Protective effect of long-chain polyunsaturated fatty acids on hepatorenal syndrome in rats.

BACKGROUND: Hepatorenal syndrome (HRS) is the most prevalent form of acute kidney injury in cirrhotic patients. It is characterized by reduced renal blood flow and represents the most severe complication in cirrhotic patients with advanced disease. Previous research has indicated that antioxidants can delay the onset of a hyperdynamic circulatory state in cirrhosis and improve renal function in HRS patients. Regular omega-3 supplementation has significantly reduced the risk of liver disease. This supplementation could represent an additional therapy for individuals with HRS. AIM: To evaluated the antioxidant effect of omega-3 polyunsaturated fatty acid supplementation on the kidneys of cirrhotic rats. METHODS: Secondary biliary cirrhosis was induced in rats by biliary duct ligation (BDL) for 28 d. We used 24 male Wistar rats divided into the following groups: I (control); II (treated with omega-3, 1 g/kg of body weight); III (BDL treated with omega-3, 1 g/kg of body weight); and IV (BDL without treatment). The animals were killed by overdose of anesthetic; the kidneys were dissected, removed, frozen in liquid nitrogen, and stored in a freezer at -80℃ for later analysis. We evaluated oxidative stress, nitric oxide (NO) metabolites, DNA damage by the comet assay, cell viability test, and apoptosis in the kidneys. Data were analyzed by one-way analysis of variance, and means were compared using the Tukey test, with P ≤ 0.05. RESULTS: Omega-3 significantly decreased the production of reactive oxygen species (P < 0.001) and lipoperoxidation in the kidneys of cirrhotic rats treated with omega-3 (P < 0.001). The activity of the antioxidant enzymes superoxide dismutase and catalase increased in the BDL+omega-3 group compared to the BDL group (P < 0.01). NO production, DNA damage, and caspase-9 cleavage decreased significantly in the omega-3-treated BDL group. There was an increase in mitochondrial electrochemical potential (P < 0.001) in BDL treated with omega-3 compared to BDL. No changes in the cell survival index in HRS with omega-3 compared to the control group (P > 0.05) were observed. CONCLUSION: The study demonstrates that omega-3 can protect cellular integrity and function by increasing antioxidant enzymes, inhibiting the formation of free radicals, and reducing apoptosis.

Efficacy and safety of terlipressin and albumin vs. noradrenaline and albumin in adult patients with hepatorenal syndrome: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Hepatorenal syndrome (HRS) is a serious complication of cirrhosis treated with various medications. We aim to evaluate terlipressin and albumin's effectiveness and safety compared to albumin and noradrenaline in adult hepatorenal disease patients. MATERIALS AND METHODS: Clinical trials from four databases were included. Cochrane's approach for calculating bias risk was utilized. We rated the quality evaluation by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). We included the following outcomes: serum creatinine (mg/dl), urine output (ml/24 h), mean arterial pressure (mmHg), reversal rate of HRS, mortality rate, blood plasma renin activity (ng/ml/h), plasma aldosterone concentration (pg/ml), urine sodium (mEq/l), and creatinine clearance (ml/min). RESULTS: Our analysis of nine clinical studies revealed that the noradrenaline group was associated with higher creatinine clearance (MD = 4.22 [0.40, 8.05]), (P = 0.03). There were no significant differences in serum creatinine levels (MD = 0.03 [-0.07, 0.13]), urinary sodium (MD = -1.02 [-5.15, 3.11]), urine output (MD = 32.75 [-93.94, 159.44]), mean arterial pressure (MD = 1.40 [-1.17, 3.96]), plasma renin activity (MD = 1.35 [-0.17, 2.87]), plasma aldosterone concentration (MD = 55.35 [-24.59, 135.29]), reversal rate of HRS (RR = 1.15 [0.96, 1.37]), or mortality rate (RR = 0.87 [0.74, 1.01]) between the two groups (p-values > 0.05). CONCLUSIONS: Noradrenaline is a safe alternative medical therapy for HRS.

Terlipressin in combination with albumin as a therapy for hepatorenal syndrome in patients aged 65 years or older.

INTRODUCTION AND OBJECTIVES: Clinical data for older patients with advanced liver disease are limited. This post hoc analysis evaluated the efficacy and safety of terlipressin in patients aged ≥65 years with hepatorenal syndrome using data from 3 Phase III, randomized, placebo-controlled studies (OT-0401, REVERSE, CONFIRM). PATIENTS AND METHODS: The pooled population of patients aged ≥65 years (terlipressin, n = 54; placebo, n = 36) was evaluated for hepatorenal syndrome reversal-defined as a serum creatinine level ≤1.5 mg/dL (≤132.6 µmol/L) while receiving terlipressin or placebo, without renal replacement therapy, liver transplantation, or death-and the incidence of renal replacement therapy (RRT). Safety analyses included an assessment of adverse events. RESULTS: Hepatorenal syndrome reversal was almost 2-times higher in terlipressin-treated patients compared with patients who received placebo (31.5% vs 16.7%; P = 0.143). Among surviving patients, the need for RRT was significantly reduced in the terlipressin group, with an almost 3-times lower incidence of RRT versus the placebo group (Day 90: 25.0% vs 70.6%; P = 0.005). Among 23 liver-transplant-listed patients, significantly fewer patients in the terlipressin versus placebo group needed RRT by Days 30 and 60 (P = 0.027 each). Fewer patients in the terlipressin group needed RRT post-transplant (P = 0.011). More terlipressin-treated patients who were listed for and received a liver transplant were alive and RRT-free by Day 90. No new safety signals were revealed in the older subpopulation compared with previously published data. CONCLUSIONS: Terlipressin therapy may lead to clinical improvements in highly vulnerable patients aged ≥65 years with hepatorenal syndrome. CLINICAL TRIAL NUMBERS: OT-0401, NCT00089570; REVERSE, NCT01143246; CONFIRM, NCT02770716.

Lista de espera para transplante hepático: impacto clínico e econômico / Waiting list for liver transplantation: clinical and economic burden

ABSTRACT Background Burden of disease is an indicator that relates to health status. United States and European epidemiological data have shown that the burden of chronic liver disease has increased significantly in recent decades. There are no studies evaluating the impact of complications of chronic liver disease on the waiting list for deceased donor liver transplantation (LTx). Objective: To determine the clinical and economic burden of complications of liver disease in wait-listed patients from the perspective of a transplant center. Methods The study retrospectively analyzed medical records of 104 patients wait-listed for deceased donor LTx from October 2012 to May 2016 and whose treatment was fully provided at the study transplant center. Clinical data were obtained from electronic medical records, while economic data were collected from a hospital management software. To allocate all direct medical costs, two methods were used: full absorption costing and micro-costing. Results: The most common complication was refractory ascites (20.2%), followed by portosystemic encephalopathy (12.5%). The mean number of admissions per patient was 1.37±3.42. Variceal hemorrhage was the complication with longest median length of stay (18 days), followed by hepatorenal syndrome (13.5 days). Hepatorenal syndrome was the costliest complication (mean cost of $3,565), followed by portosystemic encephalopathy ($2,576) and variceal hemorrhage ($1,530). Conclusion: The burden of chronic liver disease includes a great cost for health systems. In addition, it is likely to be even greater as a result of the insidious course of the disease.

RESUMO Contexto O impacto da doença é um indicador relacionado ao estado de saúde. Dados epidemiológicos norte-americanos e europeus mostraram que, nas últimas décadas, o impacto da doença hepática crônica tem aumentado significativamente. Não há estudos que avaliem o impacto das descompensações da doença hepática crônica na lista de espera para transplante hepático (TxH) com doador falecido. Objetivo: Determinar o impacto clínico e econômico das descompensações da doença hepática nos pacientes em lista de espera sob a perspectiva do centro transplantador. Métodos Foram analisados, retrospectivamente, os prontuários de 104 pacientes incluídos em lista de espera para TxH com doador falecido entre outubro de 2012 e maio de 2016 e acompanhados integralmente no centro transplantador. Dados clínicos foram obtidos do prontuário eletrônico, enquanto dados econômicos foram coletados através de software de gestão hospitalar. A apropriação dos custos médicos diretos foi realizada sob duas metodologias: custeio por absorção pleno e microcusteio. Resultados: A descompensação com maior incidência foi a ascite refratária (20,2%) seguida de encefalopatia portossistêmica (12,5%). A média de internações por paciente foi de 1,37±3,42. A hemorragia digestiva alta varicosa foi a descompensação com maior tempo mediano de internação (18 dias), seguida da síndrome hepatorrenal (13,5 dias). A descompensação mais onerosa foi a síndrome hepatorrenal (custo médio de US$ 3.565), seguida encefalopatia portossistêmica (US$ 2.576) e a hemorragia digestiva alta varicosa (US$ 1.530). Conclusão O impacto da doença hepática crônica inclui um custo importante para os sistemas de saúde. Além disso, é provável que seja ainda maior em decorrência do curso insidioso da doença.

Albumin administration in patients with cirrhosis: Current role and novel perspectives.

Mortality in cirrhosis is mostly associated with the development of clinical decompensation, characterized by ascites, hepatic encephalopathy, variceal bleeding, or jaundice. Therefore, it is important to prevent and manage such complications. Traditionally, the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis, but it is currently understood that decompensation might also be driven by a systemic inflammatory state (the systemic inflammation hypothesis). Considering its oncotic and nononcotic properties, albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events. There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis, patients with spontaneous bacterial peritonitis, those with acute kidney injury (even before the etiological diagnosis), and those with hepatorenal syndrome. Moreover, there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites (long-term albumin administration), individuals with hepatic encephalopathy, and those with acute-on-chronic liver failure undergoing modest-volume paracentesis. Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications, such as individuals with extraperitoneal infections, those hospitalized with decompensated cirrhosis and hypoalbuminemia, and patients with hyponatremia.

Current Medical Treatment for Alcohol-Associated Liver Disease.

Alcohol-associated liver disease is one of the main causes of chronic liver disease. It comprises a clinical-histologic spectrum of presentations, from steatosis, steatohepatitis, to different degrees of fibrosis, including cirrhosis and severe necroinflammatory disease, called alcohol-associated hepatitis. In this focused update, we aim to present specific therapeutic interventions and strategies for the management of alcohol-associated liver disease. Current evidence for management in all spectra of manifestations is derived from general chronic liver disease recommendations, but with a higher emphasis on abstinence and nutritional support. Abstinence should comprise the treatment of alcohol use disorder as well as withdrawal syndrome. Nutritional assessment should also consider the presence of sarcopenia and its clinical manifestation, frailty. The degree of compensation of the disease should be evaluated, and complications, actively sought. The most severe acute form of this disease is alcohol-associated hepatitis, which has high mortality and morbidity. Current treatment is based on corticosteroids that act by reducing immune activation and blocking cytotoxicity and inflammation pathways. Other aspects of treatment include preventing and treating hepatorenal syndrome as well as preventing infections although there is no clear evidence as to the benefit of probiotics and antibiotics in prophylaxis. Novel therapies for alcohol-associated hepatitis include metadoxine, interleukin-22 analogs, and interleukin-1-beta antagonists. Finally, granulocyte colony-stimulating factor, microbiota transplantation, and gut-liver axis modulation have shown promising results. We also discuss palliative care in advanced alcohol-associated liver disease.

Síndrome hepatorrenal en asociación con hepatitis alcohólica y síndrome de Zieve / Hepatorenal syndrome in association with alcoholic hepatitis and Zieve's syndrome

RESUMEN La enfermedad hepática alcohólica tiene un amplio espectro de enfermedades, incluida la hepatitis alcohólica, que en sus formas graves puede conducir al síndrome hepatorrenal. La anemia es común en pacientes alcohólicos, pero una anemia hemolítica asociada con hiperlipidemia e ictericia se reconoce como síndrome de Zieve. Un varón de 42 años con consumo excesivo de alcohol fue admitido por ictericia y dolor abdominal. Durante su evolución presentó azoemia progresiva y anemia hemolítica. Se realizó el diagnóstico de síndrome hepatorrenal asociado a hepatitis alcohólica, así como un síndrome de Zieve. Fue tratado con corticoterapia y la combinación de albúmina y noradrenalina, además del retiro de alcohol, con resultados favorables.

ABSTRACT Alcoholic liver disease has a broad spectrum of diseases, including alcoholic hepatitis, which in its severe forms can lead to hepatorenal syndrome. Anemia is common in alcoholic patients, but a hemolytic anemia in association with hyperlipidemia and jaundice is recognized as Zieve's syndrome. A 42 year old man with heavy alcohol consumption was admitted for jaundice and abdominal pain. During his evolution, he presented progressive azotemia and hemolytic anemia. The diagnosis of hepatorenal syndrome associated with alcoholic hepatitis was made, as well as a Zieve's syndrome. He was treated with corticosteroid therapy and the combination of albumin and norepinephrine, in addition to alcohol withdrawal, with favorable results.

Custo efetividade do uso da terlipressina no tratamento da síndrome hepatorrenal / Cost effectiveness of using terlipressin to treat hepatorenal syndrome

ABSTRACT Background Hepatorenal syndrome (HRS) is the most severe form of acute kidney injury in patients with advanced cirrhosis, and it is associated with high mortality. It is usually diagnosed according to criteria defined by the International Ascites Club. Currently, the most frequently indicated pharmacological therapy for the treatment of HRS is a combination of splanchnic vasoconstrictors (terlipressin or norepinephrine) in combination with albumin. With the progressive increase in healthcare spending, it is important to conduct a cost-effectiveness analysis of pharmacological treatment in patients who are diagnosed with HRS. Objective: To perform a cost-effectiveness assessment for the use of terlipressin in combination with albumin to treat HRS in patients with cirrhosis. Methods: Economic evaluation of cost-effectiveness based on secondary data from studies showed the efficacy of terlipressin therapy compared with norepinephrine combined with albumin or albumin alone. The cost-effectiveness analysis was calculated using an incremental cost-effectiveness ratio (ICER), and a sensitivity analysis was developed by varying the values of therapies and probabilities. The Brazilian real was the currency used in the analysis, and the results were converted to US dollars. Results: After selection, eligibility, and evaluation of the quality of publications, the results demonstrated that administration of terlipressin or norepinephrine in combination with albumin in patients diagnosed with HRS type 1 was efficacious. The cost of treatment with terlipressin in combination with albumin was USD $1,644.06, administration of albumin alone was USD $912.02, and norepinephrine plus albumin was USD $2,310.78. Considering that the combination therapies demonstrated effectiveness, the incremental cost of terlipressin and norepinephrine in combination with albumin was USD $666.73, and an effectiveness of 0.570 was found for terlipressin in combination with albumin and 0.200 for norepinephrine in combination with albumin. The incremental effectiveness was 0.370, and the ICER was USD $1,801.97. Thus, the parameters of increasing cost per therapy and ICER indicated that the combined therapy of terlipressin plus albumin was cost effective compared to albumin alone or norepinephrine plus albumin in a public single-payer healthcare system. Conclusion: A cost-effectiveness analysis showed that terlipressin in combination with albumin when administered concomitantly to patients who were diagnosed with type 1 HRS is cost-effective compared to norepinephrine in combination with albumin administered in a controlled environment.

RESUMO Contexto: A Síndrome Hepatorrenal (SHR) é a forma mais grave de lesão renal aguda em pacientes com cirrose avançada, estando diretamente associada a alta taxa de mortalidade. Normalmente é diagnosticada seguindo critérios definidos pela International Ascites Club (IAC). Atualmente, as terapias farmacológicas mais indicadas no tratamento da SHR são a combinação de vasoconstritores esplâncnicos (terlipressina ou norepinefrina) associados à albumina. Com o aumento progressivo dos gastos em saúde, torna-se relevante realizar uma análise de custo-efetividade do tratamento farmacológico em pacientes com diagnóstico de SHR. Objetivo: Realizar avaliação de custo-efetividade do uso da terlipressina associada à albumina no tratamento da SHR em pacientes com cirrose. Métodos: Avaliação econômica de custo-efetividade, com base em dados secundários de estudos publicados com resultado da eficácia da terapia com terlipressina, em comparação com norepinefrina combinada com albumina ou apenas albumina. A análise de custo-efetividade foi calculada usando a razão de custo-efetividade incremental (RCEI) e uma análise de sensibilidade foi desenvolvida variando os valores das terapias e probabilidades. O real foi a moeda utilizada na análise. Resultados: Após a seleção, elegibilidade e avaliação da qualidade das publicações, os resultados demonstraram que a administração da associação de terlipressina ou norepinefrina com albumina em pacientes diagnosticados com SHR tipo 1 possui eficácia comprovada. Os custos do tratamento com a terapia combinada de terlipressina com albumina foram de USD $1,644.06, administração de somente albumina USD $912.02 e norepinefrina mais albumina USD $2,310.78. Considerando as terapias combinadas com efetividade terapêutica comprovada, isto é, terlipressina e norepinefrina associada a albumina, o custo incremental foi de USD $666.73 e efetividade de 0,570 para o grupo da terlipressina associada a albumina e de 0,200 para o grupo da norepinefrina associada a albumina. A efetividade incremental foi de 0,370 e o valor da RCEI foi de USD $1,801.97. Assim, os fatores de incremento do custo por terapia e razão de custo-efetividade incremental definem que a terapia combinada de terlipressina mais albumina é custo efetiva quando comparada a administração de somente albumina ou norepinefrina no cenário do sistema único de saúde. Conclusão: O estudo demonstrou por meio de uma análise de custo-efetividade que a terlipressina associada à albumina quando administrada concomitantemente a pacientes com diagnóstico de SHR tipo 1 é custo-efetiva quando comparada à albumina sozinha e com norepinefrina associada à albumina administrada em um ambiente controlado.

Position statement on the use of albumin in liver cirrhosis.

Cirrhosis is characterised by a prolonged asymptomatic period in which the inflammation persists, increasing as the disease progresses. Characteristic of this is the increase in pro-inflammatory cytokines and pro-oxidant molecules which are determining factors in the development of multiple organ dysfunction. In the early development of cirrhosis, splanchnic arterial vasodilation, activation of vasoconstrictor systems (renin-angiotensin-aldosterone) and the sympathetic nervous system (noradrenaline) bring about bacterial translocation and systemic dissemination via portal circulation of bacterial products, and molecular patterns associated with damage, which exacerbate the systemic inflammation present in the patient with cirrhosis. Albumin is a molecule that undergoes structural and functional changes as liver damage progresses, affecting its antioxidant, immunomodulatory, oncotic and endothelial stabilising properties. Our knowledge of the properties of albumin reveals a molecule with multiple treatment options in patients with cirrhosis, from the compensated then decompensated phases to multiple organ dysfunction. Its recognised uses in spontaneous bacterial peritonitis, post-paracentesis circulatory dysfunction, acute kidney injury and hepatorenal syndrome are fully validated, and a treatment option has opened up in decompensated cirrhosis and in acute-on-chronic liver disease.

Síndrome hepatorrenal: revisión de la literatura

Contexto: el síndrome hepatorrenal es una disfunción renal que ocurre en pacientes con enfermedad hepática crónica como cirrosis hepática o enfermedad hepática aguda, caracterizada por la activación de mecanismos reguladores que conducen a la disminución de la tasa de filtrado glomerular. Clínicamente, el síndrome hepatorrenal se divide en dos tipos: el tipo 1 se caracteriza por una pérdida rápida y progresiva de la función renal, mientras que el tipo 2 se caracteriza por ser de progresión lenta y de mejor pronóstico. Objetivo: analizar la historia natural de la enfermedad que presentan los pacientes que desarrollan síndrome hepatorrenal. Metodología: se realizó una revisión de la literatura científica de manuscritos publicados sobre síndrome hepatorrenal, para evaluar la historia natural de esta patología. Resultados: no existen hallazgos clínicos específicos, sin embargo, sus manifestaciones clínicas reflejan la enfermedad hepática avanzada subyacente, la insuficiencia renal y las anomalías circulatorias presentes. Conclusiones: la opción terapéutica más adecuada es el trasplante hepático, pero no todos los pacientes pueden recibirlo, mientras se accede a dicho manejo una opción es el tratamiento medicamentoso con vasoconstrictores y albúmina.

Background: Hepatorenal syndrome is a renal dysfunction that occurs in patients with chronic liver disease such as liver cirrhosis or acute liver disease, characterized by the activation of regulatory mechanisms that lead to a decrease in the glomerular filtration rate. Clinically, hepatorenal syndrome is divided into two types, type 1 and type 2. Type 1 is characterized by a rapid and progressive loss of kidney function while type 2 is characterized by slow progression and a better prognosis. Purpose: To analyze the natural history of the disease presented by patients who develop hepatorenal syndrome. Methodology: A review of the scientific literature of published manuscripts on hepatorenal syndrome was carried out to evaluate the natural history of this pathology. Results: There are no specific clinical findings, however, its clinical manifestations reflect the underlying advanced liver disease, kidney failure, and circulatory abnormalities present. Conclusions: The most appropriate therapeutic option is liver transplantation, but not all patients can receive it, while accessing said management an option is drug treatment with vasoconstrictors and albumin.

Insuficiencia renal en cirrosis: revisión de la literatura

Contexto: en el curso de la enfermedad del paciente cirrótico, la insuficiencia renal es un evento de mal pronóstico. Objetivo: identificar en estos pacientes los factores de riesgo de IRA, tales como: presencia de procesos infecciosos, hipovolemia inducida por hemorragia, pérdidas gastrointestinales o renales y agentes nefrotóxicos, ya que conocer de su aparición es primordial para dar comienzo a las medidas terapéuticas y las acciones profilácticas. Metodología: se realizó una búsqueda bibliográfica en las bases de datos PubMed, EMBASE, Scopus y Google académico, usando los términos MeSH como insuficiencia renal aguda, creatinina, cirrosis hepática, síndrome hepatorenal. Se obtuvieron resultados entre artículos originales, metaanálisis, reportes de casos, series de casos y revisiones de la literatura, y se escogieron 16 documentos para la elaboración de esta revisión. Resultados: los nuevos criterios definidos por el Club Internacional de Ascitis (AKI-IAC), los cuales eliminan el gasto urinario, se determinan por un aumento de la creatinina sérica ≥ 0,3 mg/dL en menos de 48 horas y, mejoran el pronóstico, permitiendo realizar intervenciones oportunas. Conclusiones: la creatinina sigue siendo el biomarcador más utilizado en insuficiencia renal aguda (IRA), incluso en pacientes cirróticos, a pesar de sus múltiples limitaciones. Un criterio dinámico modificado a partir de los criterios de AKIN, se convierte en el patrón de oro para el diagnóstico de IRA en cirrosis.

Introduction: During the cirrhotic patient's disease, renal failure is a poor prognostic event. Purpose: Knowing the risk factors for AKI in these patients given by the presence of infectious processes, loss of fluids due to hemorrhage, gastrointestinal or kidney, and nephrotoxic agents are essential for initiating therapeutic measures and prophylactic actions. Methodology: A bibliographic search was carried out in the PubMed, EMBASE, Scopus and academic Google databases, using the terms MeSH acute renal failure, creatinine, liver cirrhosis, hepatorenal syndrome. Original articles, meta-analyzes, case reports, case series and literature reviews were obtained, choosing 16 documents for the preparation of this review. Results: The new criteria defined by the International Ascites Club (AKI-IAC), which eliminate urinary output, are determined by an increase in serum creatinine ≥ 0.3 mg / dL in less than 48 hours and improve the prognosis, allowing timely interventions. Conclusions: Creatinine continues to be the most widely used biomarker in AKI, even in cirrhotic patients, despite its multiple limitations. A dynamic criterion modified from the AKIN criteria becomes the gold standard for the diagnosis of AKI in cirrhosis.

Evidence-based protocol for diagnosis and treatment of hepatorenal syndrome is independently associated with lower mortality.

BACKGROUND: Hepatorenal syndrome (HRS) is the deadliest complication of cirrhosis. The purpose of this study is to analyze if the use of a protocol for HRS is associated with higher survival in these patients. METHODS: An evidence-based protocol for the diagnosis and treatment of HRS was instituted in 2013. Data from medical records from 2010 to 2016 were obtained by searching the hospital database for patients who received terlipressin, in the three years before and after the institution of the protocol. Data were reviewed to confirm the diagnosis of HRS and multiple variables were collected. Liver-specific scores were calculated and a stepwise Cox regression approach was used for univariate and multivariate analysis. RESULTS: The study included 46 patients, 20 from the pre-protocol period and 26 from the post-protocol period. Respectively, mortality at 30 days, 90 days and 365 days was 75%, 75% and 90% for the pre-protocol period, and 61%, 69% and 80% for the post-protocol period. In the multivariate analysis, an aspartate aminotransferase (AST) of <40U/L, the pre-protocol period and higher Child-Turcotte-Pugh scores were associated with higher 30-day and 90-day mortality. The total mean dose of terlipressin and human albumin used per patient was reduced from 27mg to 22mg and from 236g to 144g, respectively, after the institution of the protocol. This was not associated with higher mortality. CONCLUSION: The use of an evidence-based protocol for the treatment of HRS translated into a higher survival. The authors suggest that the use of evidence-based protocols for the diagnosis and treatment of HRS could reduce cost and mortality in tertiary hospitals.

Síndrome hepatorrenal en falla hepática aguda sobre crónica / Hepatorrenal syndrome in acute on chronic hepatic failure

Resumen La insuficiencia hepática aguda sobre crónica (ACLF, por su nombre en inglés: Acute-on-Chronic Liver Failure) es una entidad de reciente caracterización que se presenta como una descompensación aguda de una hepatopatía crónica, la cual puede ir asociada a falla en diferentes órganos y presentar una alta mortalidad. Su incidencia alcanza hasta un 30% de pacientes que consultan por complicaciones asociadas a cirrosis de base. Dentro de los factores precipitantes más frecuentes se encuentran las infecciones bacterianas, el alcoholismo y la reactivación de hepatitis virales; no obstante, hasta en un 40% de los casos no se identifica ningún factor precipitante. La fisiopatología de esta entidad aún es desconocida en cierta medida, pero se plantea la existencia de una respuesta inflamatoria excesiva en su desarrollo. No existe ningún tratamiento específico y su manejo se basa en el tratamiento para complicaciones asociadas, soporte y finalmente trasplante hepático. La disfunción renal es un hallazgo común en pacientes con enfermedad hepática. Se pensaba que el síndrome hepatorrenal era de carácter meramente funcional. Ahora, ante la evidencia de algún grado de daño tubular relacionado, se ha mejorado la comprensión de la fisiopatología de dicha entidad, lo que ha obligado recientemente a replantear los criterios diagnósticos y la clasificación de la enfermedad. Describimos el caso clínico de una paciente atendida en un centro hospitalario en la ciudad de Pereira, Risaralda. Ella presentó bacteriemia por cocos Gram positivos de origen no claro, lo que se consideró como el factor precipitante; tuvo deterioro clínico, con aparición de síndrome hepatorrenal y falla multiorgánica, lo que finalmente la llevo a la muerte, a pesar del manejo multidisciplinario.

Abstract Acute-on-chronic liver failure (ACLF) is a recently characterized entity that presents as an acute decompensation of chronic liver disease. It can be associated with failure in different organs and presents a high mortality rate. Its incidence reaches up to 30% on patients consulting for complications derived from cirrhosis. Among the most frequent precipitating factors, there are bacterial infections, alcoholism, and reactivation of viral hepatitis; however, in up to 40% of the cases, no precipitating factor is identified. The pathophysiology of this entity is still unknown to a certain extent, but the existence of an excessive inflammatory response in its development is suggested. There is no specific treatment and its management is based on treatment for associated complications, support, and finally liver transplantation. Kidney dysfunction is a common finding in patients with liver disease. The understanding of the pathophysiology of this entity, previously thought to be purely functional in nature, yet now given the evidence of some degree of related tubular damage, has improved and has recently entailed a rethink of the diagnostic criteria and the classification of the illness. We describe the clinical case of a patient treated at a hospital in the city of Pereira, Risaralda, who presented bacteremia due to Gram-positive cocci of unclear origin, considered as the precipitating factor. The patient had clinical deterioration, as well as the onset of hepatorenal syndrome and multi-organ failure, finally leading to death despite multidisciplinary treatment.

Improvement of renal function prior to liver transplantation is not associated with better long-term renal outcome or survival.

INTRODUCTION AND OBJECTIVES: Since MELD implementation renal impairment in liver transplant (LT) recipients has become of increasing importance. This is the first study evaluating the course of renal function immediately prior to LT as predictor for long-term renal and overall outcome. PATIENTS AND METHODS: In this retrospective study, 226 adults undergoing LT at the University Medical Center Hamburg-Eppendorf (2011-2015) were included. The impact of renal function over a period of 3 months prior to LT compared to renal function at the day of LT on long-term renal outcome and survival was assessed. RESULTS: According to GFR at day of LT renal function improved (≥1 CKD stage) in 64 patients (28%), remained stable in 144 (64%) or deteriorated in 18 (8%). Improvement of renal function prior to LT did neither significantly affect 90-day (13% vs. 14%, p = 0.83), nor 5-year post-LT mortality (35% vs. 41%, p = 0.57). 50 patients (22%) with hepatorenal syndrome (HRS) received terlipressin prior to LT, but only 18 (37%) showed prolonged stabilization of renal function (improvement ≥1 CKD stage). Response to terlipressin did neither improve 90-day (p=1), 5-year mortality (p = 0.52) nor long-term renal function (p = 0.843). Nevertheless, need for dialysis pre-LT (59% vs. 34%, p = 0.005) and post-LT (62% vs. 17%, p<0.001) was associated with increased 5-year mortality. CONCLUSIONS: Improvement of renal function immediately prior to LT, either spontaneously or following terlipressin therapy, did neither ameliorate long-term renal outcome nor survival in LT recipients. Future studies need to clarify the impact of terlipressin in HRS on the transplant waiting time in LT candidates.

An Integrated Review of the Hepatorenal Syndrome.

Among the complications of cirrhosis, hepatorenal syndrome (HRS) is characterized by having the worst survival rate. HRS is a disorder that involves the deterioration of kidney function caused primarily by a systemic circulatory dysfunction, but in recent years, systemic inflammation and cirrhotic cardiomyopathy have been discovered to also play an important role. The diagnosis of HRS requires to meet the new International Club of Ascites-Acute Kidney Injury (ICA-AKI) and Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI) criteria after ruling out other causes of kidney injury. At the time of diagnosis, it is important to start the medical treatment as soon as possible where three types of vasoconstrictors have been recognized: vasopressin analogs (ornipressin and terlipressin), alpha-adrenergic agonists (norepinephrine and midodrine) and somatostatin analogues (octreotide); all should be combined with albumin infusion. Among them, terlipressin and albumin are the first lines of treatment in most cases, although terlipressin should be monitor closely due to its adverse events. The best treatment of choice is a liver transplant, because it is the only definitive treatment for this disease.

Hepatorenal syndrome in children: a review.

Hepatorenal syndrome (HRS) occurs in patients with cirrhosis or fulminant hepatic failure and is a kind of pre-renal failure due to intense reduction of kidney perfusion induced by severe hepatic injury. While other causes of pre-renal acute kidney injury (AKI) respond to fluid infusion, HRS does not. HRS incidence is 5% in children with chronic liver conditions before liver transplantation. Type 1 HRS is an acute and rapidly progressive form that often develops after a precipitating factor, including gastrointestinal bleeding or spontaneous bacterial peritonitis, while type 2 is considered a slowly progressive form of kidney failure that often occurs spontaneously in chronic ascites settings. HRS pathogenesis is multifactorial. Cirrhosis causes portal hypertension; therefore, stasis and release of vasodilator substances occur in the hepatic vascular bed, leading to vasodilatation of splanchnic arteries and systemic hypotension. Many mechanisms seem to work together to cause this imbalance: splanchnic vasodilatation; vasoactive mediators; hyperdynamic circulation states and subsequent cardiac dysfunction; neuro-hormonal mechanisms; changes in sympathetic nervous system, renin-angiotensin system, and vasopressin. In patients with AKI and cirrhosis, fluid expansion therapy needs to be initiated as soon as possible and nephrotoxic drugs discontinued. Once HRS is diagnosed, pharmacological treatment with vasoconstrictors, mainly terlipressin plus albumin, should be initiated. If there is no response, other options can include surgical venous shunts and kidney replacement therapy. In this regard, extracorporeal liver support can be a bridge for liver transplantation, which remains as the ideal treatment. Further studies are necessary to investigate early biomarkers and alternative treatments for HRS.

Disfunción renal en el paciente cirrótico / Renal dysfunction in the cirrhotic patient

La disfunción renal es una complicación común en pacientes con cirrosis avanzada y está asociadaa un incremento significativo en la mortalidad. Este deterioro de la función renal puede ser reversible en algunos casos, si se identifica y se trata su etiología. La lesión renal aguda (LRA) de origen prerrenal y la necrosis tubular aguda (NTA) son las entidades más frecuentes en pacientes con enfermedad hepática crónica y cirrosis, constituyendo un desafío en los escenarios clínicos actuales. La aparición de nuevos biomarcadores como la lipocalina asociada a la gelatinasa de neutrófilos (NGAL), puede ser un factor determinante para esclarecer el origen de estas dos entidades. En la actualidad, la clasificación de la enfermedad renal establece que un aumento en la creatinina sérica basal >0,3 mg/dL dentro de las primeras 48 horas, o un incremento mayor al 50% desde la línea de base, son suficientes para definir lesión renal aguda, por lo cual, cambios leves en la creatinina sérica en un periodo corto de tiempo, contribuyen a una identificación temprana y previenen desenlaces negativos. Esta revisión de tema abordará la lesión renal aguda en cirrosis desde la fisiopatología, la clasificación actual según guías internacionales, los avances en biomarcadores y las principales etiologías, finalizando con un abordaje general y estrategias de prevención.

Kidney dysfunction is a common complication in patients with advanced cirrhosis and is associated with a significant increase in mortality. This deterioration of kidney function may be reversible in some cases, if its etiology is identified and treated. Acute kidney injury (AKI) of prerenal origin and acute tubular necrosis (ATN) are the most frequent entities in patients with chronic liver disease and cirrhosis, constituting a challenge in current clinical scenarios. The emergence of new biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL), may be a determining factor in clarifying the origin of these two entities. Currently, the classification of renal disease establishes that an increase in basal serum creatinine >0,3 mg/dL within the first 48 hours, or an increase higher than 50% from the baseline, are enough to define acute kidney injury, therefore slight changes in serum creatinine in a short period of time contribute to an early identification and prevent negative outcomes. This literature review will address acute kidney injury in cirrhosis from its pathophysiology, current classification according to international guidelines, advances in biomarkers and the main etiologies associated with it, ending with a general approach and prevention strategies.

Características clínicas y complicaciones de la cirrosis hepática en una población de altura (Huancayo, 3250 m s. n. m.) / Clinical features and complications of liver cirrhosis in a high-altitude population (Huancayo, 3,250 m a.s.l.)

RESUMEN Objetivo La cirrosis hepática ocasiona significativa mortalidad y morbilidad. Esta investigación trata de determinar la presentación clínica, la etiología y las complicaciones de los pacientes con cirrosis hepática en una población que habita en una región de altura del Perú. Materiales y métodos Evaluación retrospectiva de la presentación clínica y las complicaciones de la cirrosis hepática. Se estudiaron 108 historias clínicas de pacientes cirróticos ingresados en el Servicio de Medicina del Hospital Nacional Ramiro Prialé Prialé de la ciudad de Huancayo entre el 2010 y el 2012. Resultados El promedio de edad de los pacientes fue de 60,50 años (rango 12-82 años) y el 62,90 % fueron varones. La etiología más frecuente fue la ingesta alcohólica (63,00 %) seguida por las hepatitis B y C crónicas (7,40 % y 2,80 %, respectivamente). El 58,30 % de los casos correspondía al estadio B de la clasificación de Child-Pugh y el 31,30 % se encontraba en estadio C. La manifestación clínica más frecuente fue la distensión abdominal (87,00 %). Las complicaciones más comunes fueron la ascitis (56,00 %), la encefalopatía hepática (47,20 %) y el síndrome hepatorrenal (8,30 %). Conclusiones La cirrosis alcohólica fue la etiología más común y las complicaciones más frecuentes fueron la ascitis y la encefalopatía hepática.

ABSTRACT Objective Liver cirrhosis is responsible for significant morbidity and mortality. This research aims to determine the clinical presentation, etiology and complications of patients with liver cirrhosis from a population living at a high altitude region in Peru. Materials and methods A retrospective study of the clinical presentation and complications of liver cirrhosis was conducted. One hundred eight (108) medical records of patients with liver cirrhosis admitted to the Internal Medicine Service of the Hospital Nacional Ramiro Prialé Prialé, Huancayo, were evaluated between 2010 and 2012. Results Patients' mean age was 60.5 years (range: 12-82 years) and 62.9 % were males. The most common etiology was alcohol consumption (63 %), followed by chronic hepatitis B and C (7.4 % and 2.8 %, respectively). Fifty-eight point three percent (58.3 %) of the patients had a Child-Pugh class B score and 31.30 % of them had a Child-Pugh class C score. The most frequent clinical presentation was abdominal distension (87 %). The most common complications were ascites (56 %), hepatic encephalopathy (47.2 %) and hepatorenal syndrome (8.3 %). Conclusions Alcoholic liver cirrhosis was the most common etiology. The most frequent complications were ascites and hepatic encephalopathy.

Insuficiencia renal aguda en cirrosis hepática / Acute renal failure in hepatic cirrhosis

Resumen La asociación de la insuficiencia renal aguda en pacientes con cirrosis hepática siempre se ha establecido en el contexto del síndrome hepatorrenal, pero hay varias causas además de ésta. La insuficiencia renal aguda es un desafío terapéutico en pacientes con cirrosis hepática. La insuficiencia renal aguda se debe a factores prerrenales, factores intrínsecos del riñón o posrenales. La prevalencia de insuficiencia renal aguda en la cirrosis se ha informado de 14 a 50% en pacientes con cirrosis. Su prevalencia es de aproximadamente 50% en pacientes con cirrosis y ascitis y de 20% en los pacientes con cirrosis en etapa avanzada que están hospitalizados. En 2015, el Club Internacional de Ascitis estableció una nueva definición y estadificación de la insuficiencia renal aguda en pacientes con cirrosis hepática.

Abstract The association of acute renal failure in patients with liver cirrhosis has always been established in the context of hepatorenal syndrome, but there are several etiologies in addition to this cause. Acute renal failure is a therapeutic challenge in patients with liver cirrhosis. Acute renal failure is due to prerenal factors, intrinsic factors of the kidney or post-renal. The prevalence of acute renal failure in cirrhosis has been reported from 14 to 50% in patients with cirrhosis. Its prevalence is approximately 50% in patients with cirrhosis and ascites and 20% in patients with advanced stage cirrhosis who are hospitalized. In 2015, the International Ascitis Club established a new definition and staging of acute renal failure in patients with liver cirrhosis.