Biomarker discovery

Biomarkers of renal tubular damage in predicting response to terlipressin and albumin in patients with hepatorenal syndrome

The issue

The combination of vasoconstrictors and albumin is the treatment of choice in patients with hepatorenal syndrome (HRS-AKI). Predictors of response to vasoconstrictors and albumin may be useful in clinical practice, because can anticipate the clinical course of the disease and may mitigate the risk of side effects. So far, clinical predictors have been identified, such as baseline serum creatinine, serum bilirubin, acute-on-chronic liver failure (ACLF) grade and changes in mean arterial pressure. The association of a higher ACLF grade with a lower response to terlipressin and albumin is of particular interest, because may suggest a role for severe inflammation affecting renal tubular function. Plasma samples of patients with HRS-AKI showed a high degree of systemic inflammation, supporting this hypothesis. Systemic inflammation may induce kidney tubular damage regardless of impairment of circulatory function. In fact, the release of reactive oxygen species and nitric oxide can cause a direct tubular damage as it occurs in sepsis. Furthermore, the inflammatory response can cause a mitochondrial dysfunction that can induce metabolic changes in tubular cells causing a shift from oxidative phosphorylation to glycolysis, a feature that is commonly observed in ACLF.

Urinary biomarkers may be useful to predict response to terlipressin and albumin. Urinary NGAL can unveil the presence of some degree of tubular dysfunction. In addition, quinolinic acid, a downstream product of the kynurenine pathway, which is highly expressed in ACLF and has shown to be associated with risk of AKI in both experimental models and critically ill patients, could be useful for this purpose.

The approach

The aim of this study is to identify whether urinary biomarkers of tubular damage can predict response to treatment with terlipressin and albumin in patients with HRS–AKI within PREDICT and ACLARA. We will assess the ability of investigated biomarkers to predict the reversal of HRS–AKI and in-hospital mortality, 28-day mortality and 90-day mortality, in patients with HRS–AKI. Urinary biomarkers (NGAL, albumin, IGFBP7, EGF, Cystatin C, osteopontin) will be tested with a multiplex ELISA. Targeted (tryptophan kynurenine pathway, transulfuration pathway) and untargeted metabolomics will be performed in urine samples using ultraperformance liquid chromatography (UPLC) coupled with quadrupole time-of-flight (Q-TOF) mass spectrometry .

The project wants to identify novel predictors of response to vasoconstrictors and albumin in patients with HRS-AKI using urinary biomarkers/metabolites. The use of vasoconstrictors and albumin can cause relevant side effects and the identification of predictors of response to those treatment can help to personalize the therapeutic approach and to avoid the use of a futile and potentially dangerous treatment in patients that are unlikely to have a benefit. Moreover, the analysis of urinary metabolites can unveil novel pathways involved in the pathogenesis of the syndrome and can pave the way for the development of new treatments for those patients less likely to benefit from vasoconstrictors and albumin

Department of Medicine, University of Padova, Grant no. BIRD215787.