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PREEMPTIVE TRANSPLANT
Abbreviations (read twice please):
o
AAKHI: Advancing American
Kidney Health initiative.
o
AB: antibody
o
Ac Rj: acute rejection
o
AKI: acute kidney injury
o
Bc: biocompatible
o
CKD: chronic kidney
disease
o
CKD: chronic kidney
disease
o
CST: Canadian Society of
Transplantation.
o
DCGF: death-censored graft
failure
o
DDK: deceased-donor
kidney
o
DGF: delayed graft
function
o
DNOTR: Dutch National Organ
Transplant Registry
o
DW: dry weight
o
DX: dialysis
o
eGFR: estimated
glomerular filtration rate
o
ESKD: end-stage kidney
disease
o
HDX: Hemodialysis.
o
Hptn: hypotension
o
KTx: kidney transplant
o
LDK: living-donor kidney
o
MDRD: Modification of
Diet in Renal Disease equation.
o
MR: mortality rate
o
Nc: nephrectomy
o
NKF/KDOQI: National Kidney
Foundation/Kidney Disease Outcomes Quality Initiative guidelines
o
NS: nephrotic syndrome
o
Preetx: Preemptive
transplantation
o
RRT: renal replacement
therapy
o
Sms: symptoms
o
Sns: signs
o
TR: transplant recipients
o
Tx: transplantation
o
UF: ultrafiltration
o
UNOS: United States,
United Network for Organ Sharing
o
USRDS: United States Renal
Data Systems
o
W/L: waiting-list
Ptns receiving a KTx have marked decline in MR as compared
to ptns maintained on DX. Preetx,
defined as elective Tx
prior to
the need for chronic DX,
allows the TR
to avoid DX entirely. Preetx
can improve ptn survival as compared to Tx after commencing DX.
However, DX
is usually required by ptns awaiting Tx
or receiving Tx that does not start
immediate function.
TIMINE OF TX: Preetx can be defined as elective Tx prior to commencing
chronic DX. The improved ptn &
graft survival observed with Preetx
may be attributed to lowered rates of DGF as well as biopsy-proven Ac Rj for
both DDK & LDK-Tx.
Furthermore, a relatively diminished clearance given by DX,
as compared to a Tx kidney, leading
to accumulated harmful substances associated with atherosclerotic
lesions, malnutrition, and
chronic inflammatory states. Generally,
ptns undergoing Preetx seem to have
more educated level, with high socioeconomic standard, and be early referred to
their nephrologist along all stages of CKD,
each factor have been participating in a better longevity post-Tx. This effect has been further highlighted
by the new payment model (US) rewarding/penalizing the clinician performance in
Preetx via the AAKHI.
Indications
for Preetx: Preetx is mostly indicated in ptns with ESKD with suitable candidate for Tx. Preetx
is generally preferred as it leads to improved allograft & ptn survival if
compared to Tx after commencing DX therapy:
o
Study: about 40,000 primary kidney TR,
with Preetx > 25 & 27 %
reduced relative risk for allograft failure for LDK & DDK Tx,
resp. Risk for ptn MR were also declined by 16
& 31 %.
o
Analysis: 7948 ptns identified via the DNOTR, the 10-y
survival was higher among ptns performing LDK Preetx
as compared to ptns performed DDK-Tx after 3
ys DX (73 vs 45 %, resp). Comparing to ptns on W/L on DX, ptn survival with Preetx was almost 7.5-9.9 ys for 40-y-old
ptns & 4.3-6 ys for 70-y-old ptns.
The magnitude of timing
the ptn spends on DX before Tx is directly related to the higher MR that suggests a dose-dependent impact of DX. Improving allograft and ptn longevity observed
with Preetx can be attributed to the declined
rates of DGF
& biopsy-confirmed Ac Rj for
both DDK & LDK-Tx.
Moreover, the relative lowered clearance given by DX,
as compared to Tx kidney, may induce an accumulation of several mediators
associating atherosclerosis, malnourishment, & chronic inflammatory states. Despite these clear
benefits, only 20
% of LDK &
5 % of DDK Tx are proceeded with Preetx
in the US. This is mainly can be attributed
to the rapid rise in the potential Tx candidates with no associated availability in the
donor pool. Consequently, the W/L and waiting timing for a DDK has
dramatically expanding along the last 15 ys.
Exceptions to Preetx: Ptns with severe NS may get benefits
from DX before
Tx with
the current residual kidney function, so, nephrosis, will be
greatly improved. Ptns with severe NS are hypercoagulable, if they proceed
to Tx, they
are more likely prone to thrombose the Tx
graft if they commence Preetx. On the
other hand, DX tends to limit the thrombotic
tendency associating NS. Optimal modality to limit severe nephrosis
before KTx (e.g., Nc, embolization, or medical Nc) still unclear. Ptns receiving their 2nd
Tx after the 1st Tx kidney has failed within one y may also get
benefit from a short interval of DX before the 2nd Tx.
GFR threshold for Tx: As Tx
should be mostly performed before the need for DX,
the exact level of renal function (i.e., GFR)
at which we may proceed to Tx still uncertain. Expert physicians generally
agreed that Tx should NOT be
performed until the eGFR lowered to
<20 mL/min/1.73 m2 and with an evidence
of a progressing and irreversible decline in renal function along the previous 6-12 mo. The UNOS rules inform that the eGFR needs
to be 20 mL/min/1.73 m2 or less before
commencing a Preetx. This is also in
agreement with the guidelines of the CST.
The eGFR can
be calculated via the MDRD formula.
Commencing a Tx with a high eGFR cannot be justified, even with the presence of an
irreversible renal lesions. As ptns are generally showing few Sns & Sms of ESKD requiring DX at this level of renal profile, moreover, there
is No benefit can be expected by proceeding to a Tx before it is indicated. Analysis: 19,461 1st
time, Preetx ptns reported to the UNOS between 1995 &
2009 No difference can be
determined in ptn survival or DCG survival
among ptns Tx
at eGFRs <10, from 10-15, between 15-20, & >20 mL/min/1.73 m2, resp. Once the eGFR is < 20 mL/min/1.73 m2, deciding to proceed to an elective preetx should
depend primarily on individual ptn (& donor) preference. Unlike the
decision to start chronic DX, the Tx should
not be delayed until the emergence of uremic Sms.
Referral for assessment by a
Tx team
should be initiated before this level of eGFR.
Ptn may be referred for Tx assessment with a diagnosis of a progressing CKD &
an eGFR <
30 mL/min/1.73 m2. The assessment of
a TR candidate
and the recognition and identification of potential donor are
time consuming. Hence, the early referral threshold may allow the
proper candidate to be waitlisted at the timing with eGFR
dropped to 20
mL/min/1.73 m2 and enhancing the
chance that the TR can avoid DX before Tx.
Of note, this approach is in consistency with the NKF/KDOQI
guidelines that recommending ptn referral for Tx assessment
at an eGFR <30 mL/min.
However,
referring TR
at this level of renal function is usually not proceeded for many
reasons:
1)
Many physicians are
not recognizing the benefits provided by Preetx,
2)
Ptns still reluctant in
considering RRT option until he’s currently obligated.
3)
Absence of streamlined access
to pre-Tx assessment in several zones.
Ptns already on DX: ptns who’re maintained
on DX and
are suitable for Tx should be proceeded
for Tx as early as possible. As the
adverse impacts of DX on post- Tx outcome are greatly duration dependent. As mentioned
before, Tx is associated with better
outcome than DX for almost many ptns. Only 19 % of the US'
ptns maintained on DX ptns in 2019 on
a Tx W/L.
The USRDS
data bases have declared that pre-Tx DX duration of 6 mo or more can passively
decline allograft survival. One study: DX duration for 36
mo conferred a 68
% rise in DCGF. Another analysis:
the 10-y adjusted allograft survival
for both DDK & LDK-Tx
was higher
for Preetx ptns as compared to
ptns still on DX for 2
ys before Tx (69 & 75 for Preetx vs 39 & 49 % for DX followed by Tx,
resp.). MR
risk with a functioning graft & all-cause MR is also higher among ptns
dialyzed for > 6 mo before Tx. Duration of DX before Tx may also trigger the risk of malignancy. Registry
study: ptns on DX for > 4.5 ys before Tx had a 60 % higher risk of malignancy as compared to ptns
on DX for
< 1.5 ys.
DX modality before TX: Despite the impending risks, many ptns need DX before commencing Tx. The current DX modalities may include HDX, either in a DX center or at home DX, or PD. There are no robust, objective data permitting a decision in regard to the choice of DX modality before Tx. Practiced pattern is highly center-related, and the choice the modality should be individualized, with considering ptn preferences and medical facilities. Choosing a modality generally depending on factors that’re not related to Tx including current facilities and convenience, co-morbid disorders, socioeconomic status & DX-center facilities, , etc...
Most reports comparing
pre-Tx DX
modalities with post-Tx outcome have declared no obvious benefit of certain
modality on allograft or ptn longevity. One study: almost 23,000 primary
kidney TR
showed 15
% higher risk of DCGF among PD-treated
ptns in relation to others treated with HDX
before Tx, with the risk is mostly restricted
to the early Tx timing. If the analysis was confined to the 1st
3 mo after Tx, the relative
risk for graft loss with PD was 33 % greater than that of HDX.
However, these results have not been confirmed by more recent reports. Causes
of excessive graft loss with pre-Tx PD, if present, is not certain. Limited
data may suggest: impending allograft thrombosis may be increased
among ptns on PD prior to Tx,
mechanism of PD predisposition to allograft thrombosis
is not certain.
DX IMMEDIATELY BEFORE TX:
Routine (i.e., scheduled) DX should
be held 24
hs before Tx, which is different from
ptns proceeding to a non-Tx surgery, where DX is generally advised in the 24 h.s before
surgery. DX
is not recommended within 24 h before Tx
as it may trigger the risk of DGF.
The robust likelihood of post-Tx allograft recovery
makes even very small risks associating DX less accepted. The impact of elective DX on short-term
post-Tx outcome
still uncertain. One study: DX within 24 h.s of Tx trigger the risk of DGF,
particularly if a bioincompatible
dialyzer was utilized
and UF was
included. However, trial: 110 ptns receiving HDX
(one 3-h session with no UF) or no HDX immediately before Tx, No difference could be detected in DGF or eGFR 5 d.s after Tx. So, avoiding UF
16-24 hs before Tx may limit
the risk of DGF incidence.
Added to the possible risk of DGF, DX may induce electrolyte/fluid imbalance that is requiring several h.s to be optimized, and could theoretically contributing to sudden death. Retrospective report: 80 chronic DX ptns with documented sudden death, a 1.7 relative risk was reported in the 12-h period starting with commencing the DX therapy. For non-Tx ESKD ptns, this risk may be justified by the documented benefits expected with DX therapy to ptns with no kidney function. In contrary, TR proceeding to Tx mostly restoring immediate renal function.
However, despite the
expected recovery of renal function, DX may be commenced in some TR to correct metabolic alterations that is
difficult to manage by conservative therapy or have unaccepted anesthetic risk.
Hyper-K+ is the most common indication for DX immediately
prior to Tx. Mild hyper-K+ at baseline is commonly seen with CKD ptns that could be deteriorated during intraoperative
period. Hyper-K+ related
to Tx surgery
is mostly mild and amenable to be corrected conservatively. We can dialyze TR with a K+
>5.4 mEq/L, with variable polices
among centers. The exact threshold of s. K+
at which proceeding to surgery is not safe without prior DX has not
been determined among Tx ptns, with no available data advice preoperative
normalization of s. K+.
Volume overloaded ptns is a further indication to commence DX.
Whenever DX is indicated, UF (i.e., removing fluid) should be prohibited in
most Tx ptns
as there is evidence that fluid shifting can be complicated by DGF, possibly owing to the increased risk
of intravascular volume depletion with or without Hptn. Moreover, observational data: showed
lowered incidence of DGF in PD ptns comparing to HDX
ptns. Some ptns, however, may need DX to correct volume overloading. For these ptns, performing
DX with low rate of UF (e.g., 5-10 mL/kg/ h), allowing adequate plasma refilling prior to surgery and avoiding
depleted intravascular volume and Hptn
during DX. To avoid intravascular Hptn is
particularly crucial as ptns proceeding to Tx usually receiving intraoperative AB medications
that are usually associated with Hptn
that can be deteriorated with recent, large UF.
The duration of the DX sessions
should be adjusted for every ptn according to the preoperative target of therapy.
For hyper-K+, it can be managed
safely within 2 hs of DX with no need
for a lowered-K+ bath. Ptns
requiring UF may need longer session
(3-4 hs) to be deloaded safely with limited risk of Hptn.
Unlike non-Tx ptns, urea kinetic
modelling (i.e., Kt/V) should NOT be utilized
to manage therapy, as there’s anticipated renal function
recovery and no available data to
correlate Kt/V with the Tx outcome.
The dialysate constituents is the usually similar to non-Tx ptns.
However, Ca+, Mg+, Na+,
and glucose fluxing should be limited during therapy, and choosing K+ & HCO3 baths should be managed carefully to avoid
the evolution of hypo-K+ &
metabolic alkalosis. Dialysate oC should
also be adjusted for each TR. A 3 mEq/L Ca+,
1 mEq/L Mg, 140 mEq/L constant Na+,
and 100 mg/dL glucose
dialysate bath are usually preferred. Dialysate temperature can be adjusted to
be 0-1 oC
less than ptn's body temperature.
Most out-ptns DX therapies are running with systemic anticoagulants
via heparin. It is advised NOT to utilize
heparin among TR who are proceeding Tx
within 24 hs of DX. The expected ½ -life
of the usual 10-50 IU/kg
bolus dosing of heparin with HDX is about
30-90 min that is
prolonged in an ESKD ptn as compared with a non-ESKD ptn and vary according to other factors
of the DX
therapy. Intraperitoneal heparin may be used for fibrin in PD does not
induce systemic anticoagulation. A Bc membrane should be utilized for all TR performing
DX before Tx.
Complement-activating or non-Bc membrane dialyzers (e.g., cuprophane
dialyzers) have been complicated with DGF
development. Study: 44 graft TR dialyzed within a 24-h befor Tx, recovery of renal function was higher with
dialyzing ptns with the Bc dialyzers.
IMMEDIATE DX
AFTER Tx: About 20 % of ptns may need
temporary DX
after Tx. Post-Tx requirement of DX in the 1st post-operative week
is called DGF, whatever the cause of allograft
dysfunction. DGF has independent association with about 2-3 fold rise in
ptn mortality, graft failure, & DCGF.
The risk factors of DGF have been evaluated in several studies. The
clinical indications for acute DX among TR in the immediate Tx period are similar to that in non-Tx ptns
developing AKI.
Choosing the optimal
DX modality
in the post-operative period is not certain. Most clinicians, perform HDX after Tx
that can be explained by the possibility of peritoneal membrane disruption
during Tx surgery, with the possible
leak of glucose-containing dialysate fluid with increased risk of infection.
Some experts suggested the removal of the PD catheter at the time of Tx surgery to guard against the 5 % or more risk of peritonitis
(even with no prior DX). However, PD has been
performed in some TR with DGF.
Generally, there is no reason for continuous RRT.
The prescribed DX is usually similar to that of non-Tx ptns. Large
UF rates
should be omitted to avoid graft ischemic
injury. We targeting a weight (volume parameter) within 1-2 kg of the ptn's
known DW with fluid removal not > 10 mL/kg/h.
PD CATHETER REMOVAL after
Tx: optimal time of removing
PD catheter after KTx is not certain. Unless otherwise prescribed
and despite the higher risk of peritonitis, some physicians wait 3-4 mo after
surgery as significant quantity of TR may resume temporary/ permanent DX after Tx. However, several ptns with higher risk for
peritonitis may get benefit from early catheter removal. Retrospective report:
232 PD ptns
found that the incidence of peritonitis can be enhanced via the following factors:
o
Male gender
o
Urine leaking
o
> 2 Rj episodes
o
S.
aureus peritonitis
o
Surgical technical difficulties
o
Permanently non-functioning
graft
o
Frequent peritonitis episodes before surgery (medium
3)
Post-operative catheter removal is typically performed within one month, unless DX requirement is highly suspected. However, catheter removal at the time of or within the 1st week post-operatively is proceeded in some center.
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