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In our studies to date, we have used patient and graft survival as the main end point. Although it is true that ultimately these measures are the most important, daily serum creatinine values obtained in the first month after transplantation may be a helpful indicator of long term function as will be shown here. They should also be of importance in measuring the effectiveness of various protocols of immunosuppression.
We attempt in this chapter to utilize early function data from a small subset of patients gathered from five different centers. As a trial, data was gathered, computer programs written, and cyclosporin dosages and levels were examined.
Detailed daily data was collected for the first 60 days after transplantation from 539 patients at five centers for this trial. The patient population was selected as much as possible from transplants which were performed consecutively within a center and during the same time period (1981-1985) between centers so as to obtain a representative sample of most transplants being performed. The centers that participated in this trial were the University of Texas at Houston; University of Minnesota; University of California, San Francisco; University of Pittsburgh; and the University of Southern California. For this initial analysis the serum creatinine, cyclosporin serum levels, and cyclosporin, prednisone, Imuran, Solu-Medrol and ATG/ALG dosages were used. By cross-referencing these data with the transplant registry file, studies on patient survival and matching were done. Rejection episodes were either indicated by the centers or retrospectively assigned on the basis of an increase in serum creatinine, use of Solu-Medrol, recycling of prednisone, use of ATG, increased cyclosporin dosage and biopsy results. Cases with questionable rejections were excluded from this portion of the study.
The results are presented in the following figures and legends.
The trial described here suggests that a great deal could be learned from multicenter analyses of daily data. Different immunosuppression protocols can be examined in detail and compared. We describe here only the simple first level analysis.
Even with these simple analyses, we were quite interested to see that, for example, serum creatinine values on the fifth day post transplant already distinguish between transplants from HLA-identical sibling donors, parental donors, and cadaver donors. The histocompatibility influence in transplants can be concluded to occur within five days after transplantation if these results are confirmed in larger numbers of patients. With the small numbers available for analysis, even HLA-A,B,DR matching in cadaver donor transplants seems to have an early effect on the serum creatinine levels.
A clear association with serum creatinine levels during the first month after transplantation and eventual outcome of transplants has been presented (Fig. 4). For example, two weeks after transplantation, if the serum creatinine is less than 2.4 mg/dl the one year survival rate was more than 80% whereas if it was more than 7.5 mg/dl, the one year transplant survival rate was under 30%. Intermediate serum creatinine levels led to intermediate graft survival rates. Even one week after transplantation, there was already about a 30% one year graft survival rate difference between kidneys that had serum creatinine levels less than 2.4 mg/dl and more than 7.5 mg/dl.
It is interesting to see that the average serum creatinine within the first 30 days was different at different centers (Fig. 11). This can indicate the difference in quality of preservation or types of donors utilized for transplant as well as differences in early immunosuppression regimens. Within the four centers in the original trial, the average serum creatinine levels had reached similar levels in all four centers by 30 days. Use of higher cyclosporin dosages at one center (Fig. 14) did not result in lower creatinine values at that center or higher long-term graft survival rates. Obviously other factors must be taken into account.
When comparing between related donor transplants and cadaver donor grafts, total daily cyclosporin dosage was less for the living-related transplants. In spite of the reduced cyclosporin dosage, the serum creatinine levels dropped to lower values in living-related donor grafts.
There are many opinions on the value of cyclosporin levels. Retrospective analysis of the levels in relation to rejections showed that those patients without rejections tended to have slightly higher cyclosporin levels. Further analysis will be needed to take into account other factors.
We hoped by these studies to show the potential of using daily data gathered from many centers. Much of the problem rests in data entry, manipulation and analysis, which of course must be done with computers. Other analysis has been performed by Mickey (1) and new programs for analysis are being developed.