J P Fryer

Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases.

BACKGROUND The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described. METHODS Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described. RESULTS Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposis sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant. CONCLUSIONS We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.

Low bioavailability of cyclosporine microemulsion and tacrolimus in a small bowel transplant recipient: possible relationship to intestinal P-glycoprotein activity.

With intestine transplants the allograft is dependent on itself for maintenance of adequate immunosuppression. We evaluated an intestinal transplant recipient who required very large doses of either tacrolimus or cyclosporine emulsion to achieve acceptable blood concentrations. Pharmacokinetic studies revealed bioavailabilities of 2% and 6% respectively, while D-xylose and B12 absorption were found to be within normal limits and fecal fat was only slightly increased, suggesting that there was a selective absorptive defect for these drugs. Biopsies of the allograft ileum revealed a high P-glycoprotein activity compared to the jejunum or to intestinal biopsies from other normal subjects. This may be a contributing factor to poor immunosuppressive drug absorption in this patient and others.

Frequency of hyperkalemia in recipients of simultaneous pancreas and kidney transplants with bladder drainage

Hyperkalemia is the most frequent electrolyte abnormality found in whole organ transplant recipients receiving either cyclosporine (CsA) or tacrolimus (FK506). Recipients of a simultaneous pancreas kidney (SPK) transplant with bladder drainage may be particularly susceptible to hyperkalemia secondary to sodium loss from the bladder-drained pancreas, leading to decreased sodium delivery to potassium secretory sites of the kidney. We looked at the incidence of hyperkalemia in 34 type I diabetic SPK recipients transplanted at our center over the period from 1993 to 1995 and compared this with a cohort of 25 type I diabetic recipients of a kidney alone (K(Tx)) transplant. The incidence of hyperkalemia was 73.5% in recipients of an SPK, while it was 44% in K(Tx) recipients (P<0.05). CsA levels were higher, on average, in the SPK group (339 ng/ml+/-62 versus 272 ng/ml+/-58 in the K(Tx) group, P<0.05). However, CsA levels were not different between groups at the time of hyperkalemia, 320+/-74 versus 298+/-49 for SPK and K(Tx), respectively. CsA levels at the time of hyperkalemia were not different from those at the time of normokalemia. Other medications, serum bicarbonate, and renal function were not different in the groups. SPK recipients appear to have a greater incidence of hyperkalemia than kidney alone transplant recipients. This difference cannot be explained by higher acute CsA levels, other medications, or worse renal function. The increased incidence of hyperkalemia may, in part, be secondary to decreased sodium delivery to the transplanted kidney.

Early histopathology of small intestinal discordant xenografts

A descriptive study of a new model enabling serial biopsies of ongoing hyperacute rejection of small intestinal discordant xenografts is presented. In a series of guinea-pig-to-Lewis rat small bowel xenotransplants (n=7), aboral free ends of Thierry-Vella loops constructed from the graft were sequentially biopsied at one-minute intervals up to ten minutes post-reperfusion and less frequently thereafter. In a guinea pig-to-guinea pig (n=6) isograft series, biopsy controls for preservation/ischemia-reperfusion injury were obtained. Xenoantibody sequestration in this model was evaluated in a separate series of transplants, utilizing an ELISA assay for rat anti-guinea pig natural antibodies. Pathologic evaluation revealed a unique series of events characterized with microcirculatory failure and thrombosis progressing from the submucosal vasculature to the lumen. Within the systems detection limits, complement deposition and P-selectin expression occurred as early as one minute post-reperfusion, preceding the staining for IgM and IgG. Using rat serum ELISAs, no significant difference in xenoantibody sequestration was detected between the xenograft and isograft groups. The guinea pig-to-rat discordant small bowel xenotransplantation is an efficient small animal model to dissect the very early pathophysiologic events during hyperacute rejection.