Attending Rounds

Approach to the Highly Sensitized Kidney Transplant

Candidate
Douglas S. Keith and Gayle M. Vranic

Abstract
For patients with ESRD, kidney transplant offers significant survival and quality-of-life advantages compared with
dialysis. But for patients seeking transplant who are highly sensitized, wait times have traditionally been long and
Division of
options limited. The approach to the highly sensitized candidate for kidney transplant has changed substantially Nephrology,
over time owing to new advances in desensitization, options for paired donor exchange (PDE), and changes to the University of Virginia,
deceased-donor allocation system. Initial evaluation should focus on determining living-donor availability Charlottesville,
because a compatible living donor is always the best option. However, for most highly sensitized candidates this Virginia
scenario is unlikely. For candidates with an incompatible donor, PDE can improve the prospects of finding a
compatible living donor but for many highly sensitized patients the probability of finding a match in the relatively Correspondence:
Dr. Douglas Keith,
small pools of donors in PDE programs is limited. Desensitization of a living donor/recipient pair with low levels of Division of
incompatibility is another reasonable approach. But for pairs with high levels of pathologic HLA antibodies, Nephrology,
outcomes after desensitization for the patient and allograft are less optimal. Determining the degree of University of Virginia,
sensitization by calculated panel-reactive antibody (cPRA) is critical in counseling the highly sensitized patient on P.O. Box 800133,
Charlottesville, VA
expected wait times to deceased-donor transplant. For candidates with a high likelihood of finding a compatible 22908-0133. Email:
deceased donor in a reasonable time frame, waiting for a kidney is a good strategy. For the candidate without a dsk9s@virginia.edu
living donor and with a low probability of finding a deceased-donor match, desensitization on the waiting list can
be considered. The approach to the highly sensitized kidney transplant candidate must be individualized and
requires careful discussion among the transplant center, patient, and referring nephrologist.
Clin J Am Soc Nephrol 11: 684693, 2016. doi: 10.2215/CJN.05930615

Case Presentation After completion of routine pretransplant evaluation,

A 38-year-old black man with type 2 diabetes and ESRD
due to diabetic nephropathy presented for evalua-
tion for a second kidney transplant. He was receiving
hemodialysis for 1 year before undergoing his rst
deceased-donor kidney transplant in 1997. His imme-
diate post-transplant course was uncomplicated, with-
out known episodes of rejection. The graft began to fail
about 4 years before his resumption of dialysis. A
renal allograft biopsy at that time showed calcineurin
inhibitor toxicity and chronic allograft nephropathy
but no acute rejection. He resumed peritoneal dialysis
in 2010, at which time his immunosuppression was
weaned to low-dose prednisone, 5 mg daily. He is
blood type A, which portends wait times of 34 years
in our organ procurement organization (OPO), the
geographically dened unit of organ allocation. An
historical panel-reactive antibody (PRA) on full im-
munosuppression was 0% but repeat testing at cur-
rent evaluation reveals a calculated panel-reactive
antibody (cPRA) of 100% with multiple HLA anti-
bodies against class II antigens. See candidate HLA
typing in Table 1. His other medical problems in-
clude obesity (body mass index, 40 kg/m2), hyper-
tension without signicant end-organ damage, and
diabetic neuropathy. He has no potential living donors.
His physical examination was unremarkable. A
right-lower-quadrant renal allograft was nontender.
the candidate was placed on the active waiting list
for transplant. At the time of implementation of the
new organ allocation system in December 2014, he
had accrued 48 months of waiting time and had not
received any organ offers.
HLA Testing in Kidney Transplantation
HLA molecules are highly polymorphic and vary
considerably among individuals within a population.
They are the principal mechanism by which the im-
mune system identies self from nonself and not only
are critical in responding to commonly encountered
foreign invaders, such as viruses and bacteria, but are
the key instigator in the allograft rejection response.
Exposure to nonself HLA antigens can lead to formation
of anti-HLA antibodies, a process known as sensitiza-
tion. This occurs primarily via three types of exposure
(listed here by increasing sensitizing potential): blood
transfusions, pregnancy, and solid organ transplant.
Rare cases of sensitization can occur without these
events and are thought to be due to crossreactive anti-
gens from other exposures, such as viruses. Approxi-
mately 15% of wait-listed candidates have some degree
of sensitization. High levels of sensitization are associ-
ated with longer wait times and increased likelihood of
being removed from or dying while on the wait list (1).

684 Copyright 2016 by the American Society of Nephrology www.cjasn.org Vol 11 April, 2016
Clin J Am Soc Nephrol 11: 684693, April, 2016
Table 1. HLA typing for renal transplant candidate
Candidate HLA Typing Class IA: 23
Class IIDR: 18
For the sensitized renal transplant candidate, nding a
donor for whom the candidate has no or very low levels of
preformed HLA antibodies is the preferred approach and is
associated with better allograft outcomes (25). The HLA
antigen system is broken down into two broad categories
based on their expression on cell membranes and their pep-
tide conguration. Class I antigens (HLA-A, -B, and -C
antigens) are expressed on the surface of all nucleated cells.
Class II antigens (HLA-DR, -DQ, and DP) are normally
expressed only on antigen presenting cells, but under the
inuence of cytokines can be expressed on other epithelial
and endothelial cells, and therefore can be the targets for
immune-mediated injury. The genes for the class I and II
HLA types are closely linked and found on the short arm of
chromosome 6 in humans; although crossover between
chromosomes can occur, most offspring inherit one hap-
lotype of class I and II alleles from each parent (6,7).
The modalities available to characterize the recipients
pretransplant immunologic risk and detect preformed
HLA antibodies have evolved over time. In their seminal
work in 1969, Patel and Terasaki described the rst test to
evaluate for the presence of preformed antibodies, known as
the complement-dependent cytotoxicity (CDC) crossmatch
(8). A positive CDC crossmatch very effectively predicted
the risk of hyperacute rejection, and excluding recipient/
donor pairs on the basis of this test dramatically reduced
this dreaded complication. With the use of ow cytometry,
in 1983 the ow cytometric crossmatch (FCXM) became
available, increasing sensitivity for antibody detection (9).
In the last 15 years, solid-phase assays, including the Lumi-
nex platform, have allowed the detection of specic HLA
antibody types (10). If the specicity of the HLA antibody is
against the donor, it is known as a donor-specic antibody
(DSA). The basic techniques for detection of HLA antibodies
are outlined in Table 3. Even in the setting of a negative
crossmatch, presence of DSA is associated with decreased
allograft survival (1114). Research is ongoing to better de-
ne the risk of HLA antigens in solid organ transplant, in-
cluding differences in risk by HLA IgG subtype and
importance of complement binding with C1q (15,16).
The targets for antibodies directed against HLA molecule
are known as epitopes. An epitope typically but not always
consists of a threeamino acid sequence on the HLA mol-
ecule that is exposed on the exterior of the molecule (17).
Table 2. Unacceptable antigens for renal transplant candidate
DR: 1 4 7 8 11 12 13 15 16 103
DR51\52\53: 51
DQ: 26789
An HLA antigen is designated as unacceptable at our center if
the mean uorescent intensity exceeds 4000.
Approach to the Highly Sensitized Transplant Candidate, Keith and Vranic 685
A: 30 B: 18 B: 42 CW: 5 CW: 17
DR: 14 DQ: 4 DQ: 5
Each HLA molecule has multiple antibody-binding sites,
and different polymorphisms of the HLA molecule may
share epitopes, permitting crossreactivity between HLA
types. These shared epitopes between HLA molecules
are the basis of the crossreactive groups, whereby devel-
opment of antibodies against one HLA molecule can result
in reactivity against multiple HLA types. This additive in-
crease in presensitization can signicantly hamper our
ability nd acceptable organ matches.
To better quantify the odds of nding an acceptable
match within the existing donor pool, the cPRA was
developed (18). This differs from the traditional PRA
testing in which candidate serum is tested against lym-
phocytes from randomly selected people from the pop-
ulation, and the result is expressed as a percentage of the
randomly selected lymphocyte donors with reactivity.
The advent of solid-phase assay testing now allows for
the identication of the specic HLA antibodies produced
by a candidate. Many centers use the Luminex platform,
which allows for detection of antibody as a semiquantita-
tive measure reported as mean uorescent intensity (MFI).
Given the variability in the test results, this number
provides a rough estimation of antibody levels, with lower
MFI values indicating lower levels of circulating antibody
and higher MFI values suggesting higher levels and in-
creased risk of alloimmune response. HLA antibodies de-
tected at a level anticipated to result in a high rate of
rejection in the serum of candidates are designated as un-
acceptable. Through use of HLA frequency data from the
donor population in the United States and the unacceptable
HLA antigens for a potential candidate, the probability of
nding a donor can be determined. The cPRA is the per-
centage of donors the candidate will likely react against
and is expressed as a percentage. Thus, if the candidate
cPRA is 75%, the expected odds that a donor would be
crossmatch negative is 25%.
Criteria for determining unacceptable HLA antigens
vary widely by center and have major implications for
nding acceptable donor matches. The sweet spot for
designating unacceptable antigens is to set the levels just
low enough to avoid positive crossmatches but high
enough to allow the candidate to receive as many organ
offers as possible. At our center, we designate unacceptable
antigens at MFI values exceeding 4000. These unacceptable
antigens are listed in the United Network for Organ Sharing
(UNOS) databases; recipients will not be eligible for donors
with these HLA types and will be automatically excluded
from match runs. This allows for a virtual crossmatch to
predict crossmatch results during organ allocation. Imple-
mentation of the cPRA has improved efciency of organ
allocation by decreasing the number of positive cross-
matches, which must still be performed before transplan-
tation, and late organ declines (19,20). The unacceptable
antigens for our renal transplant candidate are shown in
Table 2.
686 Clinical Journal of the American Society of Nephrology

Table 3. Techniques for detection of HLA antibodies

Technology Testing Advantages Limitations Sensitivitya Specicityb

Complement- Donor lymphocytes are Highly predictive Visual assessment of 1 111

dependent incubated with for hyperacute results can be
cytotoxic candidate serum and rejection. subjective.
crossmatch complement added. A Cannot detect
vital dye is used to noncomplement
assess for cell lysis via binding or low-level
activation of the antibodies.
complement system.
Cell death is
interpreted as a
positive result.
Flow Donor lymphocytes are Semiquantitative. Higher sensitivity of 11 11
cytometric exposed to candidate Increased testing may lead to
crossmatch serum and incubated sensitivity to false-positive
with uorescent- low-level results.
labeled antibodies for antibody.
human T and B cell Allows for
subsets. Lymphocytes independent
analyzed using ow analysis of effect
cytometry to evaluate on T and B
for IgG antibody lymphocytes.
binding. A positive Rapid results
result is reported as possible.
mean channel shift.
Solid-phase Puried HLA molecules Can detect specic Lack of 1111 1
assays: bead immobilized onto antigens a standardization and
based (e.g., solid surface. candidate has antigen variability.
Luminex) antibodies Interference by
against. external factors
(IVIG,
antithymocyte
globulin) and
intrinsic factors (e.g.,
autoantibody,
immune complexes,
high levels of IgM).
Signicant
interlaboratory
variability.
Unclear what
constitutes a
signicant result.

1, 11, 111, and 1111 indicate increasing levels of sensitivity and specicity. IVIG, intravenous immunoglobulin.
a
Sensitivity for detection of donor-specic antibody.
b
Specicity for clinically signicant antibody mediated rejection.

Evolving Approach to the Highly Sensitized Candidate
A primary goal in transplant is to nd donor/recipient pairs
with the least amount of incompatibility. The options available
to the sensitized candidate are greater if he or she has a living
donor, even if the donor is incompatible. In the highly sensitized
recipient, an organ with a negative crossmatch may not be
easily attainable and desensitization to lower the levels of pre-
formed antibodies to prevent early, hyperacute, and accelerated
acute rejection may be the only feasible option for transplant.
While hyperacute rejection is rare in the desensitized candidate,
the rates of acute antibody-mediated rejection (AMR) and
allograft loss are higher (21). Despite the less than ideal allograft
outcomes in desensitized recipients, they have a survival
advantage with transplant compared with dialysis in most
cases (22). Figure 1 outlines the basic approach to the highly
sensitized candidate for renal transplant.
Candidates with mild to moderate levels of sensitization can
expect only modest increases in wait times to deceased-donor
transplant. The theoretical number of potential donor offers
needed to have a high probability of an acceptable match can
be determined using the following equation:
Probability of finding an acceptable match51 2 cPRAn ;
where n5number of potential donors (23).
Clin J Am Soc Nephrol 11: 684693, April, 2016 Approach to the Highly Sensitized Transplant Candidate, Keith and Vranic 687

Figure 1. | Algorithm for the management of the highly sensitized patient seeking kidney transplant. There is no predefined level of in-
compatibility that is considered insurmountable and decision to pursue desensitization should be individualized for the potential recipient con-
sidering medical eligibility, degree of sensitization to the donor, and financial coverage. This decision making is highly center specific. The risks of
early graft failure are significantly increased in those pairs with positive CDC crossmatch prior to desensitization and pursuing living donor trans-
plantation in this setting should be attempted with caution. Paired donor exchange may offer candidates the opportunity to seek a more compatible
donor, possibly obviating the risks and costs associated with desensitization (14). CDC, complement-dependent cytotoxicity.

For a candidate with a cPRA of 95%, the number of donors
needed in order to have a 95% chance of nding an acceptable
match is about 60. For lower cPRA values, that number is
considerably less. For a blood type O candidate with a cPRA
of 95% who has attained enough wait time to be near the top
of the transplant list in an average-sized OPO with 60 blood
type O donors a year, the candidate could reasonably be
expected to receive an organ within one year. Because blood
types are not distributed equally among the population,
recipients with less frequently occurring blood types can
expect longer waits. Current blood type distribution among
donors is blood type O, 46%; A, 38%; B, 12%; and AB, 4%. The
current allocation system allows AB candidates to share blood
type A donor organs, effectively making blood type B the
most disadvantaged candidate group in terms of donor pool
size. For candidates with cPRAs.95% and especially those
that approach a cPRA of 100%, the number of donors needed
in order to have a high probability of nding an acceptable
match increases exponentially. For instance, to achieve a 95%
probability of nding an acceptable donor, a candidate with a
cPRA of 99% would need to be part of 300 potential donor
match runs, while a candidate with a cPRA of 99.5%, 99.9%,
or 99.99% would need to be part of 600, 3000, and 30,000
match runs, respectively (Table 4). For purposes of listing and
allocation, the cPRA is considered as a rounded integer value.
Within the 100% cPRA designation, the probability of a
match varies enormously according to the unrounded value.
Approximately 13% of the 100% cPRA listed candidates have
an unrounded cPRA$99.99%. For these candidates, waiting
on the list for an acceptable match may be futile.
688 Clinical Journal of the American Society of Nephrology

due to exposure to one HLA type can result in sensitivity to

Table 4. Estimated number of match runs needed to have a multiple HLA types, leading to high levels of sensitization.
95% probability of finding an acceptable donor based on For the purposes of this discussion, highly sensitized candi-
candidate cPRA
dates are dened as those with a cPRA.95%.
Theoretical number of match runs to have a To improve transplant rates among highly sensitized
cPRA, % patients, the Organ Procurement and Transplantation Net-
95% chance of nding an acceptable donor
work (OPTN) implemented key changes to the kidney
10 2 allocation system in December 2014 (24). Efforts were
20 2 made to increase the pool of potential donors and improve
30 3 chances of organ offers. First, a new sliding-scale point sys-
40 4 tem was implemented, which awards points based on the
50 5
cPRA level (Figure 3) (25). The additional points awarded
60 6
70 9 for sensitization begins at a cPRA of 20% and increases ex-
80 14 ponentially as the cPRA approaches 100%, ensuring that
85 19 the very highly sensitized contend for offers as soon as
90 29 they are listed. The previous system only awarded four
95 59 points to anyone with a cPRA$80%. Second, efforts were
99 300 made to expand the pool of available donors. While most
99.5 600 organs are shared on a local level by OPOs, candidates
99.9 3000 with a cPRA of 99% have been offered priority access to do-
99.99 30,000 nors at a regional level, generally increasing pool size by a
99.999 300,000
factor of ve, and candidates with a cPRA of 100% have
priority access to donors at a national level, increasing the
cPRA, calculated panel-reactive antibody.
pool size by a factor of 50. Before the implementation of
this policy, only about 2.5% of deceased-donor transplants
went to patients with a cPRA.98%. With the policy change,
Among sensitized candidates, distribution of cPRA the rate has increased to .13% of deceased-donor transplants,
values is not uniform (Figure 2). Sensitized candidates with demonstrating the benet of these changes in allocation pol-
cPRA.95% make up approximately 20% of the sensitized icy for these traditionally hard-to-transplant patients (26).
candidates and peaks at 100% cPRA. This occurs for two
reasons. First, highly sensitized candidates are less likely to
nd donors and accumulate on the list, while less sensitized Advances in Desensitization of the Highly Sensitized
individuals are more efciently transplanted and removed Candidate
from the candidate pool. Second, as stated earlier, there are Another tactic to improve the probability of transplant in
many shared epitopes between HLA types, and sensitization the highly sensitized is to desensitize candidates waiting

Figure 2. | Distribution of calculated panel-reactive antibody (cPRA) values for sensitized candidates on the waiting list for kidney trans-
plantation in the United States as of August 31, 2013 in the Scientific Registry of Transplant Recipients. The distribution of sensitization levels
among candidates with a cPRA$1% is not uniform. More than 20% of sensitized candidates have measured cPRA levels $95%.
Clin J Am Soc Nephrol 11: 684693, April, 2016 Approach to the Highly Sensitized Transplant Candidate, Keith and Vranic 689

Figure 3. | Allocation points by calculated panel-reactive antibody (cPRA) in the old versus new kidney allocation system. Candidates listed
for kidney transplant receive one point for each year on the list. Under the old kidney allocation system, candidates with cPRA scores .80%
received four additional allocation points. Under the new allocation system, additional points are awarded for sensitization on a sliding scale.
Candidates with cPRA scores of 98%, 99%, and 100% receive 24.4, 50.1, and 202.1 points respectively.

for an acceptable match on the deceased-donor waiting
list. Pioneered by Dr. Stanley Jordan, protocols generally
use infusions of intravenous immunoglobulin (IVIG) and
rituximab to lower the titers of HLA antibodies in the
candidate. After desensitization, the HLA antibody levels
are rechecked using solid-phase antibody testing and the
designation of the unacceptable antigens is modied
according to the changes in HLA antibody levels. Lowering
the number of unacceptable antigens decreases the cPRA
and improves the chances of nding an acceptable donor.
Desensitization on the wait list is labor intensive and costly,
requires careful serologic monitoring, and necessitates
exception to allocation rules from the OPTN. While some
studies of this approach have shown improved transplant
rates in highly sensitized candidates with acceptable post-
transplant outcomes, albeit with a signicant rate of early
AMR (27,28), other studies have not replicated these re-
sults in highly sensitized candidates with cPRA levels
.85%90% (2931).
The cost-effectiveness of this therapy must be balanced
against the savings and health benets associated with a
successful kidney transplant compared with dialysis (32).
Because this is not a use for these agents that is approved
by the US Food and Drug Administration, payors may be
reluctant to reimburse for treatments, so considerable ef-
fort is required to ensure that candidates are not burdened
with unmanageable bills. Finally, and perhaps most im-
portant, the high cost of desensitization and tendency for
antibody rebound after treatment requires that the candi-
dates be near the top of the waiting list so as to contend
for donor offers soon after treatment. For candidates
who already have large amounts of waiting time, this
is not an impediment. But for candidates who have not
accumulated substantial time on the list, and whose high
position on the waiting list is due to additional points
given for sensitization, changing the unacceptable anti-
gens in order to improve their chances of an offer also
reduces their allocation points for sensitization; poten-
tially moving them down the list and leading to loss of
regional or national sharing priority. To overcome this
issue, the OPTN has recommended that a variance from
the allocation rules be obtained by the transplant center,
which allows these candidates to keep the allocation
points associated with their original, higher cPRA. The
signicant effort and resources needed to successfully im-
plement this approach have limited its practice to only a
few programs across the country.
Highly sensitized candidates with living donors have
additional options for transplant with desensitization or
paired donor exchange. If a candidate has an incompatible
living donor, the recipient can be desensitized to allow
direct donation or the pair can be enrolled in several
national organizations (Alliance for Paired Donation,
National Kidney Registry, or UNOS Kidney Paired Do-
nation Program) that facilitate exchanges. As seen with
recipients on the deceased-donor waiting list, the recipi-
ents unacceptable HLA antigens are identied and used
to nd donors in the paired exchange pool that have more
favorable crossmatch results. The hope is to nd a donor
with both a negative CDC and FCXM; however, for the
very highly sensitized this may be very difcult given the
large pool size needed to nd an acceptable match. For
these candidates, considering ABO incompatible donor
pairs will increase the pool size because the ABO barrier
is much easier to overcome than HLA incompatibility.
Alternatively, one could seek a donor/recipient pair
690 Clinical Journal of the American Society of Nephrology
within the exchange with more favorable crossmatch re-
sults and pursue desensitization (33). Data from multiple
transplant centers engaged in desensitization of recipients
with living donors in the United States showed that the
poorest outcomes among living donor/recipient pairs is
between pairs with a positive CDC crossmatch before de-
sensitization. Those with a negative CDC crossmatch and
just a positive FCXM, or with just a DSA by Luminex
without a positive CDC or FCXM do much better (Figure
4) (14). Therefore, the crossmatch results and DSA deter-
mination are useful risk stratication tools of the donor/
recipient pairs with regard to allograft outcomes. Given
the limited pool size of the exchange programs, for the
highly sensitized it is often necessary to consider incom-
patible donors within the exchange, where it is felt the
incompatibility is amenable to desensitization.
Desensitization involves the use of treatment regimens
that decrease the preformed antibody levels directed toward
the potential donor. Typically, the goal of therapy is to
reduce the antibody level so the FCXM is negative or lower
than a predetermined cutoff. Many different protocols have
been used with varying success; however, most combine
plasmapheresis, IVIG, rituximab, bortezomib, and early
initiation of maintenance immunosuppression several weeks
before the transplant (21,3437). Single-center case series us-
ing these approaches for transplant have shown that 25%
50% of transplants will have an early AMR (28,36,3840).
Most of these rejections can be successfully treated, but a
high rate of transplant glomerulopathy and chronic AMR
leading to accelerated allograft failure is common (41).
Even with prolonged post-transplant blockage of the
Figure 4. | All-cause kidney allograft loss based on crossmatch and donor-specific antibody results. All-cause graft loss, by antibody strength.
PCC, positive cytotoxic crossmatch; PFNC, positive flow, negative cytotoxic crossmatch; PLNF, positive Luminex, negative flow crossmatch.
Reprinted from Orandi et al. (14), with permission.
complement system with eculizumab, which is more effec-
tive at preventing acute AMR, chronic damage to the allo-
graft occurs, presumably by complement-independent
pathways (35,42). Thus, the optimal desensitization protocol
before transplant and the best maintenance immunosup-
pression program afterward remains to be determined and
persistence of low-level DSA appears to have deleterious
long-term effects on the graft. The advantage of the desen-
sitization approach (as opposed to simply waiting for a bet-
ter match on the waiting list) is the possibility of expedited
transplant without a prolonged wait on dialysis. The disad-
vantages, however, are many, including higher cost, in-
creased risk of infections and complications related to the
higher intensity of immunosuppression, and known inferior
outcomes for both the patient and the transplanted organ.
But for some patients, this may be their only option.
Case Discussion
This patient illustrates some of the issues confronted when
attempting to transplant the highly sensitized candidate.
The rst issue concerns continuation of immunosuppression
after a failed kidney transplant. This patient did not have an
elevated PRA while receiving his maintenance immuno-
suppression but developed a high PRA after his immuno-
suppression was lowered. Weaning immunosuppression
increases sensitization in many candidates (43,44), and the
decision of whether to maintain a low dose of immunosup-
pression depends on the anticipated wait time to the next
transplant, whether from a living or deceased donor. If the
candidate has a living donor or the projected wait for a de-
ceased donor is short so the candidate can be transplanted
Clin J Am Soc Nephrol 11: 684693, April, 2016
quickly, maintaining some immunosuppression to avoid
sensitization should be considered. For candidates
without a living donor who are projected to wait years
for a transplant, the risks of infection due to continued im-
munosuppression while on dialysis may outweigh the po-
tential benet of preventing sensitization (45). In our
particular candidate, the decision was made to wean his
immunosuppression because of the expected long wait to
deceased-donor transplant in the absence of a known living
donor.
The implementation of the new kidney allocation system
has revolutionized the way in which we manage the highly
sensitized candidate. While our patients cPRA is listed as
100%, it was in reality 99.65%. To have a 95% chance of
nding an acceptable match would require about 850 do-
nor match runs. Approximately 11,500 deceased-donor
kidneys are procured and transplanted from 6000 donors
in a given year in the United States. With the signicant
advantage gained under the new allocation system, wait-
ing on the list for a deceased donor was a good option for
him. Desensitization, with its additional costs and complica-
tions, was avoided as a result of the benets of the national
priority and sharing given to highly sensitized candidates.
After implementation of the new allocation system in
December 2014, the patient received a deceased-donor kidney
transplant within 2 months (1 A, 1 B, and 1 DR mismatch).
The B and T cell FCXM were negative before transplant. The
patient received induction immunotherapy with methyl-
prednisolone and thymoglobulin, 6 mg/kg. The patient did
have several low-level DSAs, all MFI ,1500. For this he was
preemptively treated with one dose of rituximab, 375 mg/m2,
and four doses of IVIG, 0.5 g/kg, to prevent re-emergence
of high levels of DSA and decrease risk of AMR. He is
receiving a standard maintenance immunosuppressive reg-
imen with tacrolimus, mycophenolate mofetil, and predni-
sone with a serum creatinine of 1.4 mg/dl at 12 months after
transplant.
Conclusions
(1) Every effort should be made to minimize incompatibility
between donor and recipient.
(2) The new deceased-donor kidney allocation rules for can-
didates with a cPRA$98% have significantly improved
organ availability for highly sensitized candidates. For
mild to moderately sensitized candidates in most OPOs,
especially for common blood types, finding acceptable
deceased donors is usually possible without large in-
creases in waiting time.
(3) For candidates with a cPRA of 100%, knowing the un-
rounded cPRA value can help stratify the probability of
finding a donor on the waiting list. For the recipient
with a very high cPRA, such as 99.99%, the probability of
finding a donor in a realistic time frame is extraordinarily
low and desensitization may be the only feasible option
for transplant; however, there is no guarantee that de-
sensitization efforts will be successful.
(4) Candidates with incompatible living donors have additional
options through paired exchange and desensitization to their
incompatible donor.
(5) Predesensitization crossmatches and DSA determination
are useful risk stratification tools for graft outcomes.
Approach to the Highly Sensitized Transplant Candidate, Keith and Vranic 691
Recipients with high levels of sensitization to their donor
are at higher risk of rejection, require more immunosup-
pression, and have less optimal allograft outcomes. This
should be factored into the decision about whether to
desensitize versus having the candidate wait for a more
compatible deceased donor offer.
Questions
Dr. Mitchell Rosner (chair of medicine): How might you
have approached your case study patient if his cPRA had
been much higher, such as one of your listed patients with a
cPRA .99.99% that you mention?
Dr. Keith: The approach to our patient should he have
had a cPRA of 99.999% would have been quite different.
Even with the additional 202 allocation points and national
sharing for kidneys, meaning that he would have rst
priority for any organ that became available in the United
States, his anticipated likelihood of receiving a deceased
donor organ over the next 10 years is ,25%. In this case,
desensitization on the wait list would need to be considered.
Dr. Brendan Bowman (assistant professor of medicine):
You mention that blood type and its frequency in the
population can inuence the options for your highly
sensitized patients. How does this affect your patients
with blood types B and AB, which are much less common
than types O and A?
Dr. Keith: The new kidney allocation system has mark-
edly changed the prospects for transplant of our patients
who do not have living donors. But it remains a numbers
game. Blood type AB candidates are given access to the
blood type A donor pool so they are not disadvantaged by
their relative infrequency in the population. For blood type
B candidates, the situation is much different. The number of
donors a potential candidate could have access to in a given
time period depends on the OPO size and blood type
frequency. The average OPO procures about 100110 do-
nors per year, but this number varies considerably, rang-
ing from 23 to 323 in 2012. In our OPO, we have 1215
blood type B donors annually. For a blood type B candi-
date with a cPRA of 98%, the number of donors needed to
have a 95% chance of nding a suitable match is about 150.
Thus, it may take many years to get this person transplan-
ted from the wait list, despite a sizeable allocation of
points for sensitization. For smaller OPOs, the expected
wait would be even longer. If the candidates cPRA was
99% or 100%, they would have access to regional and na-
tional priority sharing, respectively, so that would increase
their access to donors and considerably improve their
transplant prospects. So approaches to the highly sensi-
tized candidate should be tailored not just to their degree
of sensitization but to their expected pool of available do-
nors, taking into account their blood type, OPO size, and
whether they qualify for regional or national sharing. For
those candidates who have long-anticipated waits, revisit-
ing efforts to nd living donors, multiply listing with
transplant centers in different OPOs, or desensitization
on the wait list should be considered.
Acknowledgments
The data reported here have been supplied by the Minneapolis
Medical Research Foundation as the contractor for the Scientic
692 Clinical Journal of the American Society of Nephrology
Registry of Transplant Recipients (SRTR). The interpretation and
reporting of these data are the responsibility of the authors and in no
way should be seen as an ofcial policy of or interpretation by the
SRTR or the United States government.
This study used data from the SRTR. The SRTR data system in-
cludes data on all donor, wait-listed candidates, and transplant
recipients in the United States, submitted by the members of the
Organ Procurement and Transplantation Network (OPTN). The
Health Resources and Services Administration, US Department of
Health and Human Services, provides oversight to the activities of
the OPTN and SRTR contractors.
Disclosures
None.
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