This randomized controlled trial compared rabbit antithymocyte globulin (ATG) induction versus basiliximab induction for allowing rapid steroid withdrawal in renal transplant recipients on tacrolimus and mycophenolate mofetil immunosuppression. The primary outcome was biopsy-proven acute rejection rates within 1 year, and secondary outcomes included patient and graft survival, post-transplant diabetes, and cardiovascular risk factors. Results showed that rabbit ATG was not superior to basiliximab in preventing acute rejection. However, rapid steroid withdrawal significantly reduced post-transplant diabetes rates without compromising efficacy or safety.

1. Rabbit-ATG or Basiliximab Induction for
Rapid Steroid Withdrawal after Renal Transplantation (Harmony):
an open-label, multicentre, randomised controlled trial
OliverThomusch, MichaelWiesener, Mirian Opgenoorth,Andreas Pascher, Rainer PeterWoitas, OliverWitzke, Bernd
Jaenigen, Markus Rentsch, HeinerWolters,Thomas Rath,Tülay Cingöz, Urs Benck, Bernhard Banas, Christian Hugo†
University Hospital of Freiburg,Albert-Ludwigs University Freiburg, Freiburg, Germany
Chaken Maniyan M.D.
Nephrology Fellow, Phramongkutklao Hospital
25.11.2016
Nov 19, 2016 Volume 388 Number 10059

2. Introduction
§ Although KT is the best RRT, many recipients die
prematurely with a functioning graft because of
complications of immunosuppression
§From ELITE-Symphony study *, standard of
immuno suppressive therapy consists of
§Monoclonal IL-2 receptor (CD-25 Ag) Ab induction
followed by
§Low-dose tacrolimus, MMF, and steroids
*Ekberg H, et al. Reduced exposure to calcineurin inhibitors in renal transplantation.
N Engl J Med 2007; 357: 2562–75.

3. Introduction
§ Low-dose tacrolimus arm compared with all other
treatment arms à highest incidence rates of PTDM
§ Steroids can induce or worsen hypertension,
hyperlipidaemia, and diabetes, which in turn can
increase a transplant recipient’s CV events.

4. § Association between PTDM and CV events or
mortality has been shown*
§Registry data as well as a case control study suggest
that steroid-withdrawal protocols lead to a lower
incidence of post-transplantation diabetes as well as
superior long-term graft and patient survival**
*Vanrenterghem Y,. Transplantation 2000; 70: 1352–59.
**Opelz G,.. Am J Transplant 2005; 5: 720–28
Introduction

5. Introduction
§A randomised, multicentre study (Harmony) to assess
which of two induction therapies was most efficacious
at permitting rapid steroid withdrawal in
tacrolimus-based and MMF-based immunosuppressive
therapy within the first year
§ Efficacy of steroid withdrawal was assessed against the
accepted gold standard immunosuppressive regimen
(low tacrolimus plus MMF plus corticosteroid regimen,
from the ELITE-Symphony trial).

6. Introduction
§ We tested whether induction therapy with rabbit
antithymocyte globulin (ATG) was superior to
induction therapy with basiliximab with respect to
frequency of biopsy-proven acute rejection (BPAR) rate
in the situation of rapid steroid withdrawal
§As secondary outcome parameters, we further tested
hypotheses that rapid steroid withdrawal does not
compromise patient or graft survival or graft function
while improving a recipient’s cardiovascular risk profile,
especially with respect to post-transplantation diabetes

7. Study design and participants
§The Harmony trial was prospective, randomised, open-
label, multicentre study in three parallel study arms of
adult renal transplant recipients.
§ Recruited from 21 centres in Germany.

8. Study design and participants
§ Per-protocol population was strictly defined to include
only patients who received treatment according to
protocol throughout the study period and reached the
final follow-up after 12 months
§21 German centres enrolled 615 randomly assigned
patients between Aug 7, 2008, and Nov 30, 2013

9. Inclusion criterion
§Age 18-75 years , scheduled to receive a single-organ
KT from either living or deceased donor
§Low immunological risk
§Donor and recipient had to be ABO compatible.
§Direct crossmatch had to be negative
(complement dependent cytotoxicity crossmatch,
CDC)
§Patients receiving a second KT were eligible (first
allograft was not lost due to acute rejection within
1styear after KT.

10. Exclusion criterion
§ Grafts with pre-existing donor-specific
HLA antibodies
§ PRA > 30%
§ Cold ischaemic time > 30 hr
§ Psychiatric disease;
§ Signs of alcohol or other drug abuse
§ Multiorgan transplantation;
§ History of cancer within last 5 years
(except for non-melanoma skin cancer)
§ Signs of ongoing infections including HBsAg +
HBcAb+ , anti-HIV+ , anti-HCV+
§ Bowel disease with malabsorption
§ Primary FSGS or MPGN
§Autoimmune disease which on steroid therapy
§ Thrombocytopenia < 70,000 , leucopenia <2500
neutropenia <1500
§Cirrhosis Child-Pugh B or C or serious liver disease
§Pregnant women and nursing mothers

11. Randomization and masking
§ Centrally randomly assigned in 1:1:1 ratio.
§ Randomisation list was computer generated with SAS (ver.
8.1) and stratified according to individual centres.
§ Each participating centre received consecutively numbered,
sealed envelopes.
§ After receiving informed consent, the envelopes were
opened to determine the type of immunosuppressive
therapy.
§ Neither patients nor those giving treatment or assessing
outcomes and analysing data were masked to the patients’
study group assignment.

12. Immunosuppression protocol
§Arm A (control group)
§ Induction: basiliximab 20 mg IV on day 0 and 4
§ Prolonged release tacrolimus OD at 0.2 MKD :
§ drug trough level 7–12 ng/mL within 1st month,
§ 6–10 ng/mL during months 2-3
§ 3–8 ng/mL during months 4–12
§ MMF at two 1 g doses/day
§ Prednisolone on day 0 and tapering with a requirement of dose of 10 mg /day
after 4 weeks
§ maintenance dose of 2.5–5.0 mg/day after 3 months

13. §In arm B, Same as in arm A with the exception that
§ Hereby, 500 mg prednisolone on day 0 were followed by
§ 100 mg on day 1,
§ 75 mg on day 2,
§ 50 mg on day 3,
§ 25 mg per day on days 4– 7
§ Corticosteroids were withdrawn from day 8
§In arm C, patients received same treatment as those in arm B, except
§ Induction with rabbit ATG instead of basiliximab.
§ Started intraoperatively, before graft reperfusion (1.5 MK Dose)
§ Rabbit ATG was given OD up to 4 days
§ Aiming for a total dose of 6.0 mg/kg bodyweight on postoperative day 3
§ The fourth dose of rabbit ATG on day 3 was omitted if the total count of lymphocytes was below
200/μL after third dose
Immunosupression protocol

15. Methods
§All patients with either high-risk infection (recipient
negative, donor positive) for CMV or EBV or patients
who had induction therapy with rabbit ATG received at
least a 3-month prophylaxis with valganciclovir.
§Additionally, Pneumocystis jirovecii pneumonia
prophylaxis with trimethoprim and sulfamethoxazole
or pentamidine was mandatory for all patients for at
least 6 months.

16. Outcome
§Primary efficacy endpoint à incidence of BPAR within
the 1st year after KT
§ Compared BPAR incidence rates of study arm A with
arm C and study arm B with arm C.
§All suspected episodes of acute rejection were
confirmed by biopsy, with histological characteristics
described according to the Banff criteria of 2005*
Banff ‘05 Meeting report: diff erential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (“CAN”).
Am J Transplant 2007; 7: 518–26.

17. Secondary Outcome
§Patient and graft survival
§Treatment failure
§Graft function (GFR Cockcroft Gault or CKD-EPI equation)
§Incidence of post-transplantation diabetes
§Systolic and diastolic blood pressure; lipids (HDL, LDL, and triglycerides); bodyweight
§ Incidence of CMV(PCR>1000 copies/μl), EBV (PCR>1000 copies/μl), or BK virus
(PCR>10 000 copies/μl) infections;
§Incidence of malignancy;
§Wound healing disorders;
§Cataract formation; and osteoporosis.

18. Secondary Outcome
§For post-transplantation diabetes assessment (according to the
American Diabetes Association [ADA] recommendations),
§ fasting glucose concentration at each visit (0, 2, and 4 weeks, and 2, 3,
6, 9, and 12 months);
§ HbA 1cconcentration was measured at each visit except after 2
weeks
§ OGTT was done at 3 and 12 months in all patients without a present
diagnosis of post-transplantation or pre-transplantation diabetes
§Treatment failure was defined any of
§ Use of additional immunosuppressive drugs, esp starting chronic
steroid drugs in arms B and C
§ Discontinuation of any study drug > 21 consecutive days
§ Allograft loss
§ Death

19. Statistical analysis
§Projected incidence primary endpoint BPAR (P A ) was estimated at 17% *
§Aim of our study was to show superiority of arm C versus arm A with respect to the BPAR rate (ie, a test
of the null hypothesis: P C – P A = 0) and to show superiority of arm C versus arm B with respect to the
BPAR rate (ie, a test of the null hypothesis: P C – P B = 0).
§The sample size was designed for both null hypotheses P C – P A = 0 and P C – P B = 0 to detect a difference
in the BPAR rate between study arm A or B and study arm C with a statistical power of 80% and a split
alpha value of 0·025.
§We calculated that 576 patients should be allocated to three study groups compensate for a dropout rate
of 5%.
§All analyses were done on the basis of an intention-to-treat principle.
§Categorical data were compared with Fisher's exact test, and continuous variables with the Wilcoxon-
Mann-Whitney test or t test.
§The time for reaching BPAR, graft loss, or death was calculated with the Kaplan-Meier method.
§Treatment comparisons were done with log-rank test.
§Incidences of adverse events and serious adverse events were tested by the Kruskal-Wallis Rank SumTest.
*Ekberg H, et al. N Engl J Med 2007; 357: pp. 2562-2575
** Asolati M, Harmon J, et al:. Am J Transplant 2004; 4: pp. 980-987

20. Results

21. Baseline characteristics

23. Cumulative probability of biopsy-proven rejection

24. Cumulative probability allograft survival

25. Outcome : primary endpoint

26. Outcome : secondary endpoint

27. Outcome : CV risk factor

28. Outcome : Post transplant infection

29. Cumulative probability of
post-transplantation diabetes mellitus

30. Discussion
§ This study done in immunological low-risk patient to
compare efficacy of two induction regimens, rabbit ATG
versus basiliximab in combination with tacrolimus-based and
MMF-based immunosuppressive regimen with or w/o rapid
steroid withdrawal
§Although rabbit ATG did not show superiority over
basiliximab induction for the prevention of BPAR after rapid
steroid withdrawal within 1 year
§ First multicentre, randomised study to show that rapid
steroid withdrawal can be safely done w/o decrease efficacy
with a tacrolimus and MMF-based regimen

31. Discussion
§Rabbit ATG versus basiliximab was not superior in our
study might be due to low immunological risk profile of
recipients and relative low total dose of rabbit ATG
§The study is the first to show that rapid steroid
withdrawal can be achieved without any negative effect
on efficacy might be related to the low immunological
risk profile of our mostly white study population

32. Discussion
§Tacrolimus level were balanced in all groups at all
timepoints except for one point shortly after
corticosteroid withdrawal.
§Therefore, patients without rapid steroid withdrawal
(arm A) had slightly lower tacrolimus trough level
§ Tendency towards decreased daily MMF doses in
rabbit ATG group compared with both basiliximab
groups à cannot exclude negative effect to BPAR

33. Discussion
§Although efficacy was equivalent in all study arms, the
second major finding of our study is that rapid
corticosteroid withdrawal decreased the incidence of
PTDM
§In trial used accepted criteria to define PTDM (ADA
criteria of fasting glucose, OGTT, and HbA1c)
§ Rapid steroid withdrawal significantly decreases the
incidence of PTDM > 40% (intention-to- treat),
an effect is enhanced in per-protocol population

34. Discussion
§Recent meta-analysis of steroid withdrawal between 3
and 6 months after KT did not show effect on PTDM
incidence*, our early timepoint of steroid withdrawal
might be crucial to this success
§ Frequency of PTDM diagnosis by ADA criteria was
about twice as high as that of centre judgement in the
Harmony study, and compared with most other trials
(not incorporating all ADA criteria), suggests that
§PTDM is overlooked, with all potential negative
consequences for transplant patient
Pascual J,et al . Systematic review on steroid withdrawal between 3 and 6 mo after kidney transplantation.
Transplantation 2010; 90: 343–49.

35. Discussion
§ Incidence of adverse events was similar in 3 study
arms.
§ Incidence of CMV, EBV infection was not statistically
different
§ valganciclovir was given to all in rabbit ATG arm,
but only to high-risk in basiliximab arm.
§ Incidence of BK virus was not significantly different in
all arms, but a numerical decrease > 40% was noted in
steroid withdrawal basiliximab treatment arm

36. Discussion
§In our study, both rapid corticosteroid withdrawal
groups were associated with a significantly higher
incidence of anaemia and ESA use.
§This effect may attributable to corticosteroids effects

37. Limitation
§ Premature study discontinuation of nearly 1/3 patients and
unexpectedly low incidence of BPAR
§ Decreased incidence of PTDM was assessed only as predefined
secondary endpoint.
§ Cannot completely exclude possibility of blinding bias ( decision
about indication for biopsy involves subjective interpretation)
§ Follow-up period of 1 year is too short to
§ Effect steroid-free maintenance therapy on BPAR
§ Lasting effect on incidence of CV events or mortality
§ (Harmony F/U period of 5 years, is being investigated
§ Limited to immunologically low-risk population of white ethnicity

38. Declaration of interests
§OT and CH received grant support, consulting fees,
and lecture fees from Astellas, Sanofi, Genzyme, Roche
Pharma, Novartis, and Wyeth/Pfizer.All other authors
declare no competing interests.

39. Conclusion
§Rabbit ATG did not reduce incidence of BPAR compared with
basiliximab with or without steroids
§ Both drugs equally successful in maintaining steroid-free
immunosuppression in > 80% of KT recipients, with benefits to PTDM
and without any loss of efficacy or safety signals besides
anaemia within the first year after KT
§ Rapid steroid withdrawal in a low-dose tacrolimus and MMF-based
regimen has potential new standard strategy for immunologically low-
risk population

40. §KDIGO suggest steroid withdrawn at evidence 2B
§Tacrolimus SE : PTDM
§ELYTE SYMPHNY PTDM only 10 % Dx based
on the notification of an adverse event,

42. Risk facotr for NODAT
§Traditional risk factors — Many of the risk factors
that predispose nontransplant patients to diabetes mellitus
have been identified as risk factors for NODAT.These
factors include:
§●Increased age (≥40 to 45 years) [10,12,19-27]
§●Obesity (body mass index of ≥30) [12,19,20,24,26-30]
§●African American race [12-14,22,26,31]
§●Hispanic ethnicity [12,27,31,32]
§●Family history of diabetes [22,33] or gestational diabetes

43. Transplant RF
§Medication
§Steroid : risk of developing NODAT was 5 percent per
0.01 mg/kg per day increase in prednisolone dose.
§CNI (Tac , cyclosporin) Tacrolimus is more diabetogenic
than cyclosporine
§Sirolimus
§Aza and MMF NOT asso NODAT
§Statin ,ACEI ARB and bactrim reduce NODAT
§HCV infectin
§HLA MM, HLA DR, HLAB27 phenotypre
§POMg
§ADPKD

44. Symphony trial
§ 12-month, prospective, randomized,open-label, multicenter study in four parallel groupsof adult renal-
transplant recipients
§Primary end point
§–Estimated GFR 12 months after transplantation,(Cockcroft–Gault formula
§4 arm stadard CYC, lo CYC, lo tac, lo siro
§Result : GFR lo tac>lo CYC>stad CYC>sirolimus
§BPAR+ Rx failure : lo tac< stand CYC<lo CYC< siro
§DGF Siro BEST
§DM : low dose tac> siro> stadard>lo CYC
§A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose
tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as
compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-
dose sirolimus or with standard-dose cyclosporine without induction