Controversies in Steroid Withdrawal

1
Controversies in Steroid Withdrawal

• Donald E. Hricik, MD
• University Hospitals
• Case Medical Center
• Cleveland, Ohio

2
Steroid-Sparing Protocols in the Modern Era

• Improving outcomes lower rates of acute
  rejection
• Uncontrolled vs randomized, controlled trials
• Paradigm shift toward earlier withdrawal or
  avoidance of steroids
• Importance of induction therapy
• Re-examination of the benefits

3
Steroid Sparing After Renal Transplantation

• Putative Benefits
• Improvements in hypertension
• Decreased lipid levels
• Improvements in glucose tolerance
• Accelerated growth
• Decreased incidence/severity of osteopenia
• Decreased cataracts
• Risks
• Acute and chronic allograft rejection

4
European Steroid-Withdrawal Trial With MMF and CsA
Incidence of Acute Rejection at Six and Twelve
Months
P 0.008
Patients with Rejection ()
Vanrenterghem Y et al. Transplantation.
2000701352-1359.
5
Canadian Multicenter Trial
Results at Five Years
P 0.60
P 0.03
Sinclair NR. CMAJ. 1992147645-657.
6
Immunosuppression Withdrawal in Renal
Transplantation

• A meta-analysis of immunosuppression withdrawal
  trials in renal transplantation
• 10 prednisone withdrawal trials
• 8 CsA/Azathioprine
• 2 CsA/MMF
• RR of acute rejection 1.14 (plt0.001)
• RR of graft failure 1.38 (p0.014)

Kasiske BL, et al. J Am Soc Nephrol 2000111910.
7
Steroid-Free Immunosuppression

• The Traditional Paradigm
• Steroid Avoidance
• Greatest benefits
• Highest risk for acute rejection
• Steroid Withdrawal (early within 1 month late
  after 3 months)
• Diminishing benefits
• Lower risk of acute rejection

8
Early Steroid Withdrawal

• 59 primary kidney transplant recipients
  randomized to steroids vs steroid withdrawal at 2
  weeks
• ALG, CsA, AZA
• Acute rejection
• 54 in steroid-treated patients
• 81 in steroid-free patients (58 required OKT3)

Schulak JA, et al. Transplantation 199049327
9
Late Steroid Withdrawal

• 1015 deceased donor kidney transplants (Europe)
• Concurrent controls (not randomized) chosen
  with equal or better renal function
• 7-year follow-up
• Equal rates of AR (10) superior patient and
  graft survival in steroid withdrawal group
• Patients withdrawn from steroids had more steroid
  side effects than the control group
• 40 of withdrawn patients returned to steroids

Opelz G, et al. Am J. Transplant 2005 5720
10
Early Steroid Withdrawal

• Thymoglobulin, MMF/Sirolimus, CsA/Tacrolimus,
  Prednisone x 5 days
• 394 patients (87 Caucasian)
• 3-year follow-up
• Acute rejection-free graft survival 92 at 3
  years
• Uncontrolled
• University of Minnesota

Khwaja et al. Am J. Transplant 20044980
11
Rationale For Steroid Avoidance or Early Steroid
Withdrawal

• Maximize benefits
• Avoid antitolerogenic effects of steroids
• Anti-apoptotic
• Upregulation of cytokine receptors

12
Steroid Avoidance or Early Withdrawal using
MMF/CsA
13
Steroid Avoidance or Early Withdrawal With
Tacrolimus/MMF
14
Immunosuppression Withdrawal in Renal
Transplantation

• 6 prednisone withdrawal trials
• 4 CsA/MMF
• 2 Tacrolimus/MMF
• RR of acute rejection 2.28 (plt0.00001)
• RR of graft failure 0.73 (NS)

Pascual J, et al. Transplantation 2004781548
15
Freedom Trial 12 Month Rejection Rates

• Basiliximab, Myfortic, Neoral (C2 monitoring),
  steroids (BPAR 14.7)
• Basiliximab, Myfortic, Neoral, early steroid
  withdrawal (7 days) (BPAR 26.1)
• Basiliximab, Myfortic, Neoral, steroid avoidance
  (BPAR 31.5)
• (n335)

WTC 2006. Abstract 54
16
Astellas Steroid Withdrawal Study Group
Prospective, Double-Blind, Stratified
Randomized PTD 3-7, SCr 30 No HD N 386
Steroid Maintenance (CCS) N 195
Steroid Withdrawal (CSWD) 7 Days N 191

• Stratification
• Live vs. deceased donor
• AA vs. non-AA

17
Immunosuppression

• Induction
• rATG 1.5 mg/kg/day PTD 0, 2, 4, 6
• IL-2R Antibody per package insert
• Tacrolimus
• 0.15 - 0.2 mg/kg/day within 72 hours
  post-transplant
• Target 10-20 ng/ml PTD 1-90
• Target 5-15 ng/ml PTD gt90
• MMF
• 1000 mg IV/PO pre-op
• 2000 mg/day IV or 3000 mg/day po PTD 1, 2
• 3000 mg/day PTD 3-14
• 2000 mg/day PTD gt14

18
Corticosteroid Dosing gt Day 7

• Long-term steroids
• PTD 8-14 0.4 mg/kg/d
• PTD 15-29 0.3 mg/kg/d
• PTD 30-89 0.2 mg/kg/d
• PTD 90-119 0.15 mg/kg/d
• PTD 120-180 0.1 mg/kg/d
• PTD gt180 5 mg/d
• Corticosteroid cessation
• PTD gt7 placebo

19
Primary Endpoint Death, Graft Loss, or Severe
Rejection
100
Probability ()
92.0
p 0.746
90
88.9
CCS
CSWD
80
0
1
2
Years Post-Transplant
20
Summary of Rejection at Month 24
Based on Fishers Exact test Severe ACR is
Banff 95 2B or greater, or Banffs 97 2A or
greater or antibody treated rejection
21
Rapamune Early Corticosteroid Cessation Study
Group

• 77 low-risk patients single-arm, multicenter
• Induction with basiliximab
• Tacrolimus (target 6-9 ng/ml) and sirolimus (8-15
  ng/ml) Steroids x 5 days
• 26 deceased donor
• 79 Caucasian African Americans excluded
• 1 year follow-up
• Overall biopsy-proven AR rate 13
• 100 patient and graft survival

Woodle ES et al. Am J Transplant 20055157-166.
22
US Steroid-Withdrawal Trial With MMF and CsA
Withdrawal / Blacks Withdrawal /
Non-black Maintenance / Blacks Maintenance /
Non-black
0.6
0.5
0.4
CumulativeIncidence of Acute Rejection
0.3
0.2
0.1
0.0
3
6
9
12
15
Months Posttransplantation
Ahsan N et al. Transplantation. 1999681865-1874.
23
Steroid Withdrawal in African Americans

• African Americans receiving sirolimus/tacrolimus
  (without induction antibody therapy)
• 30 patients withdrawn from prednisone (follow-up
  off prednisone 3-26 mos, mean 14.4 7 mos)
• 2 of 30 patients (6.7) with acute rejection.
• 1 biopsy-proven, grade 2B, OKT3
• 1 non-biopsy-proven gross noncompliance
• 27 of 30 patients (90) remain off prednisone at
  last follow-up
• Prednisone renewed in 1 patient with HUS 12
  months posttransplant.

Hricik et al. Transplantation 200376938.
24
Outcomes After 4 Years

• 15/34 patients (44) remain steroid-free
• Prednisone renewed 6 to 48 months after
  withdrawal (mean 2912 months)
• HUS (n1)
• ? Recurrent FSGS (n2)
• Acute rejection (n11) 5 cases biopsy-proven
  (32 incidence)
• Chronic allograft nephropathy (n6) 3 cases
  biopsy-proven
• Graft loss in 8/34 patients (23) including 2
  deaths with functioning grafts
• Sudden death, sepsis

25
Early Steroid Withdrawal in African Americans
3-Year Follow-up
Woodle ES at al. WTC 2006.Abstract 325.
26
Steroid Withdrawal 2 Years After Transplantation
12
10
8
6
4
Living
2
Deceased
All
0
1999
2000
2001
2002
2003
Meier-Kriesche et al. Am J Transplant.
200661111-1131
27
Steroid Avoidance
No Steroids at Discharge after Transplantation
30
25
20
15
10
Living
5
Deceased
0
All
1999
2000
2001
2002
2003
2004
Meier-Kriesche et al. Am J Transplant.
200661111-1131
28
Steroid-free ImmunosuppressionReexamining the
Benefits
29
Steroids Low-dose Versus No-dose

• Improvements in weight, BP, glycosylated
  hemoglobin when prednisone reduced from 17.5 mg
  to 10 mg/day1
• No further improvements with lower doses
• Improvements in insulin resistance when
  prednisolone reduced to 5 mg/day2
• No further improvements with elimination

1. Sivarman P et al. Am J Kidney Dis
2001371162. 2. Midtvedt K et al. J Am Soc
Nephrol 2004153233.
30
Hypertension Month 24
31
Hyperlipidemia Month 24
Based on Wilcoxon Rank-sum test mean values
32
NODAT During 24 Months
NODATnew-onset diabetes after
transplant Based on Chi-Square test ADA
criteria
33
Does Steroid Sparing Prevent Bone Loss?

• No benefit of steroid avoidance
• CG ter Meulen et al. Transplantation 2004 78101
• CE Chamberlain et al (Bethesda) ATC 2004
• No benefit of steroid reduction (10 mg to 5 mg
  daily)
• D Willingham et al (Jacksonville) ATC 2004

34
Do Steroids Protect Against CI Nephrotoxicity?

• Salt-depleted rats
• Stillman IE et al. Exp Nephrol 1997561
• University of Wisconsin
• 133 HLA-identical kidney transplant recipients
• 58 returned to steroids, most often because of
  CI toxicity
• University of Buffalo (Laftavi M, et al)
• 35 early SW vs 34 steroid-treated controls
  (Thymo,FK,MMF)
• Protocol biopsies 1, 6, 12 months
• CI toxicity 10 SW vs 3 steroid-treated
• Gaber AO, et al (WTC abstract 330) CAN in 16 SW
  patients vs 7 patients on steroids (p0.05)

35
Current Status of Steroid-Free Immunosuppression

• Acute rejection rates in recent steroid
  withdrawal protocols approaching acceptable
  levels, at least in low-risk patients
• Increasingly steroid-free protocols accepted as
  the standard of practice
• Best results in patients receiving induction
  therapy
• Most recent studies with newer immunosuppressants
  are either uncontrolled studies or lack long-term
  follow-up
• Benefits warrant scrutiny not clear if complete
  elimination of steroids offers benefits over low
  doses