Ian R. Hardie

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.

The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study.

A long-term retrospective follow-up study was performed to evaluate the risk of skin cancer in 1098 renal transplant recipients in Queensland, Australia. In a subgroup, we also assessed the influence of immunosuppressive therapy on the risk of developing skin cancer: cyclosporine alone or in combination with prednisolone; azathioprine alone or in combination with prednisolone; or the combination of cyclosporine and azathioprine with or without prednisolone. The cumulative incidence of developing skin cancer, calculated by life table analysis, increased progressively from 7% after 1 year of immunosuppression to 45% after 11 years and to 70% after 20 years of immunosuppression. Multivariate analysis in a subgroup comparing the risk of developing skin cancer in patients on either long-term cyclosporine or azathioprine (each with or without prednisolone) and in patients on the combination of cyclosporine and azathioprine (with or with- out prednisolone) showed no differences between the groups. We conclude that it is likely that the increased risk of skin cancer associated with immunosuppression is independent of the agent(s) used and is a result of the immunosuppression per se.

REDUCTION OF ACUTE RENAL ALLOGRAFT REJECTION BY DACLIZUMAB 1

BACKGROUND Acute rejection is still a major problem in renal transplantation and is one of the most important causes of chronic graft dysfunction and late graft loss. Selective immunosuppression with a humanized antibody against the alpha-chain of the interleukin (IL)-2 receptor (CD25) was evaluated to demonstrate the efficacy of this type of immunoprophylaxis in combination with dual immunosuppression. METHODS We studied the effect of daclizumab, a humanized monoclonal antibody against the alpha-chain of the IL-2 receptor, in a randomized double-blind, prospective phase III clinical trial in 275 patients receiving a first cadaveric renal allograft. Among them 111 (83%) in the placebo arm and 116 (82%) in the daclizumab arm received the full regimen of five doses (1.0 mg/kg) every other week. Baseline immunosuppression consisted of cyclosporine and corticosteroids. RESULTS At 6 months, 39 (28%) of the patients in the daclizumab group had biopsy-proven rejections, as compared with 63 (47%) in the placebo group (P=0.001). The need for additional antilymphocyte therapy, antithymocyte globulin, antilymphocyte globulin (ATG, ALG, OKT3) was also lower in the daclizumab group (8% vs. 16%, P=0.02), and they required significantly lower mean (+/- SD) cumulative doses of prednisone (3750+/-1981 mg vs. 4438+/-2667 mg in the placebo group, P=0.01). Graft function was significantly better (P=0.02) in the daclizumab group (graft function rate: 58 vs. 51 ml/min, mean) as was patient survival (P=0.01, 99% vs. 94%). No specific adverse events were observed in daclizumab-treated patients. Patients receiving daclizumab experienced fewer cytomegalovirus infections (18% vs. 25%), and none died from severe infectious complications, compared to four patients in the placebo arm. No patient in the daclizumab group had a lymphoproliferative disorder or any other form of immunosuppression-related tumor during the first year after transplant. CONCLUSIONS Administration of daclizumab in addition to dual immunosuppression therapy significantly reduced biopsy-proven acute rejection after renal transplantation, improved patient survival, and did not add to the toxicity of the immunosuppressive regimen.

Results of 3-year phase III clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation

BACKGROUND Daclizumab (Zenapax, Roche Pharmaceuticals), a humanized monoclonal antibody directed against the alpha chain of the interleukin 2 receptor, has been shown to reduce the incidence of acute rejection at 6 months after renal transplantation in two phase III clinical trials. This report presents the combined 1- and 3-year outcomes of kidney transplant recipients who participated in these two phase III clinical trials. METHODS Data from two multicenter, randomized, placebo-controlled trials were evaluated with regard to graft survival, patient survival, incidence of malignancies (including lymphoma), renal function (serum creatinine and glomerular filtration rate [GFR]), and current maintenance immunosuppressive regimen. In addition, the impact of acute rejection and acute rejection requiring treatment with antilymphocyte therapy upon 3-year graft survival was evaluated. Daclizumab was compared to placebo on a background of cyclosporine (CsA), azathioprine, and corticosteroids (triple therapy, TT) or CsA and corticosteroids (double therapy, DT). RESULTS Treatment with daclizumab in the pooled analysis demonstrated a significant reduction in the incidence of biopsy-proven acute rejection episodes at 12 months posttransplant (43% vs. 28%, P<0.001). The 3-year graft survival was not significantly different between placebo and daclizumab-treated patients in the TT trial (83% vs. 84%) or in the DT trial (78% vs. 82%). Pooled patient survival was excellent in both placebo- (91%) and daclizumab- (93%) treated patients. The incidence of malignancies or posttransplant lymphoproliferative disorder (PTLD) in placebo- versus daclizumab-treated groups was comparable in both clinical trials. Renal function was similar between placebo- and daclizumab-treated groups in both the TT and DT trials. The occurrence of delayed graft function, acute rejection requiring antilymphocyte therapy at 6 months, and acute rejection at 12 months posttransplant were associated with decreased graft survival rates at 3 years posttransplant. CONCLUSIONS The beneficial effect of daclizumab prophylaxis upon the incidence of acute rejection after renal transplant with TT or with DT was not associated with adverse clinical sequelae, including the development of PTLD, at 3 years posttransplant. There was no beneficial effect of daclizumab on graft survival at 3 years, but the trial was inadequately powered to detect this. Both studies showed excellent graft and patient survival at 3 years.

Routine use of indwelling ureteral stents in renal transplantation.

An extravesical ureteral implantation with the routine use of an internal stent was performed in 358 transplants (351 cadaveric and 7 living related). The 1-year patient and graft survival was 93% and 87%, respectively, with a minimum followup of 2 years. Ureteral complications developed in 9 patients (2.6%), with 3 fistulas, 2 of which resolved spontaneously, and 6 stenoses following stent removal. Nephrostomy drainage and antegrade stenting were initially attempted in all cases of stenosis, and were successful in 4. Revision of the ureteral anastomosis was required in 1 case of fistula and 2 cases of stenosis (0.9%). Extrinsic compression resulted in ureteral obstruction in 3 cases (2 lymphoceles and 1 hematoma), which resolved following drainage. Stent related complications occurred in 8 patients (2.2%), including obstruction due to the stent in 2 cases, breakage during removal in 3 leaving fragments in the upper urinary tract, proximal migration of 2 stents that were retrieved via percutaneous nephrostomy and calculus formation on 1 stent in a patient with hyperparathyroidism, necessitating extracorporeal shock wave lithotripsy for stent removal. In the cases with ureteral or stent related complications 1-year patient and graft survival was 100%. These results suggest that ureteral stents used routinely in renal transplantation are associated with a low incidence of urinary leaks, early postoperative obstruction and subsequent surgery for urological complications. However, a small number of unique problems related to stent use or malfunction may occur. Minimally invasive strategies using percutaneous nephrostomy and antegrade stenting are effective in managing the majority of complications that occur following ureteral stenting in renal transplant recipients.

Hepatic acyl-CoA: cholesterol acyltransferase. Development of a standard assay and determination in patients with cholesterol gallstones

A standard assay was developed for human liver acyl-CoA:cholesterol acyltransferase (ACAT, EC 2.3.2.26) which is more sensitive than previous methods and allows accurate activity determinations on crude microsomal fractions. ACAT activity was measured in microsomes from livers of four gallstone patients and five controls. Preincubation with exogenous cholesterol produced an increase in ACAT activity in all liver samples: gallstone samples showed a mean increase of 1.8-fold, whereas non-gallstone samples showed a mean increase of 8.2-fold. The mean ACAT activity measured in the presence of exogenous cholesterol was 52.8 +/- 22.8 (n = 4) pmol . min-1 . mg-1 for gallstone samples and 82.8 +/- 13.5 (n = 4) pmol . min-1 . mg-1 for non-gallstone samples. These results suggest that patients suffering from cholesterol gallstones have a reduced ability to esterify potentially harmful free cholesterol compared with controls. They support the proposition that cholesterol gallstone formation is related to altered hepatic cholesterol metabolism.

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.

Skin cancer in transplant recipients

T he development of cancer in organ transplant recipients is a problem ofgreat clinical concern, but it has also provided fascinating insights into the biology of tumorogenesis, immune surveillance, and the complex interactions between genetic and environmental factors in cancer development. Of the many penalties associated with the nonspecific nature of clinical immunosuppression, cancer is arguably the most sinister, because lives so successfully extended after end-stage organ failure are again prematurely cut short by cancer. In the late 196Os, after nearly a decade of immunosuppression with azathioprine and prednisone, the first reports appeared of cancers developing in kidney transplant recipients. ‘J The tumors observed in these patients were seen only rarely in the general community; their incidence was dramatically increased, whereas the commonly fatal cancers seemed to have little increase in incidence?,* These early reports were from the northern hemisphere and suggested that skin cancer was a minor problem in the transplant recipients. The obvious seriousness of the de novo visceral tumours and the difficulty of treatment tended to focus attention on them. In addition, most cancer registries exclude skin cancers from their data collection, thus leaving a general lack of data about skin cancer incidence in the general population. This made comparisons difficult and may have hindered the recognition that skin cancer was also increased in these immunosuppressed patients. However, by the

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.

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.