Hyponatremia influences the outcome of patients with acute-on-chronic liver failure: an analysis of the CANONIC study

INTRODUCTION: Hyponatremia is a marker of poor prognosis in patients with cirrhosis. This analysis aimed to assess if hyponatremia also has prognostic value in patients with acute-on-chronic liver failure (ACLF), a syndrome characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. METHODS: We performed an analysis of the Chronic Liver Failure Consortium CANONIC database in 1,341 consecutive patients admitted to 29 European centers with acute decompensation of cirrhosis (including ascites, gastrointestinal bleeding, hepatic encephalopathy, or bacterial infections, or any combination of these), both with and without associated ACLF (301 and 1,040 respectively). RESULTS: Of the 301 patients with ACLF, 24.3% had hyponatremia at inclusion compared to 12.3% of 1,040 patients without ACLF (P <0.001). Model for end-stage liver disease, Child-Pugh and chronic liver failure-SOFA scores were significantly higher in patients with ACLF and hyponatremia compared to those without hyponatremia. The presence of hyponatremia (at inclusion or during hospitalization) was a predictive factor of survival both in patients with and without ACLF. The presence of hyponatremia and ACLF was found to have an independent effect on 90-day survival after adjusting for the potential confounders. Hyponatremia in non-ACLF patients nearly doubled the risk (hazard ratio (HR) 1.81 (1.33 to 2.47)) of dying at 90 days. However, when considering patients with both factors (ACLF and hyponatremia) the relative risk of dying at 90 days was significantly higher (HR 6.85 (3.85 to 12.19) than for patients without both factors. Patients with hyponatremia and ACLF had a three-month transplant-free survival of only 35.8% compared to 58.7% in those with ACLF without hyponatremia (P <0.001). CONCLUSIONS: The presence of hyponatremia is an independent predictive factor of survival in patients with ACLF. In cirrhosis, outcome of patients with ACLF is dependent on its association with hyponatremia

Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis

Background Biomarkers are potentially useful in assessment of outcomes in patients with cirrhosis, but information is very limited. Given the large number of biomarkers, adequate choice of which biomarker(s) to investigate first is important. Aim Analysis of potential usefulness of a panel of urinary biomarkers in outcome assessment in cirrhosis. Patients and Methods Fifty-five patients with acute decompensation of cirrhosis were studied: 39 had Acute Kidney Injury (AKI) (Prerenal 12, type-1 HRS (hepatorenal syndrome) 15 and Acute Tubular Necrosis (ATN) 12) and 16 acute decompensation without AKI. Thirty-four patients had Acute-on-chronic liver failure (ACLF). A panel of 12 urinary biomarkers was assessed, using a multiplex assay, for their relationship with ATN, ACLF and mortality. Results Biomarker with best accuracy for ATN diagnosis was NGAL (neutrophil-gelatinase associated lipocalin): 36 [26-125], 104 [58-208] and 1807 [494-3,716] μg/g creatinine in Prerenal-AKI, type-1 HRS and ATN, respectively; p<0.0001 (AUROC 0.957). Other attractive biomarkers for ATN diagnosis were IL-18, albumin, trefoil-factor-3 (TFF-3) and glutathione-S-transferase-π (GST-π) Biomarkers with less accuracy for ATN AUCROC<0.8 were β2-microglobulin, calbindin, cystatin-C, clusterin and KIM-1 (kidney injury molecule-1). For ACLF, the biomarker with the best accuracy was NGAL (ACLF vs. No-ACLF: 165 [67-676] and 32 [19-40] μg/g creatinine; respectively; p<0.0001; AUROC 0.878). Interestingly, other biomarkers with high accuracy for ACLF were osteopontin, albumin, and TFF-3. Biomarkers with best accuracy for prognosis were those associated with ACLF. Conclusions A number of biomarkers appear promising for differential diagnosis between ATN and other types of AKI. The most interesting biomarkers for ACLF and prognosis are NGAL, osteopontin, albumin, and TFF-3. These results support the role of major inflammatory reaction in the pathogenesis of ACLF

Insuficiencia renal en la cirrosis: Evaluación de nuevas clasificaciones pronósticas y tratamiento del síndrome hepato-renal tipo 1 asociado a sepsis

[spa] El objetivo general de esta Tesis Doctoral es profundizar en el conocimiento sobre la insuficiencia renal, una complicación frecuente y asociada a mal pronóstico que pueden presentar los pacientes con cirrosis hepática. Los trabajos diseñados para tal objetivo están enfocados por un lado, a investigar la capacidad predictiva de mortalidad de la clasificación de pacientes acorde al grado de ACLF sobre la clasificación AKIN y a evaluar eficacia y seguridad del tratamiento con vasoconstrictores de los pacientes con SHR tipo-1 y sepsis asociada . El resultado principal del primer estudio fue que la clasificación ACLF tiene una mayor capacidad predictiva de mortalidad a 28 y 90 días en comparación con la clasificación AKIN. Se evaluó la clasificación de ACLF en todos los pacientes al momento de la inclusión y a las 48 horas, y la clasificación AKIN a las 48 horas (puesto que se basa en los cambios en la concentración sérica de creatinina en dos determinaciones distintas obtenidas con una diferencia de 48 horas). El 19,2% de los pacientes desarrollaron AKI durante las primeras 48 horas después de la inclusión. Los pacientes que desarrollaron AKI presentaron un marcado deterioro de la función hepática y niveles más elevados de CrS, recuento de leucocitos y proteína C reactiva. La presencia de AKI ha demostrado tener una asociación estadio-dependiente con el pronóstico. La presencia de ACLF en el momento de la inclusión estuvo asociada fuertemente con la mortalidad. La clasificación ACLF fue superior a la AKIN para predecir la mortalidad libre de trasplante tanto a los 28 como a los 90 días. Se analizó también la presencia y grado de ACLF luego de las 48 horas de la inclusión y coincidiendo con el tiempo en que deben determinarse los valores de creatinina sérica para el diagnóstico de AKI según los criterios AKIN. El segundo estudio proporciona evidencia que indica que el tratamiento con terlipresina y albúmina es eficaz y seguro para el SHR tipo-1 asociado a sepsis. El tratamiento con terlipresina y albúmina produce una mejora del volumen arterial efectivo y este efecto hemodinámico es beneficioso logrando revertir el SHR tipo-1 en el 67% de los pacientes. Los resultados de este estudio apoyan el concepto de que, independientemente de la presencia de infección bacteriana, los mecanismos fisiopatológicos del SHR tipo-1 son similares. La falta de respuesta al tratamiento con terlipresina y albúmina no parece estar relacionada con la gravedad de la disfunción circulatoria presente en el momento previo al inicio del tratamiento ni a un efecto hemodinámico insuficiente logrado con el tratamiento, con el retraso en el inicio del tratamiento con vasoconstrictores, con la mayor gravedad del SHR tipo-1 (determinado por los niveles de CrS previos al inicio del tratamiento), ni con la presencia de daño tubular renal significativo (evaluado mediante la medición b-2 microglobulina y NGAL, biomarcadores de daño tubular renal, antes del comienzo del tratamiento). El hallazgo más atractivo ha sido la relación observada entre la respuesta al tratamiento y la gravedad del ACLF. Nuestros resultados muestran que el tratamiento no fue eficaz en pacientes con ACLF muy severo, como se indica por un CLIF-SOFA Score igual o mayor que 11, mientras que si fue eficaz en pacientes con ACLF menos grave (CLIF-SOFA Score < 11).[eng] Cirrhosis is a chronic liver disease that accounts for approximately 1 to 2% of all deaths in Europe. Prognostic stratification of patients with cirrhosis is a common clinical practice. The first study that composes this doctoral thesis compares the prognostic accuracy (28-day and 90-day transplant- free mortality) of the Acute-on-Chronic Liver Failure (ACLF) classification to that of Acute Kidney Injury (AKI) classification. The study was performed in 510 patients with an acute decompensation of cirrhosis. The presence of ACLF and AKI were strongly associated with mortality. ACLF classification was more accurate than AKI classification in predicting 90-day mortality in the whole series of patients. Moreover, assessment of ACLF classification at 48 hours had significantly better prognostic accuracy compared to that of both AKI classification and ACLF classification at enrollment. The major conclusion of this study is that the ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis. The second study was designed with the aim to investigate the effects of early treatment with terlipressin and albumin on circulatory and kidney function in patients with type-1 HRS and sepsis and assess factors predictive of response to therapy. In this prospective study 18 consecutive patients with type-1 HRS associated with sepsis were included. Treatment was associated with marked improvement in arterial pressure and suppression of the high levels of plasma renin activity and norepinephrine. Response to therapy was achieved in 12/18 patients (67%) and was associated with improved 3-month survival compared to patients without response. Non-responders had significantly lower baseline heart rate, poor liver function tests, slightly higher serum creatinine, and higher Child-Pugh and MELD scores compared to responders. Interestingly, non- responders had higher values of CLIF-SOFA score compared to responders (14 ± 3 vs. 8 ± 1, respectively p <0.001), indicating greater severity of acute-on-chronic liver failure (ACLF). A CLIF-SOFA score ≥11 had 92% sensitivity and 100% specificity in predicting no response to therapy. No significant differences were observed between responders and non-responders in baseline urinary kidney biomarkers. Treatment was safe and no patient required withdrawal of terlipressin. Conclusions: Early treatment with terlipressin and albumin in patients with type-1 HRS associated with sepsis is effective and safe. Patients with associated severe ACLF are unlikely to respond to treatment