The term “induction therapy” (I.T.) is an im/m therapy that given at the time of KTx to limit the risk of allograft Rj.
INDUCTION THERAPY
Abbreviations (read twice please):
o ABOi : ABO-incompatible
transplants
o
ABOi: ABO incompatible Tx.
o Ac Rj: Acute Rejection.
o Ags: antigens.
o Alm: Alemtuzumab (Campath-1H).
o AMR: antibody-meditated rejection
o
Bsx: Basiliximab.
o CAN: Chronic allograft
nephropathy.
o CMV: cytomegalovirus.
o CNI: calcineurin inhibitor.
o
CRT randomized trials
o CyA: Cyclosporine.
o CXM: Crossmatch.
o CAN: Chronic allograft nephropathy.
o CLL: chronic lymphocytic
leukemia.
o DSGS: death-censored graft survival.
o
DSAs: donor-specific
antibodies.
o Dsz: desensitization.
o DGF: delayed graft function
o FSGS: focal segmental glomerulosclerosis.
o
GC: Glucocorticoids.
o
GN: glomerulonephritis.
o HLA: human leukocyte antigen.
o HLAi: human leukocyte antigen incompatible
transplant.
o IL-2 RA: IL-2 receptor
antagonists.
o I.T.: induction therapy.
o im/m: immunosuppression.
o im/mb: immunoabsorption.
o KDIGO: Kidney Disease: Improving Global Outcomes.
o KTRs: Kidney transplant
recipients.
o KTx: kidney transplantation.
o
LRKD: living-related-donor
kidneys
o MHC: major histocompatibility complex.
o MMF: mycophenolate mofetil.
o
Mthyprd:
Methylprednisolone.
o
Pph: Plasmapheresis.
o
PRA: Panel reactive
antibody.
o
PTLD: post-transplant lymphoproliferative
disease.
o rATG: rabbit
anti-thymocyte globulin-Thymoglobulin
o
Rtx: Rituximab
o
SE side effects
o
SOT: solid organ
transplant.
o SRTR: Scientific Registry of Transplant Recipients.
o Tac: Tacrolimus.
o
TMP/
SMX: Trimethoprim-sulfamethoxazole.
o
TR: Transplant
recipients.
o
UTI: urinary tract
infection.
The term “induction therapy” (I.T.) is an im/m therapy that given
at the time of KTx to limit the risk
of allograft Rj. Generally, induction plans included
in one of two
protocols. The 1st primarily relies upon high dosages of
conventional im/m agents, whilst the
more widely used strategy uses either T cell-depleting or IL2 RA in addition to lowered
doses of conventional agents. TR in the US mostly receive an AB I.T.
In 2016, almost 75 % of KTRs received T cell-depleting I.T.
and about 20 % received IL-2 RA.
Introduction: All KTRs mostly require im/m therapy to guard against Rj and allograft failure. Several RCT indicate
that I.T. composed of [biologic AB + conventional im/m agents] is superior to conventional agents alone in declining
kidney graft Rj & allograft loss.
In ptns receiving KTx, it is recommended that I.T. formed of [AB therapy + conventional im/m agents], with only one
exception of the Caucasian TR with
2-haplotype-identical, living, related allograft. Such ptns do not usually
need I.T. with AB given their highly declined immunologic risk of
Ac Rj. Suggested approach: to
select induction im/m plan in KTx considering the magnitude of risk of Ac Rj:
o
High risk Rj: rATG
is superior to IL-2 RA & placebo among ptns at high
immunologic risk and receiving concurrent im/m plan. So, we start rATG, a lymphocyte-depleting
agent, rather than IL-2 RA or no AB therapy.
o
Lower risk Rj: some updated clinicians give rATG based upon evidence that rATG offered lower Ac
Rj rates. Other clinicians use IL-2 RA
considering similar rates of Ac Rj, ptn
& graft survival, and infection with rATG
& IL-2 RA.
Exceptions to this approach
include:
o
Ptns not tolerating rATG (e.g., low BP, leukopenic, and/or
thrombocytopenic) at presentation > IL-2 RA, Bsx.
o
Caucasian TR of 2-haplotype-identical,
living related kidneys: No need for AB agent.
o
KTRs with another
functioning SOT e.g., liver, lung, or heart and currently receiving
im/m agents. No need for
induction agent, but some clinicians may use Bsx.
Types of im/m AB therapy:
include the either specific AL antilymphocyte or IL-2 RA:
o
Antilymphocyte
AB: include polyclonal &
monoclonal
AB. Polyclonal AB contain AB to a wide range of human T-cell surface Ags, including MHC Ags. Thymoglobulin
is a polyclonal im/m that generated in rabbit (rATG). N.B. Another rATG (Fresenius), while the immunogen of rATG is human
thymocytes that for rATG (Fresenius)
is a Jurkat T-cell leukemia line. Another polyclonal AB, Atgam; a purified gamma globulin obtained by immunizing
horses with human thymocytes.
Monoclonal antilymphocyte AB include Alm.
Alm (Campath-1H) is a humanized anti-CD52 panlymphocytic
(both B & T cells) monoclonal AB, (declined in US).
o
IL-2 RA: Fully activated
T-cell > IL-2 secretion (autocrine
growth agent) > T-cell
proliferation. Blocked IL-2 activity via anti-
IL-2 RA will induce im/m.
The only IL-2
RA available is Bsx.
o
Anti-CD20 AB: Rtx
= anti-CD20
monoclonal AB depleting CD20+ve B cells. It’s approved most commonly PTLD therapy
and Dsz of
HLA & ABOi Tx & ttt of AMR.
Both donor & TR should be examined for CMV; Valgancyclovir
given as primary prophylaxis in risky ptns for CMV. TMB/SMX is given to prevent Pneumocystis
carinii pneumonia, sepsis, & UTI.
RISK OF Ac Rj:
Recognizing ptns at high risk of Ac Rj is crucial, so, more aggressive im/m should be considered.
The KDIGO guidelines, 2009, risk
factors for Ac Rj
include one or more of the following:
1) DGF
2)
ABOi.
3)
PRA > 0 %
4)
Presence of DSA
5)
Cold ischemia
time > 24 h.
6)
One or more HLA mismatches
7)
Younger TR & older donor age.
8)
African-American
ethnicity (in the
US).
In those ptns, 2009 KDIGO guidelines suggest the use of lymphocyte-depleting agents that are robust
im/m agents, rather than
IL-2 RA.
On the other hand, ptns NOT with high risk, guidelines recommend IL-2 RA due, partly to meta-analysis reported
diminished risk of Rj. Updated clinicians
may give IL-2
RA to low-risk ptns; however, other clinicians may use lymphocyte-depleting
agents mostly to adult ptns receiving KTx,
regardless
the magnitude of risk for Ac Rj.
HIGH-RISK PATIENTS
High risk Ac Rj use > rATG as an induction im/m therapy. rATG is superior to Atgam,
IL-2 RA & placebo among KTRs who
are at high & low
immunologic risk (2009 KDIGO
guidelines).
rATG in high-risk TR: IV Mthyprd (7 mg/kg) + IV rATG (1-2 mg/kg) are intraoperatively given.
rATG is given if, at presentation, WBCs is > 2000/microL & platelet count > 75,000/microL. Give
Bsx if rATG
cannot be used. The intraoperative dose
of rATG is followed by 2 mg/kg of rATG/d for the next 2 d.s (i.e., total 3 doses). Dose of rATG can be skipped if WBC
< 2000/microL or platelet declined
to < 75,000/microL. Half doses of rATG is given for WBCs
between 2000
& 3000/microL or platelets
between 75,000 & 100,000/microL.
Optimal dosing for rATG is not certain.
Cumulative dose < 3 mg/kg have proved to be less
efficacious than higher doses, however, doses > 6 mg/kg are not required
for renal TR. Some centers use lower doses for
low-risk TR of LRKD & higher doses for TR
of deceased-donor allografts. These rATG plans is usually combined with preoperative
maintenance im/m.
Special populations
o
ABOi: Optimal
induction plan for KTRs with ABOi
donor is not certain. It is recommend using rATG
as an induction im/m protocol. Added to the induction plan, Pph & im/mb are
generally provided to limit circulating ABO AB titers and declining the risk of acute AMR.
o
HIV ptns: HIV TR,
compared to HIV-ve TR, often show higher
risk of Ac Rj, so, may benefit from AB induction
plans. However, considering the underlying im/m state of HIV ptns, extended lymphocytic depletion with AB
induction plan may potentially augment the risk of opportunistic
infection. I.T. in HIV KTR still controversial, there’s no consensus about
the optimum protocol. Certain centers may prohibit AB I.T in HIV
TR. Centers using AB I.T., may utilize Bsx
(IL-2 RA) considering data of HIV KTR showing higher
risk of infection with rATG. Other clinicians may prefer rATG considering its superiority in declining Ac Rj in HIV-ve
TR.
Efficacy reports: The
assessment of any trial or prophylactic AB induction
regimen necessitates considering the following items:
o
Cost magnitude.
o
Incidence of Ac Rj
o
Long-term graft longevity
& function
o
Incidence, type &
intensity of concurrent infection.
o
Mortality/morbidity,
including hospital admissions.
o
Incidence/type of cancer
with long-term following-up.
o
Incidence/intensity of
DGF/primary
non-function, the need/timing of DX after Tx.
rATG vs no induction: KTRs receiving
deceased-donor, rATG is more effective than
no I.T. in declining the rate of Ac Rj, but it has no observed significant impact
on the rates of ptn and graft survival rate in the 1st 12 mo after Tx. However, rATG
therapy is complicated by a higher risk of untoward effects e.g., leukopenia, thrombocytopenia as well as CMV
infection:
Study: TRs were randomly receiving rATG followed by Tac on d. 9 post-tx or Tac -based
triple therapy given within 24 hs of Tx. Ttt with rATG
declined the rate of Ac Rj at 12 mo. Ptn &
graft survival were the same in both gs. Ptns received rATG had significant rise in leukopenia, thrombocytopenia,
CMV infection, fever, & herpes simplex
infection.
Study: KTRs were
randomly receiving Tac -based triple therapy
started as soon as possible post Tx ,
induction via rATG followed by Tac on d. 9 post-Tx,
or induction via rATG followed by CyA on d. 9 post-tx. At 6 mo., rate of biopsy-proven Ac
Rj was significantly declined in the arm on rATG + Tac as compared with the arms on rATG + CyA and Tac-based
triple therapy. Leukopenia, thrombocytopenia,
CMV, fever, & serum sickness were
highly significant in both groups received rATG.
rATG vs Atgam: rATG
is more effective as compared to Atgam in declining Ac Rj rate
and improving allograft longevity. Trial: TRs were randomly receiving intraoperative rATG (1.5 mg/kg IV) or Atgam (15 mg/kg IV), followed by daily/6
d.s. DGF rate was only 1 % for both g.s.
At one y, the g. on rATG had a significant decline in Ac Rj
rate & increased graft survival.
Decline in Rj rate could
be partially attributed to a more sustained lymphopenia with rATG,
while the exceptionally low DGF rate seen in both groups may have been due to the
intraoperative use of rATG; these AB
have the power of blocking many adhesion
molecules, cytokines, chemokines, & their receptors responsible
for ischemia reperfusion injury & DGF.
rATG vs IL-2 RA: Ptns at higher
risk for Ac Rj, rATG
is more effective than Bsx
in Rj prevention. Effectiveness of Bsx vs rATG
in high-risk ptns was estimated in multicenter RCT:
278 deceased-donor KTRs comparing safety & efficacy of 5-ds course of rATG vs 2 doses Bsx.
TR & donors were selected according to criteria
predicting higher-than-normal risk for Rj
or DGF. Ptns in both arms were given CyA, MMF
& prednisone for maintenance im/m,
& receiving prophylactic gan-ciclovir.
Primary endpoint: Ac Rj, DGF, graft loss & death. At
one y, the following were reported:
·
No difference
between rATG & Bsx
in the incidence of endpoint, graft loss, DGF
& death.
·
rATG significantly declined Ac Rj rates & incidence of Ac
Rj requiring AB therapy.
·
Overall adverse
event & serious adverse event rates were the same, but rATG showed a higher
incidence of infectious
episodes but a lowered incidence of CMV.
So, despite the primary endpoint at one y was
similar in both groups, a significant lowered incidence of AcRj was noted with rATG. At 5 ys,
incidence of Ac Rj and the need for AB ttt
of Ac Rj still
lower among rATG group as compared to
Bsx. Ptns ttt with rATG also had a significant lowered composite endpoint
of AcRj, graft loss, &
death at 5 ys and incidence of ttt CMV infection; however, the incidence of cancer is
the same. So, the relative benefits of rATG
were mostly sustained along 5-y after surgery. Observational studies comparing rATG &Bsx
mostly showed similar results. Comparing rATG with
Bsx, the
latter may be associated with a higher rate of de
novo DSA & AMR development. Study: 114 TR receiving deceased-donor
kidneys having DSAs but -ve CXM at time of Tx. At 36 mo, compared with bsx, rATG
was accompanied with decline in de novo DSA and AMR
development. Dosing protocol of rATG:
variable dosing plans for rATG that
is generally given peripherally rather than through a central venous access. Effectiveness
of these plans has been assessed as follows:
● Safety& effectiveness of a 3-d induction protocol, given to 40 ptns, have
compared with a 7-d course 48
controls. In the 3-d course, rATG was given intraoperative 3 mg/kg followed
by postoperative 1.5
mg/kg, day: 1 & 2, while the 7-d course given rATG
at intraoperative 1.5
mg/kg IV, then daily/6 ds. At 1 y, NO
difference in Ac Rj rates, graft longevity, &
ptn survival, but the duration of initial hospitalization was highly shorter in the 3-d g. Prolonged +
more intense duration of lymphocytic depletion was seen among those given 3 ds of rATG.
●Advantages with the intraoperative rATG were observed in a trial: 58
deceased-donor TR randomly receiving either intraoperative or
postoperative rATG, with both g.s received the same subsequent
doses of this medication. Providing intraoperative rATG
leads to significant lowering the DGF
incidence and lowering post-Tx hospital admission
timing.
●Low-dose rATG
(0.5 mg/kg/d)
+ Bsx vs standard-dose rATG (2 mg/kg/d.) as I.T. was assessed in a RCT
of 33 high-risk ptns. Both g.s had similar ptn & allograft survival, but untoward
effects were significantly higher with standard-dose plan. However, ptns in
standard-dose g. received higher cumulative dosage of rATG
(up to 14
mg/kg) than those usually used for induction.
●Retrospective study: 224 adult KTRs compared
the efficacy/safety of lowered & conventional doses of rATG. Lower cumulative rATG dosing of 3 mg/kg & 4.5 mg/kg were given to
standard risk living-donor & deceased-donor TR,
resp, and a conventional dosing of 6 mg/kg to higher
risk TR (prior Tx, PRA >
20 %, or flow cytometry CXM positivity). Over 42
mo, No significant difference in ptn or graft survival among the 3 dosing arms. One-y. Rj rates in the 3 & 4.5 mg/kg gs were 8.3 & 8.8 %,
resp. that were comparable to rates observed in SRTR.
Cost analysis showed: tailoring permitted savings of USD $1,091,502 as compared to conventional dosing. Infectious
episodes were comparable to those recorded to the SRTR.
rATG induction can be
dosed: 1-6 mg/kg/dose, and its duration from
1-10 ds, despite a more typical plan =
1.5 mg/kg for 3-5 ds. Animal model:
high initial doses + short duration, like human-equivalent dose = 6 mg/kg >
more peripheral/central lymphocyte depletion + better
graft survival. So, optimal induction = total 3-6 mg/kg, total doses = 5.7 mg/kg that’re usually given as 1.5 mg/kg/d, > similar outcome in high-risk TR receiving
average 10.3 mg/kg. High doses + prolonged
duration of I.T. > higher risk of infection, serum
sickness, & potential malignancy (lymphoma),
while lower dosing = <3 mg/kg
may NOT effective for Ac Rj prevention.
LOW-RISK TR: ptns not assessed at higher risk for Ac Rj, either rATG
or IL2 RA can be given
as I.T.. Updated clinicians may give rATG considering the lowered Ac Rj rates with rATG.
However, others may give IL2 RA considering reports
showing similar rates of Ac Rj, ptn &
graft longevity & infection with rATG
and IL2 RA. The 2009 KDIGO guidelines recommend using IL2 RA as 1st -line
induction in TR NOT at higher immunological risk. In lower-risk TR, rATG
is given with the same induction plans used for high-risk TR. TR receiving
Bsx>intraoperative 20 mg & 20 mg on the 4th postoperative
day. Some evidence present that rATG,
as compared to Bsx or no induction,
may be more beneficial in lowered-risk TRs:
●Analysis of RCT of rATG
compared to Bsx, TR of a normotensive, standard-criteria-donor
kidney ttt with rATG had lowered Ac Rj, death, and achieved endpoint i.e., death,
graft loss, or Ac Rj than those receiving
Bsx.
●rATG
shown to be safe & effective in ptns with LRKD
KTx. Study: rATG compared with no induction showed superior 5-y
ptn & graft survival & one-y Ac Rj rate.
Study: rATG comparing with no
induction showed a significant lowered Ac Rj rate
with no rise in post-tx sequelae. However, other studies were showing rATG is not superior
to Bsx
in low-risk ptns:
●Multicenter study: 615 low-risk TR were randomly given to one of 3 different im/m
plans: Bsx I.T. +
long-term GC, Bsx I.T. +
rapid GC withdrawal
(within 8 d of Tx), or rATG I.T. + rapid GC
withdrawal. All TR provided low-dosing
extended-release Tac cap. + MMF
as maintenance im/m. After 12 mo, biopsy-proven Ac Rj were
similar between
rATG & both Bsx gs. NO differences in ptn/graft survival,
graft function, infection, or malignancy was observed.
●Study: 100 low-risk TR were given Bsx
or rATG. With MMF & short-term GC, CyA was given within 24 hs of Tx or with SCr was < 2.7 mg/dL (250 mmol/L) in the Bsx & rATG arms, resp. At 12 mo, Ac
Rj was similar between the 2 g.s. Fewer CMV
episodes in Bsx arm, with no difference in CMV episodes
between the 2 gs. Ptn & graft survival were comparable at 12 mo & at 5 ys.
● 105 low-risk KTRs randomly provided rATG
or Bsx, both Bsx & rATG showed similar graft & ptn survivals (& Ac Rj rates); however, Bsx
showed low incidence of CMV infection & leukopenia.
●Retrospective analysis: assessing graft
& ptn outcome in 74,627 TR of deceased-donor KTRs receiving IL-2 RA, rATG,
ALm, or no AB, and maintained on Tac & MMF
with or without GC. In the subgroup
of lowered-risk TR, Ac
Rj at one y & graft survival at 5 ys were similar with rATG & IL-2
RA. Ptns who do not require AB I.T.: Although most ptns undergoing KTx should receive induction im/m therapy,
there are select ptns to whom we can omit AB I.T.:
o
Caucasian TR of 2-haplotype-identical,
LRKD (very low risk for Ac Rj)
o
TR of KTx having another functioning SOT e.g., a
liver, lung, or heart and already on long-term maintenance im/m, so could be at a
higher risk of infection with lymphocytic depletion.
Bsx IN TR WHO CANNOT NOT
RECEIVE rATG
RATG is known to be
superior to IL2 RA for I.T. in high risk ptns. If we cannot provide rATG, we can give Bsx
with one or more of the following states at the time of Tx:
o
WBCs count < 2000/microL
o
Platelet count < 75,000/microL
o
Hypotension
(systolic BP < 90 mmHg)
Ptns can receive Bsx as intraoperative 20 mg & another 20 mg on the 4th postoperative day. Efficacy of IL-2 RA
was best reported in a systematic review conducting 71 RCT &
10,537 ptns assessing the impact of therapy on graft loss & Rj rates:
o
32 trials conducting
5784 ptns compared IL-2 RA with placebo for at least one outcome.
Compared with placebo, IL-2 RA lowered Ac
Rj rates & graft loss at one y.
o
16 trials conducting
2211 ptns testing efficacy of IL-2 RA
vs rabbit or horse ATG: there was no
difference in graft failure or clinically evident Ac Rj. Compared with ATG,
IL-2 RA
had higher incidence of biopsy-proven Ac Rj at
one y but fewer SE & less CMV & cancer. Intense acute
hypersensitivity was observed with either new exposure to Bsx
and/or re-exposure.
INFREQUENTLY APPLIED I.T.:
Alemtuzumab: ALm (Campath-1H) is a humanized
anti-CD52 panlymphocytic
(both B & T cells) monoclonal AB that’s approved for CLL. ALm I.T. is provided to 10 % of KTRs in the
US. ALm often not routinely
used as I.T. with KTx as its benefits in declining Ac Rj may disappear
with time. Other long-term criteria e.g., graft/ptn
survival & CAN, may also getting worse
with ALm as
compared to rATG & IL2 RA.
Moreover, ALm
is not often available to all Tx centers.
ALm
is given as a single IV dose of 30 mg at the time of Tx. RCT & observational reports comparing efficacy
of ALm
with rATG & IL2 RA
in KTRs shows:
●RCT (INTAC):
139 high-risk TR (re-Tx, PRAs of >20 %, or black race) > one 30 mg dosing ALm or rATG, 6 mg/kg/4 ds, & 355 low-risk TR received one 30 mg dose of ALm
or a total of 40
mg Bsx/4
ds.
o
In the high-risk cohort, there was no difference in Ac Rj in TR receiving
ALm,
compared with rATG, at 6, 12, &
36 mo.. Late Ac Rj (= Rj seen between 12
& 36 mo in ptns having no Ac Rj in the 1st 12 mo) was more prevalent with ALm, but was statistically insignificant. Other authors reported that the
beneficial effect of ALm may
decline by time.
o
In low-risk g., rate of Ac
Rj was lowered in ptns receiving ALm,
as compared to Bsx, at 6, 12, &
36 mo. Late Rj was more prevalent in the ALm as compared to Bsx g. This confirms prior reports showing: among low-risk TR, ALm
decreases Ac Rj early after Tx.
However, this effect weakened by time, as observed with high-risk group.
o
In the low-risk g., there were no differences between ALm &
Bsx
in ptn survival, overall or DSGS, or
overall rate of SE, but these reports
were not powered. Among low-risk TR, comparing
with Bsx, ALm
can decrease mean lymphocyte count at all points of time; but in high-risk TR, rATG
& ALm both induce low mean lymphocyte count in the 1st post-Tx week.
●Multicenter, open-label, RCT: comparing
ALm followed by low-dose Tac (trough: 5-7 ng/mL) & MMF
without GC with Bsx
induction followed by standard-dose Tac (trough: 5-12
ng/mL), MMF, & GC. At 6 mo, compared to Bsx and standard maintenance therapy, TR receiving ALm
show low rate
of biopsy-proven Rj. No difference in
Tx failure
or infection.
● RCT:
90 KTRs randomly
received rATG (g.A), Alm
(g. B), or daclizumab. All 3
arms received Tac & MMF,
and maintained on GC was only given to TR in
g. A & C. Target Tac & MMF were
also lower
in g. B. At 15 mo, ptn & graft survival rates and Ac Rj rate were the same in ALL g.s, suggesting:
some TR could be maintained on less severe im/m if received Alm. Follow-up at 48 mo showed: g.B (Alm without GC)
had worse DCGS. CAN was
also more prevalent.
Two RCT that have been performed assessing Alm or rATG as I.T.
in kidney, kidney-pancreas, & pancreas TR.
Despite the assumption of lowered Rj rates
with ALm, these data are difficult to
interpret considering their multiple limitations & flaws
including conducting 3
different cohorts with variable dose plans. Retrospective report: graft
survival was lower & MR higher in TR received ALm as compared to those receiving rATG or Bsx.
Reports of induction of autoimmune disorders, e.g., thrombocytopenia &
autoimmune thyroiditis, with the use of Alm.
A suggested mechanism is the expanding memory T cells after Alm-induced depletion. However, Alm, compared with IL-2 RA, does not augment the risk of post Tx recurrent GN.
Rituximab: an anti-CD20 monoclonal AB
depleting CD20 +ve B cells. We do not
routinely use Rtx as I.T. in most TR receiving
KTx, as no
added benefit and may be harmful to TR of HLA & ABO-compatible grafts.
Two RCT have been shown Rtx
as I.T. in KTRs:
[1] RCT:
comparing single-dose Rtx
(375 mg/m2) with placebo as I.T. among 136 KTRs. At 6 mo: no difference in Ac Rj rates, bacterial/viral infection, or MR between Rtx & placebo g.ps. However, the 3-y MR was higher in Rtx -ttt TR as
compared to placebo. Deaths were attributed to fungal
pneumonia, pulmonary carcinoma,
& myocardial infarction and/or cardiac arrest. The higher incidence of CVS deaths could
be related to the atheroprotective effect of B
cells (depleted by Rtx). At 3 ys: no
difference in DSAs evolution between Rtx or placebo groups.
[2] RCT:
280 TR received a single dosing of Rtx
(375 mg/m2) or placebo during Tx surgery.
All TR maintained on im/m including Tac,
MMF, & GC. At 6 mo: NO difference between g.s in Ac Rj rates. However, high-risk TR (= PRA
of >6 % or re-Tx), as compared to placebo, Rtx-ttt TR had
a lowered risk of Rj. Rtx-ttt TR had
higher incidence of neutropenia, but
the risk of infection & cancer was similar in both g.s at 2 ys. Another
systematic review: 45 records from 21 reports showed:
Rtx was useful as I.T. with ABOi Tx,
with outcome comparable to splenectomy.
Scanty evidence that Rtx decreased Rj and
improve survival for HLAi TR. Rtx can be used for Dsz for HLAi
& ABOi
TR and also used to prevent FSGS recurrence.
Experimental approach: Autologous stem cell Tx has been tried to replace AB
induction. In one open-label, RCT:
infused marrow-derived stem cells at time of Tx &
2 weeks after Tx was compared to IL-2 RA (control) among 104 TR of ABO-compatible kidneys
from LRD. All TR received same doses of CNI,
MMF,
& GC. NO difference
between g.s in ptn or graft survival at 13-30
mo. At 6 mo, there was a lower incidence of
Ac Rj among TR receiving
stem cell infusion as compared to controls. 52 more TR
receiving stem cell Tx + 20
% lower dose of CNI > similar lowered
incidence of Rj as compared to controls. At
one y: lowered risk of opportunistic
infection seen with stem
cell Tx. Long-term work is currently
required.
COMMENTS