Cytomegalovirus Disease of Late Onset Following Renal Transplantation: A Potentially Fatal Entity
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Abstract:
CMV disease (CMVD) is a recognized problem of the early post-transplant period (PTP) in renal transplant recipients. Information on CMVD in the late (< 2 years) PTP is scarce. We have observed 5 cases of CMVD during late (3–8 years) PTP during the last 15 years. Three of these patients died from CMVD. One of the patients with late-onset CMVD recovered spontaneously from mild pneumonitis, 1 patient with severe CMVD after therapy with ganciclovir/anti-CMV-IgG. CMVD was ascribed to primary infection in 4/5 patients, and transmission was attributed to blood products in 2 cases. At the time of CMVD, 4/5 patients were on stable immunosuppression with azathioprine/prednisone; 1 patient who died had received prednisone pulses 1 month prior to CMVD. Late onset CMVD is an underreported disease in renal transplant recipients, which warrants preventive measures and consideration of antiviral therapy.Keywords:
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WILKINSON, ALAN H.; SMITH, JOHN L.; HUNSICKER, LAWRENCE G.; TOBACMAN, JOANNE; KAPELANSKI, DAVID P.; JOHNSON, MARYL; WRIGHT, FRANCIS H.; BEHRENDT, DOUGLAS M.; CORRY, ROBERT J. Author Information
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<i>Background:</i> The aim of this trial was to study the effectiveness of intensive monitoring, together with an early decrease in immunosuppression, in reducing the prevalence of CMV disease in renal transplant recipients treated with prednisone, azathioprine and cyclosporine. <i>Methods:</i> From 1/95 to 11/97 a prospective, longitudinal study was conducted among 146 consecutive, unselected, renal transplant patients in our unit. Only 96 patients whose immunosuppressive regimens consisted of prednisone, azathioprine and cyclosporine and whose follow-up period was greater than 4 months were included in the study. Preemptive therapy was administered to 27 high-risk patients. CMV antigenemia (CMV-AG) and other virological tests were performed weekly for the first 4 posttransplant months. The immunosuppression was decreased when the first positive CMV-AG was detected. Azathioprine was completely withdrawn when the CMV-AG count was greater than 10 cells per 10<sup>5</sup> PBLs. The cyclosporine dose was gradually decreased in the next 4 weeks, but it was not withdrawn in any patient. The prednisone dose was modified according to the immunosuppressive protocol. <i>Results:</i> 53% (51/96) of the patients had positive CMV-AG on at least one occasion. The dose of azathioprine was decreased after CMV-AG detection in 41/51 (80.4%) patients and it was completely withdrawn in 23 of these (45%). The mean decrease in the dose of azathioprine was 73 ± 31 (25–175) mg, a mean percentage decrease of 76 ± 27% (25–100%). The dose of cyclosporine was progressively decreased during the 4 weeks after detection of the first CMV-AG (mean cyclosporine levels: 210 ± 66, 196 ± 54 and 164 ± 36 ng/ml at the time of first CMV-AG detection, 2 and 4 weeks respectively, p < 0.0001, repeated measures analysis of variance). None of the 45 patients without CMV-AG and only 2 of 51 (3.9%) patients with CMV-AG developed symptomatic CMV disease (2% of the total). CMV disease was of moderate intensity in both patients. Only 3/51 (5.8%) patients developed acute rejection after the first CMV-AG detection in the 4 posttransplant months. <i>Conclusion:</i> The results of this study suggest that intensive monitoring and an early reduction of immunosuppression, together with preemptive therapy in high-risk patients, is effective in diminishing the prevalence and severity of CMV disease.
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As a result of introduction of quadruple immunosuppression using cyclosporine, antithymocyte globulin, azathioprine and prednisone in immunological high-risk patients with a presensitization greater than or equal to 80% and/or multiple grafts the rate of immediate graft function could significantly increased, the frequency of rejection and graft rupture was reduced and the patient survival rate could improved to 100%. The problem of vascular rejection should resolved by a more aggressive biopsy approach.
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Since 1981, at the University of Minnesota, and more recently at Washington University in St. Louis, cyclosporine has been used as the main immunosuppressive agent for heart transplantation. It was initially combined with prednisone and given in a manner similar to that described at Stanford. In late 1983, concern regarding the nephrotoxic side effects of cyclosporine were heightened due to the fact that a potential recipient had chronic renal insufficiency secondary to renal damage suffered during previous heart surgery. In this patient it was decided to use lower doses of cyclosporine and to add azathioprine to maintain adequate immunosuppression. Initially, the same prednisone therapy was employed. This patient had an uncomplicated course following heart transplantation and was discharged with a normal renal function. This experience was the origin of a trial consisting of using cyclosporine, azathioprine, and prednisone as immunotherapy for heart transplantation. This report describes the results of this therapy in 17 patients.
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Since 1990, 82 unselected renal allograft recipients were evaluated in order to establish the incidence of cutaneous disorders. This pathology was related to the period of immunosuppression according to time of transplantation: 0-3 months; 3-12 months; 12-36 months and beyond 36 months. Most of them were on triple immunosuppression (cyclosporine A, azathioprine and prednisone)--(51); Twenty-two also associated anti-timocyte globulin five days after transplantation; 7 were on Azathioprine and Prednisone and two of them associated Cyclosporine with Prednisone. Iatrogenic manifestations were the most common (80.5%) followed by infections in 63.4% and pre-malignant and malignant cutaneous lesions in 13.4%, other types of manifestations were found in 20.7% of patients. A significant incidence of pre-malignant and malignant lesions confirms other reports, making a dermatological surveillance advisable.
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An immunosuppressive regimen consisting of azathioprine (AZ), prednisone, and intermittent i.v. infusions of 400 mg of cyclophosphamide (CY) in the first post-transplant month was prospectively compared with a no CY regimen. There were no significant differences in patient or graft survival, graft function, or infectious complications between the two regimens.
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