Our data shows that there is no increase in patient death or donor graft loss when SRL is used as primary therapy or when patients are converted to SRL following therapy with other immunosuppressants. Further, we have no evidence that suggests SRL has deleterious effects upon renal function. In contrast, our data suggests that primary therapy with SRL, but not conversion to SRL, reduced the incidence of acute and steroid resistant rejection in transplant recipients. This may be an effect of increased immunosuppression.
Sirolimus has been widely used in renal transplantation but is not currently approved for use in liver transplantation. There are reports that SRL has negative effects on outcome including HAT, delayed wound healing, and increased mortality compared to standard immunotherapy [14
]. Our center has used SRL therapy after liver transplantation at a number of different time points. Few other centers have this large experience using SRL in liver transplantation coupled with a nearly complete data set. Data from our previous publications did not support claims that the use of SRL is associated with negative outcomes [1
]. Rather, our previous data suggested that mTor inhibitors are safe when used as single therapy or in addition to CNI after liver transplant. We observed this when SRL was used as a primary immunotherapy or if SRL was added later.
We administered SRL to patients in two regiments: we gave SRL immediately after liver transplant or added/substituted SRL within the first year following transplantation. There was a range of reasons for different combinations of therapies over the first year mostly from evolving protocols. The Conversion and Primary Treatment Groups represents a more heterogeneous collection of immunotherapies and must be interpreted with caution. However, comparison between the categories of patients within both groups did not show significant differences. We did not find differences between patient and/or donor graft survival between our patients who received SRL compared to those who received CNI + MPS. Similarly, there were no differences in patient and graft outcome that were related to whether SRL was primary or conversion therapy.
Our secondary measures of outcome were graft rejection. Patients that received SRL as primary immunosuppression, defined as SRL administered before discharge from the hospital after liver transplant, had less ACR and SRR rejection. This was true for patients that stayed on SRL for one year and for patients that stopped using SRL before one year. This finding was statistically significant, and the rates of rejection were 50% less than the control of CNI + MPS.
Finally, we reviewed our data to see if there is a difference in renal function when SRL is used. It is well understood that CNI can cause progressive kidney injury. SRL has been used to reduce the level of CNI, thus, protecting the kidney [5
]. Our data did not support this theory. All five groups had a reduction in GFR after transplant. We believe there are two reasons why our study does not support previous publications. First, since some patients die or are re-transplanted before 6 months or 1 year, their corresponding missing GFR values create a survival biases. Thus, the estimates of mean GFR at one year in particular may be biased because sicker patients that have a high mortality and also a greater reduction in GFR. Second, as seen in , our center keeps the Tacrolimus levels in all groups at one year less than six. Thus, the lower levels of CNI may independently ameliorate the negative effects upon renal function.
We suggest that these data be interpreted with caution. First, it is a retrospective study and the Conversion and Primary Treatment Groups contain a heterogeneous group of practices. However, this data is almost 100% complete and accurately describes our practice patterns and subsequent outcome when using SRL in a variety of combinations during the first year. Secondly, because it is retrospective and we only reviewed our practice patterns for the first year, our groups are not set up to adequately assess long-term renal outcome. Rather, we can only predict kidney function within the first year of transplantation. Finally, we do not routinely perform protocol biopsies to diagnose ACR, so we could have overestimated the actual incidence of ACR in our patient population. However, the same diagnostic criteria were applied to all categories of patients that we studied. Therefore, it is unlikely that our diagnostic approach favored the diagnosis of ACR in one category of patient compared to another.
In conclusion, our goals for this study were to determine if our use of SRL during the first year after liver transplant increased mortality or morbidity. It did not. Surprisingly, SRL use as a primary therapy decreased our rates of both ACR and SRR. Based on this review, we will continue to use SRL in liver transplant recipients. With the introduction of new mTor inhibitors, such as everolimus, improved immunosuppression combinations may be developed based on our successful use of SRL.