Factors influencing renal function after liver transplantation. Results from the MOST, an international observational study.

INTRODUCTION: Renal failure, both acute and chronic, is a common complication after liver transplantation and can seriously jeopardise long-term outcome. Given organ shortage it should be essential to determine which patients will experience progressive and severe renal dysfunction after liver transplantation (LT). AIM: To correlate pre-transplant renal function and risk factors for renal failure after liver transplantation with occurrence of renal failure at 1 and 5 years after LT, with particular attention to hepatitis C virus (HCV) infection. METHODS: Data from patients enrolled in the liver section of Neoral MOST (Multinational Observational Study in Transplantation) study were used for the analysis. HCV status, pre-transplant serum creatinine level, recipient gender, recipient age, pre-transplant arterial hypertension, pre-transplant diabetes mellitus, pre-transplant antiviral therapy, the time of the transplant (before or after 2000) and immunosuppressive regimen were collected for each patient. Post-transplant occurrence of renal failure at 1 and 5 years was defined as a GFR<60 mL/min/1.73 m(2) (Stage III of the National Kidney Foundation). RESULTS: Data from 1948 patients enrolled in the study were considered. Glomerular filtration rate (GFR) was evaluated in 406 patients at 1 year and in 233 patients at 5 years after LT. The prevalence of HCV infection was 35% in the former and 37% in the latter. The median GFR was 70 mL/min/1.73 m(2) after 1 year and 69 mL/min after 5 years, significantly lower in HCV-positive (HCV+) than in HCV-negative (HCV-) patients both 1 and 5 years after LT (p<0.001). GFR before transplant correlated with GFR at 1 month, 1 and 3 years (p<0.0001 for all correlations). Multivariate analysis confirmed HCV status, pre-LT serum creatinine levels and recipient gender as significant predictors of 1-year GFR (p<0.001 for all three). Further analysis of the effect of recipient gender indicated that the only significant risk factor observed in both male and female patients was HCV positivity. Only 1-year GFR was an independent predictor of 5-year GFR (p<0.001). HCV+ status, cyclosporine (CsA) exposure, antiviral therapy and diabetes mellitus had no significant influence on 5-year GFR. CONCLUSIONS: HCV status and pre-LT serum creatinine levels were independent predictors of renal function a year after LT, together with GFR before transplant. The negative impact of HCV positivity on renal function was not confirmed in the long term, whereas the prognostic influence of an abnormal renal function in the early post-transplant period was more persistent.

HCV histological recurrence and survival following liver transplantation in patients with and without hepatocellular carcinoma.

BACKGROUND AND AIM: Hepatitis C virus (HCV)-related cirrhosis is one of the leading indication for liver transplantation (LT) and a major risk factor for the development of hepatocellular carcinoma (HCC). HCV recurrence after LT is universal. This study evaluated HCV recurrence and survival in patients transplanted for HCV and HCC. METHODS: We evaluated all adults transplanted for HCV cirrhosis between January 1999 and December 2006, HCC was diagnosed on the explant and HCV recurrence confirmed on protocol liver biopsies performed at 6 months and yearly after LT. The sustained viral response (SVR) was defined as HCV-RNA undetectable at 6 months after therapy discontinuation. The patient survival rates were assessed with Kaplan-Meier curves and the chi-square test was used when appropriate. RESULTS: Two hundred sixteen patients underwent LT for HCV including 153 men and 63 women of mean age 54 years with a mean follow-up of 35 months. There were 71 (33%) HCC(+) patients. At 1, 3, and 5 years from LT severe fibrosis (Scheuer 3-4) due to the HCV recurrence was reported in 18%, 14%, and 11% for HCC(+) and 14%, 16%, and 28% for HCC(-) patients respectively (P=NS). HCC recurred only in 3 (4%) patients at a mean follow-up of 3 years. Patients who received antiviral treatment after LT were 10% HCC(+) and 12% HCC(-) patients (P=NS). SVR was seen in 3/7 (43%) of HCC(+) and in 10/18 (55%) of HCC(-) patients (P=NS). At 1, 3, and 5 years the patient survivals was 91%, 86%, and 86% for HCC(+) and 94%, 86%, and 83% for HCC(-) patients, respectively (P=NS). CONCLUSIONS: Severe fibrosis due to HCV recurrence, which increases over time, involves one third of transplanted patients at 5 years after LT. The long-term survival was identical among HCC(+) compared to HCC(-) recipients. The recurrence of HCC was negligible and did not affect patient survival.

HCV infection in haemodialysed patients: a role for serum IL-10 and TGF-beta1 in liver damage?

BACKGROUND: Hepatitis C virus (HCV) infection is often clinically silent in haemodialysed (HD) patients and their immune response may modulate liver damage in HCV infection. IL-10 and TGF-beta1 could play a role in this setting as, IL-10 down-regulates hepatic fibrosis, while TGF-beta1 is a pro-fibrotic cytokine. AIM: To evaluate the role of IL-10 and TGF-beta1 in HD/HCV+ patients. PATIENTS: 71 HD/HCV+ patients (58 with normal [HD/HCV-N] and 13 with high serum transaminases [HD/HCV-H]), 40 non-uremic patients with chronic hepatitis C (HCV+), 56 HD anti-HCV- patients and 20 healthy volunteers (H). METHODS: IL-10 and TGF-beta1 serum levels were assessed using ELISA tests. Liver histology was assessed by Ishak's score. RESULTS: IL-10 serum levels were significantly higher in HD patients, both HCV+ (3.7+/-0.4 pg/ml; p<0.01) and HCV- (3.8+/-0.8 pg/ml; p<0.05) than in non-uremic HCV patients (2.3+/-0.4 pg/ml). Among the HD/HCV+ patients, IL-10 serum levels were similar in HD/HCV-N and in HD/HCV-H patients. Among the HD/HCV+ patients, IL-10 serum levels were similar in those with moderate histological damage compared to those with mild damage. TGF-beta1 serum levels were significantly lower in HD patients, both HCV+ (4.6+/-0.9 ng/ml) and HCV- (6.0+/-0.9 ng/ml) than in non-uremic HCV+ patients (8.1+/-1.1 ng/ml; p<0.001 and p<0.01, respectively), but similar to the values found in H (5.3+/-0.9 ng/ml; p=n.s.). No correlation was seen between IL-10 and TGF-beta1 serum levels in any of the groups considered. CONCLUSIONS: Patients on haemodialysis treatment to have high levels of IL-10, which remain high even when patients are anti-HCV+, whereas the opposite is true of TGF-beta1. The cytokine pattern observed in HD patients is compatible with the hypothesis explaining the relatively benign evolution of HCV-related liver disease in HD patients, and has a pathophysiological role.

The concept of quality of life in organ transplantation.

The goal of organ transplantation is not only to ensure the survival of individuals with end-stage heart, lung, liver, kidney, pancreas, and small bowel diseases, but also to offer patients the health they enjoyed before the disease, achieving a good balance between the functional efficacy of the graft and the patient's psychological and physical integrity. Quality of life (QoL) assessments are used to evaluate the physical, psychological, and social domains of health, seen as distinct areas that are influenced by a person's experiences, beliefs, expectations, and perceptions, and QoL is emerging as a new medical indicator in transplantation medicine too.

Algorithm for prioritization of patients on the waiting list for liver transplantation.

UNLABELLED: Prioritization of patients on the waiting list (WL) for OLT is still a critical issue. Numerous models have been developed to predict mortality before and after OLT. AIM: The aim of the study was to prospectively evaluate cirrhotics with and without hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT) severity of liver disease on the WL and at transplant, mortality on the WL and after OLT, and their correlations. MATERIALS AND METHODS: An algorithm based on seven patient variables (MELD, CTP, UNOS, HCC, BMI, waiting time, age) was created by software dedicated to prioritize patients on the waiting list. RESULTS: We evaluated 118 patients including 75 men and 43 women of age range 19 to 66 years, who underwent OLT from July 2004 to June 2006. Mean CTP and MELD at listing were 8.44 (range 6-12) and 13 (range 2-24), respectively. Overall mortality on the WL at 24 months was 13%, which was significantly higher among patients with MELD > 25 compared to patients with MELD 0 to 15 (P < .0001) or MELD 16 to 25 (P = .0007) at listing. Mean MELD at OLT was 15 (range 7-36), which was significantly lower in patients with than without HCC (MELD 12 vs 16; P = .0003). Six hundred-day patient survival was significantly lower among patients with MELD > 25 compared to patients with MELD < 25 at OLT (P = .017), whereas no difference in survival was observed between patients with and without HCC. CONCLUSIONS: The sickest patients are characterized by high mortality both on the waiting list and after liver transplantation. Patients with HCC are transplanted in better condition compared to patients without HCC with the same survival.

Combined liver and kidney transplantation: analysis of Padova experience.

BACKGROUND/AIM: The main indications for combined liver and kidney transplantation (CLKT) are as follows: (1) cirrhosis with renal damage dependent or not upon liver disease, (2) renal failure with dialysis and concomitant liver end-stage disease, (3) congenital diseases, and (4) enzymatic liver deficiency with concomitant renal failure. The aim of this study was to evaluate our results with CLKT both in adult and pediatric patients. METHODS: From September 1995 to September 2006, 15 CLKT (2.8%) among 541 liver transplantations included 4 pediatric patients (27%). The main indications for CLKT were hepatitis C virus (HCV) and polycystic diseases in adult patients, and primary hyperoxaluria in pediatric patients. RESULTS: The double transplantation was performed from the same donor in all cases. All adult patients received whole liver grafts, whereas 3 split transplants and 1 whole liver graft were transplanted in the pediatric patients. Median liver and kidney cold ischemia times were 468 and 675 minutes, respectively. After a median follow-up of 36 months (range, 1-125), the overall survival rate was 80%. Five-year patient and graft survival rates were 100% for adult CLKT, whereas they were 50% for pediatric patients. We observed only 2 cases (18%) of delayed renal function, requiring temporary hemodialysis with progressive graft improvement. There was only 1 case of kidney retransplantation due to early graft nonfunction in a pediatric patient. CONCLUSION: Although CLKT is related to major surgical risks, results after transplantation are satisfactory with an evident immunological advantage.

Antiviral therapy for hepatitis C virus recurrence following liver transplantation: long-term results from a single center experience.

BACKGROUND: Hepatitis C virus (HCV) reinfection after liver transplantation is a virtually constant finding and leads to chronic hepatitis and cirrhosis in variable proportions. This study aimed to assess the safety and efficacy of alpha-interferon (IFN) plus ribavirin for recurrent HCV following liver transplantation. PATIENTS AND METHODS: Thirty of 55 patients (54.5%) with histologically proven HCV recurrence after liver transplantation were given antiviral therapy (alpha-IFN at a dose of 6 MU x 3 x week IM associated with oral ribavirin 1 g/d for 12 months) and followed up for a further 12 months after the end of the treatment. Liver and renal function tests, hemocytometric values, and HCV-RNA were assessed every 3 months throughout the therapy and follow-up. Liver biopsy was performed before and after the treatment and after another 12 months of follow-up. RESULTS: Eight patients (26.7%) were withdrawn from the treatment due to adverse events and another 8 (26.7%) needed a dosage reduction. Eleven patients (36.7%) had a biochemical and virological response, becoming aminotransferase and HCV-RNA negative at the end of the treatment; 6 patients (20%) still had a sustained response after 12 months of follow-up. All 6 patients are clinically stable at 6 years after completing the antiviral therapy. A low viral load before therapy was a positive predictor of sustained response. No histologically significant improvement was seen at the end of the therapy or after the follow-up. CONCLUSIONS: The combination of alpha-IFN plus ribavirin induced a sustained virologic response in 20% of liver transplant recipients with recurrent HCV, but intolerance of the therapy prompted its discontinuation or a dosage reduction in a large proportion of patients. However, we have observed a long-term efficacy of the antiviral therapy in the sustained responders.

Neuropsychological and neurophysiological evaluation in cirrhotic patients with minimal hepatic encephalopathy undergoing liver transplantation.

BACKGROUND: Cirrhotic patients without overt hepatic encephalopathy may have cerebral function alterations called minimal hepatic encephalopathy (MHE). Our goal was to evaluate the role of partial pressure of ammonia (pNH3), neuropsychological, and neurophysiological assessment in detecting cognitive changes in cirrhotic patients awaiting liver transplantation. MATERIALS AND METHODS: Fourteen cirrhotic patients listed for liver transplant were studied. All patients underwent the neuropsychological battery called PSE. Neurophysiological assessment including spectral EEG (sEEG), evoked potential P300 and pNH3 and venous and arterial ammonia levels was performed in all patients. Four patients were transplanted. RESULTS: Liver disease etiology was alcoholic in four patients, viral in six mixed in two, and cryptogenic in two. PSE scores revealed MHE in 8 patients; sEEG was altered in 6, and P300 in 1. No correlations were detected between P300, sEEG, and PSE. pNH3 and arterial ammonia levels were significantly higher in the subgroup of patients with altered sEEG and were correlated with theta band increase in sEEG but not with pathological PSE scores or P300 wave abnormalities. CONCLUSIONS: The combination of sEEG and PSE, and possibly also pNH3 and arterial ammonia, is useful in detecting cerebral function alterations in cirrhotic patients with no apparent encephalopathy, whereas P300 is not. The diagnosis of MHE obtained using the multimodal approach adopted in this study may enable the adequate treatment of these patients prior to surgery, which includes advising them not to drive and adjusting their priority on the waiting list for OLTx in the light of a condition that cannot be evaluated by Child Pugh score and MELD score.

Dynamic tests to study liver function.

Two approaches have generally been used to assessing liver function: one is to measure the products of liver synthesis, the other is to monitor hepatic clearance function. The exogenous dyes that can be used to study liver function are sulphobromophthalein (BSF) and indocyanine green (ICG). One valuable way to measure hepatic function is to use non-toxic substances (stains, sugar, drugs) that are selectively metabolized by the liver and determine the rates of metabolism of these substances in vivo. The antipyrine clearance test is the most common and correlates well with the degree of liver damage. The caffeine clearance test is beneficial in severe liver lesions, but practically useless in the case of moderate liver damage. The galactose clearance test can be used early in the clinical course of jaundice to distinguish between hepatocellular disease and biliary obstruction. The MEGX test is useful as a real-time method for quantitatively assessing pre- and post-transplant liver function. In short, quantitative liver function tests are not suitable for use in screening for liver disease. They are more complex to perform and more expensive than conventional biochemical tests, but superior in monitoring the degree of liver dysfunction.