NEWS & VIEWS

T R A N S P L A N TAT I O N aggressive treatment3. Furthermore, graft sur-

vival rates tend to be lower in desensitized

Survival benefits of incompatible

transplant recipients than in those who have
received an allograft from a compatible donor4,
discouraging many transplant programs from

living donor kidney transplants attempting desensitization procedures. Small

transplant hospitals that lack resources, and
conservative programs whose overall transplant
J. Michael Cecka survival rates are affected by even a small num-
ber of failures still turn away incompatible living
A single-centre study found that desensitization therapy permits a good donors and have their patients continue to wait
success rate of kidney transplantation with an incompatible living donor. Data for a deceased donor kidney. Patients with an
from 22 US centres now suggest that this technique could be employed across incompatible living donor now have another
option that presents fewer risks and requires
multiple hospitals to prolong the lives of sensitized transplant recipients. less aggressivetreatments.
Refers to Orandi, B.J. etal. Survival benefit with kidney transplants from HLA-incompatible live donors. N.Engl. J.Med. Paired kidney exchange provides an alter-
374, 940950 (2016) native approach for patients with an HLA-
incompatible or ABO-incompatible living
donor that was not widely available during the
A recent study by Orandi etal., published in transplant that failed, or other exposures to study by Orandi. This process can provide an
the New England Journal of Medicine, reports human tissue from another individual are opportunity for sensitized patients with a living
that desensitization is an important option for a challenge for transplantation programs. donor to exchange their incompatible donor
patients with a willing, but incompatible living Approximately 35% of renal transplantation kidney for one from another donorrecipient
donor1. The study analysed the outcomes of candidates have antibodies directed against pair that is compatible. Initially, exchanges were
>1,000 patients from 22 different US transplant HLA antigens that can damage or even destroy performed between pairs within a program
hospitals who underwent renal transplantation a transplanted kidney. A crossmatch test is or among several programs that collaborated
following perioperative removal or reductionof performed prior to any kidney transplantation together, but were limited by the reciprocal
circulating antibodies directed against HLA procedure with the aim of preventing trans- nature of theexchange each pairs donor must
ofthe donor. The survival of the HLA-antibody- plantation of healthy, functioning organs into match the others recipient. Larger exchanges
incompatible recipients 8years after transplan- a hostile environment. Sensitized patients are that utilize chains of pairs do not require reci-
tation was superior to that of matched control at a distinct disadvantage compared to those procity and can facilitate many other transplan-
patients who remained on the deceased donor who do not exhibit circulating HLA antibodies tation procedures to occur beyond two pairs
waiting list and were subsequently transplanted because fewer donors will be compatible; for exchanging kidneys5. In addition, paired kidney
during the study, and to that of those who many of these patients, finding a donor will exchange can be combined with desensitization
waited but did not receive a transplant (76.5%, beimpossible. to select a less incompatible donor for whom the
62.9% and 43.9%, respectively). This study fol- patient can be desensitized6.
lows an earlier, single-centre analysis of patients Evaluating these options for sensitized
admitted at Johns Hopkins, Baltimore, USA, Turning away willing donors patients is facilitated by determining how
which was performed by the same researchers2. who are incompatible is many potential donors would be incompatible
The participants of the single-centre study with the patient. The percent panel-reactive
avoidable in many cases
were included in the subsequent multicentre antibody (PRA) value provides an estimation
analysis. The latest results suggest that desen- of this number. Based on the PRA values pro-
sitization and living donor transplantation can Desensitization may not be a viable option vided in the Orandi study, ~40% of the patients
be performed at many hospitals with similar at all transplant centres. The procedures can who were desensitized initially exhibited nar-
patient survival rates as those observed at Johns be lengthy, resource intense, and costly to rowly reactive antibodies (<50% PRA) that were
Hopkins, and may encourage other transplant perform. The procedure is not successful in directed against the intended donor1 but one
hospitals to consider this option for sensitized all patients, and given that the reduction of could expect that one out of two other ABO-
patients with an incompatible living donor. antibodies can be temporary, it is logistically compatible donors would be HLA compatible
These data might also help to reduce financial difficult to attempt in patients who do not with these patients. For narrowly sensitized
disincentives to the desensitization technique, have a living donor ready for transplantation. patients, exchanges for a compatible donor
which can be an expensive procedure. Although desensitization reduces the risk of kidney could happen quickly through larger,
Candidates for transplantation who have HLA-antibody-mediated rejection, a high per- national consortia such as the National Kidney
become sensitized to HLA antigens through centage of desensitized recipients experience Registry, United Network for Organ Sharing
pregnancy, blood transfusions, a prior early antibody-mediated rejection that requires (UNOS), or the Alliance for Paired Donation.

NATURE REVIEWS | NEPHROLOGY www.nature.com/nrneph

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NEWS & VIEWS

Cell-based assays Living donors provide about one-third of

Complement
+ CDC cross-match
Donor
lymphocytes
Fluorescent-conjugated
anti-human globulin Flow cross-match
Patient sera
containing
anti-HLA
donor-specic + zation combined with paired exchange could
antibodies
Puried HLA antigens Fluorescent-
embedded in polystyrene conjugated
microspheres anti-human
Solid-phase assays globulin Luminex
Figure 1 | Identification of anti-HLA antibodies. Traditional cell-based, low-resolution
Nature Reviews | Nephrology
techniques have been the standard method for identification of anti-HLA antibodies in the sera of
transplant candidates, but are dependent on the availability of specific cell types and cell viability.
Solid-phase testing of sera for HLA antibodies now enables precise identification of each individual
HLA antigen against which a patient is sensitized, using techniques based on the Luminex bead-
based multiplex assay principle. The Calculated Panel Reactive Antibody value can be determined
from the data obtained from solid-phase assays and is the percentage of historical kidney donors
who express any HLA antigen reported as unacceptable because of the patients antibody
specificities. CDC, complement dependent cross-match. Permission obtained from 2013
Dhedaetal.; licensee InTech. Dheda, S. etal. in Current Issues and Future Direction in Kidney
Transplantation 1st edn Vol. 1Ch. 5 (ed. Rath, T.) 105131 (InTech, 2013).
The PRA values used to group patients in CPRA, the calculation differs because histor-
the Orandi study1, which included patients ically, the values were rounded to the nearest
who underwent renal transplantation between percent; apatient with 99.50% CPRA could be
1997 and 2011, were determined using the tra- HLA compatible with1in 200 donors, whereas
ditional serological method of testing panels of a patient with 99.99% CPRA would expect <1 in
donor lymphocytes (using cell-based assays). 10,000 donors to be compatible for transplanta-
In 2009, the calculated PRA (CPRA) method7, tion. The four digit values have now been added
which is based on solid-phase tests (FIG.1), was to the CPRA calculator, which evaluates candi-
introduced. CPRA is now considered a more dates for kidney, pancreas and kidney/pancreas
precise and consistent assessment of reactiv- transplants based on the candidates unaccept-
ity than traditional methods, and can be an able antigens, and was derived and validated by
important tool for evaluating whether desen- the Organ Procurement and Transplantation
sitization should be the first option for sensi- Network/UNOS Histocompatibility Com
tized patients. CPRA is an accurate indicator of mittee8. By considering the number of donors
the probability of finding a compatible donor available, knowing the probability of finding a
for example, a CPRA value of 80% indicates compatible donor within a given time period
the kidneys transplanted in the USA each year.
Turning away willing donors who are incom-
patible with their intended recipient is avoid
able in many cases given the options of paired
exchange and desensitization. Paired exchange
might provide patients with a compatible trans-
plant, particularly if the patient is not broadly
sensitized. For those with a very small chance
of finding a compatible donor quickly through
paired exchange, desensitization or desensiti-
be the appropriate first choice. In light of this
recent study, there is now sufficient data to
suggest that it is better for patients to undergo
desensitization than remain on dialysis and the
transplant waiting list.
J. Michael Cecka is at the UCLA Immunogenetics
Center, Pathology and Laboratory Medicine, University
of California Los Angeles, 1000 Veteran Avenue
1520, Los Angeles, California 90095, USA.
mcecka@mednet.ucla.edu
doi:10.1038/nrneph.2016.55
Published online 18 Apr 2016
1. Orandi,B.J. etal. Survival benefit with kidney
transplants from HLA-incompatible live donors.
N.Engl. J.Med. 374, 940950 (2016).
2. Montgomery,R.A. etal. Desensitization in
HLA-incompatible kidney recipients and survival.
N.Engl. J.Med. 365, 318326 (2011).
3. Orandi,B.J. etal. Eculizumab and splenectomy as
salvage therapy for severe antibody-mediated
rejection after HLA-incompatible kidney
transplantation. Transplantation 98, 857863
(2014).
4. Orandi,B.J. etal. Quantifying the risk of
incompatiblekidney transplantation: a
multicenterstudy. Am. J.Transplant. 14, 15731580
(2014).
5. Melcher,M.L. etal. Chain transplantation: initial
experience of a large multicenter program.
Am.J.Transplant. 12, 24292436 (2012).
6. Montgomery,R. A. Renal transplantation across
HLAand ABO antibody barriers: integrating paired
donation into desensitization protocols.
Am.J.Transplant. 10, 449457 (2010).
7. Cecka,J.M. CalculatedPRA (CPRA): the new
measureof sensitization for transplant candidates.
Am. J.Transplant. 10, 2629 (2010).
8. US Department of Health & Human Services. CPRA
calculator. [online], https://optn.transplant.hrsa.gov/
resources/allocation-calculators/cpra-calculator/.

that 20% of potential ABO-compatible donors may help identify those patients who should Competing interests statement
would be expected to be compatible. At 100% proceed directly to desensitization. J.M.C. declares no competing interests.

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