What is the Best Induction Immunosuppression Regimen in Kidney Transplantation? Richard Borrows: Queen Elizabeth Hospital Birmingham

SYMPHONY Study Ekberg et al. NEJM 2008

Excluded: DCD kidneys; CIT>30hours; PRA>20%; positive cross match; retransplantwhere 1 st graft lost to AR within first year All received MMF and steroid Basiliximab to all except standard dose Cyclosporine

SYMPHONY Study: Acute Rejection

SYMPHONY Study

SYMPHONY Study Anti CD25 mab Tacrolimus MMF Steroid

Alternative Induction Agents Alternative CNI or CNI avoidance MMF or AZA? Steroids or Steroid Avoidance?

1. Induction or no induction and which agent?

Anti CD25 mab induction meta analysis: acute rejection Adu et al. BMJ 2003

Anti CD25 mabinduction meta analysis: Graft Failure Adu et al. BMJ 2003

Another Anti CD25 mab induction meta analysis: 24 Studies Anti CD25mAb versus Placebo Death Censored Graft Failure at 1 year (24 studies) Reduced Overall Graft failure Reduced Death No difference Webster AC et al. Transplantation 2004; Webster AC et al. Cochrane Review 2010

Another Anti CD25 mab induction meta analysis: 24 Studies Anti CD25mAb versus Placebo Death Censored Graft Failure at 1 year (24 studies) Reduced Overall Graft failure Reduced Death No difference BPAR within 1 st year Reduced Malignancy within 6 months CMV disease within 1 st year Decreased Decreased Webster AC et al. Transplantation 2004; Webster AC et al. Cochrane Review 2010

Is there a further advantage with ALG induction over anti CD25 mab: meta analysis ALG versus Anti CD25mAb in allcomers BPAR within 1 st year 30% reduction Death Censored Graft Failure No difference Overall Graft failure No difference Death No difference Malignancy Increased CMV disease within 1 st year Increased Webster AC et al. Transplantation 2004; Webster AC et al. Cochrane Review 2010

Anti CD25 versus ALG in High Immune Risk Settings: Noel et al. JASN 2009 Current PRA>30% Peak PRA>50% 2 nd Transplant with 1 st lost to Acute Rejection 3 rd or 4 th Transplant (Cytotoxic cross match negative) Thymoglobulin versus Daclizumab Tacrolimus MMF Steroid

Anti CD25 versus ALG in High Immune Risk Settings: Noel et al. JASN 2009

Anti CD25 mabinduction meta analysis: Do we need it in low immune risk settings Anti CD25mAb versus placebo (11 studies) BPAR within 1 st year 32% reduction Death Censored Graft Failure No difference Overall Graft failure No difference Death No difference Malignancy No difference CMV disease within 1 st year No difference Webster AC et al. Cochrane Review 2010

Alemtuzumab( Campath ; anti CD52 mab) Morgan et al. Transplantation 2012

Alemtuzumab( Campath ) Morgan et al. Transplantation 2012

INTAC Study Hanawayet al. NEJM 2011

INTAC Study Excluded: ECD and DCD kidneys; CIT>36 hours; positive cross match; fully matched live donor First Transplant and Peak or Current PRA<20% and Not Black Race Not low risk!

INTAC Study Rejection Graft Failure Death

INTAC Study: Adverse Events

INTAC Study

INTAC Study Increased rates of late biopsyproven acute rejection: 8% vs 2% (p=0.03)

INTAC Study: Lymphocyte repopulation

Alemtuzumab compared with alternative contemporary induction regimens LaMattina et al. Transplant International 2012 UW experience 2002-2007 Campath(n=632; 2002-4) Basiliximab(n=690; low risk ) ATG (n=125; high risk ) Campath vs Other Overall Graft Survival Decreased 1 st Deceased Donor Graft Survival Decreased Repeat Deceased Donor Graft Survival Decreased 1 st Live Donor Graft Survival Decreased Antibody Associated Rejection Increased Overall Infection Increased CMV infection Increased Death due to Infection Increased Patient Survival Same

Rituximab(anti CD20 mab) Rituximab versus Daclizumab Tacrolimus; MMF; Induction MP only Clatworthy. NEJM 2009

Rituximab(anti CD20) Rituximab versus Placebo Tacrolimus; MMF; Steroid Transplantation 2009

2. Choice of CNI Tacrolimus versus Ciclosporin

Tacrolimus versus Ciclosporin meta analysis: Acute rejection Webster et al. BMJ 2005

Tacrolimus versus Ciclosporin meta analysis: Death censored graft failure

Tacrolimus versus Ciclosporin meta analysis: Death censored graft failure Meta-regression p=0.04

SYMPHONY Study

SYMPHONY Study vs vs

3. Can we avoid CNIsaltogether de novo?

CNI versus mtori meta analysis: Overall graft failure Sharif et al JASN 2011

CNI versus new agents meta analysis: Overall graft failure CP 690,550 Tazocitinib Belatacept Tofacitinib Sharif et al JASN 2011

4. Alternative adjunctive antimetabolites Azathioprine versus Mycophenolate

Meta analysis: Mycophenolate versus Azathioprine 3143 patients 19 studies CNI: Neoral or Tacrolimus MMF versus Azathioprine Transplantation 2009 MMF vs Azathioprine Acute Rejection Decreased (0.62[95%CI: 0.55-0.87]) Overall Graft Failure Decreased (0.76[95%CI: 0.59-0.98]) Mortality No difference Transplant Function No difference Infection No difference CMV No difference Anaemia No difference Leucopaemia No difference Malignancy No difference Diarrhoea Increased

5. Steroid avoidance

Steroid avoidance or withdrawal: a meta analysis 34 RCTs (n=5637 patients) Knight and Morris. Transplantation 2010 Acute Rejection

However... Hypercholesterolaemia NODAT

N=397 Exclusions Rejection or dialysis in first 7 days; n=5 (five!) Current PRA>25% CIT>36 hours 55% live donor Ann Surgery 2008

Early corticosteroid withdrawal (Day 7) versus 5mg prednisolone maintainance Woodleet al. Ann Surgery 2008 Biopsy confirmed Moderate/Severe Acute Rejection Graft Failure Death No difference No difference No difference

Metabolic complications through 5 years

Metabolic complications through 5 years Hypolipidaemic Agent commencement and ongoing therapy Lower (50% vs 67%; p=0.04) NODAT No difference (21.5 vs 21%) Insulin requirement Lower (3.7 vs 11.6%; p=0.05) Bone Complications Lower (5% vs 11%; p=0.04) Cataract No difference Weight Gain (median) Less (5.1 vs 7.7kg)

Acute rejection Biopsy confirmed Rejection For cause Biopsies Biopsiesshowing Chronic Allograft Nephropathy Increased Increased Increased Risk Factors for Graft Loss Acute Rejection RR: 5.0; 95% CI: 1.7-15; p=0.003 CAN RR: 41; 95% CI: 12-135; p<0.001

In Summary

So what is the best induction immunosuppression regimen? 1] Anti CD25 mab induction reduces rejection and graft failure 2] ATG and Campath further reduce rejection but not graft failure, and an increase in toxicity 3] The spectre of late rejection and antibody-associated rejection remains with Campath 4] Further data on Rituximab required 5] Tacrolimus reduces rejection compared with Ciclosporin 6] This may not translate into a clinically relevant reduction in graft survival in low dose setting 7] CNI avoidance with mtori is fraught 8] Newer Agents improve graft survival and may herald breakthrough of true CNI avoidance 9] MMF reduces rejection and graft failure compared with Azathioprine 10] Steroid avoidance is associated with increased rates of rejection 11] Metabolic complications of 5mg prednisolone are slight / manageable