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• W2048871566 abstract "The short-term mortality of cirrhotic patients who develop renal dysfunction remains unacceptably high, and as such the treatment of this condition is an unmet need. Although features of kidney injury are well recognized in these patients, the pathophysiology is complex and not completely understood. Improved understanding of the pathophysiological mechanisms involved in renal dysfunction occurring on a background of cirrhosis is key to developing effective treatment strategies to improve survival. Renal dysfunction due to hepatorenal syndrome (HRS) is characteristic of cirrhosis. Our current understanding is that HRS is functional in nature and occurs as a consequence of hemodynamic changes associated with portal hypertension. However, there is evidence in the literature suggesting that, histologically, the kidneys are not always normal in the vast majority of patients who present with renal dysfunction on the background of cirrhosis. Furthermore, there is emerging data implicating nonvasomotor mechanisms in the pathophysiology of renal dysfunction in cirrhosis. This mini-review aims to present the evidence suggesting that factors other than hemodynamic dysregulation have an important role in the development of this major complication for patients with progressive cirrhosis. The short-term mortality of cirrhotic patients who develop renal dysfunction remains unacceptably high, and as such the treatment of this condition is an unmet need. Although features of kidney injury are well recognized in these patients, the pathophysiology is complex and not completely understood. Improved understanding of the pathophysiological mechanisms involved in renal dysfunction occurring on a background of cirrhosis is key to developing effective treatment strategies to improve survival. Renal dysfunction due to hepatorenal syndrome (HRS) is characteristic of cirrhosis. Our current understanding is that HRS is functional in nature and occurs as a consequence of hemodynamic changes associated with portal hypertension. However, there is evidence in the literature suggesting that, histologically, the kidneys are not always normal in the vast majority of patients who present with renal dysfunction on the background of cirrhosis. Furthermore, there is emerging data implicating nonvasomotor mechanisms in the pathophysiology of renal dysfunction in cirrhosis. This mini-review aims to present the evidence suggesting that factors other than hemodynamic dysregulation have an important role in the development of this major complication for patients with progressive cirrhosis. Renal dysfunction is a common manifestation of advanced cirrhosis that is associated with significant mortality and morbidity. Although acute renal dysfunction in cirrhosis can be due to a number of causes such as hypovolemia and nephrotoxins, hepatorenal syndrome (HRS) is the most characteristic. However, it is becoming increasingly evident that renal dysfunction in cirrhosis is a heterogeneous condition, and some patients who were previously diagnosed with HRS actually have renal dysfunction associated with infection/inflammation, which is likely to have a different pathophysiological basis. An estimated 11% of patients with advanced cirrhosis and refractory ascites develop HRS.1.Planas R. Montoliu S. Balleste B. et al.Natural history of patients hospitalized for management of cirrhotic ascites.Clin Gastroenterol Hepatol. 2006; 4: 1385-1394Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar This condition is traditionally ascribed to functional renal failure in patients with chronic liver disease associated with no significant morphologic changes in renal histology and with largely preserved tubular function.2.Papper S. Belsky J.L. Bleifer K.H. Renal failure in Laennec’s cirrhosis of the liver. I. Description of clinical and laboratory features.Ann Inter Med. 1959; 51: 759-773Crossref PubMed Scopus (75) Google Scholar,3.Goresky C.A. Kumar G. Renal failure in cirrhosis of the liver.Can Med Assoc J. 1964; 90: 353-356PubMed Google Scholar This is because kidneys from patients with HRS have been reported to recover function post liver transplantation,4.Iwatsuki S. Popovtzer M.M. Corman J.L. et al.Recovery from hepatorenal syndrome after orthotopic liver transplantation.N Engl J Med. 1973; 289: 1155-1159Crossref PubMed Scopus (206) Google Scholar and they have also been successfully used as renal allografts for kidney transplantation.5.Koppel M.H. Coburn J.W. Mims M.M. et al.Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. Evidence for the functionalnature of renal failure in advanced liver disease.N Engl J Med. 1969; 280: 1367-1371Crossref PubMed Scopus (230) Google Scholar However, only a small proportion of patients who develop renal dysfunction in association with cirrhosis suffer from HRS. Two types of HRS are recognized. Type 1 HRS occurs in an acute setting, with a rapidly progressive decline in renal function, which is characterized by a doubling of the initial creatinine to a level >226μmol/l (2.5mg/dl) in <2 weeks.6.Salerno F. Gerbes A. Gines P. et al.Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (77) Google Scholar Untreated, type 1 HRS is associated with a mortality rate of 80% at 2 weeks.7.Gines P. Guevara M. Arroyo V. et al.Hepatorenal syndrome.Lancet. 2003; 362: 1819-1827Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar Type 2 HRS follows a more progressive course with a moderate rise in serum creatinine levels to a level >133μmol/l (1.5mg/dl).6.Salerno F. Gerbes A. Gines P. et al.Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (77) Google Scholar Type 2 HRS has a median survival of 4–6 months.7.Gines P. Guevara M. Arroyo V. et al.Hepatorenal syndrome.Lancet. 2003; 362: 1819-1827Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar In addition to the above definitions for HRS 1 and 2, in 2007, the International Ascites Club proposed a revised version of the original criteria, and this is shown in the table below (Table 1).Table 1Diagnostic criteria for hepatorenal syndrome in cirrhosis (Adapted from Salerno et al.6.Salerno F. Gerbes A. Gines P. et al.Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (77) Google Scholar)Cirrhosis with ascitesSerum creatinine >133μmol/l (1.5mg/dl)No improvement of serum creatinine (decrease to a level of ≤133μmol/l) after at least 2 days with diuretic withdrawal and volume expansion with albuminAbsence of shockNo current or recent treatment with nephrotoxic drugsAbsence of parenchymal kidney disease, as indicated by proteinuria >500mg/day, microhematuria (>50 red blood cells per high power field), and/or abnormal renal ultrasonography Open table in a new tab As is evident from the above criteria, the diagnosis of HRS requires a set of stringent criteria that rely on serum creatinine levels. Evidence suggests that a smaller increase in serum creatinine, insufficient to make a diagnosis of HRS, is also associated with a poor prognosis in patients with cirrhosis.8.Tsien C.D. Rabie R. Wong F. Acute kidney injury in decompensated cirrhosis.Gut. 2013; 62: 131-137Crossref PubMed Scopus (176) Google Scholar It is possible that the severity of renal dysfunction is underestimated by the measurement of serum creatinine levels, as it is most commonly measured using a modified colorimetric Jaffe assay, which is prone to interference from bilirubin and other compounds.9.Daugherty N.A. Hammond K.B. Osberg I.M. Bilirubin interference with the kinetic Jaffe method for serum creatinine.Clin Chem. 1978; 24: 392-393PubMed Google Scholar,10.Lolekha P.H. Jaruthunyaluck S. Srisawasdi P. Deproteinization of serum: another best approach to eliminate all forms of bilirubin interference on serum creatinine by the kinetic Jaffe reaction.J Clin Lab Anal. 2001; 15: 116-121Crossref PubMed Scopus (35) Google Scholar In addition, patients with cirrhosis often have muscle wasting, reduced hepatic creatine synthesis, and increased renal tubular creatinine secretion.11.Sherman D.S. Fish D.N. Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls.Am J Kidney Dis. 2003; 41: 269-278Abstract Full Text PDF PubMed Scopus (273) Google Scholar As such, smaller increases in serum creatinine reflect much larger changes in renal function than would be anticipated from the rises in serum creatinine. For this reason, there has been a move to redefine HRS to fall in line with the Acute Kidney Injury Network (AKIN) criteria for acute renal failure,12.Mehta R.L. Kellum J.A. Shah S.V. et al.Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.Crit Care. 2007; 11: R31Crossref PubMed Scopus (5241) Google Scholar which is more sensitive for the early detection of smaller increases in serum creatinine.13.Wong F. Nadim M.K. Kellum J.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 (311) Google Scholar Several studies have been carried out using the AKIN criteria in a cirrhotic population, but there is a lack of consensus as to whether the AKIN or classical HRS criteria best predict prognosis in cirrhotic patients with acute renal dysfunction.14.Piano S. Rosi S. Maresio G. et al.Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.J Hepatol. 2013; 59: 482-489Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 15.Fagundes C. Barreto R. Guevara M. et al.A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis.J Hepatol. 2013; 59: 474-481Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 16.Wong F. O'Leary J.G. Reddy K.R. et al.New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis and infection.Gastroenterology. 2013; 145: e1281Google Scholar Although the classical diagnostic criteria for HRS now includes patients with HRS secondary to infection (but not septic shock), it is likely that patients with renal dysfunction or HRS associated with infection are distinct from patients with ‘classical HRS’ (HRS not associated with infection).17.Barreto R. Fagundes C. Guevara M. et al.Type-1 hepatorenal syndrome associated with infections in cirrhosis. Natural history, outcome of kidney function and survival.Hepatology. 2013; 59: 1505-1513Crossref Scopus (60) Google Scholar A recent study by Barreto et al.17.Barreto R. Fagundes C. Guevara M. et al.Type-1 hepatorenal syndrome associated with infections in cirrhosis. Natural history, outcome of kidney function and survival.Hepatology. 2013; 59: 1505-1513Crossref Scopus (60) Google Scholar describing outcomes in patients diagnosed with HRS associated with infection showed that in approximately two-thirds of patients this condition is not reversible with standard of care for HRS using terlipressin and albumin, indicating a different pathophysiological underlying mechanism of disease.12.Mehta R.L. Kellum J.A. Shah S.V. et al.Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.Crit Care. 2007; 11: R31Crossref PubMed Scopus (5241) Google Scholar In addition, patients with renal dysfunction associated with infection have been shown to have higher levels of urinary biomarkers of tubular damage compared with patients with classical HRS.13.Wong F. Nadim M.K. Kellum J.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 (311) Google Scholar It therefore stands to reason that different pathophysiological mechanisms may be responsible for the development of renal dysfunction in the patients with classical HRS compared with patients with renal dysfunction associated with infection.18.Fagundes C. Pepin M.N. Guevara M. et al.Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.J Hepatol. 2012; 57: 267-273Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar In 1970, Epstein et al.19.Epstein M. Berk D.P. Hollenberg N.K. et al.Renal failure in the patient with cirrhosis. The role of active vasoconstriction.Am J Med. 1970; 49: 175-185Abstract Full Text PDF PubMed Scopus (391) Google Scholar demonstrated using renal angiography that in cirrhotic patients with renal failure, the main pathophysiological feature is marked vasoconstriction of the renal vasculature associated with a redistribution of blood flow away from the renal cortex. The hypothesis is that vasoconstriction of the renal circulation, which occurs in HRS, develops as a result of the hemodynamic dysregulation associated with portal hypertension. In this setting, the increase in shear stress in the splanchnic vascular bed leads to overproduction of nitric oxide and other potent vasodilators, thus resulting in splanchnic vasodilatation.20.Blendis L. Wong F. The hyperdynamic circulation in cirrhosis: an overview.Pharmacol Ther. 2001; 89: 221-231Crossref PubMed Scopus (115) Google Scholar The consequence of this is a decrease in effective arterial volume, which leads to severe renal vasoconstriction via activation of the renin–angiotension–aldosterone system, causing renal hypoperfusion.13.Wong F. Nadim M.K. Kellum J.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 (311) Google Scholar,21.Ring-Larsen H. Renal blood flow in cirrhosis: relation to systemic and portal haemodynamics and liver function.Scand J Clin Lab Invest. 1977; 37: 635-642Crossref PubMed Scopus (65) Google Scholar Impaired cardiac function in patients with decompensated cirrhosis leads to further arterial underfilling, decreased mean arterial pressure, and further impairment of renal blood flow and function.22.Krag A. Bendtsen F. Henriksen J.H. et al.Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.Gut. 2010; 59: 105-110Crossref PubMed Scopus (264) Google Scholar In addition, activation of the sympathetic nervous system through a hepatorenal reflex arc also contributes to the pathophysiology of HRS.23.Solis-Herruzo J.A. Duran A. Favela V. et al.Effects of lumbar sympathetic block on kidney function in cirrhotic patients with hepatorenal syndrome.J Hepatol. 1987; 5: 167-173Abstract Full Text PDF PubMed Scopus (83) Google Scholar There is an altered autoregulation of renal blood flow in patients with HRS (Figure 1).24.Stadlbauer V. Wright G.A. Banaji M. et al.Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis.Gastroenterology. 2008; 134: 111-119Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar The evidence in the literature implicating the above factors in the pathophysiology of HRS is strong, as increasing the mean arterial pressure in patients with HRS by using splanchnic vasoconstrictors and albumin improves renal function.25.Angeli P. Volpin R. Gerunda G. et al.Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide.Hepatology. 1999; 29: 1690-1697Crossref PubMed Scopus (471) Google Scholar,26.Velez J.C. Nietert P.J. Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a pooled analysis of clinical trials.Am J Kidney Dis. 2011; 58: 928-938Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Furthermore, a recent pilot study showed that patients with diuretic-refractory ascites, who have the highest risk of developing HRS, have lower renal plasma flow and higher right main kidney and arcuate artery resistive indices compared with patients without ascites.27.Mindikoglu A.L. Dowling T.C. Wong-You-Cheong J.J. et al.A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements.Am J Nephrol. 2014; 39: 543-552Crossref PubMed Scopus (24) Google Scholar However, this study only involved 10 patients and was therefore underpowered for any statistical inferences to be made. Clearly, there is a need to investigate whether these findings are reproducible in a larger cohort. Despite the evidence summarized above, attempts to restore the circulatory dysfunction associated with HRS using splanchnic vasoconstrictors and volume expanders do not reverse the syndrome in up to 40% of patients.28.Nazar A. Pereira G.H. Guevara M. et al.Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome.Hepatology. 2010; 51: 219-226Crossref PubMed Scopus (174) Google Scholar,29.Fabrizi F. Dixit V. Martin P. Meta-analysis: terlipressin therapy for the hepatorenal syndrome.Aliment Pharmacol Ther. 2006; 24: 935-944Crossref PubMed Scopus (94) Google Scholar Therefore, it is likely that other pathophysiological mechanisms have a role in the pathogenesis of renal dysfunction in cirrhosis. Renal dysfunction is a defining feature of acute on chronic liver failure (ACLF), and it occurs in ∼35% of patients with ACLF.30.Garg H. Kumar A. Garg V. et al.Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure.Dig Liver Dis. 2012; 44: 166-171Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar ACLF is defined as ‘an acute deterioration of preexisting, chronic liver disease, usually relating to a precipitating event and associated with increased mortality at 3 months due to multisystem organ failure’.31.Olson J.C. Wendon J.A. Kramer D.J. et al.Intensive care of the patient with cirrhosis.Hepatology. 2011; 54: 1864-1872Crossref PubMed Scopus (197) Google Scholar Dysregulated inflammation and infection, considered a hallmark of ACLF, has also been implicated in renal dysfunction.32.Thabut D. Massard J. Gangloff A. et al.Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure.Hepatology. 2007; 46: 1872-1882Crossref PubMed Scopus (204) Google Scholar, 33.Follo A. Llovet J.M. Navasa M. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (466) Google Scholar, 34.Moreau R. Jalan R. Gines P. 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 (1801) Google Scholar At present, it is not clear as to which of these patients have the classical HRS and which of these patients have renal dysfunction secondary to inflammation. Thabut et al.32.Thabut D. Massard J. Gangloff A. et al.Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure.Hepatology. 2007; 46: 1872-1882Crossref PubMed Scopus (204) Google Scholar found the presence of a systemic inflammatory response syndrome (SIRS) in ∼40% of cirrhotic patients with functional renal failure (including HRS with or without infection). In these patients, the in-hospital mortality rate was 68%, which was significantly higher than in patients without SIRS. They concluded that the presence of SIRS is an independent prognostic factor in patients with cirrhosis and acute functional renal failure, and treating SIRS could potentially lead to a reduction in mortality.32.Thabut D. Massard J. Gangloff A. et al.Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure.Hepatology. 2007; 46: 1872-1882Crossref PubMed Scopus (204) Google Scholar Further evidence that SIRS has an important role in renal dysfunction is derived from studies that have shown that the use of anti-inflammatory agents such as pentoxifylline improves renal function or significantly decreases the risk of developing renal failure in patients with alcoholic hepatitis.35.Akriviadis E. Botla R. Briggs W. et al.Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.Gastroenterology. 2000; 119: 1637-1648Abstract Full Text Full Text PDF PubMed Scopus (665) Google Scholar,36.Mookerjee R.P. Sen S. Davies N.A. et al.Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis.Gut. 2003; 52: 1182-1187Crossref PubMed Scopus (127) Google Scholar The therapeutic effect of pentoxifylline in this setting may be partly owing to its hemorrheologic and beneficial effects on the microcirculation, thus leading to an improvement in renal blood flow.37.Ernst E. Pentoxifylline for intermittent claudication. A critical review.Angiology. 1994; 45: 339-345Crossref PubMed Scopus (54) Google Scholar It seems plausible that the mechanism responsible for the development of renal dysfunction in these patients with alcoholic hepatitis differs from the ‘classical’ HRS, as the presence of alcoholic hepatitis has a negative effect on survival in patients with renal dysfunction treated with terlipressin.38.Boyer T.D. Sanyal A.J. Garcia-Tsao G. et al.Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics.J Hepatol. 2011; 55: 315-321Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar Renal dysfunction may also occur following a gastrointestinal bleed.39.Wadei H.M. Mai M.L. Ahsan N. et al.Hepatorenal syndrome: pathophysiology and management.Clin J Am Soc Nephrol. 2006; 1: 1066-1079Crossref PubMed Scopus (178) Google Scholar Infection/inflammation may also have a role in this. It is well recognized that most cases of acute kidney injury following a gastrointestinal bleed occur as a consequence of acute tubular necrosis following hypovolemia. However, there is evidence that following a gastrointestinal bleed there is a transient increase in plasma endotoxin levels,40.Fukui H. Matsumoto M. Bode C. et al.Endotoxaemia in patients with liver cirrhosis and upper gastrointestinal bleeding: detection by the chromogenic assay with plasma Tween 80 pretreatment.J Gastroenterol Hepatol. 1993; 8: 577-581Crossref PubMed Scopus (17) Google Scholar and endotoxemia has a critical role in the development of acute renal dysfunction in cirrhosis.41.Clemente C. Bosch J. Rodes J. et al.Functional renal failure and haemorrhagic gastritis associated with endotoxaemia in cirrhosis.Gut. 1977; 18: 556-560Crossref PubMed Scopus (85) Google Scholar The mechanism of the inflammatory basis of renal dysfunction in cirrhotic patients is currently unknown, but one hypothesis is that in cirrhosis gut bacterial translocation is increased, which primes the kidneys to the effect of a superimposed inflammatory insult such as an infection. This hypothesis is supported by studies of selective gut decontamination using prophylactic administration of norfloxacin, which reported both reduced incidence of renal dysfunction and improved survival.42.Fernandez J. Navasa M. Planas R. et al.Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.Gastroenterology. 2007; 133: 818-824Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar Reducing the direct effects of bacterial products on the renal tubules may modulate this effect of gut decontamination. The kidneys of some cirrhotic patients with presumed HRS show histologic evidence of acute kidney injury. However, it is likely that the patients described may have renal dysfunction that is associated with infection and/inflammation. A study by Mandal et al.43.Mandal A.K. Lansing M. Fahmy A. Acute tubular necrosis in hepatorenal syndrome: an electron microscopy study.Am J Kidney Dis. 1982; 2: 363-374Abstract Full Text PDF PubMed Scopus (57) Google Scholar reported light and electron microscopy changes in five patients diagnosed with HRS. They observed evidence of acute tubular necrosis on light microscopy, whereas electron microscopy demonstrated necrosis of the proximal tubules. It is important to state that, in this study, the samples were obtained postmortem, and thus the changes observed may reflect terminal changes. Kanel et al.39.Wadei H.M. Mai M.L. Ahsan N. et al.Hepatorenal syndrome: pathophysiology and management.Clin J Am Soc Nephrol. 2006; 1: 1066-1079Crossref PubMed Scopus (178) Google Scholar further described the presence of an unusual renal lesion consisting of the reflux of the proximal convoluted tubular epithelium into Bowman’s space in ∼70% of patients diagnosed with renal dysfunction on the background of cirrhosis. However, the authors felt that this lesion was unlikely to be responsible for renal failure observed in these patients.44.Kanel G.C. Peters R.L. Glomerular tubular reflux—a morphologic renal lesion associated with the hepatorenal syndrome.Hepatology. 1984; 4: 242-246Crossref PubMed Scopus (29) Google Scholar More recently, Shah et al.45.Shah N. Mohamed F.E. Jover-Cobos M. et al.Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis.Liver Int. 2013; 33: 398-409Crossref PubMed Scopus (75) Google Scholar reported evidence of tubular injury on periodic methenamine and silver staining of five renal biopsy specimens derived from patients with ACLF and renal failure, i.e., renal dysfunction associated with inflammation. In addition to the human studies, histological examination of the kidneys in an animal model of ACLF revealed glomerular mesangial hypercellularity in the early stages of the syndrome. Furthermore, in the later stages, there was evidence of hydropic degeneration of the proximal and distal tubules.46.Rivera-Huizar S. Rincon-Sanchez A.R. Covarrubias-Pinedo A. et al.Renal dysfunction as a consequence of acute liver damage by bile duct ligation in cirrhotic rats.Exp Toxicol Pathol. 2006; 58: 185-195Crossref PubMed Scopus (31) Google Scholar Similarly, another animal study, involving a rat model of cirrhosis treated with lipopolysaccharide (which is clinically similar to a patient with renal dysfunction associated with infection), showed evidence of tubular vacuolar degeneration in the proximal tubules, and this was associated with sloughing of the tubular cells. There was also an increased expression of caspase-3 expression signifying tubular cell apoptosis.47.Shah N. Dhar D. El Zahraa Mohammed F. et al.Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.J Hepatol. 2012; 56: 1047-1053Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar It is recognized that apoptosis of tubular cells by inflammatory cytokines occurs in renal dysfunction associated with endotoxemia.48.Jo S.K. Cha D.R. Cho W.Y. et al.Inflammatory cytokines and lipopolysaccharide induce Fas-mediated apoptosis in renal tubular cells.Nephron. 2002; 91: 406-415Crossref PubMed Scopus (95) Google Scholar A similar pathophysiology may underlie infection/inflammation-associated renal dysfunction in cirrhotic patients. These observations suggest that immunologic mechanisms are important in mediating the renal injury and that hemodynamic factors do not operate in isolation. Further evidence supporting the hypothesis that renal dysfunction in cirrhotic patients is more than just functional renal failure and that tubular injury occurs is derived from studies that have shown that markers of tubular injury are elevated in some patients with renal dysfunction in cirrhosis. Rector et al.49.Rector Jr., W.G. Kanel G.C. Rakela J. et al.Tubular dysfunction in the deeply jaundiced patient with hepatorenal syndrome.Hepatology. 1985; 5: 321-326Crossref PubMed Scopus (24) Google Scholar observed an increase in urinary beta-2-microglobulin, which is an index of tubular function in cirrhotic patients with presumed HRS compared with controls. Neutrophil gelatinase–associated lipocalin is a protein expressed by the renal tubules, which is upregulated after renal tubular injury. Patients diagnosed with HRS were shown to have significantly higher plasma and urinary neutrophil gelatinase–associated lipocalin levels compared with stable cirrhotic patients.50.Gungor G. Ataseven H. Demir A. et al.Neutrophil gelatinase-associated lipocalin in prediction of mortality in patients with hepatorenal syndrome: a prospective observational study.Liver Int. 2013; 34: 49-57Crossref PubMed Scopus (34) Google Scholar In addition, neutrophil gelatinase–associated lipocalin was identified as a predictor of mortality in patients with HRS. It is likely that these investigators were indeed describing patients with renal dysfunction that is associated with infection/inflammation rather than patients with HRS. Figure 2 highlights the main features distinguishing between ‘classical HRS’ and renal dysfunction associated with infection/inflammation. A common misconception is that the kidneys are morphologically normal in HRS; thus, they function normally when transplanted into patients without liver disease and recover post liver transplantation. Howe" @default.
• W2048871566 created "2016-06-24" @default.
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• W2048871566 date "2015-03-01" @default.
• W2048871566 modified "2023-10-16" @default.
• W2048871566 title "Renal dysfunction in cirrhosis is not just a vasomotor nephropathy" @default.
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