Effect of tacrolimus on hemodynamics and absorption of experimental small intestinal transplants.

We have previously reported the adverse effects of cyclosporine on small intestine transplant physiology. In this study, we report for the first time the effect of tacrolimus (FK) on graft intestinal blood flow and intramural distribution, vascular resistance, and absorptive function. Isogeneic small intestine transplantation was performed in Lewis rats. Animals were grouped based upon the following treatment schedules: no treatment for 1 week in group 1; 0.6 ml/kg/day i.m. polyethylene glycol (PEG) for 1 week in group 2; 2 mg/kg/day i.m. FK for 1 week in group 3; 0.6 ml/kg/day PEG for 1 week and then 0.3 ml/kg/day for 5 weeks in group 4; 2 mg/kg/day FK for 1 week and then 1 mg/kg/day for 5 weeks in group 5. Group 6 was the same as in group 5 but FK was withdrawn for 1 week prior to assessment. Maltose absorption was measured to evaluate graft absorptive function. Blood flow and its intramural distribution to mucosal and serosal/muscularis layers were determined using the radioactive microsphere technique. Perfusion pressure was measured to calculate vascular resistance. One week of FK administration in group 3 did not change graft hemodynamics and absorption significantly. Prolonged FK treatment up to 6 weeks in group 5 resulted in a significant increase in mucosal vascular resistance (71.0 +/- 9.6 versus 47.7 +/- 6.7 U/g, P<0.01) and significant decreases in mucosal blood flow (1.14 +/- O.15 versus 1.69 +/- 0.24 ml/g/min, P<0.01) and maltose absorption (30 min after loading. 155.4 +/- 26.9 versus 216.4 +/- 29.6, P<0.01; 60 min after loading: 172.9 +/- 24.5 versus 229.1 +/- 32.6 glucose mg/dl P<0.01). The serosal/muscularis layer remained relatively unaffected. Withdrawal of FK for 1 week after prolonged treatment in group 6 resulted in restorations of all parameters measured to normal ranges. We conclude that a short course of FK is safe, but prolonged FK administration has harmful effects on the hemodynamics and function of small intestinal transplants. Complete recovery is achieved when FK is discontinued.

Chronic renal allograft rejection: no response to mycophenolate mofetil.

BACKGROUND: Mycophenolate mofetil (MMF) has been previously shown to prevent functional deterioration in an experimental model of chronic renal allograft rejection. METHODS: In this retrospective case-control study, patients with chronic rejection who were receiving cyclosporine or tacrolimus and who had MMF added to their immunosuppressive regimen were compared with patients with chronic rejection who were not receiving MMF. Patients were matched for serum creatinine levels and transplant duration at the time MMF was begun. RESULTS: In the MMF group, the average dose of MMF was 1482 mg/day with an average duration of 19.3 months. Over 36 months, including 12 months before MMF and up to 24 months on MMF, there was no difference in serum creatinine levels between the two groups. Cyclosporine levels and dose were no different. CONCLUSIONS: In this small, retrospective, preliminary study, adding MMF to maintenance immunosuppression provided no clear benefit to renal allograft recipients with established chronic rejection. Larger prospective randomized studies are needed.

Improved small intestinal preservation after lazaroid U74389G treatment and cold storage in University of Wisconsin solution.

The small intestine (SI) is highly sensitive to oxygen free radical-induced injury. The most common preservation solution, University of Wisconsin (UW) solution, does not adequately prevent free radical-induced injury. Lazaroids, and U74389G in particular, are a new class of compound that are potent inhibitors of superoxide-mediated lipid peroxidation. We studied the added influence of U74389G to 18-hr cold preservation of rat SI in UW solution. Three groups of rats were studied. In group 1, SI was excised and reperfused immediately. In group 2, SI was stored in UW solution at 4 degrees C for 18 hr. In group 3, U74389G was given to the SI graft before storage and again before reperfusion. Blood reperfusion of the grafts was achieved via connection to the superior mesenteric artery and portal vein of support rats. Functional recovery was assessed using a maltose tolerance test. Weight changes were calculated and histologic studies done. After 30 and 60 min of reperfusion, maltose uptake in group 3 was significantly better than that of the group 2, and returned to control levels. Significantly more tissue swelling was noted in group 3 over control, but the magnitude was less than that of group 2. Less transmural necrosis and villous blunting were noted in group 3 versus group 2; the appearance of the mucosa in group 3 approached that of group 1. We conclude that the use of U74389G treatment in addition to cold storage in UW solution improves recovery of graft function and minimizes morphologic damage to the small intestinal mucosa.

Evidence that zero antigen-matched cyclosporine-treated renal transplant recipients have graft survival equal to that of matched recipients. Reevaluation of points.

The value of HLA matching in cadaver renal transplantation (CRT) continues to be debated. It has recently been suggested that increased importance be given to HLA matching for the distribution of cadaver kidneys. Such a policy would add both delay and expense to CRT, which could be justified only by significantly improved results. The results of CRT in 252 cyclosporine treated adult patients transplanted at our institution from November 1984 to April 1989 were reviewed. Kidneys were initially transplanted into crossmatch-negative recipients based on waiting time, regardless of match. From October 1987, a points system, based on United Network for Organ Sharing (UNOS) criteria has been used. Eighty-four pts. with zero antigen match with their donors were compared with 168 pts. sharing 1-6 Ag. Actuarial graft and patient survival were determined by the cumulative life table method and compared using a log rank test. Our results indicated no statistically significant difference in graft survival because of better matching or mismatching. These findings are in keeping with our previously reported long-term results for non-CsA pts. Past predictions of improved graft survival based upon better matching at our institution have not fulfilled expectations, with the exception of 6 Ag matches. In conclusion, increased emphasis on HLA matching with fewer "points" for poorer matches does not appear justifiable.

Spontaneous rupture of human renal allografts.

Preservation of renal allografts following spontaneous rupture is a surgical challenge. Salvage was attempted in 3 patients. Despite successful repair in all 3, transplant nephrectomy was ultimately required in 2 patients because of irreversible rejection. The third patient is doing well forty-eight weeks after transplantation.