Impact of Acute Infection Requiring Hospitalization on Tacrolimus Blood Levels in Kidney Transplant Recipients.

BACKGROUND: Tacrolimus is metabolized by members of the cytochrome p450 3A subfamily, and its bioavailability depends also on P-glycoprotein. We have observed that some patients admitted for infection presented with increased tacrolimus trough levels (TLs). The aim of the study was to assess the impact of infection on tacrolimus TLs and to determine the factors involved in TL fluctuations. METHODS: This retrospective cohort study included patients transplanted with a kidney between 2009 and 2011 who were hospitalized for an acute infection. Tacrolimus TLs and dosages were recorded before hospitalization, at admission, and 1 month after discharge. Increased levels of tacolimus were defined as TL 25% higher on admission than those recorded at the last visit before hospitalization. RESULTS: Seventy-seven patients were hospitalized 138 times for infection. More than two thirds of first hospitalizations occurred during the first post-transplant year. Causes of hospitalization were urinary (33%), cytomegalovirus (27%), digestive (15%), and pulmonary (12%) infections. Thirty-five percent of kidney transplant recipients had increased tacrolimus TLs (27/77 patients) in 24% of the hospitalizations (34/138). In 34 hospitalizations occurring in 27 patients, TL at admission was ≥25% compared with the last visit before admission. Comparing these 34 hospitalizations with the other 104, no significant differences were noted, except for a greater fraction of digestive infections in the group with elevated tacrolimus TLs, independent of diarrhea occurrence. CONCLUSIONS: Up to 35% of kidney transplant recipients admitted for acute infection present with high tacrolimus TLs, requiring a dose reduction. How acute infection precisely affects metabolism and bioavailability of tacrolimus remains to be investigated.

Outcome of hepatitis B and C virus-associated hepatocellular carcinoma occurring after renal transplantation.

Kidney transplant recipients (KTR) are subjected to immunosuppressive therapy that can enhance hepatitis B and C virus replication, leading to cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to assess the prevalence and outcome of HCC in KTR. Case-control study. Patients with chronic HBV and/or HCV infection who underwent kidney transplantation between 1976 and 2011 and subsequently developed HCC were compared to a control group of patients with chronic HBV and/or HCV infection, matched for gender and age at HCC diagnosis, who did not receive kidney transplantation. Among 2944 KTR, 330 had hepatitis B and/or C. Fourteen developed HCC, a period prevalence of 4.2%. Age at HCC diagnosis was 52.6 ± 6.5 years (53.5 ± 5.7 in controls, P=.76). Time between transplantation and HCC diagnosis was 16.7 ± 2.7 years. Six HCCs were related to HBV, six to HCV and two to co-infection with HBV and HCV. Immunosuppressive therapy was comparable in HBV, HCV and HBV+HCV patients. At diagnosis, 71% of patients met Milan criteria (65% in the control group, P=.4). Alpha-fetoprotein levels, tumour characteristics and treatment modalities were comparable between both groups. Patient survival 2 years after HCC diagnosis was 28% in KTR, compared to 68% in controls (P=.024). Survival after HCC diagnosis is significantly worse in KTR compared to nontransplanted patients with HBV and/or HCV. Prevention is crucial and should be based on viral eradication/suppression before or after transplantation.

Impact of steroid-avoidance immunosuppression on long-term outcome after liver transplantation for HCV cirrhosis: the need for well documented long-term follow-up.

AIM: study impact of steroid avoidance on HCV recurrence after transplantation. METHODS AND MATERIAL: 35 HCV pats, being part of prospective, randomized, double-blind, placebo-controlled study comparing Tacrolimus (TAC)-Placebo (PLAC) (n = 14) to TAC-short-term (2 mo) low-dose steroid (STER) (n = 21), had 5 years follow-up. Primary endpoint was 1 and 5 years survival; secondary (composite) endpoint comprised HCV related cirrhosis, re-transplantation (re-LT) and death. RESULTS: 1 and 5-years survival were 93% and 75% in TAC-PLAC group; 91% and 66% in TAC-STER group (p 0.38). Two (14.3%) TAC-PLAC pats died due to HCV cirrhosis at 54 and 72 mo; 7 (33%) TAC-STER pats died due to cholestatic hepatitis at 5.8 and 9 mo, to cirrhosis at 18, 22, 34, 73 and 79 mo (p 0.20). Composite endpoint at 5 years didn't show advantage in favor of TAC-PLAC patients (5/14 [35.7%] vs. 9/21 [42.8%] pts, p.0.69). Early biopsies seemed more favorable in TAC-PLAC pats; at 5 years results were identical for both groups. Only 1 (7.1%) TAC-PLAC and 2 (9.5%) TAC-STER pats needed rejection treatment. CONCLUSION: immunosuppression using steroid avoidance or short-term use had similar outcomes. Well documented long-term follow-up, including biopsies, is necessary in order to make conclusions in relation to impact of steroid use on outcome of HCV liver recipients.

Hepatitis E virus: an underdiagnosed cause of chronic hepatitis in renal transplant recipients.

Hepatitis E virus (HEV) infection can evolve to chronic hepatitis in immunocompromised patients leading to rapidly progressive cirrhosis. Proper diagnosis is therefore important, as reducing immunosuppressive therapy can allow clearance of the virus. We report a case of chronic HEV infection in a renal transplant recipient that went undiagnosed for many years, discuss the therapeutic options, and review the current available literature.

Demyelinating sensorimotor polyneuropathy associated with the use of sirolimus: a case report.

Liver transplantation is associated with a number of neurological complications. We herein report a case of chronic inflammatory demyelinating polyneuropathy associated with the use of sirolimus-based immunosuppression. The patient was treated by converting the immunosuppression from sirolimus to cyclosporine and by a short course of oral steroids. Following this, we observed almost complete clinical and electrophysiologic resolution of this syndrome. We believe that this is the first described case of such a complication occurring in association with sirolimus. This immunosuppressive agent can, therefore, lead to neurological complications similar to the ones that have been observed with calcineurin inhibitors.

Neuroactive steroids and fatigue severity in patients with primary biliary cirrhosis and hepatitis C.

Fatigue is one of the most common non-specific symptoms associated with several disease states including liver diseases. Recently, it was reported that levels of progesterone metabolites such as allopregnanolone (3alpha,5alpha-tetrahydroprogesterone; 3alpha,5alpha-THP) and isopregnanolone (3beta,5alpha-THP) were increased in plasma of patients with chronic fatigue syndrome. We hypothesize that THP metabolites might be associated with fatigue commonly observed in chronic liver diseases. We evaluated fatigue scores and plasma levels of five progesterone metabolites in 16 patients with primary biliary cirrhosis (PBC), 12 patients with chronic hepatitis C (CHC) and 11 age-matched controls. The fatigue impact scale (FIS) ratio was significantly increased (P < 0.01) in patients with PBC and CHC compared to controls. Plasma levels of 3alpha,5alpha-THP and pregnanolone (3alpha,5beta-THP) were significantly increased in PBC and CHC patients. The other progesterone metabolites, i.e. 3beta,5alpha-THP, 3beta,5beta-THP and 3alpha,5alpha-tetrahydrodeoxycorticosterone were either undetectable or detected only in some patients. Plasma levels of 3alpha,5alpha-THP and 3alpha,5beta-THP were found to be significantly higher in patients with fatigue (P < 0.05), while those of patients without fatigue were not significantly different from controls. Both 3alpha,5alpha-THP and 3alpha,5beta-THP are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA-A) receptor and readily cross the blood-brain barrier. The present preliminary findings suggest that increased inhibition through GABA-A receptors due to the accumulation of neuroinhibitory steroids may represent an important pathophysiological mechanism of fatigue in chronic liver diseases.

Relationship between pre-TIPS liver perfusion by the portal vein and the incidence of post-TIPS chronic hepatic encephalopathy.

OBJECTIVE: In the present study we evaluated the predictive value of pretransjugular intrahepatic portosystemic shunt (TIPS) portal perfusion as assessed by Doppler ultrasonography for the onset of chronic encephalopathy after TIPS. METHODS: A total of 231 cirrhotic patients were followed-up prospectively after TIPS placement. The pattern of intrahepatic portal flow was assessed before TIPS. Patients were divided into two groups according to Doppler findings. Group 1 comprised patients with prograde portal flow (n = 200), whereas group 2 comprised those with loss of portal perfusion (hepatofugal or back-and-forth flow or portal vein thrombosis; n = 31). The presence of chronic encephalopathy during a median follow-up of 32 months was prospectively recorded. The prognostic value of the following parameters for the onset of chronic recurrent encephalopathy after TIPS was evaluated: age, presence of encephalopathy before TIPS, alcoholism, Pugh score, and loss of portal perfusion before TIPS. The independent prognostic value of each variable was tested with a multiple logistic regression analysis. RESULTS: The two groups were comparable in terms of age, incidence of prior episodes of hepatic encephalopathy, and portacaval gradient before and after the procedure; however, liver failure was more severe in patients in group 2 (Pugh score: 9.2 +/- 1.9 vs 10.3 +/- 1.7). The 3-yr survival was identical for both groups; 25% of the 200 patients in group 1 developed chronic encephalopathy as compared to 6% of the 31 patients in group 2 (p = 0.03). Multiple logistic regression analysis demonstrated that loss of portal perfusion and age >65 yr were the only independent predictors of the onset of post-TIPS chronic encephalopathy (odds ratios 0.24 and 1.98, respectively). CONCLUSIONS: Cirrhotic patients with loss of portal perfusion before TIPS were protected against post-TIPS chronic hepatic encephalopathy despite a more severe liver dysfunction at baseline. The only other independent predictive factor for the onset of this complication was age.

Intestinal involvement in Buerger's disease.

Thromboangiitis obliterans characteristically affects small- and medium-sized vessels of the limbs in young smokers. There is some controversy about the existence of visceral localizations of the disease. The case of a patient with a well-established diagnosis of thromboangiitis obliterans who presented with mesenteric ischemia is described and the literature concerning mesenteric involvement in the disease is reviewed.

A case of giant cell hepatitis recurring after liver transplantation and treated with ribavirin.

A patient who underwent orthotopic liver transplantation for giant cell hepatitis with cirrhosis and in whom giant cell hepatitis recurred twice after orthotopic liver transplantation is reported. He was treated with ribavirin with an excellent result. The literature on this subject is reviewed. This observation clearly confirms the efficacy of ribavirin for the treatment of giant cell hepatitis, thus providing evidence for its viral origin.