We have recently reported a meta-analysis of steroid avoidance/withdrawal (SAW) regimens following renal transplantation (1). Although this analysis demonstrated a significantly increased risk of acute rejection with SAW (relative risk [RR] 1.56, P<0.001), there was no apparent detriment to graft or patient survival. This risk was offset by a reduction in cardiovascular risk factors in the SAW group, with hypertension (RR 0.90, P<0.0001), hypercholesterolemia (RR 0.76, P<0.0001), and new-onset diabetes (RR 0.64, P=0.0006) all reduced in incidence.
This meta-analysis included a large number of studies reported over a long period of time, and it has been suggested that the potential benefits of SAW may be reduced when lower-dose maintenance steroids are used, as seen in many more recent immunosuppressive regimens. To address this issue, we have reanalyzed the data from our previous meta-analysis using a mixed-effects model, incorporating maintenance steroid dose as a linear moderator variable. Analysis was performed using the “metafor” package in the R statistical language. Statistical analysis within the model determined whether there was a significant interaction between maintenance steroid dose and reported outcomes (i.e., does the effect size seen vary with the steroid dose used). Significance level for interaction was set at 95%. There was some variability in the reporting of steroid dose in the maintenance arm. Where available, the actual dose was used, otherwise the mean dose administered in the maintenance arm was used. Studies only reporting the dose per kilogram body weight were excluded.
Twenty-seven of the 34 studies included in the original meta-analysis reported the steroid dose used in the maintenance arm. The remaining studies are excluded from this analysis.
There was no significant interaction between steroid maintenance dose and the risk of acute rejection, graft function, or hazard for graft loss or patient death. Significant interaction was seen between maintenance steroid dose and the risk of hypercholesterolemia, with a larger reduction in RR seen when larger steroid maintenance doses were withdrawn (slope −0.07/mg, P=0.04; Fig. 1A). A similar effect was seen with the risk of new onset diabetes mellitus (slope −0.15/mg, P=0.01; Fig. 1B).
No significant interaction was seen between maintenance dose and serum cholesterol value (slope −0.06/mg, P=0.16) and risk of hypertension (slope 0.09/mg, P=0.46). There was an interaction between dose and serum triglyceride level, with higher doses associated with smaller benefit (slope 0.09/mg, P=0.02).
This exploratory, post hoc analysis of meta-analysis data suggests a possible interaction between maintenance steroid dose and the potential benefits of SAW regimens. Although there is no interaction between maintenance steroid dose and the increased risk of acute rejection after withdrawal, the beneficial effects of SAW on the risk of hypercholesterolemia and new-onset diabetes seem to be reduced when lower steroid maintenance doses are used. This study has limitations due to the post hoc nature of the analysis and the reliance on often poorly reported steroid dose data. These findings would need to be confirmed in a prospective randomized controlled trial before firm conclusions can be made about the potential benefits of steroid withdrawal in patients on low doses of steroids (e.g., 5 mg/day or less).
Simon R. Knight
Peter J. Morris
Centre for Evidence in Transplantation
Clinical Effectiveness Unit
Royal College of Surgeons of England
London, United Kingdom
London School of Hygiene and Tropical Medicine
University of London
London, United Kingdom
1. Knight SR, Morris PJ. Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk. A meta-analysis Transplantation
2010; 89: 1.