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BACKGROUND: Renal transplant rejection cannot be diagnosed with certainty by non-invasive techniques. These techniques lack the specificity to differentiate rejection from other causes of renal dysfunction such as ATN and calcineuria toxicity. Since rejection involves lymphocytes, which the other courses of dysfunction do not, radiolabeling lymphocytes is an attractive technique to diagnose rejection non-invasively. MATERIAL/METHODS: We report our experience with this technique in a pig model of renal transplantation. We studied two groups of pigs, one with renal autografts and the other with allografts. We optimized radiolabeling of lymphocytes and also the technology for detection of these lymphocytes. The uptake of the radiolabeled lymphocyte was compared between the two groups by surface detection and, at the end of the experiment, with scintigraphy of renal tissues. RESULTS: Despite adequate labeling and viability of lymphocytes, only 1-2% of injected lymphocytes 'homed' to the renal grafts. Furthermore, although the detection technology was optimized, a poor signal to noise ratio interfered with the detection of the labeled lymphocytes. Due to these problems rejection could not be differentiated from ATN in this model. CONCLUSIONS: We conclude that increasing the specific activity of the lymphocytes and improving the signal to noise ratio will enhance the specificity and sensitivity of this technique and facilitate non-invasive diagnosis of rejection.