Peter J. Morris

A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation

Mycopehenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multi-center trial to compare the efficacy and safety of MMF and azathioprine within standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3g group (P=0.0045) and 38.2 % in the MMF 2g group (P=0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1 %, 10.4% and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were tested for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

Urological Complications in 1,000 Consecutive Renal Transplant Recipients

The urological complications in the first consecutive 1,000 renal transplants at our transplant center are reported with a minimum followup of 12 months. The kidney was implanted in the iliac fossa in all cases and in all but 3 the ureter was inserted into the bladder with a Politano-Leadbetter technique. Overall, there were 71 primary complications in 68 patients (7.1%), which included 36 ureteral obstructions, 25 ureteral or bladder leaks (including ureteral necrosis), 7 bladder outflow obstructions, 2 ureteral stones and 1 case of symptomatic vesicoureteral reflux. The use of high dose steroids in the early years was associated with a 10% urological complication rate, which decreased to 4% in patients receiving low dose steroids thereafter combined with azathioprine or cyclosporine. The urological complication was corrected after 1 procedure in 65 cases and after 2 procedures in 4. No grafts were lost due to urological complications. Two patients died, 1 of sepsis following transurethral resection of the prostate and subsequent ureteral necrosis, and 1 of hemorrhage following nephrostomy tube insertion. Most ureteral complications were treated by an open operation, although in recent years endoscopic techniques have become more common. Meticulous retrieval technique, low dose steroid protocols and rapid diagnosis are the crucial factors associated with a minimal incidence of urological complications after renal transplantation.

Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate.

Background. Renal-transplant recipients are at increased risk of developing skin cancers, especially squamous cell carcinoma. We have carried out a comprehensive epidemiologic review of skin cancers occurring in a population receiving transplants in Oxford over a 21-year period, where nearly all patients have remained under the care of the Oxford Transplant Centre. Methods. Between 1975 and 1996, 1,360 renal transplants were performed in 1,115 patients. Skin cancer data were reviewed in 979 patients from this group who remained under the care of the Oxford Transplant Centre. The lesions included in the analysis were histologically confirmed basal cell carcinoma, Bowen’s disease, squamous cell carcinoma, keratoacanthoma, malignant melanoma, Merkel cell tumor, and sebaceous carcinoma. Results. One hundred eighty-seven (19.1%) transplant patients developed at least one skin malignancy. The rate of skin cancer was 141 per 1,000 person years at risk. Sixty-four percent of patients with skin cancer had multiple lesions (maximum 50). Squamous cell carcinoma was the most common skin cancer to develop and the most common first skin cancer to present. The mean time to presentation of the first skin cancer was 8 years. Six patients developed nodal metastases, and two patients died secondary to skin cancer. Risk factors identified were increasing age at transplantation, recipient sex, total time of exposure to immunosuppression, increased creatinine levels at 1 year, and graft relation. The cumulative incidence of skin cancer reached 61% at 20 years after transplantation. Conclusion. The data from this study suggest that more patients develop skin malignancies than previously reported from Europe. It is important to advise patients before transplantation in regard to skin complications, provide regular dermatological follow-up, and tailor immunosuppressive regimen to minimum doses to be compatible with good graft function.

Separation of Pancreatic Islets by Fluorescence-Activated Sorting

To allow clinical pancreatic islet transplantation, the yield and purity of islets must be improved. Intravital staining of islets with neutral red is a specific, nontoxic technique for labeling islets of various species. Using neutral red-stained rat islets, we investigated the known fluorescence absorbance and emission spectra in comparison with unstained exocrine tissue and have shown that stimulation with light of wavelength between 500 and 560 nm produces detectable emission >610 nm, which is absent from unstained exocrine tissue. The PARTEC cell sorter is an inexpensive alternative to currently available fluorescence-activated cell sorters and has a sorting mechanism based on a piezoelectric valve. We made extensive modifications to this machine to allow passage of particles up to 300 μm diam. Using rat pancreas stained intravitally with neutral red and dispersed by intraductal collagenase technique, we have shown that islets can be accurately identified in a high-speed flow system and sorted to a purity of >90% islet tissue. The islets remain intact and viable as determined by supravital staining and isogeneic transplantation to the kidney capsule site. These studies prove the feasibility of separating intact islets by fluorescence-activated sorting.

Do re-grafts require more aggressive immunosuppression?

This study was performed to investigate whether recipients of second or subsequent renal cadaveric allografts require more intensive immunosuppression than recipients of first grafts. Oxford data demonstrates that the outcome of patients with regrafts is overall identical to those with first cadaveric grafts [1] although Registry data has shown that regrafts do not do so well [2, 3], with regraft survival up to 10% lower than first grafts [4]. In most transplant centres this difference in survival between first and second grafts has decreased in the last 15 years and this has no doubt been influenced by the use of cyclosporine [5, 6]. Hirata et al. [7] describe a difference of as little as 1% between first and second graft survival in their patients, compatible with our own data. Kidney regraft candidates now comprise about 27% of all patients awaiting renal transplantation, but only receive 13–14% of the annual cadaveric transplants [8]. The reasons for this are multifactorial, but include high sensitization and associated positive crossmatches, and a presumption of worse outcome for regrafts [9]. Patients awaiting regrafting share the common experience of having lost a previous transplant and having been exposed to foreign HLA antigens. Only some of these graft losses will be the result of rejection, others having been lost to technical problems such as renal vein or artery thrombosis or to primary non-function. It is the sub-group who have mounted an immunological response sufficient to reject the primary graft that are likely to be the more difficult group in which to achieve success with a regraft, and in whom more aggressive immunosuppression might be indicated.