Differences in rejection grading after simultaneous pancreas and kidney transplantation in pigs

Clinical observations suggest that recipients of multiorgan transplants from the same donor can have disparate immunological reactions to each organ. We studied this phenomenon in 36 diabetic (streptozotocin-in-duced), bilaterally nephrectomized immunosuppressed (cyclosporine, azathioprine, prednisone) pig recipients of simultaneous (same donor) pancreas (bladder drained) and kidney allografts by grading the histological intensity of rejection in biopsies of each organ at defined intervals posttransplant. Graft function was monitored by plasma glucose (PG) and urine amylase (UA) for the pancreas and serum creatinine (Cr) for the kidney. Interstitial rejection was graded as absent, mild, moderate, and severe in, respectively, 8%, 25%, 42%, and 5% of pancreas vs. 4%, 12%, 27%, and 50% of kidney biopsies at 1 week; and 0%, 43%, 29%, and 29% of pancreases vs. 10%, 0%, 30%, and 60% of kidneys at two weeks. Although the distribution of grades was similar in the two organs (P > 0.1), the grade of rejection for each pair at 1 week (n = 24) was discordant in 75% (41% differed by one and 35% by ≥ 2 grades) and at 2 weeks (n = 7) in 57% (29% by 1 and 29% by ≥ 2 grades). The inability to use the severity of interstitial rejection in one organ to predict the findings in the other is exemplified by the fact that for the two pancreases without interstitial rejection at one week, the corresponding kidney showed moderate or severe rejection, and for the 1 kidney without rejection the corresponding pancreas showed moderate rejection. Vascular rejection grades (absent, mild, moderate, severe) also showed a similar distribution for the pancreas (57%, 30%, 9%, 4%) vs. kidney (56%, 30%, 0%, 13%) at 1 week, and at 2 weeks (57%, 29%, 0%, and 14% for the pancreas vs. 78%, 11%, 0%, and 11% for the kidney) (P≥0.64). However, the grading of vascular rejection in organ pairs was dyssynchronous in 51% at 1 week (n = 22) and 29% at 2 weeks (n = 7). No vascular rejection in the pancreas with rejection in the kidney was seen in 5 pairs at 1 week (23%) and 0 at 2 weeks (0%), while no rejection in the kidney with rejection in the pancreas was seen in 5 pairs at 1 week (23%) and 2 pairs at 2 weeks (29%). Clinical evidence of rejection at 1 week was present in 64% of kidney (creatinine > 3 mg/dl) and 32% of exo-crine pancreas (UA decreased 50%) and 0% of endocrine pancreas (PG >200 mg/dl) grafts, and at 2 weeks in 74% of kidney, 36% of exocrine, and 9% of endocrine pancreas grafts. Neither urine amylase nor plasma glucose levels correlated with interstitial biopsy rejection grades at 1 or 2 weeks (P≥0.19). Interstitial biopsy rejection grades also did not correlate with serum creatinine levels at 1 week (P=0.36), but did at 2 weeks (P=0.009). Clinical dysfunction from rejection tends to occur more rapidly in the kidney than the pancreas following combined allografting, but histologically severe rejection can be present in one organ while the second remains unaffected. The severity of histological rejection usually varies between organs of a pair, but there is no consistent pattern in whether the kidney or pancreas is more or less afflicted. Thus, dyssynchronous rejection is unlikely due to inherent differences in alloantigen expression between the two organs, and further studies are needed to determine the factors that predispose to amplification of the alloimmune response to a greater degree in one organ than the other of a pair.