Development and validation of a score to predict response to hepatorenal syndrome treatment: role of inflammation in acute kidney injury

• Grant number: 17/23588-4
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2018
• End date: September 30, 2020
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Alberto Queiroz Farias
• Grantee: Alberto Queiroz Farias
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Daniel Ferraz de Campos Mazo ; Flair José Carrilho ; Rafael Oliveira Ximenes

Abstract

Introduction: Hepatorenal syndrome (HRS) is described as a functional type of AKI. However, studies using kidney tubular injury biomarkers (neutrophil gelatinase-associated lipocalin [NGAL]) demonstrated that some degree of tubular damage occurs in patients with HRS. In fact, response rate to HRS treatment is 20 to 50% and the presence of severe tubular injury justifies absence of response in some patients. It has also been demonstrated that urine/plasma NGAL ratio is a better biomarker of tubular damage than urinary NGAL alone, as the latter is influenced by inflammation and high plasma NGAL levels. Systemic inflammation is frequently observed in patients with decompensated cirrhosis and results in AKI by cardiocirculatory failure and/or structural tubular damage. Although described as a functional disease, HRS is frequently precipitated by inflammatory conditions such as sepsis and alcoholic hepatitis. However, the role of inflammation and its mediators in HRS have been poorly studied in the literature and it is not known whether they contribute to tubular damage that may occur in patients who do not respond to treatment. Furthermore, for reasons not explored in the literature, the response rate to HRS treatment with albumin and terlipressin in the United States (USA) is inferior to the response rate observed in Brazil and Europe (20% x 50%, respectively).Objectives: objective 1) To build and validate a score to predict response to treatment of HRS combining biomarkers of AKI, inflammation, cardiocirculatory failure and liver function. Furthermore, we will compare urine/plasma NGAL ratio, inflammatory, cardiocirculatory failure and liver function biomarkers between patients with decompensated cirrhosis with and without AKI and between different etiologies of AKI in cirrhosis (pre-renal azotemia[PRA], HRS and acute tubular necrosis [ATN]). Objective 2) To analyze the differences of AKI between patients with decompensated cirrhosis from Brazil and USA.Patients and methods: Prospective multicenter observational study conducted in the Clinic Hospital of FMUSP and Clinic Hospital of UNICAMP with collaboration of Yale University. For objective 1, the study is divided in two cohorts: training set and validation set. For objective 2, the Brazilian patients will be compared to a cohort of patients with decompensated cirrhosis from Yale University, USA. The training set is a prospective cohort of 224 patients (77 with HRS) with decompensated cirrhosis included at Clinic Hospital of FMUSP between June 2013 and May 2017. The validation set will be prospectively included at the aforementioned hospitals in a period of 18 months. The cohort of patients with decompensated cirrhosis from the Digestive Diseases Service of the Medical School of Yale University, USA, will consist of patients prospectively included in this institution database previously. Study tests are urinary and plasma NGAL, plasma renin activity and serum inflammatory biomarkers (IL-1b, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-12p70, TNF-±, IFN-³ and TFG-²). A score using variables associated with response to HRS treatment will be built and validated. For our secondary aims, training and validation sets will be analyzed together. Urine/plasma NGAL ratio, inflammatory biomarkers, plasmatic renin activity, mean arterial pressure and liver function tests will also be compared between patients with and without AKI and between patients with PRA, HRS and ATN. Clinical and routine laboratory data, the incidence and etiology of AKI, treatment administrated and the response to HRS treatment between Brazilian and American patients will be compared. (AU)