Download Sensitized Renal Transplant Recipients: Current Protocols and

Sensitized Renal Transplant Recipients:
Current Protocols and Future Directions
Reference: Gloor J, Stegall MD. Sensitized
renal transplant recipients: Current
protocols and future directions. Nat Rev
Nephrol. 2010;6: 297–306.
Overview
• Kidney transplantation is performed on patients with chronic kidney
failure, or end-stage renal disease (ESRD).
• The success of a kidney transplant graft depends on the strength of
the match between donor and recipient and the source of the kidney.
• The major human leukocyte antigen (HLA) antigens are essential
elements for immune function.
• Historically, HLA genes were identified as a result of the ability to
successfully transplant organs between HLA similar individuals.
• Classically, donor-specific antibodies (DSAs)—anti- HLA antibodies
with reactivity against a potential donor have constituted a
contraindication for proceeding to transplantation, and testing for
these antibodies has been an important component of the
pretransplantation evaluation.
Overview
• Innovative protocols have been developed to acutely lower DSA
activity to below the level that causes immediate renal allograft
injury, and to maintain this reduced level during the first weeks to
months after transplantation.
• During this time, the renal allograft develops resistance to
antibody-mediated injury, which is due to upregulation of
protective genes. This condition is referred to as ‘accommodation’.
• Multiple investigations have revealed satisfactory short-term to
intermediate-term allograft survival by positive crossmatch kidney
transplantations.
• Positive crossmatch kidney transplantation requires comprehensive
characterization of DSAs, protocols that lower DSA activity, and
prompt diagnosis and treatment of antibody-mediated rejection
(AMR).
Antibody Characterization
• Anti-HLA antibodies play a vital role in kidney
transplantation and has been recognized over 40 years.
• Researchers Patel and Terasaki in the year 1969
established that hyperacute rejection resulted from
allograft injury caused by preformed antibodies
directed against donor antigens.
• Hence, testing transplant candidates for these
antibodies became an essential component for the
evaluation of pretransplantation.
• Various laboratories chose to use sensitive assays in
which low level DSAs were present.
Antibody Characterization
• Another important technique was the implementation of solid-phase
anti-HLA antibody testing.
• Here, the purified HLA antigens are bound to solid surfaces such as
flow beads or incubation wells are incubated with recipient sera.
• These are analyzed by flow cytometric assay or enzymelinked
immune sorbent assay (ELISA).
• The solid phase tests employ individual HLA antigens and the
reactivity of individual anti-HLA antibodies can be determined easily.
• This allows recognition of donor specificity. Anti-HLA class II
antibodies technique became available only after the recognition of
solid phase testing.
• The identification of HLA antigens has led to several clinical
implications & has shortened the waiting time for highly sensitized
decreased donor kidney transplantation in highly sensitized
candidates.
Antibody Characterization
• High-dose intravenous immunoglobulin has been used for the
desensitization of highly allosensitized transplant candidates for nearly
20 years.
• An open label, single center study published in 2008 showed that highdose intravenous immunoglobulin administered in conjunction with the
anti-CD20 antibody rituximab improved transplantation rates of highly
allosensitized living and deceased donor kidney transplant candidates.
• In another study by Lefaucheur et al. on positivecrossmatch kidney
transplantation, high-dose intravenous immunoglobulin used reported a
series of 18 transplantations.
• The incidence of acute AMR was 28%. Another study of positivecrossmatch kidney transplantation following intravenous
immunoglobulin preconditioning in a series of 8 patients demonstrated
acute AMR of 13% and allograft survival was about 88% over a mean
follow-up of 15 months.
Antibody Characterization
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Plasma exchange involves physically removing the DSAs before the
transplantation procedure.
In this case, patients are supplemented with low-dose intravenous
immunoglobulin prior to transplantation in order to reduce DSA level.
Thielke et al. reported that a negative crossmatch was successfully achieved in
51 of 57 positive crossmatch patients treated with antithymocyte and anti-CD20
antibody induction therapy in addition to plasma exchange and low dose intra
venous immunoglobulin.
The allograft survival rate was 93% at 1 year and 81% at two years. AMR was
about 43%.
Magee et al. reported a series of 28 positive crossmatch transplantations in
which allograft survival rate was 90% at 1 year and 80% at 2 years.
AMR was about 42% A similar study in which 41 patients positive crossmatch
transplantations recipients were treated with preconditioning plasma exchange
and intravenous immunoglobulin.
The 1- year and 5-year allograft survival rates were 89.9% and 69.4%,
respectively. The AMR was about 12% (see Table 1).
Table 1: Acute AMR incidence and its effect on
1-year and 2-year allograft survival
• The two methods, high-dose intravenous
immunoglobulin and plasma exchange with or
without immunoglobulin, have disadvantages of
resource utilization and administering high volumes
of fluid to anuric dialysis patients was hard.
Antibody Mediated Rejection
• The incidence of AMR has often been considered as the
one which complicates antibody-incompatible
transplantation.
• It begins with acute histological lesions and progresses to
chronic changes.
• Primarily acute histological injury is characterized by
endothelial cell swelling, detachment from the basement
membrane, and fragmentation, predominantly affects
peritubular and glomerular capillaries.
• Chronic injury leads to remodeling of the peritubular and
glomerular capillary basement membrane, producing the
characteristic multilayering or lamellation pattern indicative
of transplant glomerulopathy (see Fig. 1).
• Many of the acute histological changes associated with
acute AMR are mediated through complement
activation.
• Haas et al. in 2007 reported histological evidence of
subclinical acute AMR consisting of peritubular
capillary monolytic infiltration (see Fig. 2).
• One of the key points in the treatment of AMR is the
inhibition of antibody synthesis along with lowering
the level of DSA.
• Proteasome inhibition plays an important role in cell
cycle regulation, cell–cell interactions, and apoptosis.
• Everly et al. demonstrated the use of bortezomib,
which showed rapid improvement in the allograft
function and suppression of recurrent rejection.
Conclusion
• Technological advantages in antibody
characterization have led to more comprehensive
assessment of anti-HLA antibody activity.
• Recent protocols developed have led to new
insights for successful transplantation.
• However, AMR remains a significant challenge
occurring in 20–50% of antibody incompatible
kidney transplantation.
• New interventions for preventing acute AMR that
are based on complement blockade and
proteasome inhibition seem promising.
Key Points