Jean-Paul Squifflet

BACKGROUND: To confirm the results of a number of studies conducted in Europe, the United States, and Japan, this multicenter, randomized trial compared the 12-month efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens in the prevention of renal allograft rejection. METHODS: A total of 448 renal transplant recipients were recruited from 15 centers and assigned to receive triple-drug therapy consisting of tacrolimus (n=303) or cyclosporine (n=145) in conjunction with azathioprine and low-dose corticosteroids. RESULTS: At 12 months after transplantation, tacrolimus therapy was associated with a significant reduction in the frequency of both acute (tacrolimus 25.9% vs. cyclosporine 45.7%; P<0.001 [absolute difference: 19.8%, 95% confidence interval: 10.0-29.6%]) and corticosteroid-resistant rejection (11.3% vs. 21.6%; P=0.001 [absolute difference: 10.3%, 95% confidence interval: 2.5-18.2%]). Actuarial 1-year patient (tacrolimus 93.0% vs. cyclosporine 96.5%; P=0.140) and graft survival rates (82.5% vs. 86.2%; P=0.380) did not differ significantly between the two treatment groups. Overall, the safety profiles of the tacrolimus- and cyclosporine-based regimens were quite comparable. Infections, renal impairment, neurological complications, and gastrointestinal complaints were frequently reported but were mostly reversible in both groups. Higher incidences of elevated serum creatinine, tremor, diarrhea, hyperglycemia, diabetes mellitus, and angina pectoris were reported in the tacrolimus treatment group, whereas acne, arrhythmia, gingival hyperplasia, and hirsutism were more frequent with cyclosporine treatment. CONCLUSIONS: The significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival.

BACKGROUND: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. METHODS: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. RESULTS: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05). CONCLUSIONS: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

Renal graft recipients with hepatitis B virus (HBV) infection are at increased risk of fatal outcome when they have serological evidence of active viral replication, such as HBV DNA and/or hepatitis B e antigen (HBeAg) in the serum (1). Interferon-α therapy is precluded in such cases by its attendant high risk of severe graft rejection(2,3). Rostaing and co-workers(4) now report the benefits of lamivudine in six renal graft recipients with active HBV replication. Lamivudine, a new nucleoside analog, inhibits HBV replication in patients infected by HBV (5,6) and prevents HBV recurrence after liver transplantation(7,8). In the six reported patients, HBV DNA cleared rapidly from the serum, whereas elevated alanine aminotransferase(ALT) levels in five cases promptly returned to normal. Unfortunately, withdrawal of the drug in four patients after 6 months resulted in a prompt biochemical and virological relapse. The rarity of such reports prompted us to report our experience with an additional four cases of kidney graft recipients with severe HBV infection who were given 100 mg of lamivudine daily. We extend the observations of Rostaing et al., as our follow-up period was longer (range, 15-21 months), and illustrate two potential drawbacks of the therapy, i.e., a major flare-up of the liver disease after inadvertent withdrawal of treatment and the emergence of a resistance to the drug in another patient. The four male patients, aged 52 years (range, 44-62 years), had maintained their transplants for an average period of 13 years (range, 0.5-21 years)(second transplantation in one patient). Maintenance immunosuppression at the time of lamivudine onset consisted of prednisolone and cyclosporine in three patients and prednisolone and azathioprine in one patient(Table 1). They were known to be hepatitis B surface antigen (HBsAg)-positive for an average of 20 years (range, 15-23 years); HBV status at lamivudine onset was HBsAg (n=4), HBeAg (n=1), hepatitis B core antibody (HBcAb) (n=4), and hepatitis B e antibody (HBeAb)(n=3) (Abbott Laboratories). HBV DNA (detection limit of 1.5 pg/ml; Abbott hepatitis B viral DNA, Abbott Laboratories) was detected in the serum of all patients. None of them had anti-hepatitis C virus antibody (ELISA-III, Abbott Laboratories). All had severe impairment of liver function, as assessed by a very low level on the aminopyrine breath test (mean value at beginning of therapy: 1.10% [range, 0.37-1.46%; normal value: 2.8%]). A transjugular liver biopsy performed in three patients demonstrated severe liver cirrhosis (n=1), chronic aggressive hepatitis (n=1), and a normal HBsAg carrier status (n=1) (Table 1).Table 1: Individual characteristicsAs shown in Figure 1, lamivudine promptly reduced the HBV DNA serum concentration in all patients; the other HBV markers remained unchanged. Within 6 months of therapy, ALT levels normalized in all patients (from an average of 78.5±76.7 IU/L [median ± SEM] to 20±5.2 IU/L; normal value: 5-32 IU/L). The aminopyrine breath test, repeated in two patients after 12 and 18 months of treatment, increased from 1.11% and 0.37% to 1.74% and 0.77%, respectively. The serum creatinine level (median ± SEM) rose slightly in all patients, from 1.73±0.16 mg/dl at baseline to 1.89±0.17 mg/dl at 6 months and 1.90±0.07 mg/dl (n=3) at 12 months. Cyclosporine trough levels remained unchanged. No adverse effect of lamivudine was reported. Patients 2 and 3 are currently doing well 21 and 16 months after onset of treatment. In patient 1, both ALT and HBV DNA levels rose sharply between 9 and 12 months of treatment (Fig. 1). He subsequently developed severe hepatic failure and eventually died after surgery for massive hemochesia 17 months after lamivudine onset. A mutation in the YMDD locus of the HBV polymerase gene (9-11) was thereafter demonstrated. In patient 4, lamivudine was inadvertently withdrawn after aortic dissection surgery. Severe transient hepatic encephalopathy occurred. Despite the fact that lamivudine was resumed after 10 days of interruption, ALT levels rose from 31 to 545 IU/L and the HBV DNA level sharply increased(see Fig. 1). The branched DNA concentration (detection limit of 0.7 mEq/ml; Chiron Corp.), which was 2004 mEq/ml at lamivudine resumption and 7359 mEq/ml 19 days later, has decreased to 927.5 mEq/ml. Unfortunately, the patient developed hepatic encephalopathy and liver failure, and he eventually died.Fig. 1: HBV DNA levels.We therefore confirm that in kidney graft recipients with sever HBV infection, lamivudine effectively inhibits HBV replication with an attendant improvement of liver tests. This effect was observed despite the continuation of maintenance immunosuppression. A severe flare-up of the hepatitis, however, was observed in two patients during follow-up. In one of them, the flare-up was caused by the emergence of a resistance to the drug after less than 12 months of treatment; in the other patient, the flare-up followed lamivudine withdrawal. Both findings have previously been reported(4,5,8-11). The latter complication suggests that once started, lamivudine treatment should not be withdrawn. Given the unfavorable prognosis of chronic HBV infection in kidney graft recipients, the advent of a drug able to inhibit HBV replication is welcome. Together with the data of Rostaing and co-workers, our data are sufficiently encouraging for a larger study of the effect of lamivudine in HBV DNA-positive kidney graft recipients to be undertaken. This study should be reserved for patients with advanced HBV liver disease, since lamivudine is likely to be a lifetime therapy. The risk of resistance to the drug with its attendant effect on the course of liver disease should be evaluated in the long-term. Eric Goffin Yves Horsmans Chantal Cornu Jean-Paul Squifflet Yves Pirson Departments of Nephrology, Hepatology, Virology, and Renal Transplantation; Louvain Medical School; Hôpital Saint-Luc; 1200 Brussels, Belgium

Background System factors increasingly are suggested as important yet understudied correlates of nonadherence. Objective To explore the relationship between healthcare system and prevalence of nonadherence with immunosuppressive regimen by studying variation in nonadherence between European and US kidney transplant recipients and as well as nonadherence in European countries. Methods We performed a secondary data analysis on data collected in 3 independent cross-sectional studies using comparable methodology including patients from the United States, the Netherlands, Belgium, and Switzerland. Nonadherence was measured using 1 item of the Siegal questionnaire. Patients were categorized as nonadherent if they reported missing a dose of immunosuppression in the last 4 weeks. Analyses were performed by multiple mixed logistic regression, with center as a random effect and clinical and demographical differences between groups as fixed effects. Results 1563 US and 614 European patients from 3 different countries (Belgium [n=187], the Netherlands [n=85], and Switzerland [n=342]) were included. Prevalence of nonadherence in the United States and Europe was 19.3% and 13.2.%, respectively. This higher nonadherence in US patients was confirmed in a multiple logistic regression analysis (OR=1.78; 95% CI, 1.10–2.89). Nonadherence differed between Belgium (16%) and the Netherlands (14.1%) (OR=0.27; 95% CI, 0.09–0.80) and between Belgium and Switzerland (11.4%; OR=0.17; 95% CI, 0.0–0.42). Conclusion This is the first study showing differences in prevalence of nonadherence between European and US patients and among European patients. Further research should aim at unraveling the dynamics explaining these differences.

Abstract Malakoplakia is a rare pseudotumoral inflammatory disease known to affect immunocompromised subjects, mainly with a history of recurrent Escherichia coli infection. The urinary tract is the most frequent site of the disease, although all organs can be involved. In the present article, we report a case of malakoplakia of the caecum, that developed in a 52-year-old man, who had received a kidney transplant 9 years before and had a history of recurrent E. coli urinary tract infections. Malakoplakia presented as acute intestinal perforation, and, despite aggressive surgical and medical management, disease progressed toward a fatal outcome due to sepsis and multiple organ failure 9 months later. A defect in the macrophage activity was demonstrated.