M.P. Nair

Induction immunosuppression with interleukin-2 receptor antibodies (basiliximab and daclizumab) in renal transplant recipients

KIDNEY transplantation is the treatment of choice for patients with end-stage renal disease. Acute rejection (AR) episodes are still a major problem in renal transplant recipients (RTR), predisposing them for chronic allograft dysfunction and graft loss. The search for more specific immunosuppressive agents to prolong graft survival has recently led us to focus on anti-interleukin (IL)-2 receptor antibodies (anti-IL-2Rab) in induction therapy. Two anti-IL-2 Rab are now approved for clinical use. They are biologically engineered to contain more human gene regions and fewer murine-derived regions. These are basiliximab (Simulect; Novartis, Basel, Switzerland) and daclizumab (Zenapax; Hoffman-La Roche, Switzerland). Reports of successful clinical trials of these agents in induction treatment of RTR is already available in the literature. These authors found anti IL-2 Rab useful for prevention of AR episodes and reported good tolerability. This paper reports on a prospective study of use of basiliximab (Simulect) and daclizumab (Zenapax) in induction immunosuppression in mismatched first renal transplants in our unit.

Cytomegalovirus infection in kidney transplant recipients: early diagnosis and monitoring of antiviral therapy by the antigenemia assay.

CYTOMEGALOVIRUS (CMV) is one of the most frequent infections in renal transplant recipients. After primary infection the virus remains dormant in various cells/organs for years. There are many factors that may reactivate virus replication; among them, organ transplantation certainly is the most important one, often causing serious disease and often associated with decreased graft survival. Though treatment is available, its timing and dosage should be tailored according to the ongoing CMV disease. There are different approaches for the diagnosis of CMV infections. The “gold standard” is cell culture in which the virus can be isolated. However, it is a timeconsuming and expensive procedure. Though combining virus isolation with immunofluorescence technique reduces the time from weeks to days, it is still not enough to meet the demand of a rapid diagnosis. Polymerase chain reaction (PCR) may have a strong impact on the diagnosis of CMV infection, but there is a need for further standardization and simplification. Many of the kidney transplant recipients fail to produce antibodies due to immunosuppressive therapy, making serological diagnosis undependable in CMV infections. Recently, detection of a specific CMV replication-related antigen (CMV antigen pp65) directly in leukocytes of patients has shown a good correlation with the clinical condition of the patient. This, CMV antigenemia assay (AA) seems to provide not only a reliable, specific, and sensitive diagnostic tool, but also facilitates monitoring the effectiveness of antiviral therapy.

Inferior Long-Term Outcome of Renal Transplantation in Patients with Diabetes mellitus

Objective: To retrospectively review the long-term outcome of renal transplant in diabetics at Mubarak Al-Kabeer Hospital and Hamad Al-Essa Organ Transplant Center, Kuwait from 1983 to 1998. Methods: There were 631 renal transplant patients, comprising 79 (12.5%) patients with pretransplant diabetes mellitus (pre-TDM), 117 (18.5%) patients with post-transplant diabetes mellitus and 435 (69%) nondiabetics (ND). Subjects with post-transplant diabetes mellitus were excluded from the comparative analysis. Distribution of sex, source of donors and mode of immunosuppression were similar in pre-TDM and ND groups. Results: Fifty-three (67%) recipients in pre-TDM and 90 (20.5%) in the ND group (p < 0.01) were above 45 years of age. However, 26 (33.3%) pre-TDM and 345 (79.5%) ND were below age 45. Among those who died, coronary artery disease led to death in 36% of pre-TDM and 27% in ND. Hyperlipidemia requiring drug therapy was observed in 37% pre-TDM and 6% ND. The incidence of severe infections was nearly twice in pre-TDM over ND recipients (1.9 vs. 1.0 per patient, p < 0.001). Acute rejection episodes were more frequently seen in pre-TDM (43%) than ND (33%), however the difference was not statistically significant. The patient survivals at 1, 5, 10, 14 years were significantly lower in pre-TDM (84, 65, 58 and 58%, respectively) than in ND (97, 93, 86 and 82%, respectively). The major contributory factors were severe infections and coronary artery disease. The cumulative graft survival showed a similar pattern (52% in pre-TDM, 73% in ND at 10 years). However, when death is excluded, the 10-year pure graft survival probability was similar for the pre-TDM and ND groups (76% vs. 80%). Conclusion: Our study indicates poor patient survival in pre-TDM due to coronary artery disease and infections, whereas the pure long-term graft survival was equally good in pre-TDM and ND transplant recipients.

Long-Term Follow-up of 100 High-Risk Renal Transplant Recipients Converted From Calcineurin Inhibitors to Sirolimus: A Single Center Experience

While conversion of stable renal transplant recipients (RTR) from calcineurin inhibitors (CNI) to sirolimus (SRL) is safe and effective, it is still under investigation for recent, high-risk cases. We studied the long-term effects of conversion of high-risk subjects maintained on a CNI, mycophenolate mofetil, plus steroid regimen to SRL, mycophenolate mofetil, plus steroid on graft and patient outcomes. We retrospectively reviewed the first 100 RTR converted to SRL treatment over approximately 5 years. The main indications for conversion were biopsy-proven acute rejection (BPAR), CNI toxicity, CNI elimination, and acute-tubular necrosis (ATN). Exclusion criteria were limited to bone marrow suppression. The overall mean +/- SD age was 38.5 +/- 15.6 years, including pediatric and geriatric age groups. Mean +/- SD body mass index (BMI) was 28.99 +/- 8.0 and 40% had a BMI > 30. There were 40% RTR from deceased donors and 60% showed 4 to 6 HLA mismatches. Preconversion total BPAR and steroid-resistant rejection incidences were 35% and 14%, respectively. Mean +/- SD time to start of SRL was 11.9 +/- 22.8 months posttransplantation. Proteinuria > 2 g/d, leukopenia, and hyperlipidemia increased significantly after conversion (P = .001, P = .0003, and P = .0001, respectively). Patient and graft survivals were 95% and 90%, respectively. There was significant improvement in graft function postconversion (P < .0001). There was a high incidence of side effects and cases of SRL discontinuation. Multivariate analysis demonstrated the influence of bone marrow suppression, obesity, hyperlipidemia, nutritional status, proteinuria, and graft function on graft and patient outcomes. We concluded that conversion from CNI to SRL was effective among high-risk RTR, but with a high incidence of adverse events during long-term follow-up.

Early sirolimus therapy in renal transplant recipients at high risk: is it justified?

BACKGROUND We studied early sirolimus (SRL) therapy in renal transplant recipients at high risk after administration of antithymocyte globulin or interleukin-2 receptor blockade induction. PATIENTS AND METHODS In 45 patients, SRL therapy was started within 1 month after transplantation. The primary indications for conversion of treatment from calcineurin inhibitors (CNIs)-mycophenolate mofetil (MMF)-steroid to SRL-MMF-steroid were biopsy-proved rejection (after treatment), CNI toxicity, CNI elimination, and acute tubular necrosis. Pediatric, geriatric, and other patients with medical comorbidities were not excluded. RESULTS Post-SRL rejection episodes were reported in 22.2% of recipients including 15.6% who were resistant to steroid therapy. Mean (SD) follow-up after SRL therapy was 59.9 (8.1) months. Proteinuria greater than 2 g/d (P = .001), leukopenia (P < .001), hyperlipidemia (P < .001), and transaminases values (P = .02) increased significantly after SRL therapy. Graft survival was 88.8%, and patient survival was 93.3%. There was significant improvement in serum creatinine concentration and estimated creatinine clearance by the end of the study (P < .001). A high incidence of adverse effects and infections was noted post-SRL therapy, and the drug was discontinued in 31% of patients because of multiple adverse effects. At multivariate analysis, age, hypertension, nutritional status, bone marrow suppression, hyperlipidemia, and graft dysfunction were identified as risk factors for worse graft and patient outcome. CONCLUSION Early treatment with combined SRL-MMF-steroid may be effective as a CNI-free immunosuppression regimen in patients at high risk; however, there is a high rate of adverse effects during long-term follow-up.

Successful therapy of acute vascular rejection with combined plasma-exchange and monoclonal antibody

ESPITE advances in the immunological monitoring of transplant recipients, better immunosuppressive drugs and understanding of humoral and cellular host responses, rejection remains a major cause of graft loss in kidney transplant recipients. The majority of grafts with acute vascular rejection (AVR) undergo irreversible loss of function as they fail to respond to increased levels of immunosuppression. 1 AVR is a clearly defined histological entity characterized by endothelial swelling and intimal mononuclear cell infiltration with or without fibrin deposits. Immunoflourescence examination shows deposits of IgM and C3 in the vessel wall in most cases. 2 While acute cellular rejection (ACR) usually responds to high dose steroids and/or antilymphocyte globulin, appropriate treatment of AVR is still not clear. There have been attempts at treating AVR with monoclonal CD3 antibody (OKT3), plasma exchange (PE) and steroids with variable results. 1‐ 6 Combined use of OKT3 and PE in the treatment of AVR has not been reported until today to the best of our knowledge. Hence, we report our limited experience in the treatment of AVR with combined use of OKT3 and PE.