M.D. Pascoe

Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial.

Background. The efficacy and safety of converting maintenance renal transplant recipients from calcineurin inhibitors (CNIs) to sirolimus (SRL) was evaluated. Methods. Eight hundred thirty renal allograft recipients, 6 to 120 months posttransplant and receiving cyclosporine or tacrolimus, were randomly assigned to continue CNI (n=275) or convert from CNI to SRL (n=555). Primary endpoints were calculated Nankivell glomerular filtration rate (GFR; stratified at baseline: 20–40 vs. >40 mL/min) and the cumulative rates of biopsy-confirmed acute rejection (BCAR), graft loss, or death at 12 months. Enrollment in the 20 to 40 mL/min stratum was halted prematurely because of a higher incidence of safety endpoints in the SRL conversion arm. Results. Intent-to-treat analyses at 12 and 24 months showed no significant treatment difference in GFR in the baseline GFR more than 40 mL/min stratum. On-therapy analysis of this cohort showed significantly higher GFR at 12 and 24 months after SRL conversion. Rates of BCAR, graft survival, and patient survival were similar between groups. Median urinary protein-to-creatinine ratios (UPr/Cr) were similar at baseline but increased significantly after SRL conversion. Malignancy rates were significantly lower at 12 and 24 months after SRL conversion. Post hoc analyses identified a subgroup with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11, whose risk-benefit profile was more favorable after conversion than that for the overall SRL conversion cohort. Conclusions. At 2 years, SRL conversion among patients with baseline GFR more than 40 mL/min was associated with excellent patient and graft survival, no difference in BCAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation. Superior renal function was observed among patients who remained on SRL through 12 to 24 months, particularly in the subgroup of patients with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11.

Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial.

Background. Long-term immunosuppression imposes increased malignancy risk in renal allograft recipients, significantly contributing to overall morbidity and mortality. This study examined malignancy rates in renal allograft recipients at 2 years after conversion to a sirolimus (SRL)-based, calcineurin inhibitor (CNI)-free regimen. Methods. This open-label, randomized, multicenter study (the CONVERT Trial) randomly assigned 830 patients to SRL conversion (n=555) or CNI continuation (n=275). Patients with history of posttransplant lymphoproliferative disease or known/suspected malignancy within 5 years before screening were excluded. As part of standard safety measurements, subjects were monitored for any malignancy occurrence; both skin and nonskin malignancies were reported, even if the patient discontinued from the therapy. Malignancy rates were analyzed based on exposure time to study drugs (i.e., number of events per 100 person-years of follow-up). Results. At 2 years postconversion, the total number of malignancies per 100 person-years of exposure was significantly lower among SRL conversion patients compared with CNI continuation (2.1 vs. 6.0, P<0.001). Patients undergoing SRL-based, CNI-free therapy had significantly lower rates of the subset of nonmelanoma skin carcinomas through 2 years postconversion (1.2 vs. 4.3, P<0.001). This difference persisted after excluding patients with a history of malignancy before randomization. The rate of all other malignancies was not significantly different between treatment groups (P=0.058). Conclusion. In renal allograft recipients, SRL-based immunosuppression was associated with a lower rate of malignancy at 2 years postconversion compared with continuation of CNI-based immunosuppression. This reduction was driven by a significant reduction in nonmelanoma skin carcinoma rates; the rate of all other malignancies was numerically lower but did not achieve statistical significance.

Increased accuracy of renal allograft rejection diagnosis using combined perforin, granzyme B, and fas ligand fine-needle aspiration immunocytology

BACKGROUND Two major routes by which cytotoxic T lymphocytes induce apoptosis in target cells are the perforin-granzyme and the Fas ligand/Fas pathways. Intragraft expression of message for these immune activation genes has been shown to correlate very closely with clinical rejection. We have immunolabeled fine-needle aspiration biopsy samples using a panel of cytotoxic T-cell activation markers to evaluate the immunocytochemical identification of the protein products of these genes in the verification of human renal allograft rejection. METHODS In this retrospective pilot study, 140 fine-needle aspiration biopsy samples from 50 human renal allografts were labeled using alkaline phosphatase/ anti-alkaline phosphatase immunocytochemistry incorporating monoclonal antibodies to perforin, granzyme B, and Fas ligand. Levels of positive labeling for these markers were compared with the original clinical diagnosis of rejection. RESULTS An excellent correlation with clinical rejection was obtained when all three antibodies were positive. The false positive rate for each antibody was sufficient to make any one alone or in combination with one other unreliable for diagnosing rejection. When all three antibodies gave positive labeling, agreement with clinical rejection status was superior to using conventional morphological cytology. CONCLUSIONS In addition to providing valuable morphological information regarding the composition of inflammatory leukocyte populations and the preservation status of renal parenchymal cells, fine-needle aspiration biopsy samples may be labeled using combined perforin, granzyme B, and Fas ligand immunocytochemistry to offer a safe and reliable method for diagnosing rejection with an excellent level of accuracy.

Effect of Rifampicin on Cyclosporin A Blood Levels in a Renal Transplant Recipient

Dr. M.J.D. Cassidy, Departments of Medicine and Surgery, University of Cape Town, Medical School and Groote Schuur Hospital, Cape Town (South Africa) Dear Sir, Rifampicin is a powerful enzyme inducer acting on the cytochrome P 450 enzyme system in the liver and thus may affect the metabolism of a number of drugs [1]. The interaction of rifampicin with glucocorticoids is well recognised and the adverse effect of this combination of drugs on renal allograft function has previously been reported [2]. It has been recommended that renal transplant recipients have their dose of prednisolone increased, by a factor of at least 2, should they be treated concurrently with rifampicin [3]. We report on a renal transplant recipient who developed low whole blood levels of cyclosporin whilst being treated with rifampicin for tuberculosis. A 57-year-old man with Balkan ne-hropathy and end-stage renal failure received a cadaveric renal allograft in March 1984. He had a past history of pulmonary tuberculosis and a grossly abnormal chest radiograph. At the time of surgery he received 250 mg of methylprednisolone intravenously, and immunosup-pression was achieved thereafter with methylprednisolone, 24 mg/day by mouth and cyclosporin A, 4 ml twice daily (13 mg/kg/day) diluted in orange juice. In addition, antituberculous therapy consisting of isoniazid, 300 mg, pyrazinamide 1,500 mg, and rifampicin, 450 mg, daily was commenced. There was immediate graft function following transplantation, the serum creatinine falling to 334 μmol/l (3.8 mg/dl) by day 2 and 165 μmol/l (1.9 mg/dl) by day 20 after transplantation. Whole blood cyclosporin levels (Sandoz Radioimmunoassay) fell progressively and remained low despite an increased dose of cyclosporin. Blood samples were drawn for the trough levels 1 h prior to the administration of the morning dose of cyclosporin and the peak levels were obtained at 4 h following the dose. On the withdrawal of rifampicin, blood levels of cyclosporin rose dramatically (fig. 1). Renal function has remained satisfactory and cycloCyclosporin dose, ml 9 9 8 8 8 8 8 9 10 10 10 10 10 10 10 10 9.5 95 9 9

Microalbuminuria and the metabolic syndrome in non-diabetic black Africans

It is recognised that the metabolic syndrome promotes the development of cardiovascular disease. Although several studies have shown a relationship between the metabolic syndrome and kidney disease, few of these have used non-diabetic subjects, especially in the African population. This was a cross-sectional study of subjects of African origin, using the metabolic syndrome (MS) criteria of the National Cholesterol Education Program (NCEP) third Adult Treatment Panel (ATP III). Subjects with impaired fasting glucose, with two-hour glucose ≥ 11.1 mmol/L after a glucose tolerance test, were excluded. Spot urine for albuminto-creatinine ratio (ACR) was measured and the glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) equation. Microalbuminuria was defined as ACR between 3–30 mg/mmol. There was a significant decline in GFR and a significant increase in ACR with increasing number of MS traits. ACR increased four-fold between subjects with no MS traits and those with four or more traits. In subjects with the metabolic syndrome, there was a significant correlation between ACR and systolic blood pressure (SBP), diastolic blood pressure (DBP) and fasting glucose. Estimated GFR correlated significantly and inversely with body mass index (BMI) and serum leptin. These observations raise major clinical and public health concerns for developing countries, where both the metabolic syndrome and kidney disease are being reported more and more frequently. The potential economic impact is huge.

Acute renal failure in community-acquired bacteraemia

Over a 1-year period, 239 patients with community-acquired bacteraemia in positive blood culture were prospectively evaluated to establish the prevalence and outcome of acute renal failure (ARF). Fifty-eight patients (24%) were identified as having ARF defined by a doubling or more in serum creatinine. The overall mortality in this group was 53% compared with 22% for patients with bacteraemia but without ARF (p less than 0.001). Within the ARF group there were two identifiable subgroups. Thirty patients had resolution of renal failure with treatment of the bacteraemia, and only 6 (20%) of these died. Of the remaining 28 where ARF persisted, 25 (89%) died (p less than 0.000001). Nine patients were dialysed, and only 2 survived. The majority of the remaining 24 patients died of overwhelming bacteraemia before dialysis was indicated. ARF is a common finding in community-acquired bacteraemia, and this has a poor prognosis particularly in those without early resolution of renal failure.

Does rural follow-up of renal allografts give impaired graft survival?

Abstract In this study, we compared the patient and graft survival after renal transplantation in patients followed up in rural centers against those in a major transplant center. There was a greater proportion of patients having a living related donor transplant and having prolonged cold ischemic times in the group followed up in a rural centre. The patient and graft survival at 1, 3 and 5 years were similar for local and rural patients. We conclude that a centralized transplant unit with follow‐up of patients in rural centers optimizes the use of highly skilled personnel.

Pentoxifylline Does Not Prevent Haemodialysis Induced Neutropaenia or Hypoxaemia

The aim of the study was to determine if oral pentoxifylline prevented dialysis induced hypoxaemia and neutropaenia. Fifteen stable chronic haemodialysis patients were routinely dialysed using either a cuprophane or cellulose acetate membrane. Bloods for white blood count (WCC) and pO2 were taken at time 0, 20, 80, 140 and 200 min. The procedure was repeated in the same patients 2 h after the ingestion of 400 mg of pentoxifylline. There was a highly significant drop in WCC at time 20 min and pO2 over the dialysis period, which was not prevented by pentoxifylline. Pentoxifylline levels taken at time 0 in 11 patients were in the therapeutic range and it is concluded that pentoxifylline does not prevent dialysis induced neutropaenia or hypoxaemia.