The growing disparity between the number of patients on the waiting list for a kidney transplant and the number of deceased donors has compelled transplant programmes to seek ways to increase the number of organs available for transplantation. Unfortunately many recipients with willing living kidney donors will be excluded from living donation due to blood type incompatibility or positive crossmatch. As a solution to this dilemma Rapaport formulated the principle of paired exchange named ‘kidney paired donation’ in 1986. He envisaged a process involving two otherwise incompatible donor-recipient pairs, treated at separate transplant centres simultaneously, with an immediate exchange of two kidneys to produce two compatible pairs. The aim of this study was to work out the cornerstones mandatory for a Portuguese living donor exchange programme by reviewing the international experience. Such a national programme should include five steps: 1) registration, 2) computerised matching, 3) crossmatching, 4) acceptance of the exchange donors by transplant centres, and 5) transplantation. The primary objective of such a programme should be the maximisation of the number of living donor transplants from participating donor-recipient pairs. Barriers to this kind of programme can be avoided by defining nonacceptable HLA mismatches and properly selecting donors and recipients before each match run. Centralized allocation and crossmatch procedures are instrumental to this flexibility.

1. 123
A Portuguese living donor
exchange programme
Bruno A. Lima1, 2
, Helena Alves1
1
Centro de Histocompatibilidade do Norte, Porto, Portugal
2
Faculdade de Ciências, Universidade do Porto, Portugal
Keywords - Kidney paired donation, kidney transplantation, live donation, match algorithm
Received December 22nd
, 2011, revised March 16th
, 2012, accepted May 18th
, 2012
Summary - The growing disparity between the number of patients on the waiting list for a kidney transplant and the
number of deceased donors has compelled transplant programmes to seek ways to increase the number of organs avail-
able for transplantation.
Unfortunately many recipients with willing living kidney donors will be excluded from living donation due to blood type
incompatibility or positive crossmatch. As a solution to this dilemma Rapaport formulated the principle of paired exchange
named ‘kidney paired donation’ in 1986. He envisaged a process involving two otherwise incompatible donor-recipient
pairs, treated at separate transplant centres simultaneously, with an immediate exchange of two kidneys to produce two
compatible pairs.
The aim of this study was to work out the cornerstones mandatory for a Portuguese living donor exchange programme
by reviewing the international experience.
Such a national programme should include five steps: 1) registration, 2) computerised matching, 3) crossmatching, 4)
acceptance of the exchange donors by transplant centres, and 5) transplantation. The primary objective of such a pro-
gramme should be the maximisation of the number of living donor transplants from participating donor-recipient pairs.
Barriers to this kind of programme can be avoided by defining nonacceptable HLA mismatches and properly selecting
donors and recipients before each match run. Centralized allocation and crossmatch procedures are instrumental to this
flexibility.
Correspondence: Bruno A. Lima, Centro de Histocompatibilidade do
Norte, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal; e-mail:
bruno@chnorte.min-saude.pt
Introduction
Renal transplantation is the most effective medical treat-
ment for the majority of patients with renal insufficiency.
The limited number of organs available from deceased
donors emphasizes the increasing importance of living
kidney donors for the growing demand of renal replace-
ment therapy in patients with end stage renal failure.1
The long-term outcome for kidney transplantation from
living donors seems to be superior to that of organs from
deceased donors, while the risks to donors are minimal.2-5
Living kidney donation should be proactively encouraged .
But the failure of nearly one third6
of all donors to accom-
plish their desire to donate a kidney to a family member or
friend due to an ABO blood type or tissue incompatibility
is frustrating. High expectations exist in the community to
overcome these barriers. Therefore, health care profession-
als have an obligation to establish an exchange programme
for living kidney donors.
Living donor exchange
Rapaport formulated the principle of paired exchange in
1986, naming it ‘kidney paired donation’.7
He envisaged
a process involving two otherwise incompatible donor-
recipient pairs, treated at separate transplant centres simul-
ORGANS, TISSUES & CELLS, (15), 123-129, 2012

2. 124 B.A. LimA et al.
Portuguese law
For establishing a LDE programme the legal precondi-
tions must exist according to national laws:
• Law No. 22/2007 dated 29th
June 2007 partially trans-
posed Directive No. 2004/23/EC of the European
parliament and council into Portuguese legislation re-
garding donation or recovery of organs, tissues and cells
of human origin for therapeutic use or transplant, and
transplant surgery.
Article 6 of this law states that the entity for admissibil-
ity verification in the harvest for transplantation is the
body entrusted with the issuance of a binding opinion
in the procurement of organs from living donors for
transplant.
Article 7 identifies the duty of the physician to fairly,
adequately and intelligibly inform the donor and recip-
ient of the possible risks and consequences of donation,
treatment and side-effects and further precautions.
Article 8 states that the consent of the donor and recipi-
ent must be free, enlightened, informed and unequivo-
cal; the donor can identify the beneficiary.
• Regulatory circular No. 01 / DQS dated 7th
January
2009 issued by the Directorate General of Health
defines a therapeutic protocol for the registration and
maintenance of the list of active kidney transplant op-
erations in both the initial evaluation of patients and in
its quarterly review.
• Resolution CM/Res(2008)6 on transplantation of kid-
neys from living donors who are not genetically related to
the recipient (adopted by the Committee of Ministers on
26th
March 2008 at the 1022nd
meeting of the Ministers’
Deputies). The fourth point provides that member
states may allow or prohibit donations from emotion-
ally or genetically unrelated living donors in donor
exchange (i.e., “paired exchange”).
• Ordinance No. 802/2010 dated 23rd
August 2010
states that the Authority for Blood Services and Trans-
plantation (Autoridade para os Serviços de Sangue e
Transplantação - ASST) must maintain data, according
to the leges artis, on the inclusion criteria for donor-re-
cipient pairs in the designated National Programme of
Kidney Crossover Donation (PNDRC) and crossover
selection and respect the requirements of admissibility
of living donation and the procurement of organs for
transplantation.
Therefore no conflict of interest with the national laws
was detectable.
Clinical fitness for the new treatment
Any patient who is eligible for a kidney transplant can
participate in the LDE programme. These patients should
have a living donor who is willing but unable to donate
due to immunological incompatibility. Such donors must
taneously, with an immediate exchange of two kidneys to
produce two compatible pairs.
Although different approaches to solve the problem for
immunologically incompatible donors and recipients
were suggested,8
participation of such incompatible
living-kidney-donor-recipient pairs in a living donor ex-
change (LDE) programme enables them to benefit: they
donate to another recipient and receive from another
donor out of the LED pool. The aim of this work is to
review the preconditions for establishing a Portuguese
LDE programme based on the knowledge gained inter-
nationally.
Review of preconditions mandatory to establishing a
living donation exchange programme
Kidney exchange classification
In an LDE the methods of kidney exchange must be de-
fined by a mathematical algorithm:
Pi = Pi,i = (Ri, Di) with i = 1, …,n, an incompatible ABO or
human leukocyte antigen ( HLA) pair (Recipient-Donor).
It is defined by a two-way exchange between two incom-
patible pairs, the exchange Pi - Pj with i ≠ j and i, j = 1, …,
n, from which we obtain Pi,j and Pj,i, two ABO blood type
compatible pairs without known HLA antibodies against
the donor. The recipient Ri is paired with donor Dj and
recipient Rj is paired with donor Di.
A three-way exchange between three incompatible pairs is
defined by an exchange of Pi - Pj - Pk with i ≠ j ≠ k and i,
j, k = 1, …, n, from which we obtain Pi,j, Pj,K and Pk,i three
ABO blood type compatible donor-recipient pairs without
known HLA alloantibodies against the donor.9
FIGURE 2 - Three-way exchange between incompatible pairs.
FIGURE 1 - Two-way exchange between incompatible pairs.
Donor 1
Donor 2
Recipient 1
Recipient 2
incompatible
incompatible
Donor 1
Donor 2
Donor 3
Recipient 1
Recipient 2
Recipient 3
incompatible
incompatible
incompatible

3. A Portuguese living donor exchange programme 125
• Monitors programme execution times in the form of
indicators with predefined targets.
2. The head of the central laboratory who:
• Ensures and maintains immunological information
and the communication between the CHL and trans-
plant units;
• Determines the unacceptable HLA mismatches in
transplantation;
• Collects the historical and current sera for final donor-
recipient crossmatch tests.
3. The clinical director of the programme who:
• Oversees the overall management of the programme;
• Oversees and advises the programme coordinator;
• Reviews the practices and protocols of the LDE pro-
gram;
• Is the preferred interlocutor between the CHL and
local transplant units;
• Informs transplant units of the dates on which the
selection of new pairs will be held;
• Contributes to the development of programme infor-
mation materials for patients.
4. An advisory committee for the LDE programme which:
• Ensures evidence that the recommendations to the
programme are maintained;
• Audits the progress, inputs and outputs of the pro-
gramme;
• Advise the programme’s medical director of the needs
and demands of the transplant units assigned to the
programme;
• Organises meetings of nephrologists, surgeons, immu-
nologists and programme coordinators in transplant
units and histocompatibility centres.
Shipment of living donor kidneys
Two options for surgical procedures are considered in an
LDE programme: the shipment of donor kidneys between
transplant units or donor travel to the recipient transplant
unit.
Donor travel to the recipient transplant unit should be
ensured when possible, and the transplantation procedures
involved in an exchange should occur simultaneously.
However, the inability to move the donor should not
inhibit kidney exchanges.16,17
Donor travel ensures a lower
cold ischaemia time, which provides a clear benefit to the
recipient.16
Donor travelling also minimises any logistical
problems13
and complications during transplantation, such
as an unsuitable kidney for transplantation or an unsuitable
recipient for the graft.9
Match algorithm for paired kidney exchange
The choice of donor-recipient pairs must maximise the
utility of the programme and respect the principles of
equity and medical ethics. A potential recipient may enter
participate in donating their kidney to a stranger.
The success of incompatible donor-recipient transplant
pairs in an LDE programme depends on the accuracy and
reproducibility of tissue typing and data entry because
this programme is based on the recognition of acceptable
HLA mismatches. Portugal has three histocompatibility
centres that ensure donor selection for patients on the
national kidney transplant from a deceased donor waiting
list. The European Federation of Immunogenetics labora-
tory accreditation and/or quality assurance of these cen-
tres is an asset and guarantees the quality of the results.
The software that permits the exchange of incompatible
donor-receiver pairs is the most important component of
an LDE programme. This software should ensure that
the new pairs are ABO compatible with no known HLA
antidonor antibodies. Opportunities for transplantation
are directly proportional to the number of donors and
patients willing to be considered for an exchange.9,10
The transplant units must certify the clinical fitness of the
recipients for an LDE programme, using the guidelines of
the International Conference for the Care of Renal Trans-
plantation, Lisbon 2006.11
Candidates on the national
kidney transplant from a deceased donor registry should
be considered medically fit for the programme.
Infrastructure and personnel
A national LDE programme requires a single National
Coordinator Centre (NCC) and a Central Histocompat-
ibility Laboratory (CHL)10,12,13
that maintains immune
information (e.g., HLA data, identification of sera, specif-
ic antibodies, crossmatch results, virological data) in the
LDE database, defines unacceptable antigens and delivers
the new crossmatch results for donor-recipient pairs using
state-of-the-art laboratory techniques.
A CHL that defines rules for a virtual crossmatch ap-
proach would maximise the number of potential exchang-
es in an LDE programme.14
These rules would reduce
the likelihood of possible positive crossmatches without
reducing the number of possible transplants, which saves
time for patients. Therefore, the CHL would identify and
define the clinical relevance of anti-HLA antibodies in
donor kidney transplantation.15
The staff of the National Coordinator Centre would
include:
1. A programme coordinator who:
• Ensures that the requirements of incompatible donor-
recipient pairs for the national LDE program are met;
• Maintains databases and records of the LDE national
programme;
• Ensures the proper functioning of the donor trading
software;
• Ensures a good information exchange between the
CHL and the local transplant units;

4. 126 B.A. Lima et al.
LDE national programme procedure
A month before the start of pair selection for donor
exchange, the clinical director of the LDE programme
will announce the selection procedure date to transplant
unit coordinators. The registration of incompatible pairs,
both new pairs and pairs that were unsuccessful in previ-
ous selections, by the local transplant units should be
performed up to two days before the date of the selec-
tion procedure. Histocompatibility centres will remove
enrolled recipients from the deceased donor transplanta-
tion waiting list on the day of selection. The results will
be communicated to the transplant units two days after
the selection procedure, and the recipients who are not
selected for any exchange will be returned to the deceased
donor transplantation waiting list. Recipient transplant
units have up to one month after the crossmatch results
are available to accept their assigned donors, schedule the
date of transplantation with the donor transplant units
and inform the national clinical programme director of
this date. The software will be activated in the event of a
positive crossmatch selection to identify a new pair that
does not detract from the first selection.
The transplant units should inform the clinical programme
director of the reasons for possible complications with
donor-recipient pairs. The severity of these complications
may delay the exchange, or incompatible pairs can be re-
enrolled in a new selection procedure.
The renal transplant recipients of the programme will be
subject to an annual follow-up examination by a nephrolo-
gist and the CHL will annually perform a new antidonor
antibody search. Donors should be followed annually by
the nephrology department of the transplant unit10
pursu-
ant to Council of Europe Resolution CM/Res(2008)6.
Right to withdraw consent
Donors may withdraw their consent to participate in the
LDE programme at any time. Transplantation procedures
must occur simultaneously to ensure that the recipients
in the LDE programme receive the graft (i.e., none of the
donors withdraw their consent).7
Privacy and confidentiality
The privacy and confidentiality of donor-recipient pairs
in the LDE programme should be maintained. Although
recipients may want to express their gratitude to donors,
frustration and anger are possible if one recipient (or
donor) has not performed as well as another recipient (or
donor). Privacy and confidentiality may be more difficult
when the transplantations occur simultaneously in the
same hospital, but this difficulty should not be an impedi-
ment to the completion of the LDE. All of the parties in
the programme should be educated about the importance
of protecting patient confidentiality.
the programme with more than one incompatible donor
who has been properly assessed (P1,1a, P1,1b, P1,1c, …). The
registration of donor-recipient pairs may be conditioned by
transplant units that can establish a priori criteria for recipi-
ents, such as an age limit for potential donors for a given
recipient or the number of HLA mismatches the recipient
can accept. However, these conditions should only be used
occasionally.12
Therefore, the choice of donor-recipient
pairs shall consider the following criteria:
1. Maximise the number of possible transplants using Ed-
monds’ algorithm;18
2. Group O donors preferentially assigned to group O
recipients;
3. Scoring criteria applied in the selection of donor-recipi-
ent pairs.
The greater number of possible pairs for a given exchange
increases the number of solutions.9
Theoretically, com-
binations of four, five or more factors may aid a larger
number of patients, but these solutions are more difficult
to achieve. Therefore, only two- and three-way exchanges
are advised initially.19
Donor exchange software
The software for the exchange of incompatible pairs is
the key component in an LDE programme. This software
should:
1. Be in a Web-based format that allows all programme
participants to enter information (e.g., demographic,
clinical, immunological or otherwise) directly into the
database;
2. Define appropriate safety measures and the database
back-up responsibilities of the programme coordinator;
3. Provide programme results in real time to the parties
involved;
4. Ensure password access to a Web-based format and that
each user will have their access profile defined by the
clinical director of the programme on the advice of the
local coordinators of transplant units.
Removal of the candidates from the deceased donor
transplant waiting list
All recipients must be temporarily removed from the wait-
ing list for deceased donor transplantation prior to running
LDE software. These patients will be replaced on the list
after running the programme if and only if they are not se-
lected for any exchange, if they have a positive crossmatch
result or if a donor in the exchange withdraws his/her con-
sent. The NCC will notify the Histocompatibility Centres
where the recipients are enrolled in a deceased donor trans-
plantation programme to remove these patients from the
waiting list temporarily. Pair selection for donor exchange
will occur every six months to integrate the largest possible
number of incompatible pairs in each survey.1,20

5. A Portuguese living donor exchange programme 127
Clinical benefits and cost efficiency
The five year graft survival rate from living kidney do-
nors is 80%, which exceeds that of deceased donor grafts
(70%).5
The average cost of dialysis per patient year is about
e 30,000,30,31
while the cost of a kidney transplant is ap-
proximately e 60,000 in the first year, but increases during
the next two years by only a further e 15,000.31
Therefore
a kidney recipient will economize by saving e 15,000
within the first three years after transplantation compared
to haemodialysis patients.
The costs of an LDE programme include:
• The purchase of a flexible software package;
• An exclusive team that ensures the feasibility of the pro-
gramme;
• Crossmatch laboratory tests for the newly identified
pairs.
An estimated cost for implementation is e 60,000
(e 50,000 for the software and e 10,000/year for histo-
compatibility testing), which is easily amortised after the
first three years. The gain per patient is sufficient to justify
the cost of this programme.
The main beneficiaries of a national LDE programme
are patients who receive a more or less healthy kidney
compared to organs from deceased donors. Each living
donor transplant decreases the patient waiting list for
deceased donor transplantation.9
Therefore, patients with
renal failure and without a living donor also benefit from
this type of programme. An LDE programme offers a
relatively low-cost option for subverting the incompatible
barrier without imposing an increased immunosuppres-
sion burden.32
Audits and transparency
A national programme to exchange living kidney donors
should publish an annual report of the programme ac-
tivities. All meetings of the advisory committee for the
national LDE program should be witnessed in the form
of minutes. Each semiannual search and selection process
of the pairs that result in an LDE shall be recorded and
preserved for subsequent audits.
Discussion
A national LDE programme for Portugal
The proposed LDE program extends existing and estab-
lished kidney transplantation from living donors, which
represented more than 10% of kidney transplants in Por-
tugal in 2010. The primary objective of a national LDE
program is the maximisation of the number of living donor
transplants from participating donor / recipient pairs. The
establishment of a National Coordination Centre is essen-
tial to the success of such programme.9,10,12,13
Canada, the United States, Mexico, the Netherlands,
the United Kingdom, Romania, Sweden, Spain, Israel,
Turkey, India, South Korea and Australia10,12,21-29
have im-
plemented LDE programmes on a national or local basis.
The Dutch programme began in 2004, and is the most
successful. During the first four years, 256 incompatible
pairs participated, and 120 combinations of successful
transplants were performed.
The creation of an LDE programme, designated the Na-
tional Programme of Kidney Crossover Donation (PN-
DRC), in Portugal was announced through the Regulatory
Circular No. 1/GDG on 21st
March 2011 from ASST
but in December 2011 no exchange of Portuguese donors
had been performed. The ASST PNDRC’s origins lie in
the Spanish programme ending up having the same issues
of the programme it is based on. The ASST coordinates
the PNDRC, and a group of experts select the pairing of
incompatible pairs. The ASST also delegates to “Histocom-
patibility Centres from the referral area of the transplant cen-
tre where the incompatible pairs are originated, the immuno-
logical studies needed for carrying out the trading of donors for
transplantation”. These principles are contrary to those of
the Dutch programme, which is the most efficient national
exchange donor programme.10,29
The Dutch programme
assigned all immunological studies of pairs who enter the
programme to a central histocompatibility laboratory and
implemented a new pair selection algorithm in which the
primary criterion is the maximisation of the number of
potential transplants.29
In summary for performing LDE the mentioned precon-
ditions are fulfilled in accordance with national laws of
Portugal and international practice.
FIGURE 3 - Countries with living donors exchange programmes at
national, regional or local level. The Netherlands and the United
Kingdom were the only countries with a national programme in 2012.

6. 128 B.A. Lima et al.
13
DeKlerk M., Witvliet M., Haase-Kromwijk B., Claas F., Weimar
W.: Hurdles, barriers, and successes of a national living donor
kidney exchange program. Transplantation, 2008; 86:1749-
1753.
14
Ferrari P., Fidler S., Wright J., et al.: Virtual Crossmatch Ap-
proach to Maximize Matching in Paired Kidney Donation. Am
J Transplant, 2010; 10:1-7.
15
Lefaucher C., Suberbielle-Boissel C., Hill G., et al.: Clinical Rel-
evance of Preformed HLA Donor-Specific Antibodies in Kidney
Transplantation. Am J Transplant, 2008; 8:324-331.
16
Waki K., Terasaki P.: Paired kidney donation by shipment of
living donor kidneys. Clin Transplant, 2007; 21:186-191.
17
Simpkins C., Montgomery R., Hawxby A., et al.: Cold ischemia
time and allograft outcomes in live donor renal transplantation:
Is live donor organ transport feasible? Am J Transplant, 2007;
7:99-107.
18
Edmonds J.: Paths, trees and flowers. Canadian Journal of
Mathematics, 1993; 17:449-467.
19
DeKlerk M., Deijl W., Witvliet M., Haase-Kromwijk B., Claas
F., Weimar W.: The optimal chain length for kidney paired
exchanges: an analysis of the Dutch program. Transplant Inter-
national, 2010; 23 (11):1120-1125.
20
Gentry S., Segev D., Simmerling M., Montgomery R.: Expand-
ing kidney Paired donation through participation by compat-
ible pairs. Am J Transplant, 2007; 7:2361-2370.
21
Juarez F., Barrios Y., Cano L., et al.: Domino (crossover) kid-
ney transplantation using low doses of Neoral. Transplant Proc,
1998; 30:2289-2290.
22
Montgomery R., Zachary A., Ratner L., et al.: Clinical results
from transplanting incompatible live kidney donor/recipient
pairs using kidney paired donation. JAMA, 2005; 13:1655-
1663.
23
Keizer K., DeKlerk M., Haase-Kromwijk B., Weimar W.: The
Dutch algorithm in living donor kidney exchange. Transplant
Proc, 2005; 37:589-591.
24
Kranenburg L., Visak T., Weimar W., et al.: Starting a Cross-
over kidney transplantation program in the Netherlands: ethi-
cal and psychological considerations. Transplantation, 2004;
78:194-197.
25
Hantor R., Reistma W., Delmonico F.: The development of
a successful multiregional kidney paired donation program.
Transplantation, 2008; 86:1744-1748.
26
Domínguez-Gil B., Valentím M., Escobar E., et al.: Situación
actual del trasplante renal de donante vivo en España y otros
países: pasado, presente y futuro de una excelente opción
terapéutica. Nefrologia, 2010; 30 (S2):3-13.
27
Gumber M., Kute V., Goplani K., et al.: Transplantation With
Kidney Paired Donation to Increase the Donor Pool: A Single-
Center Experience. Transplant Proc, 2011; 43:1412-1414.
28
Gurkan A., Kacar S., Varilsuha C., et al.: Exchange kidney
transplantation: a good solution in living kidney transplanta-
tion. Transplant Proc, 2004; 36 (10):2952-2953.
29
Ferrari P., DeKlerk M.: Paired kidney donations to expand the
Conclusions
The implementation of an algorithm to maximise the
number of potential exchanges of donor-recipient pairs and
therefore the number of transplants and the definition of
a CHL responsible for the immunological study of donors
and recipients guarantees the efficiency and effectiveness of
a national LDE programme.
As 30 years ago Eurotransplant was the inspiration for the
creation of Lusotransplante, ASST should now be able to
look beyond the Pyrenees (in particular to the Nether-
lands) to define the rules for the creation of a national LDE
programme in Portugal.
The authors declare that they have no conflict of interest.
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