Infectious Complications in Renal Transplant Recipients: Changing Epidemiology under Modern Immunosuppression / 대한이식학회지

BACKGROUND: Immunosuppressive agents with higher potencies, such as tacrolimus and mycophenolate mofetil (MMF), have been introduced and widely accepted in clinical practice. This study evaluated the impact of these newer immunosuppressive drugs on the pattern and timing of post-kidney transplantation infections. METHODS: Data of kidney transplant recipients at the Seoul National University Hospital between January 1990 and November 2005 were analyzed. Recipients were divided into double immunosuppression (double group, n=198), triple immunosuppression including MMF (MMF group, n=253), and azathioprine (AZA, n=184) groups. RESULTS: The MMF group demonstrated higher graft survival and reduced rates of acute rejection within the fifth post-transplant year than both the AZA (P<0.001) and the double (P<0.001) groups. The overall incidence of infection in the first month was significantly higher in the MMF group (2.17/1,000 transplant-days) than in the AZA (0.73/1,000 transplant-days) and double (0.84/1,000 transplant-days) groups (P=0.01, ANOVA), and this was caused by viral infections that were significantly higher in the MMF (1.57/1,000 transplant-days) group than in the AZA (0.54/1,000 transplant-days) and double (0.67/1,000 transplant-days) groups. MMF was identified as a significant risk factor for viral infection (P=0.013; OR, 2.04; 95% CI, 1.16-3.60) in a multivariate logistic regression analysis. CONCLUSIONS: The results suggest that viral infection rates were higher in the MMF group and should be considered the primary source of perioperative infectious complications in MMF-receiving recipients.

Eficacia del mofetil micofenolato en el tratamiento de la hepatitis autoinmune en pacientes resistentes o intolerantes a tratamiento convencional

Evaluar la eficacia del Mofetil Micofenolato (MMF) como opción terapéutica en pacientes con Hepatitis Autoinmune (HAI), que no responden o no toleran la prednisona y/o azatioprina. Pacientes y métodos: se evaluaron 6 pacientes con diagnóstico de HAI tipo 1, entre 36 a 61 años, quienes fueron tratados inicialmente con Azatioprina sola o combinada con esteroides sin respuesta bioquímica, o con intolerancia a estos medicamentos. Se administró 1 g B.I.D a todos los pacientes, 2 pacientes recibieron sólo MMF y 4 pacientes recibieron esteroides a dosis mínimas y MMF. Se evaluó el efecto del MMF en el valor de las enzimas hepáticas (AST y ALT), de la bilirrubina y en la concentración de inmunoglobulina G (IgG), los cuales se determinaron después del inicio del MMF cada 3 a 6 meses. Los pacientes fueron evaluados durante 27-19 meses. Resultados: los valores de AST, ALT mejoraron de 3 a 26 veces en los 6 pacientes y se normalizaron en 3 pacientes; la bilirrubina y la concentración de IgG disminuyeron de 1 a 5 veces su valor en los 6 pacientes. Conclusiones: el MMF en HAI, solo o en combinación con esteroides resulta eficaz para el control de la inflamación hepática demostrado por la mejoría de los parámetros bioquímicos y disminución de IgG, por lo que puede ser una alternativa para el tratamiento de pacientes seleccionados con HAI.

To assess the value of mycophenolate mofetil (MMF) as a therapeutic option in patients with autoimmune hepatitis (AIH), who did not respond or not tolerate prednisone and/or azathioprine. Patients and methods: Six patients with AIH were studied; age range between 36 and 61 years old, were evaluated. Initial treatment in all patients was azathioprine alone or combined with prednisone who did not demonstrate biochemical response or patients who could not tolerate this former treatment. All patients received MMF 2 g/day, 2 patients received MMF alone and 4 patients received minimal doses of steroids and MMF. Endpoints were normalization or improvement in liver function tests and immunoglobulin G (IgG) concentration. Patients were followed-up after they started treatment with MMF every 3 months during 27 μ19 months. Results: AST and ALT levels improved in 6 patients 3 to 26 times their value, and normalized in 3 patients; bilirrubin and IgG were in the normal range after treatment in all patients. Conclusions: MMF in AIH was effective and well tolerated and all patients showed improvement in liver function test (AST, ALT, and TB) and normalization of IgG. MMF seems to be an alternative treatment in selected patients with AIH.

Analysis of Long Term Follow Up Result between Cycolosporine Based Azathioprine versus Mycophenolate Mofetil Groups Randomized after Renal Transplant / 대한이식학회지

PURPOSE: Mycophenolate mofetil (MMF) has been used widely due to lesser acute rejection episode, better renal function and graft survival than azathioprine (AZA). But currently, there is controversy that which combination of immunosuppressants is most beneficial and cost-effective for renal transplant, because some authors reported MMF was related to more infectious complications and no actual superiority to AZA in aspect of graft survival. So, the aims of this study is to compare the long term outcome of renal transplants and the infectious complications between two groups treated with AZA and MMF in CSA based immunosuppressant treatment at our hospital. METHODS: We retrospectively reviewed allograft recipients who had been transplanted from January of 1998 to July of 2000. 301 patients were enrolled (AZA=150/MMF=151) and analyzed for the incidence of acute rejection, infectious complication, renal function and graft survival. RESULTS: Patients treated with MMF had fewer episodes of acute rejection (AR) within 3 months; 4/151 (2.6%) in MMF versus 15/150 (10%) in AZA (P=0.017), but after 3 months there was no difference in the incidence of AR. However, the patients treated with MMF had more infectious complications such as pneumonia, cytomegalovirus (CMV) infection, but there were no differences in urinary tract infection. There were also no differences in creatinine level at postoperative 1 week, discharge, 1 year, 3 year and 5 year. Graft survival and patient survival after 1 year and 5 showed no statistical differences between two groups. CONCLUSION: MMF combined with CsA was more effective in the prevention of acute rejection within 3 months than AZA, but there was no long term significant difference in renal function, graft and patient's survival. Due to higher incidence of pneumonia and CMV infection in MMF group, it is necessary to choose the combination of immunosuppressants (AZA versus MMF) more appropriately considering efficacy of immunosuppression and infectious complication as well.

Effects of Mycophenolate Mofetil on Minimal Change Nephrotic Syndrom / 医学研究杂志

Objective To detecte the changes of nephrin in adriamycin nephropathy rats, study the effects of mycophenolate mofetil on minimal change nephrotic syndrome, investigate its possible mechanism. Methods 18 SD rats were randomly divided into three groups: control group(CG, n=6), adriamycin model group(AG, n=6), MMF treated group(TG, n=6). Rats in MG and TG were given adriamycin 7.5mg/kg through vena caudalis. At the same time, an equal volume of normal saline was given to the rats in CG by the same method. The rats in TG received MMF 20mg/(kg?d) by daily gastric gavage from the second day. Urinary protein excretion of each rat were measured at the day before adriamycin injection,and the 14th day and the 28th day after adriamycin injection. Six rats of each group were killed at the 28th day. Serum urea nitrogen, creatinine, cholesterol, triglyceride and albumin were measured at the end of the study. Immunohistochemistry and western blot were used to examine the expression of nephrin. Results The urinary protein excretion of AG at 28th day was the highest. Serum albumin decreased markedly at the 14th day(p

Mycophenolate Mofetil Therapy in Severe Membranous Nephropathy and Diffuse Proliferative Lupus Nephritis: Clinical Observation / 대한신장학회잡지

OBJECTIVE: Although cyclophosphamide (CYC) is effective for the treatment of diffuse proliferative lupus nephritis (DPLN) and severe membranous nephropathy (MN), it has serious adverse effects. Therefore, we evaluated our clinical observations with mycophenolate mofetil (MMF) for empirical treatment of DPLN and severe MN. METHODS: Seventeen patients with biopsy proven severe MN (n=8) and DPLN (n=9) received MMF for > or = 6 months as primary treatment (n=9) or subsequent maintenance therapy after CYC treatment (n=8). Treatment outcome was evaluated by random urine protein/creatinine ratio (UP/Cr) and serum creatinine (sCr) at the start and at 12 months and compared by the Wilcoxon signed-rank test. RESULTS: Overall, the mean (+/-SD) UP/Cr decreased in both MN (6.48+/-3.03 vs. 1.31+/-1.22, p= 0.016) and DPLN (3.77+/-2.34 Vs 0.83+/-0.53, p=0.043) patients. No significant change in serum Cr was detected in both MN and DPLN patients. Adverse events included nausea/abdominal discomfort (n=1) and menstrual irregularity (n=1). CONCLUSION: Short term empirical treatment with MMF in the majority of patients with severe MN and DPLN was well tolerated and effective in decrease of proteinuria and stabilization of renal function. Controlled clinical trials are necessary to define the role of MMF in the treatment of severe MN and DPLN.

MMF-related Colitis Carrying GVHD-like Pathologic Feature in Renal Transplant Recipient / 대한이식학회지

BACKGROUND: Graft-Versus-Host Disease (GVHD) is known to be associated with bone marrow transplantion. It is very rare in solid organ transplantation, especially in renal transplantation. There were only a few reported cases of GVHD in pancreas, liver transplant recipients or transfusion associated GVHD in immunocompromised patients. CASE: A 36 years-old man received renal transplantation from his mother on May 20th, 1996. Cyclosporine A, azathioprine & prednisolone were used as immunosuppressants. There was no episode of acute rejection after transplantation. After transplantation, he suffered from cytomegalovirus (CMV) cystitis, bile duct stones. He had never been transfused blood products since transplantation. Thereafter, his post-transplantation course was quite favorable until December 20th, 2003, when troublesome diarrhea and weight loss developed. At that time, he was taking 1.25 g/day of MMF (25 mg/kg/day). Hospital course: The MMF dose was reduced to 500mg bid (312 mg/m2/dose or 20 mg/kg/day) under the suspicion of CMV colitis. The results of serologic test and culture for CMV were all negative. The colonoscopic biopsy revealed pathologic features such as crypt drop-out, crypt abscess, crypt atrophy, single cell apoptosis and goblet cell depletion just like in GVHD. He had no necrotic skin lesion and his liver function test was in normal range. However, his complete blood count showed pancytopenic features. The MMF was discontinued immediately after the pathologic results were reported. His diarrhea and other clinical sym-ptoms were disappeared, and the pancytopenic features recovered gradually after discontinuation of MMF. He also gained 2.6 kg weight and discharged with good graft function.

Mycophenolate Mofetil Versus Azathioprine in Cyclosporine Based Triple Immunosuppression / 대한이식학회지

PURPOSE: Recent studies have demonstrated improved outcome in renal transplant recipients treated with mycophenolate mofetil (MMF). We compared the outcome of allograft treated with MMF versus AZA in CsA/prednisolone based immunosuppressant treated renal transplant at our center. METHODS: We retrospectively reviewed allograft recipients who had been transplanted from Jan. to Dec. 1998 in AZA group (n=87) and Jan. to Dec. 1999 in MMF group (n=99). The variables of donor and recipient as well as the survival factors were compared between the two groups. And the adverse effects of MMF and AZA were analyzed. Duration of follow-up was one year, respectively. RESULTS: Between the two groups, there were no significant differences in sex, age, type of donor, ABO and HLA mismatches. Patients treated with MMF and CsA had significantly fewer episodes of rejection; 5/99 (5.1%) in MMF versus 13/87 (14.9%) in AZA (P<0.05). In the MMF group, patients with higher dose (1.5 g/d) had lower rejection rate than those with lower dose, illustrating the dose dependant immunosuppressive effect. However one-year allograft survival did not show any significant difference between two groups (96.9% in MMF versus 97.7% in AZA). Gastrointestinal symptoms such as diarrhea were more common in MMF group but hepatotoxicity and leukopenia were more prevalent in AZA group. CONCLUSION: While the one-year graft survival following renal transplantation was similar between the MMF and AZA group, lower rejection rate in MMF group suggests the favorable long term graft survival with MMF.

The Influence of Mycophenolate(MMF) and Azathioprine(AZA) in the Same Cadaveric Renal Transplantation / 대한신장학회잡지

OBJECTIVE: In order to evaluate how immunosuppressive agents such as MMF and AZA would influence on the outcome of the graft kidney, we analyzed the incidence of acute rejection episodes and one year graft survival rate after minimizing influences of donor factors by grafting the same cadaveric donor kidney. METHODS: From April, 1998 to January, 2000, sixty eight patients grafted by 34 cadaver donors were enrolled in our study. From the same donor, one was randomly assigned to the MMF group(n=34) who were treated with cyclosporine, MMF, prednisolone while the other kidney was assigned to the AZA group(n=34) with cyclosporine, AZA, prednisolone. We analyzed the incidence of acute rejection episodes and CMV infection within the first 6 months of renal transplantation and one year graft survival rate was studied prospectively. RESULTS: There were no significant differences in sex, HLA mismatch, cold ischemic time, and patients' weight between two group. Acute rejection or treatment failure occurred in 35.3% in the MMF group by 6 months after transplant, compared with 32.4% in the AZA group without statistic significance(12/34 vs. 11/34, p>0.05). One year graft survival rate was 91.2% and 97.1%, respectively, and CMV infection was documented in 4 patients(1/34 vs. 3/34, p>0.05). CONCLUSION: There were no significant differences in the incidence of acute rejection episodes and one year graft survival rate between two groups. In contrast, previous studies showed that MMF could have lowered the incidence of acute rejection episodes and improved graft survival rate. This discrepancy in results might be explained that donor factors were important to cadaveric renal transplantation. Thus, we suggest that the influences of donor factors should be considered in further clinical study of cadaveric renal trans-plantation.

Protective role of mycophenolate mofetil on renal tubulointerstitial injury of diabetic rats / 中国药理学通报

Aim To observe the effect of mycophenolate mofetil(MMF) on expressions of MCP-1 and CD68 in renal tubulointerstitial injury of diabetic rats and explore the mechanism of MMF′s protective role.Methods Diabetes was induced in uninephrectomized male Wistar rats by peritoneal injection of STZ (65 mg?kg-1). Rats were randomly divided into three groups:control group (NC),diabetic group (DM) and treated group (DM+MMF) with MMF(15 mg?kg-1?d-1).This study lasted for 8 weeks. 24 h urinary protein,blood glucose and the ratio of left kidney weight/body weight were determined after 8 weeks.The renal tubulointerstitial morphological change was observed,immunohistochemical method was used to analyze expressions of MCP-1 protein and CD68. Expression of MCP-1 mRNA in renal tissue was measured by quantitative Real-time PCR.Results Compared with NC group, serum glucose level,24 hour urinary protein and the ratio of left kidney weight/body weight were significantly increased(P