KDIGO (page S6 of PDF) and the UK renal association have recently published guidelines for the clinical care of kidney transplant recipients. Both of these documents suggest that recipients at ‘higher immunological risk’ should be considered for induction therapy with lymphocyte depleting antibodies (LDAs) such as anti-thymoctye globulin (ATG,) anti-lymphocyte globulin (ALG) and anti-T cell (CD3) antibody (OKT3). The US scientific registry of transplant recipients (SRTR) annual report for 2008 states that 44.8% of patients received ATG as induction therapy in that year. As a nephrologist practicing in the UK, I find this surprising. None of the 3 major transplantation centres I have worked at have used LDAs for induction under any circumstances and I have found only a single unit using the drug for induction in the UK; and then only in recipients receiving non-hearting beating kidneys.
This is an intriguing discrepancy and seems to invite the question; which side of the Atlantic is right? I think the question has two parts:
- Are LDAs and IL-2 receptor antibodies, the other main class of induction agents (IL2-RAs; such as basiliximab and daclizumab), of comparable efficacy and safety?
- What data justifies preferential use of LDAs in high immunological risk patients as recommended in the guidelines?
A reasonable body of evidence addresses the first question and was summarised in a recent Cochrane review. With regards to efficacy, patients induced with ATG as compared to IL2-RAs showed less episodes of biopsy-proven rejection at one year but no benefit to rates of graft loss or clinically diagnosed or steroid-resistant rejection. Concerning safety, the review found significant reductions in CMV disease and malignancy when IL2-RAs were used over LDAs. The authors derived a number needed to treat of 16 to avoid one case of CMV disease and of 58 to prevent one case of cancer.
The evidence base for question 2 has been accumulating since at least 1998 when a meta-analysis showed that LDA induction mediated reduction in graft loss (compared to placebo) was greater in patients with high panel-reactive antibody. Since then, two recent high-quality randomised controlled trials (Brennan et al. and Noel et al.) have been performed specifically in high risk recipients. The trials addressed diverse patient populations and used different IL2-RAs and maintenance regimes but produced similar findings of significant reductions in rejection rates at one year without differences in graft or patient survival (although Brennan et al. used a composite end point).
So, the recommendations about the use of ATG in high-risk patients are based on decreased rates of rejection. However, decreased rejection has not translated into increased graft survival in a number of studies looking at ATG vs IL2-RAs (summarised in this editorial).
Having looked through the evidence I feel that almost 45% ATG induction is too high, and the UK’s avoidance of ATG probably unwise too. I think the next challenge would be to produce an evidence based decision algorithm for assigning patients into high and low risk groups. Anybody else have any thoughts?
Tom Oates, MD