A. Laures

Safety of the Allopurinol-Mycophenolate Mofetil Combination in the Treatment of Hyperuricemia of Kidney Transplant Recipients

Accessible online at: www.karger.com/journals/nef Dear Sir, Hyperuricemia is common in cyclosporine-treated renal allograft recipients. Its incidence is about 84% [1], and gout arthritis has been reported in 7–24% [1–3]. The mechanism of cyclosporine-induced hyperuricemia consists in increased proximal tubular urate reabsorption rather than decreased secretion [4, 5]. Other hyperuricemia risk factors are concurrent diuretic use and renal insufficiency due to allograft rejection. Allopurinol is the most effective treatment for hyperuricemia, but should generally be avoided in patients treated with azathioprine. The association of azathioprine and allopurinol frequently induces bone marrow depression. The mechanism of action of the antimetabolite agent mycophenolate mofetil (MMF) is similar to that of azathioprine, but it is relatively selective on lymphocyte activation and its interference with other cellular lines is minor. A study was conducted in renal transplant recipients with severe hyperuricemia and articular gout, with the aim of investigating whether the combination of allopurinol and MMF also induces bone marrow depression. Twenty-two patients were studied, 15 males and 7 females. The mean age was 44 B 14 years. Three patients were excluded, 1 for MMF intolerance and 2 for defective data collection. Nineteen patients were available for study. Allopurinol was administered at a dose of 100 mg/day. Determinations of uric acid, leukocytes, hemoglobin, platelet count, alanine aminotransferase, serum creatinine and cyclosporine levels were measured before treatment and after 30 and 60 days. Clinical symptoms and related adverse effects were also recorded. The immunosuppressive protocol treatment consists of prednisone, cyclosporine and MMF (2 g/day). Results are expressed as mean B SE. Comparisons were made suing Friedman’s test. p values ! 0.05 were considered statistically significant. Uric acid levels (mg/dl) were 13.5 B 1.5 before treatment, 8.7 B 1.5 after 30 days and 8.3 B 1.3 after 60 days (p ! 0.0001; fig. 1). Leukocyte counts (n/mm3) were 8,564 B 3,294 before treatment, and 8,499 B 2,102 and 8,019 B 2,143 at days 30 and Fig. 1. Uric acid levels before treatment, on days 30 and 60. p ! 0.0001 (Friedman’s test). 0

Influence of anticalcineurinic therapy in plasma homocysteine levels of renal transplant recipients: a prospective study.

Hyperhomocysteinemia is an independent factor for cardiovascular disease. Renal function and folate level are important determinants of total plasma homocysteine levels. The influence of anticalcineurin drugs on homocysteine levels is controversial. The aims of the study were: (1) to analyze changes in homocysteine levels after the first year of 73 renal transplants and (2) to determine the influence of immunosuppressive anticalcineurin drug therapy on fasting homocysteine concentrations. We examined homocysteine, serum creatinine, folate, and vitamin B12 concentrations immediately after transplant, at 6 months, and after 12 months from renal transplant. Also, MTHFRC677T polymorphism was investigated. Tacrolimus was administered in 28 patients and cyclosporine in 45. Homocysteine levels decreased from 28.41+/-13.71 micromol/L to 18.59+/-8.31 micromol/L after 6 months and to 17.13+/-7.06 micromol/L after 1 year. No relationship was found between homocysteine and folate levels. When anticalcineurin drugs were considered, the homocysteine levels in patients treated with tacrolimus was lower than that in patients treated with cyclosporine at month 6 after transplant (16+/-7.4 micromol/L vs 20.1+/-8.5 micromol/L, P=.03) and after 1 year (15+/-7.6 micromol/L vs 18.4+/-6.4 micromol/L, P=.04). Serum creatinine levels followed the same evolution: they were lower in patients treated with tacrolimus at 6 months (1.35+/-0.36 mg/dL vs 1.57+/-0.45 mg/dL, P=.03) and to a lesser extent at 1 year after renal transplant (1.38+/-0.35 mg/dL vs 1.54+/-0.45 mg/dL, P=.09). The homocysteine value closely related with serum creatinine in both groups. In conclusion, 1 year posttransplant, the homocysteine level was lower among patients treated with tacrolimus, the cohort that also showed the lower serum creatinine concentrations.

Disseminated Herpes simplex Virus Infection in a Renal Transplant Patient as Possible Cause of Repeated Urinary Extravasations

Disseminated herpes simplex virus type 2 (HSV-2) infections are infrequent in patients receiving organ transplants, but usually have a poor outcome. We describe the case of a renal transplant patient who developed a disseminated HSV-2 infection with repeated urinary extravasations. The diagnosis was carried out using a multiplex polymerase chain reaction nested assay and it suggested HSV-2 as a possible cause of repeated urinary fistulas.

Control of Cytomegalovirus Disease in Renal Transplant Patients Treated with Prednisone, Azathioprine and Cyclosporine Using Intensive Monitoring and Decreased Immunosuppression

Background: 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. Methods: 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 105 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. Results: 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. Conclusion: 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.

Ganciclovir prophylasis and β‐herpesvirus in renal transplant recipients

The use of ganciclovir prophylaxis to avoid cytomegalovirus (CMV) disease (CMVD) is extended, but little is known about its effect to inhibit the replication of the new b-herpesviruses (HHV-6 and HHV-7), associated with development of allograft rejection, marrow suppression and predisposition to CMVD[1]. The purpose of this study was to analyze the effects of oral ganciclovir (GCV) prophylaxis on CMV, HHV-6 and HHV-7 viremia in renal transplant recipients (RT), in the first 3 months after transplantation. The study included 134 patients (50 ± 13 years old) undergoing cadaveric kidney transplantation (according the local ethics committee), which received triple immunosuppressive therapy, including cyclosporine A, steroids and mycophenolate–mofetil (114 RT), or azathioprine (11 RT), or rapamicin (nine RT). According GCV prophylaxis (1 g/8 h adjusted to renal function), three groups were established: 54 without GCV (G1), 29 with <30 days of GCV prophylaxis [short-term prophylaxis (STP)] and 51 with more than 60 days of GCV [long-term prophylaxis (LTP)]. From the 134 RT, 2178 peripheral blood leukocytes samples (PBL) collected weekly after transplant to detect CMV viremia by nested-PCR and antigenemia, and 1242 of them collected every 2 weeks to detect HHV-6 and HHV-7 DNAemia by nested-PCR, were analyzed. Protocols were developed in our laboratory, according standards recommendations. The results of incidence, apparition and duration of CMV, HHV-6 and HHV-7 viremia are shown in Table 1. In our study, the use of GCV prophylaxis decreased significantly CMV replication as other authors had previously described [2]. Nevertheless, CMV viremia was present in 14 patients during the course of GCV prophylaxis (two STP and 12 LTP). In STP, maximum CMV-Ag was higher than in the other two groups: 59.3 ± 83.8 (1–290) positive cells per 10 PBL versus 27.2 ± 41.9 (1–200) and 22.8 ± 54.2 (1–200) for G1 and LTP respectively. CMVD occurred in eight RT (15%) from G1, in three (10.4%) from STP, and in two (3.9%) from LTP (P 1⁄4 0.1). All these facts may imply a potential emergence of GCV resistance as it has been described [3–5], and suggest increasing vigilance for antiviral resistance. No influence has been reported from GCV on HHV-6 incidence. But, HHV-6 replication suffered a delay with prophylaxis, and the duration of viremia was shorter significantly in patients with antiviral prophylaxis (Table 1), according with Yoshida et al. [6]. No relationship has been observed between GCV prophylaxis and incidence, apparition or duration of HHV-7 viremia, as it has been described [7].