Overcoming antibodies

barriers in renal transplant

Hanan Fathy
Assistant lecturer
Pediatric Nephrology Department
Alexandria University
❂ The shortage of donor organs, especially in
renal transplantation, leads to an increasing
discrepancy between the number of end-stage
renal disease patients on waiting lists and the
number of available deceased donor kidneys.

❂ Expansion of the donor pool can be achieved by

increasing the numbers of living kidney
transplantation and by overcoming the
immunological barriers of ABO-incompatibility
and HLA-sensitization.
 HISTORY
✆ Attempts to overcome barriers to kidney transplants
are not new. In the 1980s some patients were
successfully transplanted following plasmapheresis,
But it was not embraced by the transplant
community because it was expensive.
✆ In Japan, however, where deceased donor kidney
transplantation is unpopular, scientists saw the
procedure as the only way to save many lives.
✆ In 1998, they surprised the transplant community
when they reported an eight-year follow-up study on
61 patients who had had ABO incompatible
transplants
How are anti bodies produced
❂ Plasma cells make up an important part of
your immune system.
❂ They are mature B lymphocytes (white blood
cells), often referred to as B cells. They are
produced and mature in the bone marrow and
concentrate in the spleen and lymph nodes.
❂ They produce millions of types of B cells
every day. Each type has a unique receptor
protein, called the B cell receptor (BCR) on its
membrane that is designed to fit one specific
antigen.
How are anti bodies produced

❂ When an antigen combines with a B cell’s antigen

receptors and is stimulated by T cell secretions called
cytokines, the B cell undergoes clonal expansion.
❂ The result is many plasma cells, which produce
specific antibodies against this antigen along with
memory B cells.
❂ After the infection, or exposure passes, plasma cells
undergo apoptosis.
❂ Memory B cells, which keep the ability to recognize
this antigen, are retained in the body.
Antibody Production Factories

Antibodies at work
 Antibody barriers to kidney
transplant
❂ ABO incompatibility or a positive crossmatch due to
anti-HLA (Human Leukocyte Antigen) antibodies was
once an absolute roadblock to kidney transplantation.

❂ Most of patients die while waiting for a negative cross-

match deceased donor kidney, yet most of them would
be candidates for living donor kidney transplantation if
we could overcome the destructive effect of
antibodies.

❂ In addition, these procedures are cost-effective when

compared to maintenance dialysis therapy.
❂ As blood group antigens are expressed by the
endothelium of solid organs including the kidney,
transplantation across the blood group barrier can result
in hyperacute antibody-mediated allograft rejection.
❂ ABO-incompatible transplantation was already performed
as early as in the 1970s, but due to hyperacute rejection,
results were discouraging.
❂ Due to a severe shortage of available deceased donor
organs, most ABO-incompatible kidney transplantations
have taken place in Japan.
Four to five pre-operative
The Johns Hopkins protocol:
plasmapheresis sessions to remove
anti-A/B antibodies.

 Each session followed by the

administration of cytomegalovirus
hyperimmune globulin.

 After achieving a pre-transplant

A/B-antibody titre of <1: 16, 1 or 2
The Johns Hopkins protocol (cont):
 Immunosuppression with tacrolimus
and mycophenolate mofetil was
initiated, followed by steroids and
daclizumab after transplantation

 Post-operative treatment included

another three plasmapheresis/CMVIg
sessions on days 1, 3 and day 5.
 Specific
The anti-A or anti-B
immunosuppressive regimen consisted of:
immunoadsorption columns (Glycosorb®)
are currently avaliable.
 Four pre-operative immunoadsorption
sessions were performed, aiming for a
pre-operative ABO antibody titre of <1:8.
After the last pre-operative Session, 0.5
g/kg of intravenous immunoglobulin (IVIG)
was administered.
 To avoid early post-operative rebound
of ABO antibodies, three more
The immunosuppressive regimen consisted of:
 One dose of rituximab (375 mg/m2)
given 2–4 weeks before
immunoadsorption.

 Followed by a conventional triple-drug

Immunosuppression consisting of
tacrolimus, mycophenolate mofetil and
prednisolone, starting 1 week before
immunoadsorption
 Splenectomy of the recipient was
performed due to the
role of the spleen in anti-A/B antibody
production.
 Immunosuppressive triple therapy was
based on calcineurin inhibitors, steroids and
antimetabolites, differing among centres,
on the basis of which additional
immunosuppressive agents, such as
antilymphocyte globulin, deoxyspergualin
or cyclophosphamide, were administered.
 Antibody removal was usually not
performed after transplantation
Since 2004, a desensitization protocol
without splenectomy starting 4 weeks
prior to transplantation, including
 Double filtration plasmapheresis, anti-CD20
treatment, mycophenolate mofetil and steroids,
was introduced, showing a successful short-
term outcome.
 No additional post-operative antibody removal
or administration of IVIG was performed .
Combination of the following therapies before transplantation
:

❂ Plasmapheresis — to physically remove

antibodies.
❂ Immunoglobulin — also called gamma
globulin, which appears to decrease
antibody activity destructive to the graft.
❂ Splenectomy — the spleen concentrates B
lymphocytes around its blood vessels to
fight infection so removing it in a person
with very high levels of antibodies wards
off graft rejection.
❂ Anti-CD20 antibody (rituximab) — depletes
the CD20 protein, which is found on the
wall of most B cells.
❂ Recipient antibodies are monitored during the
first two weeks following transplantation and
treated by plasmapheresis if they rise above a
predetermined level.

❂ Like all transplant recipients, the patients must

remain on drugs that suppress the immune
system, such as thymoglobulin, tacrolimus,
mycophenolate mofetil, and prednisone, for as
long as the grafted kidney survives.
ABO-incompatible
ABO-incompatiblekidneykidney
transplantation
transplantationoffers
offersaasafe
safe
option
optiontotoperform
performrenal
renal
transplantation
transplantationsuccessfully
successfullyin in
patients
patientswhose
whoseonly
onlyliving
living
donor
donorisisblood-group-
blood-group-
incompatible.
incompatible.
❂ Each of us has a set of histocompatibility
molecules that are like fingerprints in that
probably no other human being has an
identical set.

❂ A positive crossmatch to the

histocompatibility antigens blood test means
you have antibodies against donor HLA
antigens—a decidedly negative result for
anyone waiting for transplant.
❂ Inthe case of transplants,
however, they are responsible for
antibody-mediated rejection of a
transplanted organ because they
act as antigens when introduced
into a different person.
❂ Mayo initiated its clinical trial for a positive
cross match kidney transfusion in January
2000.

❂ Protocols similar to those of ABO incompatible

transplant were employed.

❂ Protocols from Johns Hopkins and the

University of Maryland were very similar to
ABO protocols.
❂ Both positive-crossmatch and ABO-incompatible living-
donor kidney transplantations can be performed with
survival rates approaching those of negative-crossmatch
and ABO-compatible transplantations.

❂ However, for them to become more successful, additiona

methods to prevent antibody-mediated damage need to b
developed.
❂ These include therapies that result in
prolonged suppression of antibody formation.

❂ The lab is currently evaluating the necessity of

splenectomy versus intensive therapy with
plasmapheresis and anti-CD20 monoclonal
antibody.

❂ The next phase is to test therapies that may

decrease antibodies.