Type-1 hepatorenal syndrome in patients with cirrhosis and infection vs. sepsis-induced acute kidney injury: What matters?
Authors: Claire Francoz, François Durand
Journal: Journal of Hepatology (2014)

Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsisJournal of HepatologyVol. 60Issue 5PreviewTerlipressin and albumin is the standard of care for classical type-1 hepatorenal syndrome (HRS) not associated with active infections. However, there is no information on efficacy and safety of this treatment in patients with type-1 HRS associated with sepsis. Study aim was 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. Full-Text PDF Type-1 hepatorenal syndrome (HRS) is considered to be a specific complication of advanced cirrhosis characterized by an abrupt pre-renal like deterioration in renal function, unresponsive to volume expansion and associated with an especially poor prognosis [[1]Gines P. Guevara M. Arroyo V. Rodes J. Hepatorenal syndrome.Lancet. 2003; 362: 1819-1827Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar]. With the aim of better reflecting the specificity of HRS, the original definition was very stringent with a number of exclusion criteria such as ongoing sepsis [[2]Arroyo V. Gines P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. et al.Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International ascites club.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar]. With increasing experience, it was felt that these diagnostic criteria were too restrictive since HRS is frequently triggered by precipitating factors. Accordingly, since revised guidelines have been proposed in 2007, bacterial infection is no longer considered to be an exclusion criterion for the diagnosis of HRS [[3]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention, and treatment of hepatorenal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar]. The main mechanism of HRS is an extreme renal vasoconstriction due to the activation of sodium-retaining and vasoconstrictor systems resulting in a major decrease in glomerular filtration rate (GFR) [[4]Gines P. Schrier R.W. Renal failure in cirrhosis.N Engl J Med. 2009; 361: 1279-1290Crossref PubMed Scopus (606) Google Scholar]. This cascade of events results from marked splanchnic vasodilatation and a state of low effective arterial blood volume. Insufficient cardiac output may also contribute to renal hypoperfusion. A paradox is that the reference treatment of HRS, where renal vasoconstriction is central, is based on a potent vasoconstrictor agent: terlipressin. Practically, this apparent paradox could be explained by the fact that terlipressin-induced vasoconstriction predominates in the splanchnic system. Terlipressin may reverse, at least in part, splanchnic arterial vasodilatation with redistribution to systemic vascular bed and reversal of reduced effective arterial blood volume. While only few data are available on type-2 HRS, several studies have shown that terlipressin improves renal function in up to 65% of patients with type-1 HRS with a significant improvement in survival [5Moreau R. Durand F. Poynard T. Duhamel C. Cervoni J.P. Ichai P. et al.Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study.Gastroenterology. 2002; 122: 923-930Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 6Gluud L.L. Christensen K. Christensen E. Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.Hepatology. 2010; 51: 576-584Crossref PubMed Scopus (233) Google Scholar, 7Martin-Llahi M. Pepin M.N. Guevara M. Diaz F. Torre A. Monescillo A. et al.Terlipressin and albumin vs. albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.Gastroenterology. 2008; 134: 1352-1359Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, 8Sanyal A.J. Boyer T. Garcia-Tsao G. Regenstein F. Rossaro L. Appenrodt B. et al.A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome.Gastroenterology. 2008; 134: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar]. Unfortunately, in the absence of transplantation, short term mortality remains very high. However, in all these studies patients with ongoing sepsis were excluded according to the original definition of HRS. In this issue of the Journal of Hepatology [[9]Rodriguez E. Elia C. Sola E. Barreto R. Graupera I. Andrealli A. et al.Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.J Hepatol. 2014; 60: 955-961Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar], Rodriguez E. and colleagues report on the results of a pilot study exploring the role of terlipressin and albumin in patients with type-1 HRS and sepsis. Interestingly, the authors found that in this subgroup, results similar to those previously reported in patients without sepsis could be achieved. Response to therapy (decrease in serum creatinine below 1.5 mg/dl or 133 μmol/L) was observed in 67% of patients. The response rate was higher as compared to a historical group of patients with type-1 HRS not treated by terlipressin and albumin even if the difference did not reach significance (67% vs. 40%, p = 0.06). Three-month survival rate was significantly higher in responders as compared to non-responders. These results strongly support the use of terlipressin and albumin in patients with type-1 HRS and bacterial infection. However, they should be interpreted with caution since the study population was relatively small and there was no control group. Even though controlled studies are unlikely to be performed in this uncommon condition, the results might be validated in other centers. The results of this study also support the concept that, whatever patients with cirrhosis have bacterial infection or not, the mechanisms of type-1 HRS are similar. Indeed, in this population of patients with infection, response to terlipressin was characterized by an improvement of circulatory function along with a significant decrease in plasma renin activity and plasma norepinephrine concentration. However, these results should be interpreted in the light of the recently revisited mechanisms of sepsis-induced acute kidney injury (AKI) in non-cirrhotic patients, suggesting that many factors other than renal hypoperfusion are involved. An increasing body of evidence shows that sepsis-induced AKI is a complex process where several factors including microcirculatory changes, patchy areas of tubular cells with apical vacuolization but no necrosis or apoptosis and, finally, metabolic downregulation of tubular cells induced by inflammation and oxidative stress come into play [[10]Gomez H. Ince C. De Backer D. Pickkers P. Payen D. Hotchkiss J. et al.A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury.Shock. 2014; 41: 3-11Crossref PubMed Scopus (460) Google Scholar]. Besides microcirculatory changes and extraglomerular shunting, these tubular changes may lead to decreased GFR through activation of the tubuloglomerular feedback, constriction of the afferent arteriole and decreased hydrostatic pressure in the glomerulus. These mechanisms may explain why sepsis-induced AKI can be observed in the absence of overt renal hypoperfusion [[11]Langenberg C. Wan L. Egi M. May C.N. Bellomo R. Renal blood flow in experimental septic acute renal failure.Kidney Int. 2006; 69: 1996-2002Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar]. Whether similar mechanisms are involved in type-1 HRS associated with infection is an important issue, especially in those who do not respond to terlipressin. The absence of significant increase in urinary neutrophil gelatinase associated lipocalin (a biomarker of acute tubular necrosis) in non-responders as compared to responders is consistent with the changes observed during sepsis-induced AKI, as described above. However, the respective role of renal vasoconstriction and hypoperfusion on the one hand and the mechanisms involved in sepsis-induced AKI other than hypoperfusion on the other hand needs to be further investigated. In general efforts should be made in the development of tools to monitor renal blood flow. Such tools may obviously help optimize the management. According to the definition proposed recently by the EASL-CLIF Consortium [[12]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1658) Google Scholar], all patients in the study by Rodriguez E. and colleagues [[9]Rodriguez E. Elia C. Sola E. Barreto R. Graupera I. Andrealli A. et al.Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.J Hepatol. 2014; 60: 955-961Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar] met the criteria for acute-on-chronic liver failure (ACLF). Indeed, all patients had cirrhosis and serum creatinine above 2 mg/dl (180 μmol/L). ACLF and the derived CLIF-SOFA score [[12]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1658) Google Scholar] allow to categorize patients with cirrhosis and acute deterioration according to the number and severity of organ/system failures. The CLIF-SOFA score is a prognostic score derived from the widely used SOFA score in general intensive care unit patients [[13]Vincent J.L. Moreno R. Takala J. Willatts S. De Mendonca A. Bruining H. et al.The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.Intensive Care Med. 1996; 22: 707-710Crossref PubMed Scopus (6876) Google Scholar], with some modifications aimed at better reflecting the impact of organ/system failures in the context of cirrhosis. The higher the CLIF-SOFA score, the higher the mortality rate in patients with ACLF. The study by Rodriguez E. and colleagues offers an original approach allowing to analyze the impact of type-1 HRS not only as a single event during the course of cirrhosis but rather as one of the extra-hepatic complications that may occur during end stage cirrhosis. It is not surprising that in this study, non-responders had a significantly higher CLIF-SOFA score as compared to responders. Nor is it surprising that the higher the CLIF-SOFA score, the higher the mortality rate. Interestingly, the authors found that patients with ACLF grade 3 as well as those with a CLIF-SOFA score over 11 had a very low probability of response to terlipressin and albumin. Since there was a strong interaction between resolution of infection and severity of ACLF, the absence of resolution of infection was also associated with a low probability of response to therapy. Altogether, these findings illustrate the determining impact of extra-hepatic organ failures on reversibility of type-1 HRS with terlipressin. Whether in this subgroup of patients, terlipressin is ineffective because the mechanisms involved are relatively independent of renal hypoperfusion (such as in sepsis-induced AKI) or because patients relentlessly progress to acute tubular necrosis needs to be clarified. Finally, another factor that should be taken into account is the presence or absence of underlying chronic kidney changes. In advanced cirrhosis, indeed, normal baseline serum creatinine does not exclude a major impairment in renal function [14Nadim M.K. Kellum J.A. Davenport A. Wong F. Davis C. Pannu N. et al.Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.Crit Care. 2012; 16: R23Crossref PubMed Scopus (112) Google Scholar, 15Francoz C. Nadim M.K. Baron A. Prie D. Antoine C. Belghiti J. et al.Glomerular filtration rate equations for liver-kidney transplantation in cirrhotic patients: validation of current recommendations.Hepatology. 2014; (in press)PubMed Google Scholar]. In a series of patients with cirrhosis who had transvenous renal biopsy for increased serum creatinine (>1.5 mg/dl) and no proteinuria, some of whom met the criteria for HRS, none had normal histology [[16]Trawale J.M. Paradis V. Rautou P.E. Francoz C. Escolano S. Sallee M. et al.The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study.Liver Int. 2010; 30: 725-732Crossref PubMed Scopus (132) Google Scholar]. Chronic kidney changes were found in 77% of patients. In most patients injuries to different structures were combined. Significant glomerular lesions could be observed in the absence of proteinuria. Such lesions are likely to be related to comorbidities. It is conceivable, although not clearly demonstrated, that patients with end-stage cirrhosis, underlying chronic kidney changes and a precipitating event such as sepsis are at higher risk to develop "acute-on-chronic renal failure" [[17]Wong F. Nadim M.K. Kellum J.A. Salerno F. Bellomo R. Gerbes A. et al.Working party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.Gut. 2011; 60: 702-709Crossref PubMed Scopus (300) Google Scholar]. In those meeting the criteria for type-1 HRS, chronic kidney changes may preclude improvement with terlipressin and favor the occurrence of extra-hepatic organ failures. Unfortunately, renal biopsy is impractical in these patients and biomarkers that clearly differentiate acute (reversible) from chronic (irreversible) kidney changes are missing. In summary, the study by Rodriguez E. and colleagues [[9]Rodriguez E. Elia C. Sola E. Barreto R. Graupera I. Andrealli A. et al.Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.J Hepatol. 2014; 60: 955-961Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar] suggests that the response rate to terlipressin and albumin of type-1 HRS in patients with cirrhosis is similar whatever sepsis is present or absent. There is no clear evidence that the complex mechanisms involved in sepsis-induced AKI have a significant impact on type-1 HRS associated with sepsis since response to therapy and general course are similar to those observed in cirrhotic patients without infection. These findings suggest that renal macro and microvascular changes induced by sepsis are different in cirrhotic patients as compared to non-cirrhotic patients. However, not all patients with type-1 HRS and sepsis respond to terlipressin and albumin. In non-responders, the prognosis remains especially poor. What matters in this subgroup seems to be the number and severity of organ failure(s). The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.