R. Rigby

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.

A COMPARISON OF THE EFFECTS OF DIALYSIS AND RENAL TRANSPLANTATION ON THE SURVIVAL OF OLDER UREMIC PATIENTS

BACKGROUND Patients over age 60 constitute half of all new patients accepted into the renal replacement therapy programs in Australia. However, the optimal treatment of their end-stage renal disease remains controversial. The aim of the present study was to compare survival for dialysis and renal transplantation in older patients who were rigorously screened and considered eligible for transplantation. METHODS The study cohort consisted of 174 consecutive patients over 60 who were accepted on to the Queensland cadaveric renal transplant waiting list between January 1, 1993 and December 31, 1997. Follow-up was terminated on October 1, 1998. Data were analyzed on an intention-to-transplant basis using a Cox regression model with time-varying explanatory variables. An alternative survival analysis was also performed, in which patients no longer considered suitable for transplantation were censored at the time of their removal from the waiting list. RESULTS There were 67 patients receiving a renal transplant, whereas the other 107 continued to undergo dialysis. These two groups were well matched at baseline with respect to age, gender, body mass index, renal disease etiology, comorbid illnesses, and dialysis duration and modality. The overall mortality rate was 0.096 per patient-year (0.131 for dialysis and 0.029 for transplant, P<0.001). Respective 1-, 3- and 5-year survivals were 92%, 62%, and 27% for the dialysis group and 98%, 95%, and 90% (P<0.01) for the transplant group. Patients in the transplant group had an adjusted hazard ratio 0.16 times that of the dialysis group (95% confidence interval 0.06-0.42). If patients were censored at the time of their withdrawal from the transplant waiting list, the adjusted hazard ratio was 0.24 (95% confidence interval 0.09-0.69). CONCLUSIONS Renal transplantation seems to confer a substantial survival advantage over dialysis in patients with end-stage renal failure who are rigorously screened and considered suitable for renal transplantation.

The kinetics of mycophenolic acid and its glucuronide metabolite in adult kidney transplant recipients

Mycophenolic acid kinetics have been reported to vary after renal transplantation, and mycophenolic acid area under the concentration–time curve (AUC) is the best predictor of suppression of graft rejection.

A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients.

OBJECTIVES Although monitoring of cyclosporin (CsA) is standard clinical practice postrenal transplantation, mycophenolic acid (MPA) concentrations are not routinely measured. There is evidence that a relationship exists between MPA area under the concentration-time curve (AUC) and rejection. In this study, a retrospective analysis was undertaken of 27 adult renal transplant recipients. METHODS Patients received CsA and MPA therapy and had a four-point MPA AUC investigation. The relationship between MPA AUC performed in the first week after transplantation, as well as median trough cyclosporin concentrations, and clinical outcomes in the first month posttransplant were evaluated. RESULTS A total of 12 patients experienced biopsy proven rejection (44.4%) and 4 patients had gastrointestinal adverse events (14.8%). A statistically significant relationship was observed between the incidence of biopsy proven rejection and both MPA AUC (p = 0.02) and median trough CsA concentration (p = 0.008). No relationship between trough MPA concentration and rejection was observed (p = 0.21). Only 3 of 11 (27%) patients with an MPA AUC > 30 mg x h/L and a median trough CsA > 175 microg/L experienced acute rejection, compared with a 56% incidence of rejection for the remaining 16 patients. Patients who experienced adverse gastrointestinal events had significantly lower MPA AUC (p = 0.04), but median trough CsA concentrations were not significantly different (p = 0.24). Further, 3 of these 4 patients had rejection episodes. CONCLUSIONS In addition to standard CsA monitoring, we propose further investigation of the use of a 4-point sampling strategy to predict MPA AUC in the first week posttransplant, which may facilitate optimization of mycophenolate mofetil dose at a time when patients are most vulnerable to acute rejection.

Abdominal hernias complicating continuous ambulatory peritoneal dialysis

Twenty-five percent of all CAPD patients reviewed in this study developed abdominal hernias. Eleven hernias (32.4%) occurred at the catheter insertion site, 17.6% were inguinal, 26.5% were epigastric and umbilical and 23.5% occurred at the site of previous abdominal incisions. The risk of developing a hernia was significantly greater in patients over 40 years of age, women of parity greater than 3, patients who had had undergone more than 3 laparotomies and those with a previous hernia repair. Three hernias became incarcerated, one with intestinal strangulation. Early surgical repair is advisable to avoid these complications.

Recovery of gastrointestinal function after renal transplantation in a patient with sclerosing peritonitis secondary to continuous ambulatory peritoneal dialysis

We describe the rapid and dramatic improvement in gastrointestinal function that occurred after successful renal transplantation in a women with severe sclerosing peritonitis secondary to continuous ambulatory peritoneal dialysis (CAPD). We postulate that the antiinflammatory effect of the immunosuppressive agents was the most important factor leading to the patients recovery.

Advanced donor-origin melanoma in a renal transplant recipient: Immunotherapy, cure, and retransplantation

BACKGROUND A kidney transplant recipient inadvertently contracted donor-origin melanoma, which was found to be very advanced at presentation. Withdrawal of immunosuppression failed to induce rejection, and interferon-alpha was required. When florid allograft rejection was in progress, the allograft was removed, before it was recognized that the transplanted melanoma was not being simultaneously rejected. METHODS Subsequent immunotherapy was required, which largely recapitulated treatment of recognized value in autologous melanoma and included interferon-alpha, use of cultured melanoma cells as tumor vaccine, pooled allogeneic cell vaccination, and adoptive immunotherapy using lymphokine-activated killer cells. RESULTS Prolonged immunotherapy eradicated the widespread malignancy, and the patient went on to a successful second renal transplant, with follow-up of over 24 months. CONCLUSIONS This unique case demonstrates the successful cure of advanced transplanted melanoma through the use of immunotherapy, which did not require sophisticated tumor vaccine technology, and successful retransplantation.

Algal peritonitis complicating continuous ambulatory peritoneal dialysis.

A 41-year-old woman on continuous ambulatory peritoneal dialysis (CAPD) presented with algal peritonitis. Prototheca wickerhamii was isolated from multiple dialysate effluent cultures. Despite treatment with amphotericin B, catheter removal was required. An attempt to reinsert a Tenckhoff catheter 3 months later was unsuccessful because of dense intraperitoneal adhesions. Prototheca sp are a rare cause of human disease, this being the first reported case of algal peritonitis complicating CAPD.

A double‐blind placebo controlled trial of simvastatin for the treatment of dyslipidaemia in renal allograft recipients

Background: With current techniques, renal failure patients are now able to regain near‐normal health following renal transplantation. However, the development of premature cardiovascular disease is a major problem. Dyslipidaemia may be an important contributor to this. The use of lipid lowering agents in renal allograft recipients has been limited by potential interaction of these agents with the now widely used immunosuppressive agent, cyclosporine.Aim: This study was designed to investigate efficacy and safety of simvastatin in subjects taking either cyclosporine or azothioprine post renal transplantation.Methods: Fifty‐one subjects (32 females, 19 males – mean age 51±12.5 yr) who were at least 1 yr post transplant, had creatinine ≤2.5 mmol/L and a total cholesterol ≥6 mmol/L were enrolled in a prospective, double‐blind, placebo‐controlled study. After an initial 10‐wk dietary period, the last 4 wk on placebo, subjects were randomised to receive either 5 mg simvastatin/d for 6 wk followed by 10 mg simvastatin/d for 6 wk, or matching placebo. After this 12‐wk double‐blind phase, there was an open‐label phase when all subjects were treated with 10 mg simvastatin/d for a period of 36 wk.Results: Compared to placebo, 5 mg simvastatin/d significantly decreased total cholesterol by 20% (p<0.01), low‐density lipoprotein cholesterol (LDL cholesterol) by 29% (p<0.01), and Apolipoprotein B (ApoB) by 26% (p<0.01). Increasing simvastatin to 10 mg/d did not lead to further significant changes. But high‐density lipoprotein cholesterol (HDL cholesterol) increased by 9% (p<0.01) and Apolipoprotein A1 (ApoA1) by 7% (p<0.01) only on 10 mg simvastatin/d. During the open‐label phase, subjects previously randomised to placebo achieved similar significant changes to their lipoprotein profile. The benefits achieved from simvastatin were maintained to the end of the study. There were three withdrawals from the study, all from the simvastatin/cyclosporine group. Two subjects had musculoskeletal pain and 1 had abdominal pain. Minor adverse events were similar in both the simvastatin‐ and placebo‐treated groups.Conclusion: Low‐dose simvastatin is an effective and well‐tolerated agent in the treatment of dyslipidaemia in renal allograft recipients.

Effect of OKT3 in steroid-resistant renal transplant rejection.

Between January 1, 1982, and November 1, 1986, 169 cadaver renal graft transplantations were performed at this hospital with CsA as induction therapy. OKT3 was not available in this period. Of these grafts, 15.9% were lost within 6 months, 10.7% from acute rejection (AR). Between November 1, 1986, and October 1, 1992, 483 cadaver renal graft transplantation were performed. Induction therapy included CsA and OKT3 was available. Of these grafts, 8.7% were lost inside 6 months, 3.1% from AR. Of these last 483 grafts, 113 received 125 courses of OKT3. Ten courses were prophylactic, and 115 courses in 103 patients were for rejection resistant to steroid therapy (biopsy proven in all but 2 cases. Ninety-three percent of rejection episodes treated with OKT3 responded, at least initially. Graft survival in OKT3-treated patients was 81%, 77%, and 76% at 6 months, 1 year, and 2 years, respectively. In contrast, graft survival in steroid-resistant rejection during the first period (without OKT3) was 59%, 57%, and 57% at these intervals. There were 8 infective deaths within 6 months in the 113 OKT3-treated patients, compared with 2 in the 343 who did not receive OKT3 (P <0.001). There were 7 viral deaths in the OKT3 group compared with none in those not receiving OKT3 (P < 0.001). Prophylaxis with oral acyclovir and cotrimoxazole was instituted in October 1990 in OKT3-treated patients and ganciclovir use was increased. Since this change, no further viral deaths have occurred. OKT3 is a very effective antirejection agent, but its use is associated with an increased mortality from viral infections. With appropriate prophylaxis and treatment, however, this mortality can be reduced.