Kidney Transplantation in Sensitized Patients

128 Pages·2020·5.486 MB·English

by  Duck Jong Han

Kidney Transplantation
in Sensitized Patients
Duck Jong Han
Editor
123
Kidney Transplantation
in Sensitized Patients
Duck Jong Han
Editor
Kidney Transplantation
in Sensitized Patients
Editor
Duck Jong Han
Department of General Surgery
Asan Medical Center
Seoul
South Korea
ISBN 978-981-10-7045-7 ISBN 978-981-10-7046-4 (eBook)
https://doi.org/10.1007/978-981-10-7046-4
© Springer Nature Singapore Pte Ltd. 2020
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Contents
1 Introduction to Kidney Transplantation
in sensitized patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Duck Jong Han
2 Preoperative Evaluation of Sensitized Patients . . . . . . . . . . . . . . . 11
Soo-Kyung Kim and Hyosang Kim
3 Preoperative Management (Desensitization) . . . . . . . . . . . . . . . . . 27
Chan-Duck Kim
4 Induction and Maintenance Immunosuppressants
in Sensitized Renal Allograft Recipients . . . . . . . . . . . . . . . . . . . . . 41
Jin Min Kong
5 Postoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Chung Hee Baek
6 Complication from Desensitization . . . . . . . . . . . . . . . . . . . . . . . . . 63
Duck Jong Han
7 Treatment of Rejection in Desensitized KT Patients . . . . . . . . . . . 91
Joong-Kyung Kim
8 Pathology of the Allograft Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Yong-Jin Kim
9 Postoperative Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Beom Seok Kim, Juhan Lee, and Kyu Ha Huh
v
1
Introduction to Kidney
Transplantation in sensitized
patients
Duck Jong Han
Definition of Sensitization has no antibodies and their PRA titer should be
0%. Accordingly, all patients with at least one
Renal transplantation is widely acknowledged potentially harmful HLA-specific antibody are
as the best therapeutic treatment modality for sensitized. In practice, only patients with a PRA
patients requiring renal replacement therapy. >5% are traditionally considered as sensitized.
For the majority of patients with end-stage Highly sensitized patients are the proportion with
renal disease, kidney transplantation provides sig- the highest and multiple antibody titers, and are
nificant benefits compared with dialysis in terms defined to having a PRA of >85% (Eurotransplant
of improved patient survival, better quality of life, criteria) or >80% (US criteria) [10].
and lower ongoing cost after the first year [1–6]. The highly sensitized patient remains particu-
Sensitization to human leukocyte antigens larly challenging. Generally this has been defined
remains one of the major clinical challenges for as patients with a calculated panel-reactive anti-
successful kidney transplantation [7]. body (CPRA) greater than 95% [11].
Contributing to the reduction in posttransplant
acute and chronic rejection is the recognition of
the importance of the role of pretransplant allo- Donor-Specific Antibody (DSA)
immune sensitization to HLA antigen [8].
The definition of sensitization is variable, but Donor-specific antibody identified before kidney
the general consensus is a panel-reactive antibody transplantation (preformed antibody) can cause
(PRA) value of greater than 20%. In further char- early rejection, such as hyperacute rejection,
acterizing a kidney transplant recipient to be highly accelerated acute rejection, early acute antibody
sensitized, the level is even more variable, with prior rejection, and graft loss.
literature starting at a PRA of 80% and above [9]. Alternatively, de novo developed DSA after
Despite the long history of use, there is no transplant are associated with late onset acute
universally agreed PRA threshold to define sen- antibody-mediated rejection, chronic anti-
sitization. In theory, a non-sensitized patient body rejection, and transplant glomerulopathy.
However there are also “benign” DSA that may
not be clinically relevant, because they are not
D. J. Han (*)
Department of General Surgery, Asan Medical associated with antibody-mediated rejection or
Center, Seoul, South Korea graft failure [12–15].
e-mail: [email protected]
© Springer Nature Singapore Pte Ltd. 2020 1
D. J. Han (ed.), Kidney Transplantation in Sensitized Patients,
https://doi.org/10.1007/978-981-10-7046-4_1
2 D. J. Han
Not all DSA leads to AMR, and the mere pres- angiotensin 2 receptor, and anti-basal membrane
ence of DSA does not necessarily portent unfa- antibodies [22].
vorable outcomes [16]. Among the patients with DSA, proximately
The strongest independent predictor for 75% anti-HLA and 25% anti-MICA antibodies
ABMR and death censored graft survival was are reported [23].
pretransplant DSA. cPRA was not predictive for In contrast with anti-HLA antibodies, anti-
ABMR, TCMR, or death censored graft survival. MICA antibodies are neither easily nor routinely
It can be concluded that with current DSA assign- evaluated in most transplant centers.
ment, the broadness of sensitization measured by
cPRA does not imply an immunologic risk [17].
DSA at the time of transplantation in immuno- Histocompatibility Testing
logically unmodified patients had the increased and Virtual Crossmatching
risk of acute rejection. Posttransplant incidence
of acute rejection was significantly greater in the Cell-based assay, either complement-dependent
MFI ≥1,000 group (35%:8/22) compared to the cytotoxicity crossmatch or flow cytometric cross-
MFI <1,000 group (7%: 2/28) (p < 0.001) [18]. match test has been the cornerstone of compat-
All assessment pretransplant aims to provide ibility testing. Solid phase immunoassays use
a risk profile for transplantation but clinical risk antigen-coated beads to identify HLA antibodies of
assessment in transplant, as with other areas of known specificity in recipient serum, which enables
medicine, is never absolute. A very-low-risk determination of a virtual crossmatch (VXM) in
transplant may still be acutely rejected, while deceased donor organ transplantation [20].
a high-risk transplant in a highly sensitized The virtual crossmatch is an extension of tra-
patient across DNA with augmented immuno- ditional crossmatching and relies on having cur-
suppression and desensitization may fare well. rent and carefully interpreted HLA antibody test
No single result absolutely contraindicates results along with an accurate and comprehensive
transplantation [19]. assessment of the donor HLA antigens [24].
Preformed DSA is typically unacceptable for Now UNOS policy mandate that complete donor
deceased donors, as there is no time to desensi- typing (A, B, BW4, BW6, C, DR, DRBI, DRB3–5,
tization pretransplant, but lower strength DSA DQA1, DQB1, DPB1) is reported which increased
can often be managed with treatment that begins VXM accuracy. Additionally, most donor typing
posttransplant [20]. centers also test for HLA-D PA1 [20, 24].
Assessing complement fixation can identify a The technology used to detect PRA has pro-
subclass that poses a particular risk for rejection, gressed from complement-dependent cytotoxic-
such as IgG1 and IgG3 [21]. ity assay to more modern purified HLA antigen
coupled to specialized microparticles (luminex,
flow cytometry). The reactive antigens are then
Non-HLA Antibody assigned as unacceptable antigens [25].
The non-HLA antibodies are directed against
antigens that are expressed on endothelial cells, Epitope
epithelial cells, keratinocyte, dendritic cell, and
monocytes, but not on peripheral blood lym- The targets for antibodies directed against HLA
phocytes. They include antibodies against MHC molecule are known as epitope. An epitope typi-
class I chain-related protein A (MICA) and cally but not always consists of a 3 amino acid
MHC class I chain-related protein B (MICB) sequence on the HLA molecules that is expressed
which are encoded by genes within the MHC on the exterior of the molecule [26].
and are genetically linked to HLA-B. They also Each HLA antigen is seen as patches of poly-
include anti- platelet, anti-endothelial cell, anti- morphic amino acid residuals (eplet), which
1 Introduction to Kidney Transplantation in sensitized patients 3
constitutes the essential components of HLA epi- the proportion with a PRA level of 0% at the time
topes [27]. of transplant have declined from 72.9% in 1998
HLA antibodies specifically recognize a wide to 59.7% in 2009. Over the same period, the pro-
range of epitope present on HLA antigens and portion with a PRA of 80–100% has increased
molecularly defined high-resolution alleles cor- from 2.2 to 8.1% [10].
responding to the same low-resolution antigen
can possess different epitopes repertoires. Hence
the determination of HLA compatibility at the Causes of Sensitization
allele level represents a more accurate approach
to identify suitable donors for sensitized patients, Sensitization is caused by previous exposure to
and this is what is referred to as high-resolution HLA antigens, usually through organ transplant,
typing [25]. pregnancy, or blood transfusion [10, 33–35].
Each HLA molecule has multiple antibody- Particularly relevant is the exposure of a
binding sites, and different polymorphisms of the woman to her partner’s HLA during pregnancy.
HLA molecule may share epitopes, permitting This results in direct sensitization against the
cross-reactivity between HLA types [28]. partner, potentially making the partner and/or her
All specific HLA antibodies might cross-react child an unsuitable donor [15, 36].
with other HLA specificities. Rare causes of sensitization can occur without
This is due to the fact that all HLA antibod- these and thought to be due to cross-reactive anti-
ies are not against the complete HLA molecule gens from other exposures, such as viruses [28].
but are directed against distinct epitopes on HLA An adjuvant H1N1 influenza vaccine was
molecules that are shared with other HLA anti- found to be associated with the development of
gens. This explains the sensitization against other DSA [36, 37].
non-donor-directed HLA molecules [29]. In retransplant patients, repeated HLA Ag
mismatch may be the risk in patient who under-
went graft nephrectomy of the first graft [38].
Prevalence of Sensitization Anti-HLA sensitization after renal allograft
in Kidney Transplantation nephrectomy was illustrated as such that at base-
line, anti-HLA sensitization was significantly
Approximately 15% of wait-list candidate lower in the early and late asymptomatic groups
have some degree of sensitization [3]. Today than in the group of graft intolerance syndrome,
25% of the patient wait-listed for renal trans- but increased considerably within the 3 months
plantation in the USA have a PRA of >10% following allograft nephrectomy. All patients
while in the Eurotransplant zone, 14% have a undergoing a clinically indicated allograft
PRA of >5% [10]. nephrectomy become highly sensitized within
Sensitized kidney transplant candidates com- 12 months after surgery [39].
prise approximately 30% of the deceased donor It is obvious that mere HLA mismatch will
waiting list and have the longest wait times inevitably lead to a higher potential for sensiti-
because of difficulty in finding a compatible zation. They might be particularly important in
donor [30, 31]. patient with a long life expectancy because of the
Currently 35% patients on transplant waiting high likelihood of needing a second transplant
list in the United States are sensitized with panel- during their life [10].
reactive antibody (PRA) level >0% and 15% Many chronic graft losses are a direct conse-
patients are highly sensitized with PRA level quence of chronic AMR: even after a very short
>80% [32]. engraftment under heavy immunosuppression,
The percentage of patient with >80% PRA DSA and non-DSA appeared in more than 60%
in the USA has also been increasing in the last of patients secondary to the loss of the “sponge
decade. For recipients of deceased donor kidney effect” and stopping immosuppression [40–42].
4 D. J. Han
Stopping immunosuppression also could con- Table 1.1 Estimated number of match runs needed to
have a 95% probability of finding an acceptable donor
tribute to 47.6% of emerging of DSA without
based on candidate cPRA
nephrectomy. However continuation of immu-
nosuppressant need to be weighed against the
Theoretical number of match runs to have a
cPRA, %
risk of infection and is only appropriate in a few 95% chance of finding an acceptable donor
selected HLA-antibody negative patients while 10 2
only retransplants are scheduled [43]. 20 2
30 3
The 10-year actuarial graft survival for highly
40 4
sensitized recipient was 43.9% compared with 50 5
60 6
52.4% for non-sensitized patients (p < 0.01).
70 9
The combination of being highly sensitized by 80 14
85 19
either pregnancy or blood transfusion increased
90 29
the risk of graft loss by 23% (HR:1.230), and the 95 59
99 300
combination of being highly sensitized from a
99.5 600
prior transplant increased the risk of graft loss by 99.9 3,000
99.99 30,000
58.1% (HR 1.581). As a result the mode of sen-
99.999 300,000
sitization predicts graft survival in highly sensi-
tized kidney recipients (>98%). Patients who are cPRA, calculated panel-reactive antibody
highly sensitized from re-transplant have infe-
rior graft survival compared with patients who a 95% probability of finding an acceptable donor
are highly sensitized from other mode of sensi- based on cPRA is illustrated as 300 match in
tized [44]. 99%, 3,000 match in 99.9%, and 300,000 match
in 99.999% (Table 1.1) [28]
To improve transplant rates among highly sen-
Approach to the Highly Sensitized sitized patient, the organ procurement and trans-
Candidate plant network (OPTN) implemented key changes
to the kidney allocation system in which candi-
Allocation System dates with cPRA scores of 98%, 99%, and 100%
receive 24.4, 50.1, and 202.1 points, respectively
The new US national KAS of the organ procure- (Fig. 1.1) [28].
ment and transplantation network effective as of In Italy, a nationwide hyperimmune program
December 2014, was designed to improve the was begun in February 2011. All available kid-
chances of transplanting the most highly sensi- neys are primarily proposed to highly sensitized
tized patients in the waiting list, and these were patients with a panel-reactive antibody above
designed a patients with a calculated PRA value 80% [47].
of 98%, 99% and 100% [45].
Theoretical number of potential donor offers
needed to have a high probability of an accept- Acceptable Mismatch Program
able match can be determined using the follow-
ing equation [46]. HLA antibody detected at a level anticipated to
result in a high rate of rejection in the serum of
Probability of finding an acceptable match
candidates are designated as unacceptable [28].
=1-(cPRA)n
The sweet spot for designating acceptable anti-
n = number of potential donor. gens is to set the level just low enough to avoid
For the purpose of listing and allocation, positive crossmatches but high enough to allow
cPRA is considered as rounded integer value. the candidate to receive as many organs as pos-
Estimated number of match runs needed to have sible. At the University of Virginia the designate
1 Introduction to Kidney Transplantation in sensitized patients 5
(cPRA<98%)
20
17.30
18
16 New
14
s 12.17
nt 12
oi
P
n 10 10.82
o
ati
Alloc 8 Old 6.71
6
4.05
4
2.46
1.58
2 1.09
0.48 0.81
0 0 0 0.08 0.21 0.34
0
0 10 20 30 40 50 60 70 80 90 100
cPRA
Fig. 1.1 Allocation points by calculated panel-reactive antibody (cPRA) in the old versus new kidney allocation
system
value of unacceptable antigens at MFI values The methods for detection of acceptable HLA
exceeding 4,000. This allows for a virtual cross- antigens are single Ag expressing cell line, solid
match to predict crossmatch results during organ phase technique, CDC, and HLA matchmaker
allocation in USA [28]. algorithm to evaluate the role of HLA matching
The Eurotransplant Acceptable Mismatch at the amino acid sequence level. Each HLA anti-
(AM) program was launched in 1989 for highly gen is seen as patches of polymorphic amino acid
sensitized patients (PRA >85%) awaiting a renal residuals (eplet), which constitutes the essential
transplantation within Eurotransplant region. components of HLA epitopes. Non-inherited
When a blood group compatible organ become maternal HLA antigens are often acceptable mis-
available within the Eurotransplant region that matches [27].
matched the AM patient’s own HLA plus accept- For high-risk sensitized patients there are two
able antigens, this organ was mandatorily shipped different strategies:
to this patient [48]. As organisatory measure, patient are given
All patients with an historical or current PRA additional score points for organ allocation and
of 85% or more for three consecutive months enrolled into special program, such as acceptable
are eligible for the Eurotransplant AM program, mismatch program of Eurotransplant or paired
where HLA antigen toward which the patient kidney donation scheme in living donor kidney
never formed allo-antibodies are defined. transplantation. Another is desensitization.
A patient will not produce antibodies against However either approach alone will not be
self-antigens or closely related HLA antigens successful and that a combination of measures,
that share multiple epitope with the recipient, such as inclusion in special allocation program
and these antigens can be defined as “acceptable” plus desensitization, will be necessary to finally
HLA antigens [10]. allow transplantation [49].