induction agents

1. IMMUNOSUPRESSIVE DRUGS
INDUCTION AGENTS +
STEROIDS
PRESENTER- DR SPOORTHI SREERAM
MODERATOR- DR RAJASHEKAR

2. INTRODUCTION
• Immunosuppressive therapy in renal
transplantation is divided into two phases based
on the time of use, as
Induction and
Maintenance therapy
• A different classification distinguishes drugs
based on their use to control
Acute cellular rejection (TCMR) and
Acute antibody rejection (ABMR)

3. • Induction therapy is an intense immunosuppressive
therapy administered at the time of kidney
transplantation when the immune system of the recipient
has the first contact with donor antigens
• to reduce the risk of acute allograft rejection
• lymphocyte-depleting antibodies- rabbit antithymocyte
globulin, alemtuzumab, muromonab- CD3, rituximab,
and bortezomib
• lymphocyte- nondepleting antibodies - interleukin 2
receptor antibodies

4. • Maintenance therapy is administered lifelong in all
transplant patients to avoid both acute and chronic
rejection with subsequent organ loss.
• Steroids,
• Antimetabolite drugs (azathioprine, mycophenolate
mofetil [MMF], sodium mycophenolate enteric coated
[EC-MPS]),
• Calcineurin inhibitors (cyclosporine [CyA] and tacrolimus
[TAC]),
• The inhibitors of mammalian target of Rapamycin
(mTOR) (sirolimus and everolimus)
• Belatacept

5. INDUCTION
• The primary aim of induction therapy is to
reduce the risk of acute rejection that may predict
graft loss.
1. One approach relies upon high doses of conventional
immunosuppressive agents
2. while the other uses antibodies directed against T cell
antigens with lower doses of conventional agents
• Induction therapy with mono or polyclonal antibodies is
more efficient than induction therapy with high doses of
maintenance drugs

6. PURPOSE
• To reduce the risk of acute rejection
• Decrease maintenance immunosuppressive doses
• Improve outcomes in high-risk patients children, African
Americans, HLA mismatches, who are sensitized to
HLAs.
• Augment immuno-suppression
• Facilitate delayed introduction of calcineurin inhibitors,
• Induce tolerance

7. KDIGO 2009
• (i) that induction therapy with a
• biological agent be a routine part of the initial immune
suppressive regimen (grade 1B) and
• (ii) that an IL2RA agent be the first-line therapy (grade
1B).
• lymphocyte-depleting agents be used selectively in
patients at high immunological risk

8. • Depleting antibodies are polyclonal or monoclonal
antibodies that deplete lymphocytes in transplant
recipients by binding to antigens on lymphocytes such as
the major histocompatibility complex antigens

9. INDUCTION AGENTS
• Polyclonal antibodies (rATG) obtained
from the rabbit are used more frequently.
The monoclonal antibody includes
Alemtuzumab (Campath 1-H), a humanized
antibody against CD-52

10. IL-2
• T-cell proliferation after transplantation is linked to IL-2
production.
• Compared to rATG, IL-2R antibodies have a higher
acute rejection
• incidence, but fewer side effects like infections and
malignancies

11. HIGH RISK
• high number of HLA mismatches,
• younger recipient age, older donor age, black ethnicity
• panel reactive antibodies >0%,
• presence of a donor-specific antibody,
• blood group incompatibility,
• delayed onset of graft function
• cold ischemia time >24 h.

12. • recipients at low immunological risk, ATG was no more
effective in preventing rejection than IL2RA agents, and
the safety profile favoured IL2RA induction.
• For kidney transplant patients at standard immunological
risk treated with tacrolimus, MPA and maintenance
steroids, the benefit of IL2RA is very modest or
nonexistent in terms of reducing acute rejection and
does not confer a graft or patient survival advantage.

13. The advantage of induction therapy appears to be more
clear cut in high-risk kidney transplant recipients found
rejection rates to be almost halved in high-risk patients
given Ratg versus IL2RA at 1 year.
The severity of acute rejection episodes was also
significantly lower with rATG

14. ATG
• grade 1A or 1B TCMR, intravenous boluses of
• methylprednisolone (500 mg) repeated up to 3–
5 times control the rejection. It is often
necessary
• to increase the level of maintenance therapy. In
patients with TCMR grade 1B, in the first period
• after transplantation, the use of rATG added to
the steroids is preferred [16]. In patients with
• acute rejection, grade II or III, in addition to
steroid boluses, administration of rATG at the
doses of

15. • immunogens for rATG (Thymoglobulin) are
human thymocytes and the immunogen for
rATG (Fresenius) is a Jurkat T-cell
leukemia cell line, and these rATG
preparations differ in potency and efficacy
• approved by the United States Food and
Drug Administration (FDA) for
corticosteroid-resistant rejection and acute
cellular rejection (dose, 1.5 mg/kg for 7-14
d)

16. • ; typical regimen, 1.5 mg/kg for 3-5 d).7
Common adverse events include cytokine
release syndrome, leukopenia, and
thrombocytopenia
• he benefit of rATG in the combined
endpoint was attributed to the decreased
incidence of acute rejection with rATG
(14.2%) than basiliximab

17. • work
• through three different mechanisms viz
• a) apoptosis via activation-induced cell
• death, b) antibody-dependent
cell-mediated
• cytotoxicity, and c) complement-dependent
• cytotoxicity (CDC).

18. • THYMOGLOBULIN includes antibodies against T-cell
markers such as CD2, CD3, CD4, CD8, CD11a, CD18,
CD25, CD44, CD45, HLA-DR, HLA Class I heavy chains,
and ß2 micro-globulin
• T-cell depletion is usually observed within a day after
initiating THYMOGLOBULIN therapy

19. • Both are prepared in rabbits.
• Grafalon ATG-Fresenius or ATG-F) is produced by
immunizing rabbits with the T-cell leukemia line Jurkat,
• thymoglobulinis produced by immunizing with human
thymocytes
• Grafalon has greater selectivity for activated T-cells and
also depletes CD4+ CD28- T-cells
• Grafalon was introduced in India in 2016

20. • grafalon had high biopsy proven acute
rejection (BPAR) but the dose of grafalon used (4 mg/kg)
was lower
• no difference in the infection rate, no difference in the
incidence of CMV and BKV infections.
patient survival was comparable
• thymoglobulin was inferior when compared to ATG-F in
preventing patient mortality
• higher incidence of post-transplant malignancy in
patients receiving thymoglobulin.
• Grafalon’s cost is Rs. 33000 / 100 mg (Rs. 330 / mg),
thymoglobulin is Rs. 13800 / 25 mg (Rs. 552 / mg).

21. • The first dose should be infused over at least 6 hours;
doses on subsequent days should be infused over at
least 4 hours.
• Premedication with corticosteroids, acetaminophen,
and/or an antihistamine prior to each infusion is
recommended

22. • Dose should be reduced by one-half if the white blood
cell (WBC) count is between 2,000 and 3,000 cells/mm3
or if the platelet count is between 50,000 and 75,000
cells/mm3
• Stop if the WBC count falls below 2,000 cells/mm3 or if
the platelet count falls below 50,000 cells/mm3
• Single-use 10 mL vial containing 25 mg of anti-
thymocyte globulin (rabbit)

23. • Hematologic effects: low platelets and WBC have been
identified and are reversible following dose adjustments.
Monitor TLC and PLC
• Infections and reactivation of infections. Monitor patients
and administer anti-infective prophylaxis.
• Incidence of malignancies may increase.
• Immunization with attenuated live vaccines is not
recommended
• THYMOGLOBULIN may interfere with rabbit antibody–
based immunoassays and with cross-match or panel-
reactive antibody cytotoxicity assays

24. • urinary tract infection, abdominal pain, hypertension,
nausea, shortness of breath, fever, headache, anxiety,
chills,
• increased potassium levels in the blood,
• low counts of platelets and white blood cells

25. ALEMTUZUMAB
• humanized anti-CD52 panlymphocytic (both B and T
cells) monoclonal antibody.
• currently approved by the FDA for treatment of B-cell
chronic lymphocytic leukemia.
• a single intravenous bolus of 30 mg
• in all patients treated with rATG or
• Alemtuzumab, anantimicrobial and antivirus prophylaxis
is mandatory.

26. • Infusion reactions may occur during intravenous
administration (30 mg, 1 dose). The subcutaneous route
not approved by the FDA.
• intense and prolonged lymphocyte depletion, increased
antibody-mediated graft rejection, and increased
frequency of serious infection

27. • Acute rejection at 3 years was significantly less frequent
in low-risk patients who had alemtuzumab (10%) than
basiliximab or rATG (22%; P = .003). In high-risk
patients, alemtuzumab and rATG had similar efficacy
• The frequency of serious adverse events related to
cancer was higher in the basiliximab or rATG therapy
group, but the low-risk alemtuzumab group had
persistent leukopenia and a higher frequency of serious
infection

28. OKT3
• Muromonab-CD3 (OKT3) is a mouse
antibody that depletes T cells by binding to
the T-cell-receptor associated CD3
glycoprotein
• adverse events including first-dose effect,
pulmonary edema, nephropathy, infection,
and malignancy
• production was stopped in 2009

29. OKT3

30. RITUXIMAB
• Rituximab is a chimeric monoclonal
antibody against CD20, an antigen that is
expressed on most B cells
• approved in 1997 for treatment of
refractory B-cell lymphoma
• treatment of antibody- mediated rejection
and desensitization in transplants
incompatible in ABO antigens and/or
HLAprofile

31. RITUXIMAB
• Rituximab is a monoclonal antibody against CD20, which
induces B-cell depletion.
• post-transplant treatment of acute rejection
• induction therapy in the transplantation of ABO
incompatible pairs or recipients with preformed
antibodies against the HLA
• Rituximab is beneficial in the cases of ABO
incompatibility, while not in the case of antibodies
against donor HLA.

32. • There was a significantly lower incidence
of acute cellular rejection in patients who
received rituximab (8.2%) than patients
who did not receive rituximab (23.3%; P ≤
.05), but antibody- mediated rejection was
similar i
• In a study of transplants that did not
require desensitization, acute cellular
rejection within 3 months after transplant
was more frequent with induction with

33. BORTEZOMIB
• Bortezomib Allospecific antibody-secreting
cells are long-lived plasma cells in bone
marrow (CD138+CD20-). Therefore, the
inhibitory effect of rituximab may be weak
• Bortezomib, a selective inhibitor of the 26S
proteasome, is approved for treatment of
multiple myeloma

34. • e steroids and proteasome inhibitors such
as bortezomib may act synergistically to
target plasma cells, and a combination of
these 2 drugs may be beneficial.26

35. IL2
• anti-IL-2 receptor (IL-2R) antibodies may
interfere with IL-2 activity and prevent T-
cell–mediated rejection
• chimeric monoclonal antibody basiliximab
(Simulect, Novartis, Basel, Switzerland)
and the humanized antibody daclizumab
(Zenapax, Roche, Basel, Switzerland).
Basiliximab and daclizumab bind to the α
chain of the IL-2R complex (CD25) t

36. • expressed on activated T cells. As a result,
T-cell activation and proliferation are
prevented without cell lysis or depletion
• the best safety profile compared with other
available induction antibodies and have no
increased risk of infection or malignancy
• (basiliximab, 2 doses within 4 days of
transplant; daclizumab, 5 doses over 8
weeks)

37. • e high-risk transplants include deceased-
donor kidney transplant in highly
sensitized patients, simultaneous kidney
and pancreas transplant, and split single
pediatric donor kidney transplant.

38. EFALIZUMAB
• functions as an immunosuppressant by
binding to the CD11a subunit of
lymphocyte
• function-associated antigen 1 and
inhibiting white blood cell migration.
Efalizumab was indicated for the treatment
of chronic moderate-to-severe plaque
psoriasis
• developed lympho- proliferative disease,
and efalizumab was withdrawn from

39. ALEFACEPT
• n inhibitor of the costimulation of T cells by CD2 and
lymphocyte function-associated antigen 3.
• most common adverse event is lymphopenia, and
dosage adjustments are made by monitoring CD4+
lymphocyte counts
• Alefacept also was associated with a higher incidence of
malignancy (alefacept, 6.7%; placebo, 0.9%) and lower
levels of CD4+ and CD8+ memory T cells at 12 weeks
after transplant
• was associated with a higher frequency of
cytomegalovirus (

40. CORTICOSTEROIDS
• modulate the immune response by regulating
the gene expression related to
• several molecules, such as IL-1, IL-2, interferon-
gamma (IFN-γ), tumor necrosis factor-alpha
(TNF- α), and IL-6.
• Steroids are administrated during the transplant
often before reanastomosis intravenously at
• the dose of 500 mg/1 g and followed by
decreasing the dosage up to 5–10 mg one
month after
• transplantation

41. • Several transplant centers decrease the
steroid administration up to it reaches 5
mg/day. The
• KDIGO guidelines suggest the possibility
of safe steroid withdrawal to avoid their
side effects at
• least in low-risk patients.

42. • The steroid withdrawal should be
• decided individually based on the
immunological risk, renal function, and the
severity of the
• steroid-related side effects

44. FUTURE

46. LIVING DONOR
• There is no economic benefit of
basiliximab induction in adult living-related
kidney transplant recipients and no
differences in the incidence of acute
rejection, renal function, or frequency of
infectious complications between
recipients of living-donor kidney transplant
with or without induction.

47. • induction is important in living- unrelated
kidney transplant. There is a higher
frequency of acute rejection after 6 and 12
months, and a 3-fold greater risk of
rejection, with living- unrelated kidney
transplant without induction than
deceased-donor kidney transplant with
induction

48. • n ABO-incompatible living-donor kidney
transplant may be achieved with
plasmapheresis, splenectomy, and
induction with ATG.43 In addition, after
laparoscopic donor nephrectomy with
longer warm ischemia times, basiliximab
induction and a sirolimus and prednisolone
regimen enabled the delayed use of
cyclosporine and was associated with
excellent 1-year graft survival

49. PEDIATRICS
• Induction therapy is important in children
to minimize the risks of steroids and
calcineurin
• inhibitors and to achieve better growth and
fewer adverse events. Basiliximab (10 mg
for children who weigh < 35 kg) given at
transplant and postoperative day 4 may
cause saturation of IL-2R for 3 weeks.45
Basiliximab is safe within 1 to 2 months
after kidney transplant in children who

50. • Induction therapy in children is well
tolerated and associated with higher
glomerular filtration rate at 1 year without
significant adverse events, but longer
follow-up is advised

51. HEP C REC
• increased immunosuppression with
depleting than nondepleting induction
agents may favor the progression of
hepatitis C infection and cause adverse
outcomes
• hepatitis C virus-seropositivity may not
affect the selection of induction agents
used during kidney transplant.

52. DESENSITIZATION
• New antibody-detection techniques
(Luminex, Austin, TX, USA) show that
40% of patients on the kidney transplant
waiting list are presensitized by having
HLAantibodies. In addition, HLAantibodies
are present in all patients who lost a
previous graft and await revision
transplant.53 Antibodies against non-HLA
antigens such as the angiotensin type 1
receptor may be present on graft

53. • Desensitization protocols aim to lower
donor- specific antibodies at transplant to
safe levels. A minimum prerequisite for
transplant is a negative complement-
dependent cytotoxicity crossmatch at
transplant

54. • n, highly sensitized patients have
decreased allograft survival, probably
because of undetected donor-specific
antibodies or increased alloreactivity. The
Heidelberg algorithm combines various
measures to overcome these problems
with pretransplant plasmapheresis (1
session; deceased- donor transplant) or
repeated immunoadsorption

55. • (living-donor transplant) and rituximab
(375 mg/m2) when all crossmatches are
negative
• Treatment after transplant may include
repeated plasmapheresis (deceased-
donor transplant) or immunoadsorption
(living-donor transplant). After transplant,
donor- specific antibody levels are
monitored (days 0, 7, 30, and 180, and
every 6 months) and protocol biopsies are

56. • Recipients who have a positive
crossmatch with the prospective kidney
donor are desensitized by removal of
alloantibodies from the recipient’s
circulation by plasmapheresis,
immunoadsorption, or modulation of
antibody responses by intravenous
immunoglobulin alone or in combination
with plasmapheresis.59

57. • anti-CD20 antibody rituximab or the
proteasome inhibitor bortezomib to deplete
B lymphocytes or plasma cells and
decrease the production of donor-specific
antibodies.59,60 In addition, blocking the
complement pathway with the complement
C5 inhibitor eculizumab may prevent
allograft damage when HLA antibodies
bind to the kidney allograft endothelium

58. • Immunoadsorption is effective in the
removal of HLA alloantibodies from highly
sensitized kidney transplant candidates
• positive crossmatch with their donors.
These options include sensitive antibody
detection techniques, effective antibody
elimination devices, and new therapeutic
agents

59. • Basiliximab may be preferred for low- risk
patients and rATG may be preferred for
high- risk patients

60. • THANK YOU

61. • Patients with
• a positive CDC cross match were not
transplanted, while
• those with a positive flow cytometry cross
match underwent
• further evaluation with Luminex
single-antigen bead assay
• to look for anti-HLA antibodies. HLA
incompatibility was

62. • Immunosuppressive protocols
• Patients received the first dose of ATG on
the day of
• transplant. Total dose of Grafalon given
was 6 mg/kg IV (3
• mg/kg each on postoperative day (POD) 0
and 2), while
• that of thymoglobulin was 3 mg/kg IV (1.5
mg/kg each

63. • Patients were followed up weekly once for
the first month,
• weekly twice for the second month, once
in fortnight
• for the third month, and monthly once
thereafter for a
• year. After 1-year, patients were followed
up once in 2–3
• months lifelong. During every visit, renal
function tests