Reply to Dr. Oz et al.
The suggestion by Dr. Oz and colleagues (1) that mycophenolate mofetil (MMF) prevents Pneumocystiscarinii infection echoes the intriguing finding in the U.S. Renal Transplant Study in which none of the 335 patients receiving MMF developed P. carinii pneumonitis (PCP) (2). However the incidence of PCP in the control arm of this and other control trials was so low that even a meta-analysis of 1493 patients failed to show a statistically significant benefit (3).
The dose of sirolimus tested by Dr. Oz (4 mg/kg) was very high, with a mortality rate of 30% of treated rats. Early animal studies suggested that doses between 0.16 and 1.5 mg/kg prevent allograft rejection and graft-versus-host disease in the rat (4,5). Nonetheless only 29% of the surviving rats in Dr. Oz’s study became “mildly infected with PCP.” This represents a reduction by 70% of infection seen with steroids or calcineurin inhibition in this model. The authors imply that the severity of infection was also reduced. Despite this observation, our patients seemed to be at risk of opportunistic infection when converting from calcineurin inhibitors to sirolimus, and we continue to recommend prophylaxis against PCP (6).
The protective effect of MMF is based on rats that received dexamethasone in their drinking water, but because the animals lost 35% of their body weight, all the steroid may not have been absorbed. We believe that caution must be used when interpreting data from animal models in the clinical context. Bioavailability and effect of immunosuppressants vary between the species and within species. Monitoring of drug levels and standardization of efficacy (such as the minimum level to prevent heterotopic heart allograft rejection) of each comparator are necessary. However, studies focusing on the toxicity of immunosuppression are important.
V. C. McAlister
A. S. MacDonald
1. Oz HS, Hughes WT. Novel anti-Pneumocystis carinii
effects of the immunosuppressant mycophenolate mofetil in contrast to provocative effects of tacrolimus, sirolimus and dexamethasone. J Infect Dis 1997; 175: 901.
2. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60: 225.
3. Halloran P, Mathew T, Tomlanovich S, et al. Mycophenolate mofetil in renal allograft recipients. Transplantation 1997; 63: 39.
4. Meiser BM, Billingham ML, Morris RL. Effects of cyclosporine, FK506, and rapamycin on graft vessel disease. Lancet 1991; 338: 1297.
5. Stepkowski SM, Chen H, Daloze P, Kahan BD. Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney and small bowel transplantation in the rat. Transplantation 1991; 51: 22.
6. Dominguez J, Mahalati K, Kiberd B, McAlister VC, MacDonald AS. Conversion to rapamycin (sirolimus) immunosuppression in renal transplant recipients: report of an initial experience. Transplantation 2000; 70: 1244.