Donor selection criteria for liver transplantation in Argentina: are current standards too rigorous?

Organ shortage is the major limitation for the growth of deceased donor liver transplant worldwide. One strategy to ameliorate this problem is to maximize the liver utilization rate. To assess predictors of liver utilization in Argentina. The national database was used to analyze transplant activity in 2010. Donor, recipient, and transplant variables were evaluated as predictors of graft utilization of number of rejected donor offers before grafting and with the occurrence of primary nonfunction (PNF) or early post-transplant mortality (EM). Of the 582 deceased donors, 293 (50.3%) were recovered for liver transplant. Variables associated with the nonrecovery of the liver were age ≥46 years, umbilical perimeter ≥92 cm, organ procurement outside Gran Buenos Aires, AST ≥42 U/l and ALT ≥29 U/l. The median number of rejected offers before grafting was 4, and in 71 patients (25%), there were ≥13. The only independent predictor for the occurrence of PNF (3.4%) or EM (5.2%) was the recipient's emergency status. During 2010 in Argentina, the liver was recovered in only half of donors. The low incidence of PNF and EM and the characteristics of the nonrecovered liver donors suggest that organ acceptance criteria should be less rigorous.

Fibrosis progression in maintenance liver transplant patients with hepatitis C recurrence: a randomised study of everolimus vs. calcineurin inhibitors.

BACKGROUND & AIMS: Robust clinical data evaluating fibrosis progression in hepatitis C virus (HCV) liver transplant patients receiving an mTOR inhibitor vs. calcineurin inhibitor (CNI) are lacking. To evaluate fibrosis progression in maintenance liver transplant patients receiving everolimus- or CNI-based immunosuppression. METHODS: In a randomised, multicentre, open-label study, 43 maintenance liver transplant patients with recurrent HCV infection were randomised to continue CNI-based immunosuppression or switch to everolimus. RESULTS: For patients with biopsy data at month 12, mean Ishak-Knodell fibrosis score at baseline was 2.6 ± 0.9 (n = 14) with everolimus vs. 1.9 ± 1.1 (n = 18) with CNI (P = 0.043), and 1.9 ± 1.2 vs. 2.2 ± 1.3 at month 12. Ishak-Knodell fibrosis score decreased from baseline to month 12 by a mean of -0.7 ± 1.1 with everolimus, but increased by 0.2 ± 1.2 with CNI (P = 0.046). No acute rejection or graft losses occurred up to month 12. Estimated GFR at month 12 was 65.6 ml/min/1.73 m² with everolimus and 62.2 ml/min/1.73 m² with CNI [mean difference 3.4 ml/min/1.73 m² compared to CNI control group, 95% CI -4.9, 11.8 ml/min/1.73 m², P = 0.411 (analysis of covariance adjusting for baseline GFR)]. Adverse events occurred in 95.5% of everolimus patients and 71.4% of CNI patients (serious adverse events 31.8% and 0.0%, respectively). Adverse events led to everolimus discontinuation in five patients (22.7%). CONCLUSIONS: This exploratory study suggests that conversion from CNI to everolimus reduces progression of liver fibrosis, and preserves renal function without jeopardising efficacy in liver transplant recipients with recurrent HCV, but is associated with a higher incidence of adverse events and serious adverse events. These preliminary findings merit examination in a larger trial.

Improved waiting-list outcomes in Argentina after the adoption of a model for end-stage liver disease-based liver allocation policy.

In July 2005, Argentina became the first country after the United States to introduce the Model for End-Stage Liver Disease (MELD) for organ allocation. In this study, we investigated waiting-list (WL) outcomes (n = 3272) and post-liver transplantation (LT) survival in 2 consecutive periods of 5 years before and after the implementation of a MELD-based allocation policy. Data were obtained from the database of the national institute for organ allocation in Argentina. After the adoption of the MELD system, there were significant reductions in WL mortality [28.5% versus 21.9%, P < 0.001, hazard ratio (HR) = 1.57, 95% confidence interval (CI) = 1.37-1.81] and total dropout rates (38.6% versus 29.1%, P < 0.001, HR = 1.31, 95% CI = 1.16-1.48) despite significantly less LT accessibility (57.4% versus 50.7%, P < 0.001, HR = 1.53, 95% CI = 1.39-1.68). The annual number of deaths per 1000 patient-years at risk decreased from 273 in 2005 to 173 in 2010, and the number of LT procedures per 1000 patient-years at risk decreased from 564 to 422. MELD and Model for End-Stage Liver Disease-Sodium scores were excellent predictors of 3-month WL mortality with c statistics of 0.828 and 0.857, respectively (P < 0.001). No difference was observed in 1-year posttransplant survival between the 2 periods (81.1% versus 81.3%). Although patients with a MELD score > 30 had lower posttransplant survival, the global accuracy of the score for predicting outcomes was poor, as indicated by a c statistic of only 0.523. Patients with granted MELD exceptions (158 for hepatocellular carcinoma and 52 for other reasons) had significantly higher access to LT (80.4%) in comparison with nonexception patients with equivalent listing priority (MELD score = 18-25; 54.6%, P < 0.001, HR = 0.49, 95% CI = 0.40-0.61). In conclusion, the adoption of the MELD model in Argentina has resulted in improved liver organ allocation without compromising posttransplant survival.

[Indications and timing of liver transplantation]. / Indicaciones y oportunidad del trasplante hepático.

Liver transplantation (OLT) is indicated in patients with severe and irreversible acute or chronic liver disease without alternative therapy and in the absence of contraindications. Indications for OLT can be grouped in four categories, namely cirrhosis, fulminant hepatitis, malignant hepatic tumors and liver-based genetic defects that trigger damage of other organs. Patients with cirrhosis should be referred for OLT after the onset of any of the major complications or coagulopathy. Early referral is crucial in fulminant hepatitis due to the high mortality with medical therapy and the unpredictable nature of this condition. Ideal timing for OLT is the moment in the natural history of the disease when the expected survival of patients on the waiting list is higher with than without OLT. Recent data suggest that maximal benefit of OLT is obtained in patients with a MELD score >15. However, in some cases with no imminent risk of death, OLT is indicated to improve quality of life or to prevent contraindications such as progression of hepatocellular carcinoma. At present, there is a marked disproportion between the number of donors available and the growing number of patients listed worldwide, which in turn has resulted in prolongation of the time-interval to OLT and waitlist mortality. The rationale of allocation systems utilizing the MELD score is to prioritize on the waiting list patients with severe liver dysfunction ("the sickest first") and those with hepatocellular carcinoma who may loose the benefits of OLT when waitlist time exceeds eight months.

[Prevalence of liver diseases in a small rural community isolated in the mountain heights: clinical, biochemical and ultrasonographic study]. / Prevalencia de enfermedades hepáticas en una población rural de alta montaña: estudio clínico, bioquímico y ecográfico.

The goal of this population-based clinical, biochemical and ultrasonographic study was to assess the prevalence of liver diseases in Lara, a small rural community isolated in the mountain heights of Tucumán, a Province of Argentina with the highest reported rates of HAV infection in children. Inhabitants of Lara lack electricity, potable water and a sewer system. The study included 102 individuals representing 41% of the total population. Anti-HBc and anti-HCV were negative in all cases. No children showed clinical, biochemical or ecographic abnormalities. Among adults, 41% referred alcohol consumption and 12% blood transfusions. Only 3 adults (6%) had mildly elevated ALT. Ultrasound showed steatosis in 8 individuals (16%), gallstones in 7 (14%), parenchymal micro-calcifications in 5 (10%) and parasitic cysts in 4 (8%). Prevalence of HAV infection in Lara was 89% in adults and 35% in children, being significantly lower than that of children of medium/high (53%, p = 0.05) and low (74%, p = 0.0006) socioeconomic level from the city of Tucumán (control groups). These differences were more marked in children aged < 5 years (anti-HAV in 0%, 53% and 75% respectively). Serologic tests for echinoccocal disease were positive in 3/4 individuals with parasitic cysts, 2/5 with micro-calcifications and 17/85 (20%) with normal ultrasound, thus suggesting a high rate of false-positive results of the Elisa test utilized. This study showed that in Lara there is a high prevalence of steatosis, gallstones and equinoccocal disease in adults, absence of HBVand HCV infection and low exposure to HAV in children especially in those aged < 5 years.

Hepatitis C virus infection in Argentina: Burden of chronic disease.

AIM: To estimate the progression of the hepatitis C virus (HCV) epidemic and measure the burden of HCV-related morbidity and mortality. METHODS: Age- and gender-defined cohorts were used to follow the viremic population in Argentina and estimate HCV incidence, prevalence, hepatic complications, and mortality. The relative impact of two scenarios on HCV-related outcomes was assessed: (1) increased sustained virologic response (SVR); and (2) increased SVR and treatment. RESULTS: Under scenario 1, SVR raised to 85%-95% in 2016. Compared to the base case scenario, there was a 0.3% reduction in prevalent cases and liver-related deaths by 2030. Given low treatment rates, cases of hepatocellular carcinoma and decompensated cirrhosis decreased < 1%, in contrast to the base case in 2030. Under scenario 2, the same increases in SVR were modeled, with gradual increases in the annual diagnosed and treated populations. This scenario decreased prevalent infections 45%, liver-related deaths 55%, liver cancer cases 60%, and decompensated cirrhosis 55%, as compared to the base case by 2030. CONCLUSION: In Argentina, cases of end stage liver disease and liver-related deaths due to HCV are still growing, while its prevalence is decreasing. Increasing in SVR rates is not enough, and increasing in the number of patients diagnosed and candidates for treatment is needed to reduce the HCV disease burden. Based on this scenario, strategies to increase diagnosis and treatment uptake must be developed to reduce HCV burden in Argentina.

Hepatitis C virus diversification in Argentina: comparative analysis between the large city of Buenos Aires and the small rural town of O'Brien.

BACKGROUND: The estimated prevalence of HCV infection in Argentina is around 2%. However, higher rates of infection have been described in population studies of small urban and rural communities. The aim of this work was to compare the origin and diversification of HCV-1b in samples from two different epidemiological scenarios: Buenos Aires, a large cosmopolitan city, and O'Brien, a small rural town with a high prevalence of HCV infection. PATIENTS AND METHODS: The E1/E2 and NS5B regions of the viral genome from 83 patients infected with HCV-1b were sequenced. Phylogenetic analysis and Bayesian Coalescent methods were used to study the origin and diversification of HCV-1b in both patient populations. RESULTS: Samples from Buenos Aires showed a polyphyletic behavior with a tMRCA around 1887-1900 and a time of spread of infection approximately 60 years ago. In contrast, samples from ÓBrien showed a monophyletic behavior with a tMRCA around 1950-1960 and a time of spread of infection more recent than in Buenos Aires, around 20-30 years ago. CONCLUSION: Phylogenetic and coalescence analysis revealed a different behavior in the epidemiological histories of Buenos Aires and ÓBrien. HCV infection in Buenos Aires shows a polyphyletic behavior and an exponential growth in two phases, whereas that in O'Brien shows a monophyletic cluster and an exponential growth in one single step with a more recent tMRCA. The polyphyletic origin and the probability of encountering susceptible individuals in a large cosmopolitan city like Buenos Aires are in agreement with a longer period of expansion. In contrast, in less populated areas such as O'Brien, the chances of HCV transmission are strongly restricted. Furthermore, the monophyletic character and the most recent time of emergence suggest that different HCV-1b ancestors (variants) that were in expansion in Buenos Aires had the opportunity to colonize and expand in O'Brien.

Comparison of the applicability of two prognostic scoring systems in patients with fulminant hepatic failure.

BACKGROUND: Distinguishing those patients with fulminant hepatic failure (FHF) and who require transplantation from those FHF patients who will survive with receiving only intensive medical care remains problematic, and this distinction is important because of the chronic shortage of donor livers. METHODS: To assess the applicability of two prognostic scoring systems, referred to as the London and Clichy criteria, we compared using both systems, at the time of admission, for 43 FHF patients (15 M/28 F; age: 3716 yrs). Acetaminophen (ACM) was the etiology for 16 patients, while the remaining 27 had other etiologies. All the patients received intensive care, and 18 (8 ACM/10 non-ACM) had investigational BAL support. RESULTS: For the ACM toxicity, neither the London nor the Clichy criteria exhibited acceptable sensitivity (71 vs 86%, respectively), specificity (78 vs 56%, respectively), a positive predictive value (71 vs 60%, respectively), a negative predictive value (78 vs 83%, respectively) or predictive accuracy (75 vs 69%, respectively) to predict patient survival without transplantation. In contrast, applying the London and Clichy criteria to the FHF patients with non-ACM etiologies showed a sensitivity of 96 vs 80%, respectively, a specificity of 100 vs 100%, respectively, a positive predictive value of 100 vs 100%, respectively a negative predictive value of 67 vs 29%, respectively and a predictive accuracy of 96% vs 82%, respectively. CONCLUSIONS: Overall, the London criteria more accurately predicted the need for transplantation, and neither the London criteria nor the Clichy prognostic criteria accurately predicted the outcome of those patients who suffered with FHF due to ACM. BAL support may have contributed to the survival of the patients with ACM toxicity and who didn't undergo transplantation, and this survival exceeded the predictions of both prognostic systems. Additional multicenter studies should be conducted to refine these prognostic scoring systems, and this will help physicians rapidly identify those FHF patients who can survive without undergoing liver transplantation.

MELD is superior to King's college and Clichy's criteria to assess prognosis in fulminant hepatic failure.

Assessment of prognosis in fulminant hepatic failure (FHF) is essential for the need and appropriate timing of orthotopic liver transplantation (OLT). In this study we investigated the prognostic efficacy of King's College criteria, Clichy's criteria, Model for End-Stage Liver Disease (MELD), and Pediatric End-Stage Liver Disease (PELD) in 120 consecutive patients with FHF. Survival with medical therapy (18%), death without OLT (15%), and receipt of a liver transplant were similar in adults (n = 64) and children (n = 56). MELD scores were significantly higher in patients who died compared to those who survived without OLT, both in adults (38 +/- 7 vs. 26 +/- 7, P = 0.0003) and children (39 +/- 7 vs. 23 +/- 6, P = 0.0004). Using logistic regression analysis in this cohort of patients, concordance statistics were significantly higher for MELD (0.95) and PELD (0.99) when compared to King's College (0.74) and Clichy's criteria (0.68). When data was analyzed in a Cox model including patients receiving transplants and censoring the time from admission, the concordance statistic for MELD (0.77) and PELD (0.79) remained significantly higher than that of King's College criteria but not higher than that of Clichy's criteria. In conclusion, this study is the first to show that MELD and PELD are superior to King's College and Clichy's criteria to assess prognosis in FHF. However, because data was generated from a single center and included a rather low number of patients who survived or died without OLT, further confirmation of our findings is required.

High prevalence of infection with a single hepatitis C virus genotype in a small rural community of Argentina.

BACKGROUND: During the years preceding this study, we noticed a relatively unusual high number of individuals with elevated alanine aminotransferase (ALT) levels in O'Brien, a small rural town in Argentina. Moreover, four individuals from this town underwent liver transplantation owing to hepatitis C virus (HCV)-induced liver cirrhosis. These findings prompted us to conduct a large population-based survey to evaluate the prevalence of HCV in this community. METHODS AND RESULTS: A total of 1637 individuals were studied. The overall HCV-seroprevalence was 5.7% (93/1637), being slightly higher in men (45/769; 5.9%) than in women (48/868; 5.5%). HCV seroprevalence increased with age, reaching a peak rate of 23.9% among individuals between 61 and 70 years of age. HCV RNA was present in 82.7% of all HCV seropositive individuals identified and 100% of them were infected with genotype 1b. ALT elevations were detected in 44% of HCV+ patients and were only observed among viremic individuals. Hepatitis B virus infection was also prevalent (52%) among HCV-seropositive patients. The most common risk factor associated with HCV transmission identified was the apparent use of inadequately sterilized glass syringes by a health care provider serving the community; however, other risk factors may have also played a role in the dissemination of HCV. CONCLUSIONS: Our findings provide an explanation for the relative high number of individuals with elevated ALT levels observed in this community and form the basis of future prospective studies on the natural history of genotype 1b infection.

Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone.

In this study, we investigated the prognostic value of serum sodium and hyponatremia (< or =130 mEq/L) in 262 cirrhotic patients consecutively listed, 19 of which died (7%), 175 survived (67%), and 68 underwent liver transplantation (26%) during 3 months of follow-up. Hyponatremia was present in 63% of patients who died, compared to 13% of those who survived (P < .001), whereas the proportion with elevated creatinine (> or =1.4 mg/dL) was low and similar in both groups (10.5 vs. 3%). Prevalence of hyponatremia was higher than that of elevated serum creatinine across all model for end-stage liver disease (MELD) categories. Using logistic regression, hyponatremia and serum sodium were significant predictors of mortality with concordance statistics (c-statistics) .753 for hyponatremia, .784 for sodium, .894 for MELD, .905 for MELD plus hyponatremia (P = .006 vs. MELD alone), and .908 for MELD plus serum sodium (P = .026 vs. MELD alone). Risk of death across all MELD scores was higher for patients with hyponatremia than without hyponatremia. Cox regression considering data within 6 months of follow-up yielded qualitatively similar results, with hyponatremia being a significant predictor of greater mortality risk with an odds ratio of 2.65 (P = .015). Each increase of 1 mEq/L of serum sodium level was associated with a decreased odds ratio of .95 (P = .048). Our results indicate that hyponatremia appears to be an earlier and more sensitive marker than serum creatinine to detect renal impairment and / or circulatory dysfunction in patients with advanced cirrhosis. In conclusion, addition of serum sodium to MELD identified a subgroup of patients with poor outcome in a more efficient way than MELD alone and significantly increased the efficacy of the score to predict waitlist mortality.

How common is delayed cyclosporine absorption following liver transplantation?

The mean time to peak absorption of cyclosporine (CsA) in liver transplant patients is approximately 2 hours, but in some patients the peak occurs later. The goal of this study was, therefore, to investigate the incidence of delayed absorption in 27 de novo liver transplant recipients receiving CsA > or =10 mg/kg/day (C(2) monitoring) and in 15 maintenance patients. Patients were categorized as 'normal' absorbers (C(2) exceeding C(4) and C(6)) or 'delayed' absorbers (C(4) or C(6) exceeding C(2)), and as 'good' (>800 ng/mL at C(0), C(2), C(4), or C(6)) or 'poor' absorbers (C(0), C(2), C(4) and C(6) <800 ng/mL) on the day of study. Among de novo patients, 15 (56%) had 'normal' CsA absorption and 12 (44%) 'delayed' absorption. Good CsA absorption occurred in 16 patients (59%) and poor absorption in 11 (41%). The proportion of poor absorbers was similar in patients with normal (6/15, 40%) or delayed (5/12, 42%) absorption. Among the 12 delayed absorbers, 11 had peak CsA concentration at C(4). Mean C(0) level was significantly higher in delayed absorbers (282 +/- 96 ng/mL) than in normal absorbers (185 +/- 88 ng/mL; P = .01). Delayed absorbers reverted to normal absorption (C(2) > C(4)) after a median of 6 days from the day of study, and no cases of delayed absorption were found among maintenance patients. In conclusion, almost 50% of the patients had delayed CsA absorption early posttransplant; around half of these exhibited normal CsA exposure. Measurement of C(4) in addition to C(2) differentiates effectively between delayed and poor absorbers of CsA such that over- or underimmunosuppression can be avoided.