Download Clinical Considerations for an Approach to Immunosuppression

Clinical Considerations for an
Approach to Immunosuppression
Reference: Urschel S, Altamirano-Diaz LA, West LJ.
Immunosuppression armamentarium in 2010:
Mechanistic and clinical considerations. Pediatr Clin
North Am. 2010;57(2):433–457.
• For successful organ transplantation, effective
immunosuppression is required with minimum risk
rejection with minimal drug toxicities, concomitantly.
• However, there is a lack of standardization of clinical
management regimens especially, in pediatric patients.
• In pediatric solidorgan transplantation, current
approaches are different for different organs.
• During the perioperative period, induction therapy is
found to be very common and as an early strike on the
immune system.
• But it is not accepted universally.
• Moreover, strategies used for maintenance therapy
also vary with the organ transplant groups.
• According to the Studies of Pediatric Liver
Transplantation (SPLIT) database registry,
which assessed the 5-year liver transplant
survivors reported that 64% were treated with
calcineurin inhibitors-based monotherapy
immunosuppression.
• Figure 1 represents the time-line showing the
different approaches for immunosuppression
in relation to the time of transplant.
Induction Therapy
• Induction immunotherapy is one of the common
therapies, which includes intense immunosuppression
in the immediate perioperative phase of organ
implantation.
• The aim of the induction immunotherapy is to reduce
the incidence of acute rejection in the early
• posttransplant phase.
• The immunosuppressive potential of induction therapy
is used to ease a delayed and more cautious initiation
of maintenance therapy.
• Avoiding high-doses of calcineurin inhibitors,
tacrolimus and cyclosporine A, (which cause
nephrotoxic effects) are found to be beneficial to
avoid early graft
• rejection in kidney transplant patients and delayed
kidney dysfunction following heart transplantation.
• Late initiation of calcineurin inhibitors has been used
in patients with perioperative renal dysfunction.
• Table 1 depicts the immunosuppressive agents in
pediatric transplantation.
When to Use the Induction Therapy
• The findings of the available data do not demonstrate the exact
benefits of induction therapy in pediatric transplant patients.
• Moreover, the question of which type of induction to use remains
unsolved.
• Follow-up studies and registry reports did not show any significant
long-term outcomes with available agents.
• With general improvement in the management of transplanted
children, there has been a tendency to offer organ transplantation
to more critically ill patients.
• Use of induction therapy remains controversial and highly variable
across the different organ groups in pediatric transplantation.
• Recently, use of induction therapy (CD25- directed antibodies in
22% and polyclonal cytolytic agents in 38% of patients) has
consistently increased in pediatric heart transplantation.
• About 10–15% of pediatric lung transplant recipients
received polyclonal induction and 30–50% received
CD25-directed antibodies in the past 10 years.
• The use of monoclonal antibodies has consistently
increased in the last 10 years to 50% in living-donor
and 51% in deceased-donor pediatric kidney transplant
recipients.
• Thus, considering the benefits and risks, it is
appropriate that the use and type of induction
treatment is tailored to the individual condition and
the specific needs of a transplant candidate.
Maintenance Therapy
• Since 1950, corticosteroids are used in most of the solidorgan
transplantation from induction and maintenance for the
management of acute rejection.
• Corticosteroids are potent nonspecific immunosuppressive action,
which affects all leukocytes.
• Owing to wide range of side-effect profile, only 25% of liver
transplant recipients are receiving steroids by 5 years after transplant
and steroids are successfully withdrawn in more than 45% of heart
transplant patients after the first year.
• Calcineurin-inhibitors are commonly used in organ transplantation.
• Cochrane reviews conducted in adult kidney and liver transplant
patients showed that tacrolimus improved graft survival and
prevented acute rejection more effectively than cyclosporine A.
Maintenance Therapy
• Calcineurin-inhibitors-free regimens are used with a
combination of mycophenolic acid and mammalian
target of rapamycin inhibitors.
• Azathioprine was the first immunosuppressive
maintenance therapy, which impairs the capability
• of activated lymphocytes to proliferate, resulting in
reduced adaptive immune responses.
• Studies have demonstrated the superiority of triple
drug therapies (azathioprine with cyclosporine A and
steroids) compared with dual drug regimens (without
azathioprine).
Immunosuppressive Medication in
Acute Rejection
• Use of pulse intravenous steroids with
methylprednisolone is the most common treatment for
acute organ rejection.
• A 3- to 5-day course of polyclonal lymphocyte depleting
antibodies is used in severe grades of rejection.
• This is also used in cardiac transplantation with
hemodynamic compromise.
• A Cochrane review conducted in kidney transplantation
showed that polyclonal lymphocyte depleting
antibodies was better compared to steroids in reversing
the first episode of rejection and preventing the graft
loss.
Immunosuppressive Medication in
Acute Rejection
• In order to reduce the risk or treat recurrent
rejection, maintenance immunosuppression therapy
can be modified by changing cyclosporine A to
tacrolimus.
• Different antibody removal strategies have also been
used such as plasmapheresis, plasma exchange, and
antigen-specific and nonspecific immuno-adsorption
columns, along with immunomodulatory approaches
with intravenous immunoglobulin.
New and Investigational Approaches
• Anti-CD52 antibodies and costimulation blockers such as abatacept and
belatacept are the new approaches used for various autoimmune and
lymphatic neoplastic disorders.
• Anti-CD52 antibodies are licensed for B-cell chronic lymphatic leukemia and
not for transplantation and thus, used only for off-label use for
transplantation.
• Several studies have observed reduction of maintenance therapy following
Anti-CD52 antibodies induction but may be inferior for long-term outcomes
compared to conventional immunosuppressive strategies.
New and Investigational Approaches
• Abatacept has exhibited some efficacy in preclinical
studies in transplantation as well as in autoimmune
disorders but was not pertained for clinical use.
• Thus, belatacept was introduced, which has the
increased affinity against CD86.
• A study showed that after 12 months, belatacept has
preserved the glomerular filtration rate and has
lower incidence of chronic allograft nephropathy.
Summary
• The evolution of sophisticated immunosuppressive
therapies has led to intense improvements in graft and
patient outcomes in organ transplantation.
• Safe and effective application to infants and children, is
insufficient not properly exhibited in clinical studies.
• Thus, transplant physicians are using complicated drug
regimens for the management of complex pediatric
patients.
• Despite these limitations, improved outcome has been
observed with better quality of life in infants and
children with organ transplantation.