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Steroid Withdrawal after kidney transplantation

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Review of 2 landmark papers about late steroid withdrawal after kidney transplantation

Review of 2 landmark papers about late steroid withdrawal after kidney transplantation

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  • 1. Journal Club February 24 th 2008 Christos Argyropoulos
  • 2. Opelz et al. Long term prospective study of steroid withdrawal in Kidney and Heart Transplantation. American Journal of Transplantation 5:720-728, 2006
  • 3. Background for the study
    • Steroids are associated with significant morbidity at the doses/regimens
    • Prospective randomized trials of steroid minimization have yielded conflicting results and are plagued by small, very diverse populations
    • In meta-analyses of these trials it appears that the incidence of Acute Rejection (AR) is increased and long-term outcomes may not be favourable in terms of graft survival
    • CTS initiated a prospective evaluation (case/control design) in 1994 to explore the long term safety of steroid withdrawal.
  • 4. General Study Design
    • Enrolled patients from 30 kidney and 13 heart centers that participate in the CTS (400 centers in 45 countries, very few in the US)
    • Enrollment period: 1994-2002 (majority of patients between 1994-1997)
    • Participating centers were required to follow local IRB regulations
    • No mention of whether patients provided informed consent or not
  • 5. Enrollment Criteria for Patients
    • Inclusion Criteria:
      • Serum Creatinine <3 mg/dl (Kidney) or 2.26 mg/dl (Heart)
      • “ Good” graft function for >6 mos post and >3 months preceding enrollment
    • Exclusion Criteria:
      • PRA > 80%
      • Previous vascular (?AMR) or steroid resistant rejection
      • “ Rapid” (?) rejection of a previous graft
  • 6. Control Group
    • Each patient was matched to 3 controls by:
      • Donor/Recipient Age
      • Race
      • Year of Transplant
      • First/retransplant status
      • Cause of ESRD
      • Cold Ischemia Time
      • Continent
      • # of HLA mismatches
      • % of PRA
      • Duration since current transplantation date
    • Controls were NOT matched for level of renal function (were required to have SCr < 1.5 mg/dl!)
    • Controls were NOT matched for the occurrence of treated AR prior to enrollment.
    • Controls for heart were required to have had a clinical outcome evaluation of “excellent – on minimal immunosuppression” defined by individual centers
  • 7. Intervention Protocol I
    • Left to the individual Centers: only requirement to be steroid free within 6 months after patient was enrolled
    • Usually stepwise – could he halted if allograft function deteriorated
    • In case of AR, each center was allowed to follow their own protocol, but steroid withdrawal was only allowed after 3 mos of stable allograft function post treatment
  • 8. Intervention Protocol II
    • Monitoring of renal function:
      • Every 15 days during weaning (recommended, not mandated)
      • Monthly thereafter
    • Whole blood CSA level : 150-250 ng/ml during conversion and three months afterwards
    • Patient and Graft Survival: Assessed 6 months after enrollment and yearly thereafter
    • Only patients with full data in the CTS database were analyzed.
  • 9. Primary Outcome Measures
    • Patient Survival (PO1)
    • Graft Survival (PO2)
    • Death Censored Graft Survival (“functional graft survival”) (PO3)
    • Rates of impaired renal function & AR episodes (defined by need for treatment, not by protocol biopsies)
  • 10. Secondary Outcome Measures
    • Incidence of steroid related complications: osteoporosis, osteonecrosis, cataracts
    • HTN defined as SBP > 150 mmHg or initiation of new antihypertensive medications
    • Hypercholesterolemia (TC > 300mg/dl)
    • Assessment of SOs was not specified in the protocol but was left to the discretion of the clinical center
  • 11. Statistical Methods
    • Kaplan – Meier curves
    • KM curves were compared by the log-rank test (emphasizes late differences in survival curves) with p=0.05  significant
    • Outcomes Analyzed by KM curves:
      • Patient Survival
      • Graft survival
      • Discrete Creatinine Outcome: > 1.5 mg/dl
      • First AR episode
      • Re-instatement of steroids
  • 12. Results I
    • 1110 Kidney allograft recipients (61 retransplants)
    • 450 Cardiac Allograft recipients
    • 16% of patients had SCr> 1.5 mg/dl vs 0% controls (exclusion criterion)
    • Median time from transplantation to initiation of weaning: 1.1 yrs in K, 1.4 yrs in hearts
    • Mean f/u: 5 yrs (K), 6.3 (H)
    • 94% of patients were on CsA regimens
  • 13. Results II
  • 14. Results III
    • 81.3 ± 1.7% (K), 76.9 ± 2.3% (H)
    • 87.0 ± 2.5% (CsA) 86.2 ± 1.8% (CsA/Aza) 89.8 ± 3.1% (CsA/MMF)
    • Stratified Analyses of Survival for time between transplantation and withdrawal (<1 vs >1), pre-withdrawal rejection episodes : NS
  • 15. Results IV “ Although only patients with matching controls were included in this analysis, graft survival was virtually identical to that obtained with the series as a whole” Pts 81.9 ±1.8% 88.8 ±1.5% 91.8 ±1.3% Cntrls 75.3 ±1.2% 84.3 ±1.0% 87.9 ±1.0% p 0.0001 0.0016 0.0091
  • 16. Results V Cumulative Incidence of Discrete Creatinine Outcome: 37.3 ± 1.9 % (patients) vs 35.1 ± 1.0% (controls), p –value 0.45 ( all patients ) 33.6 ± 2.6% (patients) vs 50.4 ± 3.0% (controls), p-value < 0.0001 (patients who never required steroids after weaning)
  • 17. Results VI Cumulative Incidence of Acure Rejection Outcome : 8.6 ± 1.1 % (patients) vs 10.2 ± 0.7% (controls), p –value 0.21 ( Kidney ) 35.3 ± 2.8% (patients) vs 30.6 ± 2.3% (controls), p-value 0.15 (Heart)
  • 18. Results VII Cumulative Incidence of Steroid Use at 5 years: 41.4 ± 1.5 % (K) and 55.7 ± 2.5% (H) Statin Use at 5 years: 51.3 (patients) and 59.6 (controls)
  • 19. Results VIII
    • Cumulative Incidence of Osteoporosis :
    • 13.6 ± 2.4 % (patients) vs 24.3 ± 1.9% (controls), p –value 0.002
    • Cumulative Incidence of Cataracts :
    • 7.2 ± 1.8% (patients) vs 13.6 ± 1.5% (controls), p-value 0.009
    • Cumulative Incidence of Osteonecrosis : No difference
  • 20. Summary & Conclusions
    • Steroid withdrawal after the first 6 months leads to superior patient and graft outcomes at 7 years
    • The cumulative incidence of specific steroid – related complications may be reduced
    • No impact on AR rates
  • 21. Strengths & Limitations
    • Caucasians
    • Immunologically low risk patients
    • Selection of the control group
    • Handling of missingness (? What is the true denominator)
    • Definitions of outcomes (especially the creatinine) and enrollment criteria
    • No standardized steroid withdrawal protocol
    • “ ITT” analysis without “AT” limits the ability to draw conclusions about the safety and the effectiveness of the protocol
  • 22. Vincenti et al. A Randomized, Multicenter Study of Steroid Avoidance, Early Steroid Withdrawal or Standard Steroid Therapy in Kidney Transplant Recipients. American Journal of Transplantation 8:307-316, 2008
  • 23. Background for the study
    • Steroids are associated with significant morbidity at the doses/regimens
    • Introduction of MMF based combination regimens and antibody induction protocols implies that earlier trials of steroid “minimization” (Aza regimens/no Ab induction) are not as relevant today.
    • Open label RCT of steroid avoidance/freedom (SF) v.s. steroid withdrawal (SW) v.s. conventional steroids (CS)
  • 24. General Study Design
    • 12 month, open label multi-center RCT enrolled patients in 40 transplant centers in 9 countries (including the US)
    • Randomization 1:1:1 to the three arms
    • Participating centers were required to follow local IRB regulations
    • Patients provided informed consent
  • 25. Enrollment Criteria for Patients
    • Inclusion Criteria:
      • Patients between 18-75 y/o who received a de novo non HLA identical, kidney allograft
    • Exclusion Criteria:
      • Marginal donor (>60 y/o, NHBD)
      • Previous transplant of any kind
      • PRA > 20%
      • Cold Ischemia Time > 24hr
  • 26. Intervention Protocol I
    • Three treatment arms:
      • SF: no IV or oral steroids
      • SW: Solumedrol tapered down as 500mg (D1), 250mg (D2), 125mg (D3) switched to prednisolone as 60mg (D4) ->20 mg (D7)
      • CS: Solumedrol tapered down as 500mg (D1), 250mg (D2), 125mg (D3) switched to prednisolone as 60mg (D4) ->20 mg (D7). Then prednisolone was given as: 10-30mg (M1) -> 10-20 mg (M2) -> 5-10 mg thereafter
  • 27. Intervention Protocol II
    • Additional Immuno-suppression :
      • Neoral 10mg/kgr/day within 24hrs post TxP, adjusted to achieve the C2 target by day 3.
      • C2 targets for Neoral:
        • 1700 (1500 – 2000 ng/ml) during M1
        • 1500 (1300 – 1700 ng/ml) during M2
        • 1300 (1100 – 1500 ng/ml) during M3
        • 1100 ( 900 – 1300 ng/ml) during M4-6
        • 900 ( 800 – 1000 ng/ml) after M6
  • 28. Intervention Protocol III
    • Additional Immuno-suppression :
      • Myfortic 720-1440 pre transplant, followed by 720 mg po bid indefinitely
      • Basiliximab (Simulect) 20 mg IV D1 and D4
    • Acute Rejection Regimen:
      • SM 500-1000mg/d x 1-3 d
      • Conversion to CS was recommended for patients who rejected on SF/SW arms
    • OI prophylaxis:
      • PCP left to centers
      • CMV > 3 mos (except (-) to (-) )
  • 29. Outcome Measures
    • eGFR at 12 months by the Nankivelli formula (PO1)
    • Composite outcome of death, graft loss OR Biopsy Proven AR (BPAR) at M3 and M12 (SO1)
    • Cumulative incidence of patient and graft survival at M12 (SO2)
    • Cumulative incidence of BPAR at M3 and M12 (SO3)
    • % of pts steroid free at M12 (SO4)
  • 30. Safety Outcome Measures
    • Incidence of steroid related complications: HTN, absolute lipid levels (LDL-C, HDL, TC), blood sugar levels
    • Osteoporosis inferred from BMD measured at 2 anatomic sites and expressed as % change from baseline (M3-M8) relative to M12
    • % Change in proximal femur BMD from baseline to M12
  • 31. Evaluation
    • Baseline, D1,3,5,8 W2, M1,3,6,9,12 : CBC, BMP, UA, HbA1c, VS, “adverse events”, “serious adverse events”
    • GFR calculations : Used the Nankivelli except for dead patients or patients who have lost their grafts in whom the GFR was set to zero
    • “ Observed – case analyses” : excluded patients who have died or were back on RRT
    • Staging of suspected rejection episodes used the Banf97 classification system
  • 32. Statistical Methods
    • ITT population : all patients who were randomized, received a kidney transplant and a single dose of Myfortic
    • Safety population: all patients who have received at least one dose of Myfortic and had undergone one safety evaluation
    • Interim analysis: M3 to assess SO1-3
    • Study was powered at 80% level to detect non-inferiority in eGFR (assuming a sd of 15 ml/min for the eGFR in the CS arm
    • Non-inferiority outcome : Δ eGFR ≤ 7ml/min/1.73 m 2 BSA
    • Study was powered to detect a 3% Δ BMD on lumbar spine by a t-test assuming a sd of 5.745%
    • Kaplan – Meier curves were used to assess discrete outcomes
    • KM curves were compared by the log-rank test (emphasizes late differences in survival curves) with p=0.05  significant
    • Comparison of eGFR among groups used the Wilcoxon rank sum test
    • Multiple comparisons adjustment for the interim analysis used the Benjamini-Hochberg procedure
  • 33. Results I Delayed Graft Function: 26 (SF), 26 (SW), 23 (CS)
  • 34. Results II
  • 35. Results III
    • At 12 months: 65 ( 89% ) of the SF and 82 ( 71% ) of the patients randomized to SW were steroid free. 13 pts ( 12% ) in the CS were steroid free in violation of the protocol.
    • Among the patients receiving steroids at M12 the mean dose were 11.5 ± 11.3 (SF), 12.6 ± 10.7 (SW) and 7.1 ± 4.2 (CS)
    • There was no difference in mean Myfortic dose or need to reduce the dose
  • 36. Results IV Non – inferiority could not be demonstrated in the ITT analysis In the observed case analysis, the primary non-inferiority point was met for the SF and SW arms
  • 37. Results V
  • 38. Results VI
    • BPAR occurred significantly earlier in the SF (p=0.003) and the SW group (p =0.03)
    • [email_address] : SF group (n=31, 27.9% p=0.002) , SW (n=25, 21.7%, p=0.032) versus the CS (n =12, 11%)
    • [email_address] : SF (n=28, 25.2%, p<0.001) , SW (n=21, 18.3%, p=0.017) versus the SF (n=8, 7.3%)
  • 39. Results VII
    • Significantly fewer biopsies were performed in the CS (n=130) versus the SF (n=189) and SW groups (n=209), p <0.001
    • The median number of days to first BPAR was: 14 (SF), 53 (SW) and 104 (CS) p=0.003 and 0.022 respectively
    • In the SF group (but not the others) BPAR rejections in the first months were associated with low C2 levels: 15/60 (C2 <1500ng/ml) vs 3/40 (C2>1500ng/ml)
  • 40. Results VIII
  • 41. Summary & Conclusions
    • The authors conclusions:
      • Steroid withdrawal and steroid free ISP are non-inferior to CS in terms of the primary outcome of the study (“observed-case analysis”)
      • AR rates were increased relative to CS protocols but these rejections were mild and unlikely to impair long term outcomes
      • Statistical significant reductions in steroid related metabolic effects were observed when steroid exposure was limited
  • 42. Strengths & Limitations
    • Extremely well designed study with a well specified immunosuppression management protocol
    • Immunologically low risk patients
    • Crossovers between the SF/SW and CS arms
    • Open label study which introduced biases in the rate of biopsies (?protocol biopsies as a remedy)
    • “ ITT” analysis with “AT” allows one to draw meaningful conclusions about the safety and the effectiveness of the protocol

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