J.M Moreno

Chronic renal dysfunction after liver transplantation in adult patients: prevalence, risk factors, and impact on mortality

INTRODUCTION Although chronic renal dysfunction (CRD) is a common complication among patients undergoing liver transplantation (OLT) its prevalence, risk factors, and impact on outcome have not been well defined. We aimed to assess the incidence of CRD, its associated risk factors and its impact on outcome. PATIENTS AND METHODS The cohort of 289 consecutive adult first liver transplant patients with posttransplant follow-up longer than 6 months received cyclosporine in 230 patients (153 oil-based and 81 microemulsion formulation), tacrolimus in 55. CRD was defined as serum creatinine levels greater than 1.3 mg/dL for more than 6 months. RESULTS After a mean follow-up of 67 months, 138 patients (47.8%) displayed CRD. The prevalence of CRD was 30.9%, 41.5%, and 38.9% at 1, 5, and 13 years after OLT, respectively. Twelve patients (4.1%) developed end-stage renal failure. Male gender, older recipient age, pretransplant renal dysfunction and hyperuricemia, posttransplant in-hospital renal dysfunction and hyperuricemia, and renal dysfunction during the first 6 months after OLT were each significantly associated with the development of CRD. Survival was significantly lower (63%) among liver transplant patients with CRD than those without this complication (71%, P=.024). CONCLUSIONS CRD is an important cause of morbidity after OLT, although end-stage renal disease is infrequent. Because early renal dysfunction is associated with the development of CRD, and decreased long-term patient survival, efforts should be made to avoid early renal dysfunction after liver transplantation.

Effectiveness and safety of mycophenolate mofetil as monotherapy in liver transplantation

Introduction Calcineurin inhibitors (CIs) cause substantial long-term morbidity and mortality among orthotopic liver transplantation (OLT) patients. Our aim was to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) among OLT patients with CI-related side effects. Patients Thirty three adult patients, including 29 men and 4 women of mean age 57 years, underwent OLT between 1986 and 2000 under treatment with CIs (28 cyclosporine and five tacrolimus). Mean follow-up after OLT was 59 months. Adverse effects were renal dysfunction in 26, hypertension in 23, and neurotoxicity in two. MMF was added gradually while simultaneously reducing the dosage of CI. Results After a mean 15-months follow-up of MMF treatment, CIs had been withdrawn in 28 patients (85%). The mean time from the initiation of MMF and CI withdrawal was 5 months. During the first year of follow-up chronic renal dysfunction improved in 16 of 26 patients (61.6%) accompanied by a decreased serum creatinine and urea and an increase in creatinine clearance. Among 13/23 (56.5%) hypertensive patients, there was a significant decrease in blood pressure or the number of antihypertensive drugs (P < .05). One patient with neurotoxicity improved. Twenty-two patients (66%) displayed adverse events: five rejections (15%) including four acute episodes, controlled by CI re-introduction, and one chronic reaction. The most frequent adverse effects were herpes simplex infection in 10 patients (30%), asthenia in nine (27%), diarrhea in five (15%) and thrombocytopenia in four (12%). Nevertheless, only six patients (19%) required MMF dose reduction, namely, three patients with GI intolerance, two with repeated VHS infections, and one with anemia. Conclusions MMF monotherapy improves renal function and blood pressure levels in more than 50% of patients with chronic renal impairment and hypertension after OLT. Many of the side effects of MMF were mild; it was safe accompanied by a low incidence of rejection reactions.

Cardiovascular morbidity and obesity in adult liver transplant recipients

There is a direct relationship between the grade of obesity and mortality based on the increased cardiovascular diseases, cancer, etc. However, the results of studies in renal and liver allograft recipients relating obesity to morbidity and mortality are contradictory. A retrospective cohort study of 170 patients transplanted between March 1987 and July 1997 showed obesity to be identified in 77 (45.3%) patients. During the mean follow-up of 5 years posttransplantation, 16 (9.4%) patients experienced cardiovascular complications, including 10 patients with ischemic cardiac syndromes (five acute infarctions and five angina), five patients with acute cerebrovascular accidents, and one patient with intermittent lower limbs claudication. The prevalence of obesity at 1, 3, 5, 7, and 9 years after transplantation was 58.2%, 56.9%, 60.3%, 59.5%, and 66.4%, respectively. Compared with the baseline value, the BMI was increased at 1 year posttransplantation (25.78), a significant difference. No significant differences were found between the mean BMI values of patients with and without cardiovascular diseases, or overweight and morbidly obese patients compared to the normal weight population. Among liver transplant recipients, obesity was a frequent complication after transplantation, but it was not clearly associated with increased morbidity and mortality secondary to cardiovascular disease.

Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury

BACKGROUND & AIMS Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. METHODS 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. RESULTS Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis. CONCLUSIONS One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. LAY SUMMARY Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.

De novo malignancies and liver transplantation

INTRODUCTION De novo tumors (DNTs) are the leading cause of late death among liver transplant recipients with an incidence of 5% to 15%, which is significantly greater than the general population. In this retrospective study, we compared this complication in liver transplant recipients to sex- and age-matched controls. PATIENTS Among 410 patients who received liver allografts between March 1986 and December 2000, 32 (7.8%) developed a DNT. Epidermoid tumors were the most frequent histologic lineage. A complete response was observed in 19 patients (59.4%), a partial response in eight (25%), and no response in five (15%). Survival was lower among liver transplant recipients than controls, a difference that was statistically significant. Treatment consisted of surgery in 76.7%, radiotherapy in 16.7%, chemotherapy in 13.3%, and reduction of immunosuppression in 10%. RESULTS The mean survival time in transplant patients of 122.97 months (95% CI; range 98-147 months) was significantly shorter than controls, 156.5 months (95% CI; range 141-171 months). About 50% of patients were smokers (active or ex-smokers), compared to 20.7% of controls (P=.049). Significant differences were also found when the three subgroups (smokers, previous smokers, and nonsmokers) were analyzed separately (P=.013). Patients were smokers (active or nonactive) among 45% of cases of skin tumors; 60% of hematological tumors; 71.4% of epidermoids; and 33% of sarcomas. CONCLUSIONS DNTs, a complication of long-term immunosuppression in patients after liver transplantation, most frequently presented as skin tumors and PTLD. Occurrence of a DNT was an adverse prognostic factor for survival. Smoking represents an independent risk factor for these tumors.

Effectiveness of low-dose intramuscular Anti-VHB immune globulin in the prophylaxis of viral B hepatitis reinfection after liver transplantation: preliminary report

INTRODUCTION Prophylaxis using high-dose intravenous anti-HBV immune globulin (HBIG) is effective to prevent reinfection due to hepatitis B virus (HBV) after orthotopic liver transplantation (OLT). However, this treatment is expensive and intravenous administration is difficult during outpatient care. Our aim was to assess the effectiveness of low-dose intramuscular HBIG to prevent HBV reinfection after OLT. PATIENTS Six patients (all men, mean age 41 years, negative HBV DNA without hepatotropic virus coinfection) were transplanted in our institution due to HBV cirrhosis and included in a prospective noncomparative study. Intramuscular HBIG (2000 IU) was administered during the anhepatic phase of OLT, followed by daily 2000 IU doses for 7 days and then monthly. HBV antibody titers were measured every month. Reinfection was defined as the recurrence of surface HBV antigen in serum after transplantation. RESULTS After 1 year follow-up, none of the six patients had detectable HBV surface antigen and the liver biopsies were normal in all cases. Using 2000 IU, anti-HBs levels were: 880+/-356 IU/L at 1 month, 191+/-123 at 6 months, and 225+/-49 after 1 year. In all cases anti-HBs titers were above 100 IU/L during the follow-up. CONCLUSIONS Monthly administration of low-dose (2000 IU) intramuscular HBIG effectively prevents recurrence of HBV infection as well as attains a protective level of anti-HBs antibodies (over 100 IU/L) for at least the first year after transplantation.

Imatinib assay by high-performance liquid chromatography in tandem mass spectrometry with solid-phase extraction in human plasma

We have developed a method of liquid chromatography in tandem with mass spectrometry to monitor therapeutic levels of imatinib in plasma, a selective inhibitor of protein tyrosine kinase. After solid-phase extraction of plasma samples, imatinib and its internal standard, imatinib-D8, were eluted with Zorbax SB-C18 at 60 °C, under isocratic conditions through a mobile phase consisting of 4 mm ammonium formate, pH: 3.2 (solution A) and acetonitrile solution B. The flow rate was 0.8 mL/min with 55% solution A + 45% solution B. Imatinib was detected and quantified by mass spectrometry with electrospray ionization operating in selected-reaction monitoring mode. The calibration curve was linear in the range 10-5000 ng/mL, the lower limit of quantitation being 10 ng/mL. The method was validated according to the recommendations of the Food and Drug Administration, including tests of matrix effect (bias < 10%) and recovery efficiency (>80 and <120%). The method is precise (coefficient of variance intra-day <2% and inter-day <7%), accurate (95-108%), sensitive and specific. It is a simple method with very fast recording time (1.2 min) that is applicable to clinical practice. This will permit improvement of the pharmacological treatment of patients.

Usefulness of chemotherapy as prophylaxis of tumor recurrence after liver transplantation in advanced hepatocellular carcinomas

INTRODUCTION The effectiveness of chemotherapy as prophylaxis of tumor recurrence after liver transplantation in patients with advanced hepatocellular carcinoma is controversial. AIM Our goal was to assess the outcomes of patients with advanced hepatocellular carcinoma treated with chemotherapy after liver transplant. METHODS Ten patients with liver transplants performed between 1993-2002 were men of mean age 55 years. The etiology of cirrhosis was hepatitis C in four patients, alcoholic cirrhosis in four, and cryptogenic cirrhosis in two. Immunosuppressive therapy was cyclosporine in five patients and tacrolimus in five. The chemotherapy regimen used adriamycin (20 mg/m2 weekly for 20 weeks). Six patients were stage IVA and four stage III. Hepatocellular carcinoma was known in five patients and incidental in the other five. Pathology revealed well-differentiated hepatocellular carcinoma in six patients and moderately differentiated hepatocellular carcinoma in four. Five patients had vascular invasion. RESULTS After a mean posttransplant follow-up of 28 months, six patients (60%) were alive without tumor recurrence, three (30%) had died from tumor recurrence and one due to P. carinii pneumonia. Disease-free survival among patients with stage III was 50% and 80% for stage IVA. Three patients with vascular invasion died of tumor recurrence, and the other two are alive and free of disease. Disease-free survival rates were 83% in patients with well-differentiated hepatocellular carcinoma and 25% in those with moderately differentiated hepatocellular carcinoma. Tolerance of chemotherapy was good with two withdrawals due to nephrotoxicity and myelotoxicity and one death from pneumonia. CONCLUSION The use of adriamycin in patients undergoing liver transplant due to advanced hepatocellular carcinoma may be useful to prevent tumor recurrence; it is well tolerated. The presence of vascular tumor invasion and a lower grade of histologic differentiation were associated with a poor prognosis.

High efficacy of Sofosbuvir plus Simeprevir in a large cohort of Spanish cirrhotic patients infected with genotypes 1 and 4.

Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real‐world clinical practice, showed high rates of sustained virological response (SVR) in non‐cirrhotic genotype (GT)‐1 and GT‐4 patients. These results were slightly lower in cirrhotic patients. We investigated real‐life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients.

Usefulness of mycophenolate mofetil in patients with chronic renal insufficiency after liver transplantation

NEPHROTOXICITY is a common side effect after liver transplantation (LT). Chronic renal insufficiency (CRI) appears in 50% to 79% of patients during long-term follow-up. The incidence of end-stage renal disease (ESRD) ranges between 2% and 9.5%. The use of calcineurin inhibitors (CNI) is the main cause of CRI after LT. Although acute renal failure related to CNI responds to dosage adjustment, the management of patients with CRI is difficult because cyclosporine or tacrolimus dose reduction generally does not improve renal function and withdrawal can be associated with graft rejection. In contrast to CNI, the newer immunosuppressive agents, mycophenolate mofetil (MMF) and sirolimus, are not nephrotoxic. Therefore, trials have been designed to withdraw CNI with the use of these new immunosuppressive agents in patients with chronic renal insufficiency. MMF is an inhibitor of inosine monophosphate dehydrogenase, which inhibits proliferation of T and B lymphocytes. The aim of our study was to evaluate the evolution of the renal function in patients with chronic renal dysfunction after liver transplantation with the use of mycophenolate mofetil, associated with a slow tapering and withdrawal of CNI.