The term “induction therapy” (I.T.) is an im/m therapy that given at the time of KTx to limit the risk of allograft Rj.
Abbreviations (read twice please):
o ABOi : ABO-incompatible transplants
o ABOi: ABO incompatible Tx.
o Ac Rj: Acute Rejection.
o Ags: antigens.
o Alm: Alemtuzumab (Campath-1H).
o AMR: antibody-meditated rejection
o Bsx: Basiliximab.
o CAN: Chronic allograft nephropathy.
o CMV: cytomegalovirus.
o CNI: calcineurin inhibitor.
o CRT randomized trials
o CyA: Cyclosporine.
o CXM: Crossmatch.
o CAN: Chronic allograft nephropathy.
o CLL: chronic lymphocytic leukemia.
o DSGS: death-censored graft survival.
o DSAs: donor-specific antibodies.
o Dsz: desensitization.
o DGF: delayed graft function
o FSGS: focal segmental glomerulosclerosis.
o GC: Glucocorticoids.
o GN: glomerulonephritis.
o HLA: human leukocyte antigen.
o HLAi: human leukocyte antigen incompatible transplant.
o IL-2 RA: IL-2 receptor antagonists.
o I.T.: induction therapy.
o im/m: immunosuppression.
o im/mb: immunoabsorption.
o KDIGO: Kidney Disease: Improving Global Outcomes.
o KTRs: Kidney transplant recipients.
o KTx: kidney transplantation.
o LRKD: living-related-donor kidneys
o MHC: major histocompatibility complex.
o MMF: mycophenolate mofetil.
o Mthyprd: Methylprednisolone.
o Pph: Plasmapheresis.
o PRA: Panel reactive antibody.
o PTLD: post-transplant lymphoproliferative disease.
o rATG: rabbit anti-thymocyte globulin-Thymoglobulin
o Rtx: Rituximab
o SE side effects
o SOT: solid organ transplant.
o SRTR: Scientific Registry of Transplant Recipients.
o Tac: Tacrolimus.
o TMP/ SMX: Trimethoprim-sulfamethoxazole.
o TR: Transplant recipients.
o UTI: urinary tract infection.
The term “induction therapy” (I.T.) is an im/m therapy that given at the time of KTx to limit the risk of allograft Rj. Generally, induction plans included in one of two protocols. The 1st primarily relies upon high dosages of conventional im/m agents, whilst the more widely used strategy uses either T cell-depleting or IL2 RA in addition to lowered doses of conventional agents. TR in the US mostly receive an AB I.T. In 2016, almost % of KTRs received T cell-depleting I.T. and about % received IL-2 RA.
Introduction: All KTRs mostly require im/m therapy to guard against Rj and allograft failure. Several RCT indicate that I.T. composed of [biologic AB + conventional im/m agents] is superior to conventional agents alone in declining kidney graft Rj & allograft loss. In ptns receiving KTx, it is recommended that I.T. formed of [AB therapy + conventional im/m agents], with only one exception of the . Such ptns do not usually need I.T. with AB given their highly declined immunologic risk of Ac Rj. Suggested approach: to select induction im/m plan in KTx considering the magnitude of risk of Ac Rj:
o High risk Rj: rATG is superior to IL-2 RA & placebo among ptns at high immunologic risk and receiving concurrent im/m plan. So, we start rATG, a lymphocyte-depleting agent, rather than IL-2 RA or no AB therapy.
o Lower risk Rj: some updated clinicians give rATG based upon evidence that rATG offered lower Ac Rj rates. Other clinicians use IL-2 RA considering similar rates of Ac Rj, ptn & graft survival, and infection with rATG & IL-2 RA.
Exceptions to this approach include:
o Caucasian TR of 2-haplotype-identical, living related kidneys: No need for AB agent.
o KTRs with another functioning SOT e.g., liver, lung, or heart and currently receiving im/m agents. No need for induction agent, but some clinicians may use Bsx.
Types of im/m AB therapy: include the either specific AL antilymphocyte or IL-2 RA:
o Antilymphocyte AB: include polyclonal & monoclonal AB. Polyclonal AB contain AB to a wide range of human T-cell surface Ags, including MHC Ags. Thymoglobulin is a polyclonal im/m that generated in rabbit (rATG). N.B. Another rATG (Fresenius), while the immunogen of rATG is that for rATG (Fresenius) is a leukemia line. Another polyclonal AB, ; a purified gamma globulin obtained by immunizing with human thymocytes. Monoclonal antilymphocyte AB include Alm. is a humanized anti-CD52 panlymphocytic (both B & T cells) monoclonal AB, (declined in US).
o Anti-CD20 AB: Rtx = anti-CD20 monoclonal AB depleting CD20+ve B cells. It’s approved most commonly PTLD therapy and Dsz of HLA & ABOi Tx & ttt of AMR. Both donor & TR should be examined for CMV; Valgancyclovir given as primary prophylaxis in risky ptns for CMV. TMB/SMX is given to prevent Pneumocystis carinii pneumonia, sepsis, & UTI.
RISK OF Ac Rj:
Recognizing ptns at high risk of Ac Rj is crucial, so, more aggressive im/m should be considered. The KDIGO guidelines, 2009, risk factors for include one or more of the following:
In those ptns, 2009 KDIGO guidelines suggest the use of agents that are robust im/m agents, rather than IL-2 RA. On the other hand, ptns NOT with high risk, guidelines recommend due, partly to meta-analysis reported diminished risk of Rj. Updated clinicians may give IL-2 RA to low-risk ptns; however, other clinicians may use agents mostly to adult ptns receiving KTx, regardless the magnitude of risk for Ac Rj.
High risk Ac Rj use > rATG as an induction im/m therapy. rATG is superior to Atgam, IL-2 RA & placebo among KTRs who are at high & low immunologic risk (2009 KDIGO guidelines).
IV Mthyprd (7 mg/kg) + IV rATG ( mg/kg) are intraoperatively given. rATG is given if, at presentation, WBCs is > /microL & platelet count > /microL. Give Bsx if rATG cannot be used. The intraoperative dose of rATG is followed by 2 mg/kg of rATG/d for the next 2 d.s (i.e., total 3 doses). Dose of rATG can be skipped if WBC < /microL or platelet declined to < /microL. Half doses of rATG is given for WBCs between & /microL or platelets between & /microL. Optimal dosing for rATG is not certain. Cumulative dose < have proved to be less efficacious than higher doses, however, doses > TR. Some centers use lower doses for low-risk TR of LRKD & higher doses for TR of deceased-donor allografts. These rATG plans is usually combined with preoperative maintenance mg/kg are not required for renal im/m.
o ABOi: Optimal induction plan for KTRs with ABOi donor is not certain. It is recommend using rATG as an induction im/m protocol. Added to the induction plan, Pph & im/mb are generally provided to limit circulating ABO AB titers and declining the risk of acute AMR.
o HIV ptns: HIV TR, compared to HIV-ve TR, often show higher risk of Ac Rj, so, may benefit from AB induction plans. However, considering the underlying im/m state of HIV ptns, extended lymphocytic depletion with AB induction plan may potentially augment the risk of opportunistic infection. I.T. in HIV KTR still controversial, there’s no consensus about the optimum protocol. Certain centers may prohibit AB I.T in HIV TR. Centers using AB I.T., may utilize Bsx (IL-2 RA) considering data of HIV KTR showing higher risk of infection with rATG. Other clinicians may prefer rATG considering its superiority in declining Ac Rj in HIV-ve TR.
Efficacy reports: The assessment of any trial or prophylactic AB induction regimen necessitates considering the following items:
o Cost magnitude.
o Incidence of Ac Rj
o Long-term graft longevity & function
o Incidence, type & intensity of concurrent infection.
o Mortality/morbidity, including hospital admissions.
o Incidence/type of cancer with long-term following-up.
o Incidence/intensity of DGF/primary non-function, the need/timing of DX after Tx.
rATG vs no induction: KTRs receiving deceased-donor, rATG is more effective than no I.T. in declining the rate of Ac Rj, but it has no observed significant impact on the rates of ptn and graft survival rate in the 1st 12 mo after Tx. However, rATG therapy is complicated by a higher risk of untoward effects e.g., leukopenia, thrombocytopenia as well as CMV infection:
Study: TRs were randomly receiving rATG followed by Tac on d. 9 post-tx or Tac -based triple therapy given within 24 hs of Tx. Ttt with rATG declined the rate of Ac Rj at 12 mo. Ptn & graft survival were the same in both gs. Ptns received rATG had significant rise in leukopenia, thrombocytopenia, CMV infection, fever, & herpes simplex infection.
Study: KTRs were randomly receiving Tac -based triple therapy started as soon as possible post Tx , induction via rATG followed by Tac on d. 9 post-Tx, or induction via rATG followed by CyA on d. 9 post-tx. At 6 mo., rate of biopsy-proven Ac Rj was significantly declined in the arm on as compared with the arms on and Tac-based triple therapy. Leukopenia, thrombocytopenia, CMV, fever, & serum sickness were highly significant in both groups received rATG.
rATG vs Atgam: rATG is more effective as compared to Atgam in declining Ac Rj rate and improving allograft longevity. Trial: TRs were randomly receiving intraoperative rATG (1.5 mg/kg IV) or Atgam (15 mg/kg IV), followed by daily/6 d.s. DGF rate was only % for both g.s. At one y, the g. on rATG had a significant decline in Ac Rj rate & increased graft survival.
Decline in Rj rate could be partially attributed to a with rATG, while the exceptionally low DGF rate seen in both groups may have been due to the intraoperative use of rATG; these AB have the power of blocking many adhesion molecules, cytokines, chemokines, & their receptors responsible for & DGF.
rATG vs IL-2 RA: Ptns at higher risk for Ac Rj, rATG is more effective than Bsx in Rj prevention. Effectiveness of Bsx vs rATG in high-risk ptns was estimated in multicenter RCT: 278 deceased-donor KTRs comparing safety & efficacy of 5-ds course of rATG vs 2 doses Bsx. TR & donors were selected according to criteria predicting higher-than-normal risk for Rj or DGF. Ptns in both arms were given CyA, MMF & prednisone for maintenance im/m, & receiving prophylactic gan-ciclovir. Primary endpoint: Ac Rj, DGF, graft loss & death. At one y, the following were reported:
· rATG significantly declined Ac Rj rates & incidence of Ac Rj requiring AB therapy.
· Overall adverse event & serious adverse event rates were the same, but rATG showed a higher incidence of infectious episodes but a lowered incidence of CMV.
So, despite the primary endpoint at one y was similar in both groups, a significant Ac Rj and the need for AB ttt of Ac Rj still lower among rATG group as compared to Bsx. Ptns ttt with rATG also had a significant lowered composite endpoint of AcRj, graft loss, & death at 5 ys and incidence of ttt CMV infection; however, the incidence of cancer is the same. So, the relative benefits of rATG were mostly sustained along 5-y after surgery. Observational studies comparing rATG &Bsx mostly showed similar results. Comparing rATG with was noted with . At 5 ys, incidence of Bsx, the latter may be associated with a higher rate of de novo DSA & AMR development. Study: 114 TR receiving deceased-donor kidneys having DSAs but -ve CXM at time of Tx. At 36 mo, compared with bsx, rATG was accompanied with decline in de novo DSA and AMR development. Dosing protocol of rATG: variable dosing plans for rATG that is generally given peripherally rather than through a central venous access. Effectiveness of these plans has been assessed as follows:
● Safety& effectiveness of a 3-d induction protocol, given to 40 ptns, have compared with a 7-d course 48 controls. In the 3-d course, rATG was given intraoperative 3 mg/kg followed by postoperative 1.5 mg/kg, day: 1 & 2, while the 7-d course given rATG at intraoperative 1.5 mg/kg IV, then daily/6 ds. At 1 y, NO difference in Ac Rj rates, graft longevity, & ptn survival, but the duration of initial hospitalization was highly shorter in the 3-d g. Prolonged + more intense duration of lymphocytic depletion was seen among those given 3 ds of rATG.
●Advantages with the intraoperative rATG were observed in a trial: 58 deceased-donor TR randomly receiving either intraoperative or postoperative rATG, with both g.s received the same subsequent doses of this medication. Providing intraoperative rATG leads to significant lowering the DGF incidence and lowering post-Tx hospital admission timing.
●Low-dose rATG (0.5 mg/kg/d) + Bsx vs standard-dose rATG (2 mg/kg/d.) as I.T. was assessed in a RCT of 33 high-risk ptns. Both g.s had similar ptn & allograft survival, but untoward effects were significantly higher with standard-dose plan. However, ptns in standard-dose g. received higher cumulative dosage of rATG (up to 14 mg/kg) than those usually used for induction.
●Retrospective study: 224 adult KTRs compared the efficacy/safety of lowered & conventional doses of rATG. Lower cumulative rATG dosing of 3 mg/kg & 4.5 mg/kg were given to standard risk living-donor & deceased-donor TR, resp, and a conventional dosing of 6 mg/kg to higher risk TR (prior Tx, PRA > 20 %, or flow cytometry CXM positivity). Over 42 mo, No significant difference in ptn or graft survival among the 3 dosing arms. One-y. Rj rates in the 3 & 4.5 mg/kg gs were 8.3 & 8.8 %, resp. that were comparable to rates observed in SRTR. Cost analysis showed: tailoring permitted savings of as compared to conventional dosing. Infectious episodes were comparable to those recorded to the SRTR.
rATG induction can be dosed: more typical plan = Animal model: high initial doses + short duration, like human-equivalent dose = mg/kg > more peripheral/central lymphocyte depletion + better graft survival. So, optimal induction = total mg/kg, total doses = mg/kg that’re usually given as mg/kg/d, > similar outcome in high-risk TR receiving average mg/kg. High doses + prolonged duration of I.T. > higher risk of infection, serum sickness, & potential malignancy (lymphoma), while lower dosing = < mg/kg may NOT effective for Ac Rj prevention. mg/kg/dose, and its duration from ds, despite a
LOW-RISK TR: ptns not assessed at higher risk for Ac Rj, either rATG or IL2 RA can be given as I.T.. Updated clinicians may give rATG considering the lowered Ac Rj rates with rATG. However, others may give IL2 RA considering reports showing similar rates of Ac Rj, ptn & graft longevity & infection with rATG and IL2 RA. The 2009 KDIGO guidelines recommend using IL2 RA as 1st -line induction in TR NOT at higher immunological risk. In lower-risk TR, rATG is given with the same induction plans used for high-risk TR. TR receiving Bsx>intraoperative mg & mg on the postoperative day. Some evidence present that rATG, as compared to Bsx or no induction, may be more beneficial in lowered-risk TRs:
●Analysis of RCT of rATG compared to Bsx, TR of a normotensive, standard-criteria-donor kidney ttt with rATG had lowered Ac Rj, death, and achieved endpoint i.e., death, graft loss, or Ac Rj than those receiving Bsx.
●rATG shown to be safe & effective in ptns with LRKD KTx. Study: rATG compared with no induction showed superior 5-y ptn & graft survival & one-y Ac Rj rate. Study: rATG comparing with no induction showed a significant lowered Ac Rj rate with no rise in post-tx sequelae. However, other studies were showing rATG is to Bsx in :
●Multicenter study: 615 low-risk TR were randomly given to one of 3 different im/m plans: Bsx I.T. + long-term GC, Bsx I.T. + rapid GC withdrawal (within 8 d of Tx), or rATG I.T. + rapid GC withdrawal. All TR provided low-dosing extended-release Tac cap. + MMF as maintenance im/m. After 12 mo, were similar between rATG & both Bsx gs. NO differences in ptn/graft survival, graft function, infection, or malignancy was observed.
●Study: 100 low-risk TR were given Bsx or rATG. With MMF & short-term GC, CyA was given within 24 hs of Tx or with SCr was < mg/dL (250 mmol/L) in the Bsx & rATG arms, resp. At 12 mo, Ac Rj was similar between the 2 g.s. Fewer CMV episodes in Bsx arm, with no difference in CMV episodes between the 2 gs. Ptn & graft survival were comparable at 12 mo & at 5 ys.
● 105 low-risk KTRs randomly provided rATG or Bsx, both Bsx & rATG showed similar graft & ptn survivals (& Ac Rj rates); however, Bsx showed low incidence of CMV infection & leukopenia.
●Retrospective analysis: assessing graft & ptn outcome in 74,627 TR of deceased-donor KTRs receiving IL-2 RA, rATG, ALm, or no AB, and maintained on Tac & MMF with or without GC. In the subgroup of lowered-risk TR, Ac Rj at one y & graft survival at 5 ys were similar with rATG & IL-2 RA. Ptns who do not require AB I.T.: Although most ptns undergoing KTx should receive induction im/m therapy, there are select ptns to whom we can omit AB I.T.:
o Caucasian TR of 2-haplotype-identical, LRKD (very low risk for Ac Rj)
o TR of KTx having another functioning SOT e.g., a liver, lung, or heart and already on long-term maintenance im/m, so could be at a higher risk of infection with lymphocytic depletion.
Bsx IN TR WHO CANNOT NOT RECEIVE rATG
RATG is known to be superior to IL2 RA for I.T. in high risk ptns. If we cannot provide rATG, we can give Bsx with one or more of the following states at the time of Tx:
o WBCs count < /microL
o Platelet count < /microL
o Hypotension (systolic BP < mmHg)
Ptns can receive Bsx as intraoperative 20 mg & another 20 mg on the 4th postoperative day. Efficacy of IL-2 RA was best reported in a systematic review conducting 71 RCT & 10,537 ptns assessing the impact of therapy on graft loss & Rj rates:
o 32 trials conducting 5784 ptns compared IL-2 RA with placebo for at least one outcome. Compared with placebo, IL-2 RA lowered Ac Rj rates & graft loss at one y.
o 16 trials conducting 2211 ptns testing efficacy of IL-2 RA vs rabbit or horse ATG: there was no difference in graft failure or clinically evident Ac Rj. Compared with ATG, IL-2 RA had higher incidence of biopsy-proven Ac Rj at one y but fewer SE & less CMV & cancer. Intense acute hypersensitivity was observed with either new exposure to Bsx and/or re-exposure.
INFREQUENTLY APPLIED I.T.:
Alemtuzumab: ALm (Campath-1H) is a humanized anti-CD52 panlymphocytic (both B & T cells) monoclonal AB that’s approved for CLL. ALm I.T. is provided to 10 % of KTRs in the US. ALm often not routinely used as I.T. with KTx as its benefits in declining Ac Rj . Other long-term criteria e.g., graft/ptn survival & CAN, may also getting worse with ALm as compared to rATG & IL2 RA. Moreover, ALm is not often available to all Tx centers. ALm is given as a single IV dose of mg at the time of Tx. RCT & observational reports comparing efficacy of ALm with rATG & IL2 RA in KTRs shows:
●RCT (INTAC): 139 high-risk TR (re-Tx, PRAs of >20 %, or black race) > one 30 mg dosing ALm or rATG, 6 mg/kg/4 ds, & 355 low-risk TR received one 30 mg dose of ALm or a total of 40 mg Bsx/4 ds.
o In the high-risk cohort, there was no difference in Ac Rj in TR receiving ALm, compared with rATG, at 6, 12, & 36 mo.. (= Rj seen between 12 & 36 mo in ptns having no Ac Rj in the 1st 12 mo) was more prevalent with ALm, but was statistically insignificant. Other authors reported that the beneficial effect of ALm may .
o In low-risk g., rate of Ac Rj was lowered in ptns receiving ALm, as compared to Bsx, at 6, 12, & 36 mo. was more prevalent in the ALm as compared to Bsx g. This confirms prior reports showing: among low-risk TR, ALm decreases Ac Rj early after Tx. However, this effect weakened by time, as observed with high-risk group.
o In the low-risk g., there were no differences between ALm & Bsx in ptn survival, overall or DSGS, or overall rate of SE, but these reports were not powered. Among low-risk TR, comparing with Bsx, ALm can decrease mean lymphocyte count at all points of time; but in high-risk TR, rATG & ALm both induce low mean lymphocyte count in the 1st post-Tx week.
●Multicenter, open-label, RCT: comparing ALm followed by low-dose Tac (trough: ng/mL) & MMF without GC with Bsx induction followed by standard-dose Tac (trough: ng/mL), MMF, & GC. At 6 mo, compared to Bsx and standard maintenance therapy, TR receiving ALm show low rate of biopsy-proven Rj. No difference in Tx failure or infection.
● RCT: 90 KTRs randomly received rATG (g.A), Alm (g. B), or daclizumab. All 3 arms received Tac & MMF, and maintained on GC was only given to TR in g. A & C. Target Tac & MMF were also lower in g. B. At 15 mo, ptn & graft survival rates and Ac Rj rate were the same in ALL g.s, suggesting: some TR could be maintained on less severe im/m if received Alm. Follow-up at 48 mo showed: g.B (Alm without GC) had worse DCGS. CAN was also more prevalent.
Two RCT that have been performed assessing Alm or rATG as I.T. in kidney, kidney-pancreas, & pancreas TR. Despite the assumption of lowered Rj rates with ALm, these data are difficult to interpret considering their multiple limitations & flaws including conducting 3 different cohorts with variable dose plans. Retrospective report: graft survival was lower & MR higher in TR received ALm as compared to those receiving rATG or Bsx. Reports of induction of autoimmune disorders, e.g., thrombocytopenia & autoimmune thyroiditis, with the use of Alm. A suggested mechanism is the after Alm-induced depletion. However, Alm, compared with IL-2 RA, does not augment the risk of post Tx recurrent GN.
Rituximab: an anti-CD20 monoclonal AB depleting CD20 +ve B cells. We do not routinely use Rtx as I.T. in most TR receiving KTx, as no added benefit and may be harmful to TR of HLA & ABO-compatible grafts. Two RCT have been shown Rtx as I.T. in KTRs:
 RCT: comparing single-dose Rtx (375 mg/m2) with placebo as I.T. among 136 KTRs. At 6 mo: no difference in Ac Rj rates, bacterial/viral infection, or MR between Rtx & placebo g.ps. However, the 3-y MR was higher in Rtx -ttt TR as compared to placebo. Deaths were attributed to fungal pneumonia, pulmonary carcinoma, & myocardial infarction and/or cardiac arrest. The higher incidence of CVS deaths could be related to the (depleted by Rtx). At 3 ys: no difference in DSAs evolution between Rtx or placebo groups.
 RCT: 280 TR received a single dosing of Rtx (375 mg/m2) or placebo during Tx surgery. All TR maintained on im/m including Tac, MMF, & GC. At 6 mo: NO difference between g.s in Ac Rj rates. However, high-risk TR (= PRA of > % or re-Tx), as compared to placebo, Rtx-ttt TR had a lowered risk of Rj. Rtx-ttt TR had higher incidence of neutropenia, but the risk of infection & cancer was similar in both g.s at 2 ys. Another systematic review: 45 records from 21 reports showed: Rtx was useful as I.T. with ABOi Tx, with outcome comparable to splenectomy. Scanty evidence that Rtx decreased Rj and improve survival for HLAi TR. Rtx can be used for Dsz for HLAi & ABOi TR and also used to prevent FSGS recurrence.
Experimental approach: RCT: infused at time of Tx & 2 weeks after Tx was compared to IL-2 RA (control) among 104 TR of ABO-compatible kidneys from LRD. All TR received same doses of CNI, has been tried to replace AB induction. In one open-label, MMF, & GC. NO difference between g.s in ptn or graft survival at mo. At 6 mo, there was a lower incidence of Ac Rj among TR receiving stem cell infusion as compared to controls. 52 more TR receiving stem cell Tx + % lower dose of CNI > similar lowered incidence of Rj as compared to controls. At one y: lowered risk of opportunistic infection seen with stem cell Tx. Long-term work is currently required.