific Dsnz therapy. All ptns
must be authorized from their insurance company for
all treatments related to Dsnz as
well as for the Tx surgery prior to Dsnz can be commenced.
Ptns on W/L
for DD Tx,
we offer pre-Tx Dsnz via high-dose IVIG + Rtx
with similar regimen to that applied in ptns waiting for LD Tx.
After completed the Dsnz protocol, we
do the Luminex single-Ag test on a
monthly bases for currently maintaining sera for CMX
testing. The cPRA is rarely required to be adjusted as Dsnz regimen usually doesn’t entirely eliminating
HLA AB
but commonly limiting their MFI.
If the ptn cannot receive a DD KTx within
6 mo of the initial Dsnz
course, we may provide a 2nd course of Dsnz
consisting of PE followed by high-dose IVIG + Rtx. PE is provided to decrease the circulating anti-HLA AB levels.
1)
Alternate-d. PE for 5 sessions, via 1.5 volume exchanges with 5 % replacing albumin for every PE session.
2)
One dose of IVIG 2 g/kg (max. 140 g) immediately after
the last PE session. Pre-medicate IVIG with IV Mthyprd 40 mg, oral
Aceta 650 mg,
& oral Diphen 50 mg.
3)
Rtx 375 mg/m2 one wk after
the last PE session with same pre-medication.
Rtx is usually given one wk after PE sessions and IVIG infusion to limit the impact of FcRn saturation by IVIG. FcRn that is greatly expressed on the vascular endothelial cell and the myeloid cell, can bind under acidic states to the IgG inhibiting its metabolism, so, extending the ½-life of AB. Saturated FcRn by a higher-dose of IVIG overwhelming FcRn ability to abort IgG degradation and it is one suggested mechanism, the IVIG facilitate clearing the pathogenic auto-AB in autoimmune disorders. However, IVIG can decrease the ½ -life & effectiveness of other therapeutic IgG AB given closely to IVIG therapy.
One study: ptns with multifocal motor neuropathy, ptns receiving Ecz (monoclonal
AB) in conjunction with IVIG showed
lowered serum levels of Ecz as compared
with ptns receiving Ecz alone.
Similar observations have been shown in ptns receiving the anti-C5
monoclonal AB tesidolumab in
conjunction with IVIG.
So, we should wait 7-10 ds at least after the infused IVIG
before providing any chimeric/humanized mAB.
Dsnz can be proceeded with PE, high-dose IVIG,
and Rtx every 6 mo until the ptn can
receive a DD Tx. Luminex single-Ag testing
can be performed on monthly bases to maintain current sera for CMX assay.
As an alternate, if the ptn is not receiving a KTx within 6 mo after the 2nd
round of Dsnz, we can offer treating
the ptn with the combined high-dose IVIG (2
g/kg on d. 0 & 30) +
Tocil (8 mg/kg on d. 15, then monthly repeated), a monoclonal AB against IL-6 receptor that is currently
administrated for rheumatoid arthritis as well as systemic
juvenile idiopathic arthritis therapy.
Using IVIG + Tocil was assessed in a pilot study of 10 highly sensitized
Tx ptns and not responding to Dsnz
with high-dose IVIG + Rtx
(with/without PE). Of the 8 ptns completing
the trial (2 were eliminated from the trial due to non-adherence),
5 can be Tx with a mean timing to Tx
of 8.1 mo from commencing Tocil
(25 mo from initial Dsnz regimen).
The mean RIS, a measure of DSA strength
& quantity, declined from 7.8 before therapy to 3.2
at the timing of Tx. A wide RCT may be currently warranted to validate this Dsnz regimen.
Other Dsnz
regimens:
Lower-dose IVIG +
PE: For Dsnz
before LDTx, other Tx centers may apply regimen
consisting of low-dose IVIG
combined with alternative day PE.
In this protocol, alternate-d. PE is commenced before Tx,
and IVIG (or
CMV AB Ig,
according to the institutional policy) is provided with dosing of 100 mg/kg following
each session. The quantity of pre-Tx sessions
can be assessed according to the basal DSA
titer. Tac
& MMF are typically commenced with the start of PE session, despite this policy may differ
from center to another. Once DSA values and pre-Tx CMX
are evidently accepted, Tx can be proceeded. In certain centers PE may be routinely continued after Tx for a
pre-planned number of therapies, other centers, however, only performing post-Tx PE for
the therapeutic purposes of acute AMR.
Long-term assessment of ptns Dsnz with alternative day PE +
low-dose IVIG
may suggest significant longevity benefit following this approach.
One study: ptn survival in
211 HLA-Snz ptns Tx after Dsnz
with PE + low-dose IVIG compared to that in 2 matched control g.s of ptns on W/L for KTx who continued to undergo DX (DX-only
g.) or who underwent either DX or HLA-compatible Tx (DX -or- Tx g.). Ptn longevity in Dsnz
ptns was greater at 3, 5, & 8 ys (86,
81, & 81 %, resp.), compared with
that in ptns in the DX-only g (67,
52, & 31 %, resp) and ptns in the DX
-or- Tx g.
(77, 66, & 49 %, resp).
Disadvantages of this regimen may
include its higher financial costs & resources supplements. Several pre-Tx therapeutic sessions may be mandated to achieve
adequate lowered DSA titer permitting successful Tx, and numerous post-Tx therapeutic
sessions usually required to manage any rise of DSA titer, preventing any suspected AMR. With the timing of the proceeded Tx surgery must be monitored to permit an accepted
AB titer,
however, this regimen is only accepted for candidate TR of a LD Tx.
Lowered-dose vs higher-dose IVIG: There’re no RCT
comparing utilization of lowered-dose
IVIG + PE with
high-dose IVIG for Dsnz.
Retrospective study: comparing 3
different Dsnz protocol in LD TR
with a +ve T cell CDC CMX: high-dose IVIG (2
g/kg) given 1-3 d.s before Tx; PE, low-dose IVIG
(100 mg/kg), and Rtx
375 mg/m2; and PE,
low-dose IVIG
(100 mg/kg), and Rtx 375 mg/m2 with pre-Tx rATG-Thymoglobulin with robust post-Tx DSA monitoring.
All TR with a basal CMX
titer <1:4 get a -ve CMX regardless of Dsnz protocol, compared with only 1 of 10 ptns
with a basal CMX titer >1:32. Among ptns
with a basal titer of 1:18
& 1:16, only 33 % receiving
high-dosing IVIG achieved -ve CDC CMX, as compared to 87 % in the 2 g.s
receiving PE/low-dose IVIG/Rtx. In ptns Tx,
rates of AMR
were 80, 37,
& 29 % for ptns received higher-dose IVIG, PE/IVIG/Rtx,
and PE/IVIG/Rtx/rATG-Thymoglobulin,
resp. These findings suggest that:
o
High-dose IVIG & PE/low-dose IVIG/Rtx are similarly efficacious for Dsnz if the T
cell CDC CMX is +ve with lowered titer (<1:4).
o
No one of the Dsnz regimens can be effective if the T cell CDC CMX is +ve
at a higher titer (>1:32).
o
PE/lower-dose IVIG/Rtx may be more efficacious than higher-dose IVIG if T
cell CDC CMX
is +ve with intermediate titer
(1:8-1:16).
However, it should be noted that ptns Dsnz
with higher-dosing IVIG and NOT receiving Rtx,
they are frequently vulnerable for a higher rates of AMR.
Considering the high rates of AMR within
all the 3 Dsnz
regimens, it is recommended to be cautious in proceeding to a Tx with a +ve CDC CMX.
As mentioned before, we should NOT proceed with Dsnz or Tx
in ptns with a baseline +ve CDC CMX.
Less commonly protocols:
Bortezomib (Bort): a robust,
reversible proteasome
inhibitor targeting terminal
differentiation of plasma cell that’re
responsible for AB production. Bort
has been to be successful in AMR
therapy. In certain centers, Bort did
not routinely used in HLA Dsnz regimens considering its non-obvious
efficacy and untoward effects.
Prospective trial of Bort-based Dsnz: 44 Snz ptns (current/peak
cytotoxic PRA
or cPRA >20 %), proceeded in 5 phases along 3 y.s. All ptns received
LD with +ve
CDC or Fc CMX with DSAs. Therapeutic protocol in every phase composed
of Bort (1.3
mg/m2/dose/6-8 doses), one
dose of Rtx 375 mg/m2, and
PE; phases are varying in the Bort doses and quantity of PE sessions.
Almost 19 out of 44 (43
%) ptns received Tx during the study. 6 of 15 (40 %) ptns with DSAs and a +ve
T cell Fc
CMX against a LD achieved
a -ve CMX; 4 were Tx, while 2 were not Tx due to a
persistent DSA with an MFI >3500. 6 out of 44 (13.5 %) showed a 50 %
decline in the cytotoxic PRA by 50 %; ptns with higher
titer DSAs were less likely to respond.
In responding ptns, the decline in DSAs can be durable with minimal short-term rebounding,
despite later rebounding at 3 mo and after
that was seen according to the given protocol. At 6 mo post-Tx, the rate of Ac
Rj & AMR were 18.8 & 12.5
%, resp. Generally, Bort was well tolerated medication
with currently given doses in this trial.
However, study: 10 highly senz KTx
ptns with DSAs against their candidate LD,
using 32 doses of Bort (1.3 mg/m2) as monotherapy only
induced a moderate decline in DSAs without changing the cPRA.
Moreover, Bort therapy was Not
tolerated owing to untoward effects. So, although a Bort-based
Dsnz regimen permits some Tx candidates to get a -ve CMX, this benefit was only
limited to a minority of TR; ptns did
not mostly achieved a satisfactory decline in DSAs nor were Tx,
and many ptns have shown many adverse effects.
Ecz: a humanized mAB directed to the terminal C component C5. It has received an
US FDA approval for therapy of PNH & aHUS and has been utilized as salvage therapy
in the management of refractory acute AMR,
however, it is not routinely utilized as a part of any HLA Dsnz
regimens regarding its cost and unclear impact. There’re limited data about using
Ecz for HLA Dsnz.
One study assessed the administration
of Ecz among 30 LD TR
with an initial +ve B
cell Fc CMX MCS between
200-450. TR with a
pre-Tx MCS ≥300 provided PE before Tx to get an MCS <300 by the d. of Tx.
Ecz was provided as follows: 1200 mg
immediately before Tx, 600 mg on day 1
after surgery, and 600
mg weekly thereafter/4 wks. At wk 4 post-Tx,
ptns with a B cell Fc CMX MCS >200 received another Ecz
(1200 mg
on wk 5, then biweekly
thereafter until the MCS reached <200). Outcome
were compared with TR of a historical control g. of 48 LD TR of a +ve CMX Tx
who were Dsnz with the same regimen
with no Ecz.
Ptns receiving Ecz
had a lowered incidence of acute AMR along 38 mo. As compared to historical controls along
73 mo (7 vs 44 %, resp.). However, Ecz-treated ptns showed a higher incidence of
TG due
to persisting DSAs (45 vs 64 % in controls) that suggest an impact of
other mechanisms inducing allograft injury besides C complement
activation. The % of ptns showed a B
cell Fc CMX MCS >200 at 6 mo among Ecz-treated ptns was simulating controls (46 vs
41 %) suggesting no further benefits of Ecz
on reducing DSA as compared to the standard regimens. Among these
ptns, NO difference can be detected in TG
at one y (50 vs 36 %). By contrast, ptns showed improving MCS <200 at 6 mo, none of the Ecz-treated ptns had TG at one y, as compared to 42 % in controls. Despite
non-conclusive, this observation may suggest Ecz-treated
ptns and having reduced DSA along 6 mo may be less vulnerable to
develop chronic AMR as compared with those not treated with Ecz.
Investigational agents: Several
investigational agents have been assessed as Dsnz
strategies:
[1] Imlifidase (Imli):
An IgG-degrading enzyme extracted
from Streptococcus pyogenes (Imli; IdeS) is a recombinant cysteine protease cleaving
all 4 subclasses of human IgG into F
(ab') 2 and Fc fragment (s), inhibiting CDC and AB-related cellular
cytotoxicity. Imli efficacy
as a Dsnz
regimen was assessed in 2 independent phase I/II studies from the US & Sweden including
25 greatly HLA-Snz ptns (average
cPRA of
96 & 81 % in the US & Swedish trials, resp.).
Among these ptns, 92 % had a DD Tx,
92 % showed anti-HLA DSAs at the timing of Tx (mean class I
& II MFI of 5660 & 8199, resp.), and 80 % showed
+ve Fc CMX at the timing of Tx. All ptns receiving Imli (0.24 mg/kg in the US trial and 0.25 mg/kg or 0.50 mg/kg in the Swedish trial)
provided IV 4-6
hs prior to Tx.
Ptns included in the US
study was receiving an ALm induction
(30 mg
given on d. 4 after Tx), while ptns in the Swedish trial were
receiving induction via horse ATG, ALL ptns
were receiving maintenance Im/m composed
of Tac, MMF,
& Pred. Moreover, ptns in
the US trial were receiving IVIG 2
g/kg (maximum 140
g) on ds 7-14 after Tx and Rtx
375 mg/m2 on d. 14-21 post- Tx.
The following findings were observed:
o
Imli therapy induced total cleavage of IgG into F (ab')2 & Fc fragments
within 6 h.s. Intact IgG still absent in all ptns for minimal 7 d., moreover, there
was persistent decline in IgG values for
28 d.
after infusing Imli.
o
Ptns in the Swedish trial, not receiving IVIG + Rtx after Imli,
showed DSA
rebounding at 7-14
d. post-Tx; median MFI of the ID DSA was about 11,000 at one mo. In
contrary, US trial ptns receiving IVIG + Rtx after Imli,
showed less DSA rebounding, with
median MFI
of the ID DSA showed to be 0 at one mo.
o
3 of 11 ptns (27 %) in the Swedish trial
showed AMR
at 2 wks post-Tx. 2 of 14 ptns (14 %) in the US trial
met Banff 2013 criteria of AMR at 2 & 5 mo after Tx; and more 5 ptns showed microvascular inflammatory states with no DSA.
o
One ptn in the US trial had immediate HAR
after revascularization that can be attributed to an IgM AB as ptn has
no detected DSA after Imli
therapy.
o
Mean eGFR at 1-6 mo after Tx = 49 mL/min/1.73 m2 in the Swedish trial & 70 mL/min/1.73 m2 in the US trial.
Following up, multinational
trial investigating the criteria of Imli
converting a +ve CMX testing into -ve in 19 highly Snz kidney TR (average cPRA 99 %). 13 of them have received a DD KTx,
5 received LD Tx,
and one ptn did not Tx after having an infusion-induced reaction to Imli. Imli
induced -ve CMX in 17 of 19 ptns (89 %) along 24 hs after therapy. DSA rebound
observed in most ptns between 3 & 14
ds after Imli administration, despite
MFI still
lower than pre-therapeutic values.
At 6 mo.s post-Tx,
ptn & graft survival were 100 & 89
%, resp, and the average eGFR among the 16 ptns with a functioning graft was 47
mL/min/1.73 m2. Rejected Tx was observed in 9 of 18 TR (50 %); of them, 7 have developed AMR. Generally, the early interpretation with Imli is promising indicating the permition of
use in incompatible Tx. However, long-term outcome has to be
assessed, particularly with the commonly observed DSA
rebound after Dsnz with Imli. Imli
has been approved by the EMA for Dsnz in KTR
in the European Union. However,
Imli is not yet received an approval
from the US FDA in the US.
[2] Obinutuzumab (Obinu): is a 3rd generation anti-CD20 mAB. In contrary to Rtx,
B cell death with Obinu is less reliable on CDC and is mediated mainly via AB-related cellular cytotoxicity. Both Rtx & Obinu
show robust deplete of B cells in
peripheral circulation; however, Obinu
is more effectively depleting B
cells in the secondary lymphoid system and may show more remote actions on the memory B
cells and plasma cells owing to its particular mechanism of action.
Using Obinu for Dsnz
has been assessed in a trial of 25 highly
sensitized KTR, receiving
either a single dose of Obinu 1000 mg followed by IVIG 2 g/kg (maximum 140 g) at wks 3 & 6 (n = 5) or Obinu 1000 mg on ds 1 & 15 and an optional
1000 mg dose at wk 24 with added IVIG 2
g/kg at wks 3 & 6 (n = 20). From 25 ptns enrolled, 8 proceeded to KTx (7 were Dsnz
with the frequent-dosing protocol), receiving more Obinu
infusions at Tx & 24 wks after Tx.
Only 4 of 25 ptns (16 %) had statistically significant decline in total mean MFI from base line, and MFI declining in individual ptns were not consistent
across allele (s).
However, 14 of
24 ptns (one ptn was not involved in efficacy analyses as he was receiving a Tx 6 d.s after Obinu infusion) had a decline in the quantity
of Un-Ag, and 12 of 24 showed a decrease in their cPRA enabled by moderate decline in MFI. These results may suggest that Obinu can be included as a Dsnz agent, despite its impact on HLA AB
decline is currently mild.
[3] Carfilzomib (Carf):
Carf is a 2nd generation, irreversible proteasome inhibitor showing durable impact on the plasma cell as
compared with the 1st generation, reversible
proteasome inhibitor, Bort.
Moreover, it shows a more accepted toxicity profile than Bort with remarkable less associated peripheral neuropathy. Utilizing Carf in Dsnz
protocols was shown in a small trial of 13 highly
Snz TR tailored to evaluate its safety and efficacy conjugated
with PE.
All ptns were receiving
escalating dosing of Carf from 20-36
mg/m2 along 12 doses followed by 3 sessions of PE on d. 47, 49, & 51. Further subgroup receiving
PE along
the Dsnz plan before Carf dosages. Therapy impact was well
tolerated with no reported peripheral neuropathy or HF cases.
MFI decline
with Carf alone was mostly moderate
and can be more triggered after PE. AB rebounding to baseline values seen in all ptns
within 5 mo after completing Dsnz.
Further investigations are currently warranted for better evaluation of the
safety/ efficacy of Carf as a Dsnz tool in KTR.
Im/m in Dsnz ptns, Induction therapy:
A suggested approach to induction therapy in iHLA KTR
varies from that given in most HLA-compatible
Tx. Whilst most HLA-compatible KTR
who’re considered at higher risk for rejection typically receiving rATG-Thymoglobulin as an induction therapy, ALm administration
is preferable in iHLA
TR. Moreover, immunomodula-ting therapy with IVIG & Rtx
can be provided near the timing of Tx.
●For LD TR, pre-Tx IVIG + Rtx Dsnz plan can be completed within one week
of Tx. We can give ALm 30
mg SC
on the d. of Tx, then a course of IVIG 2
g/kg (maximum 140 g) within 7-14 d. after Tx can be added.
●In DD TR,
we can provide ALm 30 mg SC + IVIG 2 g/kg (maximum 140 g) at the timing of Tx. A subsequent additional dosing of IVIG 2
g/kg within 7-14 days after Tx. Rtx 375 mg/m2 is also provided within 7-14
ds after Tx
if it has not been given within 6 mo of the Tx.
There’re no high-quality accepted data that
compare various induction protocols among iHLA
kidney TR. ALm is preferred based mainly upon clinical experience in
this ptn cohort. IVIG & Rtx are provided in addition to ALm to limit or remove
anti-HLA AB
rebound in
the early post-Tx timing. The impact
of this protocol has been shown in a report of 2 different trials assessing utilization
of a streptococcal IgG endopeptidase (Imli)
in iHLA KTR.
All ptns receiving Imli just before Tx; in one trial, ptns were given horse ATG as induction
therapy, whereas in the 2nd trial, ptns were given ALm as an induction but also was receiving IVIG & Rtx
prior to and after Tx. After one mo. after
Tx, few ptns receiving IVIG & Rtx
have developed DSA rebound as compared
to TR who
did not.
Maintenance Im/m: In TR of an iHLA KTx, we may provide a triple-therapy maintenance im/m strategy starting on the day of Tx including the Tac, MMF, & Pred. This regimen is simulating the initial maintenance im/m utilized in most HLA-compatible kidney TR in the US.
POS-TX MONITORING: After HLA Dsnz
& Tx, ptns can be monitored via
an approach simulating that used in TR
of HLA-compatible Tx. We may check SCr +
urinalysis twice weekly for the 1st mo post- Tx, then weekly for one mo, then every 2 wks for one mo, and
then every 1-2 mo for the 1st
y after Tx. Given the higher risk for
AMR in iHLA
TR, we perform a kidney graft biopsy
in all ptns developing graft dysfunction if rejection
is suspected. Moreover, routine monitoring of DSA values
on monthly
bases for the 1st 3 mo post-Tx; then at mo. 6,
9, & 12; and annually
thereafter. Ptns showing persistent or de novo DSAs should be assessed with a kidney
graft biopsy to exclude an impending AMR.
DSA assessment
in the early post-Tx timing may not
be totally reliable, however, as recent IVIG
can induce false +ve results related
to non-specific binding of AB to single-Ag
(Luminex) beadings. This impact of IVIG will
be negligible
by mostly 2 mo post-Tx.
COMPLICATIONS
Infection: Despite
there’re major variabilities between iABO & iHLA
Tx, both show many similarities in
their pre-Tx Dsnz. In view of the
data sparsity regarding infectious sequelae in iHLA
TR, data from the iABO cohort can be reflected on the iHLA population. The documented infectious
complications may vary by ptns populations, however, certain reports showed
that the rate of infection episodes is not generally higher than that in other TR groups.
Retrospective study: 361 kidney TR comparing infectious outcome between ptns receiving
Rtx + high-dose IVIG for Dsnz
before iHLA- or iABO Tx
and another group of non-Snz ABO-compatible
TR.
All ptns receiving similar antibiotic and viral
prophylaxis. After almost 18 mo, there were no clear differences in episodic
bacterial, viral, fungal, and other
opportunistic infection between
the 2 populations. However,
infectious episodes still a crucial cause of mortality in the Dsnz cohort:
o
Cohort study: Korean Organ Tx Registry
reporting the clinical outcome for 1964 LD TR, including 248 iABO TR,
144 iHLA TR,
and 31 ABO- & iHLA TR.
TR with an incompatible Tx, infectious episodes were the most common cause of
mortalities (8 of 9 deaths [89 %]). On the other hand, only 3
of 11 (27 %)
deaths in the compatible TR can be related to infection.
o
Analysis:1420 iABO LD kidney TR
in 101 European Tx centers (2005-2012), significant high rate of death-related
infection in the 1st y after Tx
in TR with iABO vs ABO-compatible
Tx. However, the absolute risk
difference was little, about 1 %. Moreover, adjusted analysis for variability in basal criteria
between g.s was not introduced, so, it cannot be deduced if the difference in
infection-induced deaths between iABO
& ABO-compatible TR can be attributed to Dsnz vs other agents. Moreover, there was no variability
in the rate of infection-related hospitalization along 1st Tx y. between iABO
& ABO-compatible TR.
For all TR
of an iHLA Tx, we give antibiotic and antiviral prophylaxis with a
regimen that is similar to that given to TR
of an HLA-compatible Tx including the prophylaxis against PCP, CMV,
and herpes simplex disease (in ptns who’re at low CMV risk). Moreover,
may provide antifungal prophylaxis, despite
this policy may differ from center to another.
Malignancy: Scanty of studies that evaluate the risk of cancer among TR of an iHLA KTx, and data from the iABO Tx cohort are usually extrapolating to the iHLA Tx cohort. Most reports have found that iABO TR do NOT show a higher risk of cancer in comparison with ABO-compatible Tx ptns. Single-center report: 69 iABO, 27 iHLA, & 10 ABO- & iHLA LD kidney TR, malignancies were entirely NOT common, and their incidence was NOT showing a significant difference between the 3 groups.
OUTCOME:
It is usually difficult to decide to proceed to
an iHLA KTx rather than waiting a longer time for a more appropriate
donor, particularly considering the higher MR seen among ptns on DX
as compared with TR proceeding to a KTx.
In almost all ptn cohorts, the long-term risk of mortality is lowered with a KTx compared with DX.
Large multicenter study: 1025 TR
of an iHLA LD KTx, there was
greater short- & long-term (8 ys) ptns’ survival
among TR of an iHLA Tx
in comparison with ptn on W/L matched controls.
These results were persistent among TR having a +ve
Luminex assay/-ve flow cytometric CMX, +ve
flow cytometric CMX,
or +ve cytotoxic
CMX. Of note, ptn & graft
survival were comparable between highly Snz TR given Dsnz
prior to Tx and less sensitized TR have no pre-Tx
Dsnz.
Analysis:
of 910 DD & LD TR
(372 receiving pre-Tx Dsnz due to HLA Snz or
iABO Tx):
no difference in graft or ptn longevity
up to 60 mo
between HLA-Snz TR
of pre-Tx Dsnz and lowered
immunological risk TR. Generally, the
greater intensity of incompatibility the higher the
risk of allograft loss & mortality. Ptns with DSA but a -ve CMX have been reported
to have a similar risk
of mortality or graft loss as compared to compatible TR; in contrary, a +ve flow or cytotoxic CMX was complicated with a 1.65- & 1.80-fold
greater risk
of allograft loss and a 1.32-
& 1.51-fold greater
risk of mortality as compared to the
compatible TR.
In this trial, 5-y.
unadjusted allograft failure was 17, 20, 29, & 40 % for
compatible TR, TR with DSA but a -ve flow CMX, TR
having a +ve flow CMX but -ve cytotoxic CMX, and TR
of a +ve cytotoxic CMX KTx,
resp. 5-y unadjusted MR was 9, 10, 13, & 19 % for compatible TR, TR
with DSA but
a -ve flow CMX, TR
with a +ve flow CMX but -ve cytotoxic CMX, and TR
of a +ve cytotoxic CMX KTx,
resp..
Cost of iHLA Tx: Costs of iHLA KTR
are currently greater than those with compatible KTR,
not only for the administration of injectable agents with or without PE for the Dsnz plans, but also due to prolonged hospitalization, more frequent allograft biopsies, and frequent rejection episodes. The mean organ
acquisition cost of an iHLA LD KTx was
reported to be USD $151,024 compared with USD $106,306 for matched TR; higher levels
of incompatibilities (DSA with -ve flow CMX, +ve
flow but -ve cytotoxic CMX, and +ve
cytotoxic CMX) were accompanied with currently
higher unadjusted costings. With adjusting the difference (s) in baseline TR & donor criteria between the incompatible
and matched controls, however, there was no significance in in cost difference with
Tx with
DSA & -ve flow CMX and Tx with +ve flow but -ve cytotoxic CMX. Tx across a +ve cytotoxic
CMX was associated with a greater cost as
compared to Tx with DSA & -ve flow CMX and Tx with +ve flow but -ve cytotoxic CMX.
COMMENTS