Review

Basic concepts in kidney transplant

immunology
Advances in the field of immunohistocompatibility and immunogenetics have been crucial for improvements
in kidney transplant outcomes. This review provides a practical outline of these important breakthroughs for
the general physician, at a time when demand for kidney transplants is increasing.

K
idney transplant remains the best type of renal T cells. Activated allospecific T cells include those with
replacement therapy in most patients suffering regulatory function and those with effector function. The
from end-stage kidney disease. Patients can former attempt to prevent allograft rejection while the
remain on the transplant waiting list for a latter mediate graft rejection. The proportion of these
number of years because of the worldwide two T cell populations will ultimately determine the
shortage of organs. Modern crossmatch techniques and clinical outcome (Afzali et al, 2008). In the absence of
human leukocyte antigen (HLA) typing play a crucial role immunosuppression these receptor–ligand interactions
to ensure better organ allocation and provide the recipient will inevitably led to graft rejection. However, despite
with a more favourable match. new and more potent immunosuppressive regimens in
Transplantation of an organ into a genetically different the modern transplantation era, the crossmatch still
recipient will invariably elicit an immune response because remains an essential tool to identify preformed donor-
of the presence of alloantigens and allorecognition by specific antibodies in recipients who have already been
the recipient. Foreign major histocompatibility complex primed to foreign antigens. Allosensitization to HLA
(MHC) proteins are recognized by recipient alloreactive proteins occurs after pregnancy, blood transfusion or
T cells via three pathways: direct, indirect and semi-direct transplantation.
(Safinia et al, 2010). In the direct pathway recipient The importance of performing a crossmatch before
T lymphocytes recognize MHC molecule–peptide renal transplantation was initially demonstrated in the
complexes on donor antigen-presenting cells. This leads landmark paper by Patel and Terasaki (1969). Since
to activation of CD4 helper or CD8 cytotoxic T cells. then, a positive complement-dependent cytotoxicity
In the indirect pathway, recipient’s antigen-presenting crossmatch (CDC-XM) has generally been considered
cells present donor peptides to recipient CD4 helper T as a contraindication to transplantation in view of the
cells via MHC class II. This also leads to interaction with associated high risk of hyperacute rejection. This type
B-lymphocytes resulting in alloantibody production. of rejection occurs immediately upon reperfusion and
The semidirect pathway is a more recently proposed is attributed to preformed donor-specific antibodies to
pathway whereby recipient antigen-presenting cells HLA.
acquire intact donor MHC–peptide complexes via cell- Although the CDC-XM is still widely used by
to-cell contact or exomes and present them to recipient many transplant centres, over the years it has mostly
been superseded by new crossmatch techniques
with higher sensitivity and specificity. These various
Dr Roberta Callus, Resident Specialist in Nephrology and crossmatch techniques, when performed and interpreted
General Medicine, Division of Nephrology, Department of simultaneously, provide invaluable information in the
Medicine, Mater Dei Hospital, Msida MSD2090, Malta and
Faculty of Health and Science, Institute of Learning and process of successful organ transplant. Another important
Teaching, University of Liverpool, Liverpool purpose of tissue crossmatch is as a risk assessment tool
Dr Jesmar Buttigieg, Resident Specialist, Division of for antibody-mediated rejection, which is one of the main
Nephrology, Department of Medicine, Mater Dei Hospital, barriers to improve long-term graft outcomes (Djamali et
Malta and Faculty of Health and Science, Institute of al, 2014).
Learning and Teaching, University of Liverpool, Liverpool Long-term graft survival is vital since patient outcomes
Dr Andrei Agius Anastasi, Basic Specialist Trainee, with a functioning allograft are superior to outcomes on
Department of Medicine, Mater Dei Hospital, Malta
dialysis (Tonelli et al, 2011). Moreover, there are medical
© 2017 MA Healthcare Ltd

Mr Ahmed Halawa, Consultant Transplant Surgeon, Sheffield economic advantages associated with prolonged graft
Teaching Hospitals, Sheffield and Honorary Senior Lecturer,
Faculty of Health and Science, Institute of Learning and survival (Flechner, 2003). This review discusses the various
Teaching, University of Liverpool, Liverpool HLA typing and crossmatch techniques (Table 1) and their
Correspondence to: Dr R Callus ([email protected]) respective roles in determining transplant decisions towards
successful outcomes.

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 Review

Table 1. Advantages and disadvantages of crossmatch techniques

Crossmatch technique Advantages Disadvantages
CDC-XM Detection of donor-specific cytotoxic antibodies Detects immunoglobulin M
False positive rate of 20%
Antihuman globulin CDC-XM Increased sensitivity over the CDC-XM Detects immunoglobulin M
Flow cytometry crossmatch Sensitive for low titre antibody May exclude patients unnecessarily
Detects non-complement binding antibody Specificity for human leucocyte antigen antibodies is low
May be falsely positive in patients having previously
received monoclonal antibodies like rituximab
Virtual crossmatch using Increased sensitivity Denatured human leucocyte antigens on single antigen
single antigen beads May be performed with stored sera therefore shortening cold beads may lead to a false positive result
ischaemia time Requires more coordination between immunology lab
Improves transplantation access for highly sensitized patients personnel and transplant team
Improves risk assessment for rejection
CDC-XM = complement-dependent cytotoxicity crossmatch.

HLA typing Figure 1. Complement-dependent cytotoxicity crossmatch showing preformed

HLA typing and quantification of donor-specific donor-specific antibodies from the recipient’s serum binding to human leukocyte
antibodies are prerequisite investigations which facilitate antigen (HLA) antigens on the donor lymphocyte. This results in activation of
the assessment of the recipient’s overall immunological risk. complement, cell lysis and uptake of vital dye.
HLA plays a central role in both cellular- and antibody-
mediated alloresponses, which determine the outcome
of a transplanted organ (Takemoto et al, 2004). For the Recipient serum
purpose of kidney transplantation, HLA typing is usually wash
required down to a low or intermediate level of resolution.
Automated extraction methods allow for a relatively rapid Cell lysis Under microscopy
typing that can be performed in 3–4 hours from the time
a sample is received. anti-HLA HLA Membrane Vital
= = = Complement = =
Sequence-specific primers and sequence-specific antibodies antigen attack complex dye
oligonucleotides probes are the most common techniques
used for low or intermediate resolution. The sequence-
specific primer method uses gene-specific primers followed Lymphocytotoxic crossmatch techniques
by amplification (DNA polymerase) and identification Complement-dependent cytotoxicity crossmatch
by agarose gel electrophoresis. The sequence-specific The CDC-XM is representative of what would happen in
oligonucleotides probe method uses a gene-specific primer vivo. Good quality T- and B-lymphocytes are isolated from
with unique fluorescent tags, which are subsequently the donor’s blood and incubated separately with the serum
identified using a flow cytometer. Sequence-based typing of potential recipients. Rabbit complement is subsequently
achieves high-level resolution HLA typing (allele level). added and after an appropriate incubation period (which
This type of typing is predominantly useful in bone marrow can vary between different methods of CDC-XM), a vital
transplant (Petersdorf et al, 1995), but is increasingly used dye (usually eosin) is added together with formalin to fix
in the context of live related donations and to fully resolve the cells. Longer incubation periods and additional wash
complex antibody profiles of sensitized potential recipients. steps, known as the Amos technique, have been introduced
It is well established that a better HLA match is associated to eliminate unbound antibodies before the addition of
with significantly better patient and graft survival (Lim et al, complement. If donor-specific antibodies are present in
2012; Opelz and Döhler, 2012). Indeed, HLA mismatches recipient serum, these will bind to HLA antigens on donor
have been significantly associated with death secondary cells resulting in complement activation via the classical
to cardiovascular disease and infection, especially during pathway. This ultimately generates the membrane attack
the first year after transplantation (Opelz and Döhler, complex, which inserts into the lipid bilayer causing cell
2012). Furthermore HLA-DR mismatches have also been rupture and uptake of vital dye. These cells are visualized
© 2017 MA Healthcare Ltd

associated with a higher risk of acute rejection, overall graft as red (dead) when seen under the microscope (Figure 1).
failure and death-censored graft failure (Lim et al, 2012). The result can be scored on a spectrum from two to eight,
When comparing one or two DR mismatches only two with two being equivalent to approximately 20% cell lysis
HLA-DR mismatches were associated with an increased and generally indicating a positive result. A score of eight
risk for all the three outcomes above (Lim et al, 2012). indicates the strongest possible reaction (Bose et al, 2013).

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Figure 2. Anti-human globulin complement-dependent cytotoxicity crossmatch CDC-XM secondary to auto-antibodies, as their presence
enhances the sensitivity of the crossmatch by increasing the number of fragment is not associated with inferior graft outcomes (Bryan et al,
crystallizable (Fc) receptors for complement binding. HLA = human leukocyte 2001). In order to remove the confounding influence of
antigen. IgM on the crossmatch result, its activity can be eliminated
by heating the serum to 55°C since IgM antibodies are cold
Anti-human globulin agglutinins that react best at 4°C. Alternatively, a reducing
agent such as dithiothreitol can be added which breaks
Recipient serum the disulphide bonds in the IgM pentamer resulting in
wash
a negative repeat crossmatch if solitary IgM is present.
When interpreting a dithiothreitol crossmatch, it is
Cell lysis Under microscopy important to compare to a control group where a diluting
= anti-human globulin agent like phosphate-buffered saline is added, in order to
Membrane Vital
=
anti-HLA
=
HLA = Complement = = control for the diluting effect that dithiothreitol may have
antibodies antigen attack complex dye
on antibody detection. Consequently if the crossmatch
becomes negative with addition of a diluting agent, then
Figure 3. Flow cytometry crossmatch showing fluorescently conjugated anti-human the results with dithiothreitol cannot be fully interpreted
globulin binding to the fragment crystallizable (Fc) portion of anti-human leukocyte (Mulley and Kanellis, 2011).
antigen (HLA) antibodies, which are bound to HLA antigens on the donor Non-HLA antibodies, which include antibodies
lymphocyte. These are detected and quantified depending on the specific light
against the minor histocompatibilty antigens, have also
scatter produced as they pass through the laser interrogation point.
been implicated in acute renal allograft rejection and
Cell sample early graft loss (Tinckam and Chandraker, 2006). There
have been reports of a false positive B-cell CDC-XM
following treatment with rituximab (Gatault et al, 2013)
and basiliximab (Schlaf et al, 2012). One disadvantage of
the CDC-XM is that it only detects complement-fixing
antibodies, but non-complement fixing antibodies may
Detector
negative positive still be detrimental to graft function (Bose et al, 2013).
anti-HLA Fluorescently conjugated
= = HLA antigen =
antibodies anti-human globulin Flow cytometry crossmatch
Flow cytometry crossmatch was developed in the 1980s.
Serial doubling dilutions of the recipient serum is another It served as a more sensitive tool in order to detect donor-
way to determine the strength of the crossmatch. The more specific antibodies that were being missed by the CDC-XM.
dilutions necessary for the test to become negative, the higher The technique involves adding recipient serum to donor
the level of donor-specific antibodies present. Antibodies have lymphocytes and then incubating them with fluorescently
to be present in sufficient quantity to link complement to the conjugated anti-human globulin (Figure 3). Additional
Fc-receptor and activate complement-mediated cytotoxicity antibodies with different fluorochromes specific for T-cell
(Gebel and Bray, 2000). The sensitivity of the CDC-XM and B-cell surface proteins respectively are later added to
is enhanced if anti-human globulin is added before the identify both cell groups. One advantage when compared
complement factors. This promotes complement fixation to the CDC-XM is that it gives a semi-quantitative result,
by binding to HLA antibody on donor cells and increases the which is therefore less subjective.
number of Fc-receptors available for complement binding The flow cytometer is calibrated using serum from
(Figure 2). Low-titre antibodies detected by this method blood group AB unsensitized male donors as a negative
were associated with a 36% 1-year allograft loss compared control and a pool of sera from highly sensitized patients
with 18% loss in those with a negative test (Kerman et al, as a positive control. Electrical impulses generated from
1991). The CDC-XM may be applied to both T cells and the specific forward and side scatter of the laser beam
B cells. The former reflects the presence of HLA class I are converted to a numerical value using special software
antibodies, while the latter reflects both HLA class I and II algorithms. The relative median fluorescence of a particular
antibodies. Since B cells express higher amounts of class I sample is calculated by dividing the median fluorescence
antigens (Pellegrino et al, 1978), a positive B cell CDC-XM of that sample by the median fluorescence of the negative
associated with a negative T cell CDC-XM may indicate low control. The relative median fluorescence is then compared
levels of class I antibodies. to a predetermined cut-off value. Results from a flow
The CDC-XM has a false positive rate of 20% (Tinckam, cytometry crossmatch may also be expressed as a median
© 2017 MA Healthcare Ltd

2012). This may arise because of auto-antibodies, which channel shift. A positive control pool is diluted to yield a
are generally of the IgM and non-HLA IgG type. An reasonable shift in fluorescence (displacement between 100
auto-crossmatch involves mixing recipient serum with and 300 channels). Usually a cut-off value of two standard
recipient lymphocytes and is usually used to detect these deviations is used to define between a positive and negative
auto-antibodies in question. It is vital to identify a positive test. Flow cytometry crossmatch may detect an antibody

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 Review

subtype according to the fluorescently conjugated anti- antibodies can be defined according to which kind of cell
human globulin used. Studies have shown a correlation they interact with (B cell vs T cell), current or historic by
between different IgG classes and adverse transplant comparison with stored sera and by their concentration as
outcomes. IgG1 and IgG3, both being complement fixing, measured in mean fluoroscopic intensity.
are associated with a higher risk (Gao et al, 2014). Luminex-SAB can also be used to identify antibodies
False positive results can occur secondary to the binding directed towards minor histocompatibility antigens.
of non-specific anti-IgG antibodies to immunoglobulin The downside of this technique is the detection of both
Fc-receptors on B lymphocytes. The enzyme pronase has complement and non-complement binding antibodies
been used routinely to remove these receptors, improving and the detection of low level donor-specific antibodies
the sensitivity and specificity of the crossmatch (Lobo et al, which may refute a potential transplant unnecessarily as it
2002). The downside of pronase is that it may reduce HLA would ultimately result in a negative crossmatch. Another
expression in a dose-dependent fashion as well as expose factor to keep in mind when interpreting these assays is
cryptic antigens that may be recognized by auto-antibodies, the panel of HLA antigens used by the local laboratory.
erroneously affecting the final crossmatch result (Park et al, Luminex-SAB may also give false positive results because of
2012). In addition, the flow cytometry crossmatch may be denatured antigens on the microbeads (Otten et al, 2013).
transiently positive in patients who have received rituximab
therapy (Gatault et al, 2013). Flow cytometry crossmatch The virtual crossmatch
also detects non-complement binding antibodies. Several Since the introduction of Luminex-SAB it is now possible
studies have suggested that among non-sensitized patients, to ‘virtually’ compare specific anti-HLA antibodies in the
a positive T or B cell flow cytometry crossmatch does recipient with the HLA profile of the donor. This is known
not predict an increased risk for rejection or worse graft as the virtual crossmatch. The correlation of the virtual
survival, whereas inferior graft survival has been reported crossmatch with flow cytometry crossmatch is greater than
in sensitized patients (Limaye et al, 2009). 85% (Bingaman et al, 2008). It requires HLA typing of
the donor and a recent anti-HLA profile of the potential
Solid-phase assays recipient. To ensure a correct anti-HLA profile at the
Nowadays the use of solid-phase assays has largely time of the transplant call, regular collection of sera every
superseded serological methods because of higher 3 months is required for antibody screening via solid-phase
sensitivity, specificity and reproducibility. They come in assays, because antibody titres and specificities can change
the form of enzyme-linked immunosorbent assays (ELISA) over time. Any potential sensitizing events like pregnancy,
or microbeads. One example is the Luminex technology, blood transfusions and previous transplantation must be
which has revolutionized the detection of donor-specific documented accurately.
antibodies. Indeed, Luminex single antigen beads A false negative virtual crossmatch can arise for a number
(Luminex-SAB) are 10% more sensitive than ELISA, which of reasons. Incomplete typing of the donor, as well as donor-
in turn are 10% more sensitive than serological methods specific antibodies in the recipient serum against a unique
(Gebel and Bray, 2000). For this particular reason most HLA epitope which is not available on the SAB panel, can
transplant centres use Luminex-SAB even though this give rise to a false negative result (Amico et al, 2009). Of
technique is more expensive. Analysis of donor-specific note, not all donor-specific antibodies detected by Luminex-
antibodies using Luminex-SAB entails the addition of SAB are detrimental to graft outcomes. Studies have shown
recipient serum potentially containing HLA antibodies that donor-specific antibodies detected by SAB but with a
to a mixture of synthetic beads each with a unique dye negative CDC-XM are a major risk factor for early allograft
signature (usually red). Each bead is also coated with a rejection and long-term graft loss (Mohan et al, 2012).
specific type of antigen so that anti-HLA antibodies in the Nonetheless, these are not an absolute contraindication for
potential recipient serum can bind to the corresponding transplantation if one is prepared to perform desensitization
bead. Phycoerythrin-labelled anti-human globulin is when required, or to use more potent immunosuppressant
subsequently added to the mixture. protocols. False positives may also occur, as mentioned
The Luminex machine itself is a special type of flow previously, as a result of antibodies directed at HLA epitopes
cytometer, which is able to report on 100 different types that come about secondary to denatured HLA antigens
of simultaneous interrogations (flow is usually able on the SAB (Otten et al, 2003; El-Awar et al, 2010). Yet
to differentiate about 3–15 different beads or cells at another cause for a false positive virtual crossmatch is the
best). Beads are channelled in a single file through the presence of null alleles, which are not expressed as antigens
flow chamber where the two laser beams intersect. Each on the cell surface in vivo (Tinckam, 2012).
unique bead can then be interrogated for the presence of One of the principal advantages of performing a virtual
© 2017 MA Healthcare Ltd

the reporter dye on its surface and phycoerythrin-labelled crossmatch is the detection of acceptable and unacceptable
anti-human globulin. The light detectors measure the antigens (Zachary et al, 2008). This avoids unnecessary
intensities of forward and side scatter, which are converted shipping of organs resulting in less surgery delays, reduces
into electrical impulses. Software will then convert these cold ischaemia time, encourages cost savings and improved
electrical signals into a meaningful result. Donor-specific odds of transplanting highly sensitized patients. A number

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 Review

Conclusions
KEY POINTS The field of transplant medicine has evolved immensely over the
■ Crossmatching before kidney transplantation has evolved immensely with the past few years. Despite huge advances in immunosuppression
introduction of the flow cytometry crossmatch and solid phase assays. protocols, long-term allograft survival remains an elusive
■ Luminex single antigen bead technology is essential for the detection of donor- goal. Evidence is attributing poor long-term graft survival to
specific antibodies both before and after transplant. chronic damage secondary to persistent antibody-mediated
■ Better HLA match has been associated with superior patient and graft survival. rejection and transplant glomerulopathy. The development
■ The virtual crossmatch ensures timely allocation of organs and increases the of de novo donor-specific antibodies plays a central role
chance of transplantation in highly sensitized individuals. in this process, which is why regular characterization and
■ A potential recipient’s immunological history and crossmatch results enable quantification is of chief importance. Interpretation of
immunological risk stratification before transplantation. these various immunological tools should be performed via
a multidisciplinary approach involving transplant physicians,
surgeons and immunologists. Integrating these results will
Table 2. Risk stratification for immunological risk pre transplant ensure an informed decision regarding the viability and safety
of proceeding with transplantation. In addition, they provide
Cross match result Immunological risk
a means of estimating the recipient immunological risks
CDC-XM positive and FC-XM negative High risk resulting in patient-tailored immunosuppression protocols
and improved outcomes. BJHM
CDC-XM negative and FC-XM positive Intermediate risk
Conflict of interest: none.
FC-XM negative and immunoglobulin G class I or II detected Standard risk
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antigen beads detection MOT.0b013e328309ee31
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CLINICAL FOCUS
Understanding
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peritoneal dialysis:
an intrinsic part of
safe patient care
Peter Ellis PREMIUM PACKAGE

Exploring the challenges of living with peritoneal dialysis

Andrew Morris, Clive Liles, Carolyn Roskell
Adherence to phosphate binders: improving patient engagement
Maria Fraser, Dawn Brannigan
National home adaptation and reimbursement guidance
Karen Jenkins, Anthony Adams
Peer support: increasing patient participation through clinician engagement
Eleri Wood
Supporting staff information: the role of the renal clinical librarian
Cathryn James

PROMOTING EXCELLENCE IN MULTIDISCIPLINARY RENAL UNITS

EVIDENCE-BASED PRACTICE PROFESSIONAL SUPPORT BROAD FOCUS ESSENTIAL INFORMATION

High-quality, clinical content that Expert guidance on all aspects In-depth, practical articles that are Breaking news, research roundups,
aims to establish best practice and of renal care, from transplants designed to strengthen multidisciplinary product updates, and insights into
enhance your knowledge and skills to dialysis, to help your working within today’s renal units current debates in the field
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ongoing development of nephrology

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British Journal of Hospital Medicine, January 2017, Vol 78, No 1 37

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