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Kidney biomarkers in cirrhosis

  • Claire Francoz
    Correspondence
    Corresponding author. Address: Service d’Hépatologie, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110 Clichy, France. Tel.: +33 1 40 87 50 91; fax: +33 1 40 87 44 55.
    Affiliations
    Hepatology and Liver Intensive Care, Hospital Beaujon, Clichy, France

    University Paris VII Diderot, Paris, France

    INSERM U1149, Paris, France

    Département Hospitalo-Universitaire UNITY, Clichy, France
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  • Mitra K. Nadim
    Affiliations
    Division of Nephrology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • François Durand
    Affiliations
    Hepatology and Liver Intensive Care, Hospital Beaujon, Clichy, France

    University Paris VII Diderot, Paris, France

    INSERM U1149, Paris, France

    Département Hospitalo-Universitaire UNITY, Clichy, France
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      Summary

      Impaired renal function due to acute kidney injury (AKI) and/or chronic kidney diseases (CKD) is frequent in cirrhosis. Recurrent episodes of AKI may occur in end-stage cirrhosis. Differential diagnosis between functional (prerenal and hepatorenal syndrome) and acute tubular necrosis (ATN) is crucial. The concept that AKI and CKD represent a continuum rather than distinct entities, is now emerging. Not all patients with AKI have a potential for full recovery. Precise evaluation of kidney function and identification of kidney changes in patients with cirrhosis is central in predicting reversibility. This review examines current biomarkers for assessing renal function and identifying the cause and mechanisms of impaired renal function. When CKD is suspected, clearance of exogenous markers is the reference to assess glomerular filtration rate, as creatinine is inaccurate and cystatin C needs further evaluation. Recent biomarkers may help differentiate ATN from hepatorenal syndrome. Neutrophil gelatinase-associated lipocalin has been the most extensively studied biomarker yet, however, there are no clear-cut values that differentiate each of these conditions. Studies comparing ATN and hepatorenal syndrome in cirrhosis, do not include a gold standard. Combinations of innovative biomarkers are attractive to identify patients justifying simultaneous liver and kidney transplantation. Accurate biomarkers of underlying CKD are lacking and kidney biopsy is often contraindicated in this population. Urinary microRNAs are attractive although not definitely validated. Efforts should be made to develop biomarkers of kidney fibrosis, a common and irreversible feature of CKD, whatever the cause. Biomarkers of maladaptative repair leading to irreversible changes and CKD after AKI are also promising.

      Abbreviations:

      HRS (hepatorenal syndrome), AKI (acute kidney injury), NO (nitric oxide), RAAS (renin-angiotensin-aldosterone system), SNS (sympathic nervous system), AVP (arginin vasopressin), PAMPs (pathogen-associated molecular patterns), PRRs (patterns recognition receptors), TNF-α (tumor necrosis alpha), IL-6 (interleukine 6), SIRS (systemic inflammatory response syndrome), TLR (toll-like receptor), ATN (acute tubular necrosis), NASH (non-alcoholic steatosis hepatitis), CKD (chronic kidney disease), GFR (glomerular filtration rate), KDIGO (kidney disease improving global outcome), SCr (serum creatinine), MDRD (modified diet in renal disease), SLK transplantation (simultaneous liver and kidney transplantation), BUN (blood urea nitrogen), β2M (beta-2 microglobulin), RIFLE (risk, injury, failure, loss, end-stage kidney disease), AKIN (acute kidney injury network), UO (urinary output), ADQI (acute dialysis quality initiative), ICA (International Club of Ascites), FENa (fractional excretion of filtered sodium), FEu (fractional excretion of urea), NGAL (neutrophil gelatinase-associated lipocalin), IL-18 (interleukin 18), KIM-1 (kim injury molecule 1), L-FABP (liver-type fatty acid-binding protein), TFF3 (trefoil factor 3), MCP-1 (monocyte chemoattractant protein-1), TIMP1 (tissue inhibitor of metalloproteinase-1), miRNA and MiR (microRNA), EMT (epithelial-mesenchymal transition), TGF β1 (transforming growth factor beta 1), suPAR (soluble urokinase-type plasminogen activator receptor), MRI (magnetic resonance imaging)

      Keywords

      Introduction

      For many years, it has been clearly established that kidney function plays a major role in the prognosis of cirrhosis [
      • Kamath P.S.
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      • Valla D.
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      ]. Hepatorenal syndrome (HRS), which is functional in nature, is a characteristic feature of advanced cirrhosis [
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      ] although it does not represent the only cause of acute kidney injury (AKI) in this context [
      • Moreau R.
      • Lebrec D.
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      ]. Several mechanisms are involved in the development of HRS, including circulatory changes [
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      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodes J.
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      ], kidney factors and systemic inflammation [
      • Durand F.
      • Graupera I.
      • Gines P.
      • Olson J.C.
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      ].
      Hypoperfusion is a central mechanism in most patients with advanced cirrhosis and HRS [
      • Gines P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      ]. In the early stages of compensated cirrhosis splanchnic vasodilation due, at least in part, to the release of nitric oxide (NO) is moderate. Decreased systemic vascular resistance resulting in a reduction in arterial pressure is balanced by increased cardiac output to maintain adequate perfusion of the kidney (Fig. 1). Glomerular filtration rate (GFR) is preserved. In advanced stages of cirrhosis, as splanchnic vasodilation intensifies, systemic vasoconstriction systems, namely renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS) and arginine vasopressin (AVP), are activated, resulting in renal sodium and water retention [
      • Moreau R.
      • Lebrec D.
      Acute renal failure in patients with cirrhosis: perspectives in the age of MELD.
      ,
      • Gines P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      ]. Indeed, major splanchnic vasodilatation is associated with a state of decreased effective blood volume. At the most advanced stages of cirrhosis, renal vasoconstriction can no longer be balanced by increased cardiac output and renal blood flow markedly decreases [
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ]. The so called cirrhotic cardiomyopathy may contribute to decreased renal perfusion [
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      • Moller S.
      Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ].
      Figure thumbnail gr1
      Fig. 1Mechanisms contributing to impaired renal function in cirrhosis. In end-stage liver diseases, several factors contribute to increase susceptibility of the kidney to AKI. Both vasodilation secondary to portal hypertension and systemic inflammation induced by gut bacterial translocation tend to induce renal arterial vasoconstriction, due to the activation of vasoconstrictive systems (SRAA, SNS and AVP) in response to decreased effective blood volume. Intrarenal inflammation induces intrarenal microvascular changes resulting in decreased GFR with an imbalance between preglomerular and postglomerular resistance (which corresponds to both preglomerular and post glomerular vascular tone) as well as impaired renal microcirculation affecting tubular and glomerular function. Underlying CKD due to associated comorbidities eventually increases the risk for AKI. Consequences of prolonged kidney vasoconstriction are not clearly elucidated but may induce tubular interstitial fibrosis and further increase the risk of AKI.
      Kidney factors involve mediators that are protective of kidney function under normal conditions. In advanced cirrhosis, the levels of the vasodilatator prostaglandins E2 and I2 are increased to compensate the activation of vasoconstrictor systems [
      • Planas R.
      • Arroyo V.
      • Rimola A.
      • Perez-Ayuso R.M.
      • Rodes J.
      Acetylsalicylic acid suppresses the renal hemodynamic effect and reduces the diuretic action of furosemide in cirrhosis with ascites.
      ]. This is possibly the reason why administration of non-steroidal anti-inflammatory drugs in patients with advanced cirrhosis frequently precipitates AKI [
      • Elia C.
      • Graupera I.
      • Barreto R.
      • Sola E.
      • Moreira R.
      • Huelin P.
      • et al.
      Severe acute kidney injury associated with non-steroidal anti-inflammatory drugs in cirrhosis: A case-control study.
      ]. In addition to changes in systemic hemodynamics, alterations of intrarenal hemodynamics along with abnormal autoregulation of renal blood flow contribute to decreased GFR [
      • Stadlbauer V.
      • Wright G.A.
      • Banaji M.
      • Mukhopadhya A.
      • Mookerjee R.P.
      • Moore K.
      • et al.
      Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis.
      ].
      Circulatory changes resulting from portal hypertension and kidney factors do not explain per se all the changes observed during HRS and other phenotypes of AKI. Recently, a theory of systemic inflammatory multiorgan disease has emerged that challenges the vasodilation theory [
      • Bernardi M.
      • Moreau R.
      • Angeli P.
      • Schnabl B.
      • Arroyo V.
      Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.
      ]. Sepsis is a common trigger of AKI in patients with cirrhosis. In patients without cirrhosis, there is increasing evidence that sepsis-associated AKI with systemic inflammation results from the combination of hemodynamic, inflammatory and immune mechanisms [
      • Alobaidi R.
      • Basu R.K.
      • Goldstein S.L.
      • Bagshaw S.M.
      Sepsis-associated acute kidney injury.
      ]. During severe sepsis, AKI may be unrelated to decreased renal blood flow [
      • Prowle J.R.
      • Bellomo R.
      Sepsis-associated acute kidney injury: macrohemodynamic and microhemodynamic alterations in the renal circulation.
      ]. Indeed, sepsis-associated AKI can occur in the context of hyperdynamic circulation with normal or even increased renal blood flow [
      • Prowle J.R.
      • Bellomo R.
      Sepsis-associated acute kidney injury: macrohemodynamic and microhemodynamic alterations in the renal circulation.
      ,
      • Langenberg C.
      • Wan L.
      • Egi M.
      • May C.N.
      • Bellomo R.
      Renal blood flow and function during recovery from experimental septic acute kidney injury.
      ,
      • Langenberg C.
      • Wan L.
      • Egi M.
      • May C.N.
      • Bellomo R.
      Renal blood flow in experimental septic acute renal failure.
      ]. In patients with preserved renal blood flow, intrarenal microvascular changes resulting in decreased GFR may include an imbalance between preglomerular and postglomerular resistance (which corresponds to both preglomerular and post glomerular vascular tone) as well as impaired renal microcirculation affecting tubular and glomerular function [
      • Prowle J.R.
      • Bellomo R.
      Sepsis-associated acute kidney injury: macrohemodynamic and microhemodynamic alterations in the renal circulation.
      ]. Finally, it has been hypothesized that sepsis could lead to internal redistribution of blood flow out of the cortex and inducing corticomedullary junction ischemia with subsequent tubular injury [
      • Prowle J.R.
      • Bellomo R.
      Sepsis-associated acute kidney injury: macrohemodynamic and microhemodynamic alterations in the renal circulation.
      ].
      Kidney impairment in cirrhosis is due to both systemic vasodilation and inflammation, leading to chronic kidney vasoconstriction.
      In most clinical situations, hemodynamic abnormalities are accompanied by or preceed systemic and/or renal inflammatory responses leading to abnormal changes in microcirculation and significant reduction of perfused capillaries [
      • Prowle J.R.
      • Bellomo R.
      Sepsis-associated acute kidney injury: macrohemodynamic and microhemodynamic alterations in the renal circulation.
      ].
      Even in the absence of bacterial infection, cirrhosis is associated with systemic inflammation, which is correlated to the severity of liver disease and portal hypertension [
      • Bernardi M.
      • Moreau R.
      • Angeli P.
      • Schnabl B.
      • Arroyo V.
      Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.
      ]. The main mechanism is the translocation of bacteria and/or pathogen-associated molecular patterns (PAMPs) from the gut. Translocation induces a wide spectrum of genes that encode molecules responsible for inflammation via specific receptors (pattern recognition receptors or PRRs) [
      • Bernardi M.
      • Moreau R.
      • Angeli P.
      • Schnabl B.
      • Arroyo V.
      Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.
      ]. Inflammatory components may extend to the systemic circulation and peripheral organs leading to extra hepatic organ dysfunction, including the kidney. Firstly, inflammation may contribute to systemic circulatory changes and compromised kidney perfusion. Patients with bacterial translocation have increased levels of proinflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]) as well as increased level of vasoactive factors (such as NO) when compared to patients without translocation [
      • Wiest R.
      • Lawson M.
      • Geuking M.
      Pathological bacterial translocation in liver cirrhosis.
      ,
      • Albillos A.
      • de la Hera A.
      • Gonzalez M.
      • Moya J.L.
      • Calleja J.L.
      • Monserrat J.
      • et al.
      Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.
      ]. Most patients with HRS have bacterial infection and/or systemic inflammatory response syndrome (SIRS) [
      • Thabut D.
      • Massard J.
      • Gangloff A.
      • Carbonell N.
      • Francoz C.
      • Nguyen-Khac E.
      • 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.
      ]. However, about 30% of patients with HRS have SIRS without documented bacterial infection [
      • Thabut D.
      • Massard J.
      • Gangloff A.
      • Carbonell N.
      • Francoz C.
      • Nguyen-Khac E.
      • 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.
      ].
      Toll-like receptor 4 (TLR4) is the main PPR that has been studied in this field. In an experimental model of cirrhosis, inflammatory insult induced by lipopolysaccharide results in an increased expression of TLR4 in proximal renal tubules and in tubular cell injury [
      • Shah N.
      • Dhar D.
      • El Zahraa Mohammed F.
      • Habtesion A.
      • Davies N.A.
      • Jover-Cobos M.
      • et al.
      Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
      ]. Expression of TLR4 as well as tubular damage is decreased in animals receiving digestive decontamination [
      • Shah N.
      • Dhar D.
      • El Zahraa Mohammed F.
      • Habtesion A.
      • Davies N.A.
      • Jover-Cobos M.
      • et al.
      Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
      ]. A similar overexpression of tubular TLR4 has been described in patients with cirrhosis and renal dysfunction [
      • Shah N.
      • Mohamed F.E.
      • Jover-Cobos M.
      • Macnaughtan J.
      • Davies N.
      • Moreau R.
      • et al.
      Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis.
      ]. Interestingly, a subset of patients with a diagnosis of HRS showed both overexpression of TLR4 in tubular cells and evidence of tubular cell damage [
      • Shah N.
      • Mohamed F.E.
      • Jover-Cobos M.
      • Macnaughtan J.
      • Davies N.
      • Moreau R.
      • et al.
      Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis.
      ]. These findings suggest that a diagnosis of HRS does not exclude some degree of structural change [
      • Kanel G.C.
      • Peters R.L.
      Glomerular tubular reflux–a morphologic renal lesion associated with the hepatorenal syndrome.
      ,
      • Mandal A.K.
      • Lansing M.
      • Fahmy A.
      Acute tubular necrosis in hepatorenal syndrome: an electron microscopy study.
      ]. More generally, during sepsis, TLR4 expression is upregulated on renal tubule epithelial cells, leading to the production of proinflammatory cytokines [
      • Wolfs T.G.
      • Buurman W.A.
      • van Schadewijk A.
      • de Vries B.
      • Daemen M.A.
      • Hiemstra P.S.
      • et al.
      In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation.
      ]. Local inflammation can activate dendritic cells and T lymphocytes [
      • van Kooten C.
      • Woltman A.M.
      • Daha M.R.
      Immunological function of tubular epithelial cells: the functional implications of CD40 expression.
      ]. Systemic and local inflammation causes damage to renal tubule epithelial cells including apical vacuolization, loss of polarity, loss of tight junctions, apoptosis, dedifferentiation and cell cycle arrest by a variety of mechanisms [
      • Emlet D.R.
      • Shaw A.D.
      • Kellum J.A.
      Sepsis-associated AKI: epithelial cell dysfunction.
      ]. Renal tubule epithelial cells injury predominates in the proximal tubule [
      • Vaidya V.S.
      • Waikar S.S.
      • Ferguson M.A.
      • Collings F.B.
      • Sunderland K.
      • Gioules C.
      • et al.
      Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans.
      ]. Tubule cell injury impairs glomerular tubular balance with afferent arterial vasoconstriction [
      • Prowle J.R.
      • Bellomo R.
      Sepsis-associated acute kidney injury: macrohemodynamic and microhemodynamic alterations in the renal circulation.
      ].
      Overall, the pathophysiology of AKI in cirrhosis is complex and a variety of factors are involved. HRS is not the only cause of impaired renal function. Prerenal azotemia and acute tubular necrosis (ATN) account for a significant number of AKI episodes. In patients with decompensated cirrhosis, precipitating factors such as hypovolemia, administration of nephrotoxic agents, infection and/or SIRS may precipitate renal hypoperfusion which is a central mechanism, whatever the phenotype of AKI. Since therapeutic approach differs, a clear distinction between these phenotypes remains a challenging issue.
      Renal impairment is frequent in patients with cirrhosis, including AKI and CKD which prevalence may be higher than that observed in the general population due to frequent comorbidities (diabetes, past history of arterial hypertension and other risk factors), as well as persistent kidney vasoconstriction.
      Apart from specific conditions such as IgA nephropathy and glomerulonephritis associated with viral hepatitis [
      • Francoz C.
      • Glotz D.
      • Moreau R.
      • Durand F.
      The evaluation of renal function and disease in patients with cirrhosis.
      ], the pathophysiology of chronic kidney disease (CKD) in patients with cirrhosis has been poorly explored. Due to the high prevalence of comorbidities including diabetes, past history of hypertension and atherosclerosis, it can be assumed that chronic kidney changes are more common in patients with cirrhosis than in the general population, especially in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis [
      • Loomba R.
      • Sanyal A.J.
      The global NAFLD epidemic.
      ]. In addition, with the growing incidence of NASH-related cirrhosis [
      • Loomba R.
      • Sanyal A.J.
      The global NAFLD epidemic.
      ], metabolic-syndrome-associated CKD will certainly increase in the future. Finally, parenchymal consequences of chronic vasoconstriction associated with the so called type 2 HRS are not known. Kidney biopsies of patients with type 2 HRS show various histological changes [
      • 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.
      ,
      • Calmus Y.
      • Conti F.
      • Cluzel P.
      • Hill G.
      • Antoine C.
      • Scatton O.
      • et al.
      Prospective assessment of renal histopathological lesions in patients with end-stage liver disease: effects on long-term renal function after liver transplantation.
      ]. These results suggest that in the long term, chronic vasoconstriction may promote inflammation and fibrosis as shown in several models [
      • Gloviczki M.L.
      • Keddis M.T.
      • Garovic V.D.
      • Friedman H.
      • Herrmann S.
      • McKusick M.A.
      • et al.
      TGF expression and macrophage accumulation in atherosclerotic renal artery stenosis.
      ,
      • Keddis M.T.
      • Garovic V.D.
      • Bailey K.R.
      • Wood C.M.
      • Raissian Y.
      • Grande J.P.
      Ischaemic nephropathy secondary to atherosclerotic renal artery stenosis: clinical and histopathological correlates.
      ]. Rather than two distinct entities, AKI and CKD should be viewed as a continuum [
      • Chawla L.S.
      • Eggers P.W.
      • Star R.A.
      • Kimmel P.L.
      Acute kidney injury and chronic kidney disease as interconnected syndromes.
      ].

      Biomarkers for the evaluation of kidney function

      By definition, a biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Beyond simple proteins, advances in cellular and molecular biology have made it possible to develop innovative biomarkers. Biomarkers can be identified in various biological fluids but also in tissue specimens.

      Gold standard and other indicators for the evaluation of kidney function

      Currently available non-invasive tools to assess renal function are inaccurate in patients with cirrhosis (creatinine and creatinine-based equations). The gold standard for measuring GFR is the clearance of exogenous markers which is impractical and costly. MDRD-6 is currently the most accurate surrogate marker.
      A decrease in GFR represents the most common indicator of impaired renal function, even though the kidney exerts a number of functions other than filtration. The gold standard method for measuring GFR is the clearance of radioactive (125I-iothalamate and 99mTc-diethylene triamine pentaacetic) or non-radioactive (inulin and iohexol) exogenous filtration markers. However, these methods are time-consuming, costly, potentially biased by changes in the volume of distribution of extracellular fluids. They are also impractical for repeated measurements.
      Several studies have shown that serum creatinine (SCr), creatinine clearance as well as SCr derived-equations (Cockcroft, modification of diet in renal disease 4 (MDRD-4), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations) tend to overestimate GFR in cirrhosis [
      • Cockcroft D.W.
      • Gault M.H.
      Prediction of creatinine clearance from serum creatinine.
      ,
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • Roth D.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.
      ,
      • Sherman D.S.
      • Fish D.N.
      • Teitelbaum I.
      Assessing renal function in cirrhotic patients: problems and pitfalls.
      ,
      • Francoz C.
      • Prie D.
      • Abdelrazek W.
      • Moreau R.
      • Mandot A.
      • Belghiti J.
      • et al.
      Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: impact on the model for end-stage liver disease score.
      ,
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • Zhang Y.L.
      • Castro 3rd, A.F.
      • Feldman H.I.
      • et al.
      A new equation to estimate glomerular filtration rate.
      ]. Table 1 summarizes the variables included in current equations estimating GFR. MDRD-6 may be more accurate in cirrhosis [
      • Gonwa T.A.
      • Jennings L.
      • Mai M.L.
      • Stark P.C.
      • Levey A.S.
      • Klintmalm G.B.
      Estimation of glomerular filtration rates before and after orthotopic liver transplantation: evaluation of current equations.
      ,
      • Francoz C.
      • Nadim M.K.
      • Baron A.
      • Prie D.
      • Antoine C.
      • Belghiti J.
      • et al.
      Glomerular filtration rate equations for liver-kidney transplantation in patients with cirrhosis: validation of current recommendations.
      ]. As a consequence, the MDRD-6 equation is proposed as the reference according to the US consensus guidelines to identify candidates for simultaneous liver and kidney (SLK) transplantation [
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      ].
      Table 1Variables Included into Current Estimates of GFR.
      ∗Black vs. non-black ethnicity. £MRDR-4 and CKD-EPI include same variables but formulae are different.
      MDRD, Modification of Diet in Renal Disease equation; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; BUN, blood urea nitrogen.

      Surrogate markers

      Cystatin C

      Cystatin C is a low molecular weight protein produced at a constant rate by all nucleated cells and eliminated almost exclusively by glomerular filtration [
      • Herget-Rosenthal S.
      • Trabold S.
      • Pietruck F.
      • Holtmann M.
      • Philipp T.
      • Kribben A.
      Cystatin C: efficacy as screening test for reduced glomerular filtration rate.
      ]. In contrast to SCr, serum cystatin C is independent of gender, age, muscle mass, inflammation and malignancy and is not affected by serum bilirubin level [
      • Cholongitas E.
      • Shusang V.
      • Marelli L.
      • Nair D.
      • Thomas M.
      • Patch D.
      • et al.
      Review article: renal function assessment in cirrhosis - difficulties and alternative measurements.
      ,
      • Gerbes A.L.
      • Gulberg V.
      • Bilzer M.
      • Vogeser M.
      Evaluation of serum cystatin C concentration as a marker of renal function in patients with cirrhosis of the liver.
      ].
      Several cystatin C-based equations have been proposed (Table 1), however, they have not been shown to be superior to creatinine-based equations [
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • Eckfeldt J.H.
      • Feldman H.I.
      • Greene T.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      ]. By contrast, equations combining cystatin C and SCr have a greater precision and accuracy in assessing GFR in specific populations, especially those with low muscle mass [
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • Eckfeldt J.H.
      • Feldman H.I.
      • Greene T.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      ,
      • Levey A.S.
      • Becker C.
      • Inker L.A.
      Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review.
      ]. According to the KDIGO 2012 guidelines, a combined cystatin C and SCr equation is required to confirm a diagnosis of CKD [
      • Levin A.
      • Stevens P.E.
      WITHDRAWN: Summary of KDIGO guideline: behind the scenes, need for guidance, and a framework for moving forward.
      ] and the combined equation is the most powerful tool to assess the prognosis of CKD (risk of deaths due to end-stage renal disease and/or cardiovascular events) [
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • Eckfeldt J.H.
      • Feldman H.I.
      • Greene T.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      ,
      • Delanaye P.
      • Mariat C.
      The applicability of eGFR equations to different populations.
      ,
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • Frei U.
      • Gaedeke J.
      • Jakob O.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      ,
      • Shlipak M.G.
      • Coresh J.
      • Gansevoort R.T.
      Cystatin C versus creatinine for kidney function-based risk.
      ].
      In patients with cirrhosis, studies have demonstrated that equations combining SCr and cystatin C may better predict GFR compared to SCr-based equations, especially when GFR is below 60 ml/min/1.73 m2 regardless of the presence of ascites [
      • Mindikoglu A.L.
      • Dowling T.C.
      • Weir M.R.
      • Seliger S.L.
      • Christenson R.H.
      • Magder L.S.
      Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis.
      ,
      • De Souza V.
      • Hadj-Aissa A.
      • Dolomanova O.
      • Rabilloud M.
      • Rognant N.
      • Lemoine S.
      • et al.
      Creatinine- versus cystatine C-based equations in assessing the renal function of candidates for liver transplantation with cirrhosis.
      ]. However, the performance of cystatin C-based equations was lower than that reported in the general population [
      • Mindikoglu A.L.
      • Dowling T.C.
      • Weir M.R.
      • Seliger S.L.
      • Christenson R.H.
      • Magder L.S.
      Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis.
      ].

      Other endogenous biomarkers

      Blood urea nitrogen (BUN) is less accurate than SCr as variations independent of GFR can be observed. In patients with cirrhosis, the production rate of urea is not stable. BUN can either increase following digestive bleeding or decrease as a consequence of impaired liver function due to impaired urea cycle and/or poor nutritional status. Beta-2 microglobulin (β2M) is a small molecule present in all nucleated cells, freely filtered by the glomerulus and then reabsorbed and metabolized in the proximal tubule. Serum levels of β2M increase when GFR declines. It has been shown that serum β2M increases earlier than SCr [
      • Bianchi C.
      • Donadio C.
      • Tramonti G.
      • Consani C.
      • Lorusso P.
      • Rossi G.
      Reappraisal of serum beta2-microglobulin as marker of GFR.
      ]. However, β2M levels are increased in a number of conditions other than kidney injury including malignancies, autoimmune diseases and inflammatory states [
      • Shinkai S.
      • Chaves P.H.
      • Fujiwara Y.
      • Watanabe S.
      • Shibata H.
      • Yoshida H.
      • et al.
      Beta2-microglobulin for risk stratification of total mortality in the elderly population: comparison with cystatin C and C-reactive protein.
      ].

      Biomarkers for determination of the phenotype of acute kidney injury (AKI)

      Definition and classification of AKI

      There is a wide variability in the reported incidence of AKI in hospitalized patients with cirrhosis [
      • Cardenas A.
      • Gines P.
      • Uriz J.
      • Bessa X.
      • Salmeron J.M.
      • Mas A.
      • et al.
      Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors, and short-term prognosis.
      ,
      • Fasolato S.
      • Angeli P.
      • Dallagnese L.
      • Maresio G.
      • Zola E.
      • Mazza E.
      • et al.
      Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features.
      ,
      • Terra C.
      • Guevara M.
      • Torre A.
      • Gilabert R.
      • Fernandez J.
      • Martin-Llahi M.
      • et al.
      Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score.
      ], which was, in part, related to the absence of consensus on the definition for AKI. RIFLE (risk, injury, failure, loss, end-stage kidney disease) [
      • Bellomo R.
      • Ronco C.
      • Kellum J.A.
      • Mehta R.L.
      • Palevsky P.
      Acute Dialysis Quality Initiative workgroup
      Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
      ] and AKIN (acute kidney injury network) [
      • Mehta R.L.
      • Kellum J.A.
      • Shah S.V.
      • Molitoris B.A.
      • Ronco C.
      • Warnock D.G.
      • et al.
      Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.
      ,
      • Wong F.
      • Leung W.
      • Al Beshir M.
      • Marquez M.
      • Renner E.L.
      Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.
      ] classifications, based on dynamic changes in SCr and urinary output (UO) have been proposed in critical care medicine [
      • Hoste E.A.
      • Clermont G.
      • Kersten A.
      • Venkataraman R.
      • Angus D.C.
      • De Bacquer D.
      • et al.
      RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis.
      ,
      • Leite T.T.
      • Macedo E.
      • Pereira S.M.
      • Bandeira S.R.
      • Pontes P.H.
      • Garcia A.S.
      • et al.
      Timing of renal replacement therapy initiation by AKIN classification system.
      ]. In 2010, a consensus was reached leading to an adaptation of the AKIN criteria proposed by the acute dialysis quality initiative (ADQI) and the International Club of Ascites (ICA). This definition has been validated in several studies of hospitalized patients with cirrhosis [
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      ,
      • Wong F.
      • Leung W.
      • Al Beshir M.
      • Marquez M.
      • Renner E.L.
      Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.
      ,
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Bhogal H.
      • Lim J.K.
      • Ansari N.
      • et al.
      Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
      ,
      • Wong F.
      • O’Leary J.G.
      • Reddy K.R.
      • Patton H.
      • Kamath P.S.
      • Fallon M.B.
      • et al.
      New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis and infection.
      ]. The definition of HRS has also been revised such that it is incorporated under the general definition of AKI [
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      ]. Recent definitions and classifications of AKI are summarized in Supplementary Table 1.
      Prerenal phenotypes account for about two thirds of AKI whereas intrarenal represent about one third [
      • Garcia-Tsao G.
      • Parikh C.R.
      • Viola A.
      Acute kidney injury in cirrhosis.
      ]. Post-renal phenotypes are very uncommon. Prerenal phenotypes are classified according to response to volume expansion. In patients who are volume-responsive, AKI can be the consequence of hypovolemia (digestive bleeding, diuretics, or diarrhea) or large volume paracentesis without albumin infusion. Type-1 HRS, by contrast, is defined by the absence of response to volume expansion [
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      ]. ATN is the most common cause of intrarenal AKI (Fig. 2A). However, ATN may result from unrecognized and/or untreated prerenal failure with prolonged hypoperfusion leading to ischemic injury.
      Figure thumbnail gr2
      Fig. 2Panel of kidney lesions in patients with cirrhosis. (A) Kidney biopsy (Masson trichrome) obtained in a patient with alcohol-induced cirrhosis with recent episode of ascites and introduction of furosemide (40 mg/day), international normalized ratio: 2.3, serum bilirubin: 1 mg/dl, serum creatinine: 4.2 mg/dl (no baseline serum creatinine available), oliguria, no proteinuria, no hematuria and normal kidney on doppler-ultrasound (US) showing typical lesions of acute tubular necrosis: irregular shape of tubules (normal (a) or enlarged lumen (b)), dystrophic flattened epithelial cells (c), normal glomerulus (d) and no interstitial fibrosis. (B–D) Kidney biopsy (Masson trichrome: 2b–2c, argentaffin: 2d, IgA immunostaining: 2e) obtained in a patient with alcohol-induced cirrhosis, refractory ascites, serum creatinine 1 mg/dl, no proteinuria, no hematuria and normal kidney on doppler-US showing mesangiocapillary glomerulonephritis with IgA deposits associated with chronic tubulo-intertitial nephritis lesions: (B) fibrous glomerulus (e), patchy areas of interstitial fibrosis (f), irregular shape of tubules (normal (g) or enlarged lumen (h)). (C) Glomerule with mesangial cellular proliferation. (D) Thickening of the capillary walls due to IgA deposits (E).

      Role of biomarkers in patients with cirrhosis and AKI

      Early identification of the phenotype of AKI and early disease-oriented interventions may facilitate recovery [
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      ,
      • Kashani K.
      • Kellum J.A.
      Novel biomarkers indicating repair or progression after acute kidney injury.
      ,
      • Belcher J.M.
      Acute Kidney Injury in Liver Disease: Role of Biomarkers.
      ]. One of the most challenging issues is the ability to differentiate HRS from ATN. HRS is considered as a functional disorder, without underlying kidney changes and is a consequence of extreme renal vasoconstriction. Systemic inflammation may play a major role in the pathophysiology of HRS [
      • Adebayo D.
      • Morabito V.
      • Davenport A.
      • Jalan R.
      Renal dysfunction in cirrhosis is not just a vasomotor nephropathy.
      ,
      • Wong F.
      The evolving concept of acute kidney injury in patients with cirrhosis.
      ]. Vasoconstrictors such as terlipressin and norepinephrine, improve the prognosis of HRS with reversal in about 50% of patients [
      • Moreau 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.
      ,
      • Sharma P.
      • Kumar A.
      • Shrama B.C.
      • Sarin S.K.
      An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response.
      ,
      • Sanyal 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.
      ]. However, in the absence of liver transplantation, short-term mortality remains very high [
      • Wong F.
      • Leung W.
      • Al Beshir M.
      • Marquez M.
      • Renner E.L.
      Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation.
      ,
      • Moreau 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.
      ,
      • Boyer T.D.
      • Sanyal A.J.
      • Garcia-Tsao G.
      • Regenstein F.
      • Rossaro L.
      • Appenrodt B.
      • et al.
      Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1.
      ,
      • Ruiz R.
      • Barri Y.M.
      • Jennings L.W.
      • Chinnakotla S.
      • Goldstein R.M.
      • Levy M.F.
      • et al.
      Hepatorenal syndrome: a proposal for kidney after liver transplantation (KALT).
      ,
      • Gonwa T.A.
      • Klintmalm G.B.
      • Levy M.
      • Jennings L.S.
      • Goldstein R.M.
      • Husberg B.S.
      Impact of pretransplant renal function on survival after liver transplantation.
      ]. By contrast, ATN is associated with intrinsic kidney changes and is characterized by patchy areas of flattened tubular cells with apical vacuolization and enlarged lumen. AKI typically represents a continuum of disease starting with one or several insults causing functional changes, followed by structural changes due to prolonged ischemic injury. The role of bilirubin on the progression of kidney diseases has been controversial. However, several studies in humans or based on animal models suggest that bilirubin has a protective effect against progression of CKDs [
      • Riphagen I.J.
      • Deetman P.E.
      • Bakker S.J.
      • Navis G.
      • Cooper M.E.
      • Lewis J.B.
      • et al.
      Bilirubin and progression of nephropathy in type 2 diabetes: a post hoc analysis of RENAAL with independent replication in IDNT.
      ,
      • Lee A.T.
      • Wang Y.Y.
      • Lin S.Y.
      • Liang J.T.
      • Sheu W.H.
      • Song Y.M.
      • et al.
      Higher serum total bilirubin concentration is associated with lower risk of renal insufficiency in an adult population.
      ]. Bilirubin, which has antioxidant properties, protects from circulating oxidative stress in animal models [
      • Boon A.C.
      • Lam A.K.
      • Gopalan V.
      • Benzie I.F.
      • Briskey D.
      • Coombes J.S.
      • et al.
      Endogenously elevated bilirubin modulates kidney function and protects from circulating oxidative stress in a rat model of adenine-induced kidney failure.
      ].
      Ideally, biomarkers should help distinguish functional from structural changes and therefore, help to differentiate patients with a potential for recovery and patients with irreversible changes or a relentless progression to CKD.
      A better knowledge of the interconnection between AKI and CKD may lead to the identification of biomarkers that indicate reversibility/irreversibility of renal dysfunction.

      Conventional markers aimed at phenotyping AKI

      In the general population, conventional tools used to define the phenotype of AKI include SCr, UO, fractional excretion of filtered sodium (FENa), fractional excretion of filtered urea (FEurea) and proteinuria over 500 mg. In advanced cirrhosis, all of these tools have limitations. In addition, neither absolute values nor changes in SCr help differentiate functional impairment from structural changes.
      In prerenal azotemia, tubular function is intact and FENa should be less than 1%. However, FENa may be artificially increased by diuretics, glycosuria or as a result of chronic adaptation [
      • Pepin M.N.
      • Bouchard J.
      • Legault L.
      • Ethier J.
      Diagnostic performance of fractional excretion of urea and fractional excretion of sodium in the evaluations of patients with acute kidney injury with or without diuretic treatment.
      ]. By contrast, low FENa can be observed in other types of AKI (acute glomerulonephritis, acute interstitial nephritis or ATN) [
      • 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.
      ,
      • Cabrera J.
      • Arroyo V.
      • Ballesta A.M.
      • Rimola A.
      • Gual J.
      • Elena M.
      • et al.
      Aminoglycoside nephrotoxicity in cirrhosis. Value of urinary beta 2-microglobulin to discriminate functional renal failure from acute tubular damage.
      ] due to the underlying activation of water and sodium retention or to an injury of proximal tubule with intact distal tubule function. In patients with cirrhosis, FENa is not independently associated with the progression of AKI and mortality [
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Thiessen-Philbrook H.
      • Peixoto A.J.
      • Perazella M.A.
      • et al.
      Urinary biomarkers and progression of AKI in patients with cirrhosis.
      ]. Similarly, the accuracy of low FEurea (less than 35%) to identify prerenal azotemia is poor [
      • Carvounis C.P.
      • Nisar S.
      • Guro-Razuman S.
      Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure.
      ]. Proteinuria exceeding 1 to 2 g/day suggests a glomerular cause (glomerulonephritis) but proteinuria is not constant [
      • Stevens P.E.
      • Levin A.
      Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group M
      Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes: clinical practice guideline.
      ]. Decreased serum protein concentration due to impaired liver function and/or poor nutritional status can be a bias. Mild proteinuria can be observed in patients with ATN [
      • Perazella M.A.
      • Coca S.G.
      • Kanbay M.
      • Brewster U.C.
      • Parikh C.R.
      Diagnostic value of urine microscopy for differential diagnosis of acute kidney injury in hospitalized patients.
      ]. Lastly, the cut-off value that determines non-physiological proteinuria in patients with cirrhosis has never been clearly determined. It can be suspected that in patients with low serum protein level, proteinuria <0.5 g/d may reflect significant glomerular changes. Overall, the conventional markers are non-specific and poorly sensitive. In candidates for liver transplantation, it has been shown that there is a poor correlation between these markers and biopsy findings [
      • Wadei H.M.
      • Geiger X.J.
      • Cortese C.
      • Mai M.L.
      • Kramer D.J.
      • Rosser B.G.
      • et al.
      Kidney allocation to liver transplant candidates with renal failure of undetermined etiology: role of percutaneous renal biopsy.
      ].

      Novel biomarkers of AKI

      In the last decade, several innovative biomarkers of AKI have been assessed in general nephrology and intensive care. Markers of acute tubular injury have been the most extensively studied since they typically reflect the earliest markers of ischemia-related events. Within the kidney, proximal tubule is located in an area that is especially exposed to hypoxic injury following hypoperfusion. Whatever the cause, hypoxia leads to proximal tubule dysfunction resulting in an increase in excreted low molecular weight proteins into urine. Fig. 3 summarizes several mechanisms leading to specific urinary protein excretion in tubular dysfunction. The most promising tubular biomarkers of tubular injury in AKI are (i) neutrophil gelatinase-associated lipocalin (NGAL), (ii) interleukin 18 (IL-18), (iii) kidney injury molecule 1 (KIM-1) and (iv) liver-type fatty acid-binding protein (L-FABP).
      In patients with AKI, an important issue is to differentiate hepatorenal syndrome (HRS) from acute tubular necrosis (ATN) since management and outcomes differ. Several novel biomarkers recently emerged in this field. Neutrophil Gelatinase-Associated Lipocalin (NGAL) has been the most extensively studied. There is an increase in serum and urine concentration of these biomarkers following tubular injury. None of them accurately predicts the potential for renal recovery.
      Figure thumbnail gr3
      Fig. 3Pathophysiology of excretion of urinary proteins in tubular dysfunction and examples of urinary biomarkers. Proximal tubule is located in an area exposed to hypoxic injury. Ischemia-related events are a common mechanism in AKI, whatever the phenotype, and lead to tubule injury. Tubular dysfunction can be evaluated by urinary biomarkers reflecting various pathophysiological mechanisms (1) tubular proteins released due to cell damage, (2) tubular proteins upregulated by injury, (3) markers of cell cycle arrest, (4) plasma proteins due to decreased tubular reabsorption and (4) markers released by recruited inflammatory cells.
      NGAL is a small protein (25 KDa) produced by several organs including kidney, lung, the stomach and colon [
      • Mishra J.
      • Ma Q.
      • Prada A.
      • Mitsnefes M.
      • Zahedi K.
      • Yang J.
      • et al.
      Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury.
      ]. In animal models, NGAL expression is markedly increased in the kidneys and released in urine following ischemic or nephrotoxic insults. Urinary concentration increases very rapidly (within 2 h) following ischemia [
      • Mishra J.
      • Ma Q.
      • Prada A.
      • Mitsnefes M.
      • Zahedi K.
      • Yang J.
      • et al.
      Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury.
      ,
      • Mishra J.
      • Mori K.
      • Ma Q.
      • Kelly C.
      • Yang J.
      • Mitsnefes M.
      • et al.
      Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin.
      ]. Human studies have shown that NGAL measurement in either urine or serum might be useful to detect AKI at an early stage in numerous clinical situations (sepsis and septic shock, contrast-enhanced imaging, cardiac surgery, polytrauma and hypothermia) [
      • Wheeler D.S.
      • Devarajan P.
      • Ma Q.
      • Harmon K.
      • Monaco M.
      • Cvijanovich N.
      • et al.
      Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock.
      ,
      • Hirsch R.
      • Dent C.
      • Pfriem H.
      • Allen J.
      • Beekman 3rd, R.H.
      • Ma Q.
      • et al.
      NGAL is an early predictive biomarker of contrast-induced nephropathy in children.
      ,
      • Mishra J.
      • Dent C.
      • Tarabishi R.
      • Mitsnefes M.M.
      • Ma Q.
      • Kelly C.
      • et al.
      Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery.
      ,
      • Wagener G.
      • Jan M.
      • Kim M.
      • Mori K.
      • Barasch J.M.
      • Sladen R.N.
      • et al.
      Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery.
      ,
      • Makris K.
      • Markou N.
      • Evodia E.
      • Dimopoulou E.
      • Drakopoulos I.
      • Ntetsika K.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of acute kidney injury in critically ill multiple trauma patients.
      ,
      • Trachtman H.
      • Christen E.
      • Cnaan A.
      • Patrick J.
      • Mai V.
      • Mishra J.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: a novel marker of renal injury.
      ,
      • Nickolas T.L.
      • O’Rourke M.J.
      • Yang J.
      • Sise M.E.
      • Canetta P.A.
      • Barasch N.
      • et al.
      Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury.
      ]. In addition, NGAL may be useful in monitoring some kidney diseases such as delayed kidney graft function [
      • Pianta T.J.
      • Peake P.W.
      • Pickering J.W.
      • Kelleher M.
      • Buckley N.A.
      • Endre Z.H.
      Clusterin in kidney transplantation: novel biomarkers versus serum creatinine for early prediction of delayed graft function.
      ,
      • Lee E.Y.
      • Kim M.S.
      • Park Y.
      • Kim H.S.
      Serum neutrophil gelatinase-associated lipocalin and interleukin-18 as predictive biomarkers for delayed graft function after kidney transplantation.
      ], kidney allograft rejection [
      • Kohei J.
      • Ishida H.
      • Tanabe K.
      • Tsuchiya K.
      • Nitta K.
      Neutrophil gelatinase-associated lipocalin is a sensitive biomarker for the early diagnosis of acute rejection after living-donor kidney transplantation.
      ], lupus nephritis [
      • Torres-Salido M.T.
      • Cortes-Hernandez J.
      • Vidal X.
      • Pedrosa A.
      • Vilardell-Tarres M.
      • Ordi-Ros J.
      Neutrophil gelatinase-associated lipocalin as a biomarker for lupus nephritis.
      ] and IgA nephropathy [
      • Ding H.
      • He Y.
      • Li K.
      • Yang J.
      • Li X.
      • Lu R.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy.
      ]. Recently, it has been suggested that NGAL may help identify the cause of AKI in patients with liver disease, especially in differentiating ATN from HRS [
      • Barreto R.
      • Elia C.
      • Sola E.
      • Moreira R.
      • Ariza X.
      • Rodriguez E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin predicts kidney outcome and death in patients with cirrhosis and bacterial infections.
      ,
      • Belcher J.M.
      • Sanyal A.J.
      • Peixoto A.J.
      • Perazella M.A.
      • Lim J.
      • Thiessen-Philbrook H.
      • et al.
      Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.
      ,
      • Fagundes C.
      • Pepin M.N.
      • Guevara M.
      • Barreto R.
      • Casals G.
      • Sola E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
      ,
      • Verna E.C.
      • Brown R.S.
      • Farrand E.
      • Pichardo E.M.
      • Forster C.S.
      • Sola-Del Valle D.A.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis.
      ]. On average, urinary NGAL is higher in patients with cirrhosis and AKI compared to patients without AKI [
      • Fagundes C.
      • Pepin M.N.
      • Guevara M.
      • Barreto R.
      • Casals G.
      • Sola E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
      ] and is significantly higher in patients with persistent AKI as compared to patients with transient AKI [
      • Barreto R.
      • Elia C.
      • Sola E.
      • Moreira R.
      • Ariza X.
      • Rodriguez E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin predicts kidney outcome and death in patients with cirrhosis and bacterial infections.
      ]. Among patients with AKI, urinary NGAL was found to be markedly higher in those with a diagnosis of ATN when compared to those with a diagnosis of type-1 HRS, prerenal azotemia or CKD [
      • Belcher J.M.
      • Sanyal A.J.
      • Peixoto A.J.
      • Perazella M.A.
      • Lim J.
      • Thiessen-Philbrook H.
      • et al.
      Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.
      ,
      • Fagundes C.
      • Pepin M.N.
      • Guevara M.
      • Barreto R.
      • Casals G.
      • Sola E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
      ]. Among patients with type-1 HRS, urinary NGAL was significantly higher in those with concomitant infections. Interestingly, two studies suggest that elevated urinary NGAL is predictive of early mortality in cirrhotic patients with AKI [
      • Barreto R.
      • Elia C.
      • Sola E.
      • Moreira R.
      • Ariza X.
      • Rodriguez E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin predicts kidney outcome and death in patients with cirrhosis and bacterial infections.
      ,
      • Verna E.C.
      • Brown R.S.
      • Farrand E.
      • Pichardo E.M.
      • Forster C.S.
      • Sola-Del Valle D.A.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis.
      ]. Initial enthusiasm for NGAL however, has been tempered by some limitations [
      • Ostermann M.
      • Joannidis M.
      Biomarkers for AKI improve clinical practice: no.
      ]. Urinary NGAL level increases during AKI but also during other conditions such as chronic and acute inflammation as well as CKD [
      • Martensson J.
      • Bellomo R.
      The rise and fall of NGAL in acute kidney injury.
      ]. The performance of NGAL in patients with cirrhosis should also be interpreted with caution for several reasons. Firstly, recent studies have shown an increase in NGAL liver synthesis during sepsis [
      • Macdonald S.P.
      • Stone S.F.
      • Neil C.L.
      • van Eeden P.E.
      • Fatovich D.M.
      • Arendts G.
      • et al.
      Sustained elevation of resistin, NGAL and IL-8 are associated with severe sepsis/septic shock in the emergency department.
      ,
      • Otto G.P.
      • Busch M.
      • Sossdorf M.
      • Claus R.A.
      Impact of sepsis-associated cytokine storm on plasma NGAL during acute kidney injury in a model of polymicrobial sepsis.
      ]. Secondly, even though urinary NGAL level is higher in ATN when compared to HRS and other causes of AKI, there is a significant overlap between groups, which is more pronounced with plasma NGAL levels [
      • Fagundes C.
      • Pepin M.N.
      • Guevara M.
      • Barreto R.
      • Casals G.
      • Sola E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
      ,
      • Verna E.C.
      • Brown R.S.
      • Farrand E.
      • Pichardo E.M.
      • Forster C.S.
      • Sola-Del Valle D.A.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis.
      ]. Finally, AKI diagnosis is based on clinical criteria without a definitive gold standard, since the gold standard of biopsy cannot be used in almost all patients with cirrhosis.
      Interleukin 18 (IL-18) is a proinflammatory cytokine overexpressed in proximal tubule and released in urine following AKI [
      • Ariza X.
      • Sola E.
      • Elia C.
      • Barreto R.
      • Moreira R.
      • Morales-Ruiz M.
      • et al.
      Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis.
      ,
      • Liu Y.
      • Guo W.
      • Zhang J.
      • Xu C.
      • Yu S.
      • Mao Z.
      • et al.
      Urinary interleukin 18 for detection of acute kidney injury: a meta-analysis.
      ]. Human studies have shown that urinary IL-18 levels are increased in AKI and/or ischemic kidney changes [
      • Wu H.
      • Craft M.L.
      • Wang P.
      • Wyburn K.R.
      • Chen G.
      • Ma J.
      • et al.
      IL-18 contributes to renal damage after ischemia-reperfusion.
      ] whereas levels remain low in nephrotoxic AKI, CKD and urinary tract infections. In intensive care unit patients with AKI, urinary IL-18 may predict a poor outcome [
      • Siew E.D.
      • Ikizler T.A.
      • Gebretsadik T.
      • Shintani A.
      • Wickersham N.
      • Bossert F.
      • et al.
      Elevated urinary IL-18 levels at the time of ICU admission predict adverse clinical outcomes.
      ]. In patients with cirrhosis, significantly higher urinary IL-18 levels have been observed in patients with a clinical diagnosis of ATN compared to non-ATN AKI [
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Thiessen-Philbrook H.
      • Peixoto A.J.
      • Perazella M.A.
      • et al.
      Urinary biomarkers and progression of AKI in patients with cirrhosis.
      ]. However, similarly to urine NGAL, an overlap between groups has been shown.
      Kidney injury molecule 1 (KIM-1) is a transmembrane protein, which is upregulated by ischemic kidney injury [
      • Ichimura T.
      • Bonventre J.V.
      • Bailly V.
      • Wei H.
      • Hession C.A.
      • Cate R.L.
      • et al.
      Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury.
      ]. It is a marker of proximal tubular injury [
      • Han W.K.
      • Bailly V.
      • Abichandani R.
      • Thadhani R.
      • Bonventre J.V.
      Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury.
      ]. Urinary KIM-1 is increased in patients with ATN whereas no increase is observed in those with prerenal azotemia, urinary tract infections or CKD [
      • Nishida M.
      • Kawakatsu H.
      • Okumura Y.
      • Hamaoka K.
      Serum and urinary neutrophil gelatinase-associated lipocalin levels in children with chronic renal diseases.
      ,
      • Parikh C.R.
      • Devarajan P.
      New biomarkers of acute kidney injury.
      ]. Few studies have explored KIM-1 in patients with cirrhosis and AKI [
      • Belcher J.M.
      • Sanyal A.J.
      • Peixoto A.J.
      • Perazella M.A.
      • Lim J.
      • Thiessen-Philbrook H.
      • et al.
      Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury.
      ,
      • Qasem A.A.
      • Farag S.E.
      • Hamed E.
      • Emara M.
      • Bihery A.
      • Pasha H.
      Urinary biomarkers of acute kidney injury in patients with liver cirrhosis.
      ]. These studies have suggested that urinary KIM-1 levels are increased in ATN compared to other causes of AKI and that high levels of KIM-1 could predict progression of AKI. However, substantial overlap in urinary KIM-1, similar to that observed with NGAL and IL-18, has been observed between patients with a diagnosis of ATN as compared to patients with other causes of AKI [
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Thiessen-Philbrook H.
      • Peixoto A.J.
      • Perazella M.A.
      • et al.
      Urinary biomarkers and progression of AKI in patients with cirrhosis.
      ].
      L-FABP is a small protein, which is expressed in the proximal tubular epithelium in humans. Free fatty acids which are freely filtered with albumin through the glomerulus are reabsorbed in the proximal tubules and bound to L-FABP which transports them to mitochondria or peroxisomes, participating in intracellular fatty acid homeostasis [
      • Furuhashi M.
      • Hotamisligil G.S.
      Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets.
      ]. Experimental models of kidney disease with tubule-interstitial damage have shown that renal L-FABP is upregulated and that its urinary excretion is increased [
      • Kamijo-Ikemori A.
      • Sugaya T.
      • Matsui K.
      • Yokoyama T.
      • Kimura K.
      Roles of human liver type fatty acid binding protein in kidney disease clarified using hL-FABP chromosomal transgenic mice.
      ]. In animal models, high urinary levels of L-FABP are correlated to sepsis and to the severity of tubule-interstitial damage [
      • Kamijo-Ikemori A.
      • Sugaya T.
      • Matsui K.
      • Yokoyama T.
      • Kimura K.
      Roles of human liver type fatty acid binding protein in kidney disease clarified using hL-FABP chromosomal transgenic mice.
      ,
      • Yokoyama T.
      • Kamijo-Ikemori A.
      • Sugaya T.
      • Hoshino S.
      • Yasuda T.
      • Kimura K.
      Urinary excretion of liver type fatty acid binding protein accurately reflects the degree of tubulointerstitial damage.
      ]. In human studies, it has been suggested that L-FABP may serve as a biomarker of AKI or sepsis complicated by AKI [
      • Doi K.
      • Noiri E.
      • Maeda-Mamiya R.
      • Ishii T.
      • Negishi K.
      • Hamasaki Y.
      • et al.
      Urinary L-type fatty acid-binding protein as a new biomarker of sepsis complicated with acute kidney injury.
      ]. In addition, urinary L-FABP could be a reliable marker to detect microcirculatory disorder in kidney tubules [
      • Yamamoto T.
      • Noiri E.
      • Ono Y.
      • Doi K.
      • Negishi K.
      • Kamijo A.
      • et al.
      Renal L-type fatty acid-binding protein in acute ischemic injury.
      ]. Urinary level of L-FABP is also increased in patients with different causes of CKD (diabetic nephropathy, glomerular nephritis), suggesting that L-FABP may act as an antioxidant and renoprotective substance [
      • Xu Y.
      • Xie Y.
      • Shao X.
      • Ni Z.
      • Mou S.
      L-FABP: A novel biomarker of kidney disease.
      ].
      Cystatin C levels is an early marker of AKI in patients with and without cirrhosis [
      • Haase-Fielitz A.
      • Bellomo R.
      • Devarajan P.
      • Story D.
      • Matalanis G.
      • Dragun D.
      • et al.
      Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery–a prospective cohort study.
      ,
      • Herget-Rosenthal S.
      • Marggraf G.
      • Husing J.
      • Goring F.
      • Pietruck F.
      • Janssen O.
      • et al.
      Early detection of acute renal failure by serum cystatin C.
      ,
      • Nejat M.
      • Pickering J.W.
      • Walker R.J.
      • Endre Z.H.
      Rapid detection of acute kidney injury by plasma cystatin C in the intensive care unit.
      ,
      • Zappitelli M.
      • Krawczeski C.D.
      • Devarajan P.
      • Wang Z.
      • Sint K.
      • Thiessen-Philbrook H.
      • et al.
      Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric cardiac surgery.
      ,
      • Belcher J.M.
      • Sanyal A.J.
      • Garcia-Tsao G.
      • Ansari N.
      • Coca S.G.
      • Shlipak M.G.
      • et al.
      Early trends in cystatin C and outcomes in patients with cirrhosis and acute kidney injury.
      ,
      • Slack A.J.
      • McPhail M.J.
      • Ostermann M.
      • Bruce M.
      • Sherwood R.
      • Musto R.
      • et al.
      Predicting the development of acute kidney injury in liver cirrhosis–an analysis of glomerular filtration rate, proteinuria and kidney injury biomarkers.
      ]. In patients eventually developing AKI, an increase in serum cystatin C is observed at an earlier stage as compared to serum creatinine. In addition, changes in cystatin C at an early stage of AKI are more closely related to dialysis and mortality than creatinine [
      • Belcher J.M.
      • Sanyal A.J.
      • Garcia-Tsao G.
      • Ansari N.
      • Coca S.G.
      • Shlipak M.G.
      • et al.
      Early trends in cystatin C and outcomes in patients with cirrhosis and acute kidney injury.
      ].
      Serum osteopontin has been shown to be predictive of early mortality in ICU patients with AKI independent of the phenotype of AKI [
      • Lorenzen J.M.
      • Hafer C.
      • Faulhaber-Walter R.
      • Kumpers P.
      • Kielstein J.T.
      • Haller H.
      • et al.
      Osteopontin predicts survival in critically ill patients with acute kidney injury.
      ,
      • Nejat M.
      • Pickering J.W.
      • Walker R.J.
      • Westhuyzen J.
      • Shaw G.M.
      • Frampton C.M.
      • et al.
      Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and predicts mortality in the intensive care unit.
      ]. Osteopontin is a broadly expressed cytokine that is upregulated during inflammation. In animal models of AKI, osteopontin expression and mRNA level are increased in proximal and distal tubular cells [
      • Verstrepen W.A.
      • Persy V.P.
      • Verhulst A.
      • Dauwe S.
      • De Broe M.E.
      Renal osteopontin protein and mRNA upregulation during acute nephrotoxicity in the rat.
      ]. Although osteopontin is supposed to be upregulated by inflammation, in critically ill patients with AKI, sepsis was not associated with a significant increase in circulating osteopontin. Urinary osteopontin level seems markedly higher in patients with cirrhosis with AKI vs. no AKI [
      • Ariza X.
      • Sola E.
      • Elia C.
      • Barreto R.
      • Moreira R.
      • Morales-Ruiz M.
      • et al.
      Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis.
      ]. Urinary osteopontin level was also higher in patients with a clinical diagnosis of ATN as compared to other causes of AKI but with overlap between groups [
      • Ariza X.
      • Sola E.
      • Elia C.
      • Barreto R.
      • Moreira R.
      • Morales-Ruiz M.
      • et al.
      Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis.
      ]. A recent study suggests that the combination of elevated plasma osteopontin and TIMP-1 levels, age <57 and absence of diabetes pre-transplantation are relatively accurate at differentiating patients with reversible AKI from patients with irreversible AKI post transplantation [
      • Levitsky J.
      • Baker T.B.
      • Jie C.
      • Ahya S.
      • Levin M.
      • Friedewald J.
      • et al.
      Plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation.
      ].
      Activation of TLRs may play a role in interstitial fibrosis, renal involvement in systemic immune disorders and more generally in AKI [
      • Anders H.J.
      • Banas B.
      • Schlondorff D.
      Signaling danger: toll-like receptors and their potential roles in kidney disease.
      ]. In AKI, irrespective of the initial trigger that leads to tubular cell injury, necrotic tubular cells release potential TLR ligands which could activate other tubular cells or resident immune cells in the kidney [
      • Anders H.J.
      • Banas B.
      • Schlondorff D.
      Signaling danger: toll-like receptors and their potential roles in kidney disease.
      ]. High levels of urinary TLR-4 have been found in patients with cirrhosis and AKI [
      • Shah N.
      • Mohamed F.E.
      • Jover-Cobos M.
      • Macnaughtan J.
      • Davies N.
      • Moreau R.
      • et al.
      Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis.
      ]. Further studies are clearly needed to determine if urinary TLR-4 could help to diagnose AKI.
      Other kidney biomarkers including β2M, trefoil factor 3 (TTF3), clusterin, MCP-1 and calbindin need to be further explored in cirrhosis. Examples of novel biomarkers in AKI are shown in Table 2.
      Table 2Examples of proteic biomarkers tested in AKI.
      AKI, acute kidney injury; CKD, chronic kidney disease.
      Overall, several urinary or plasma biomarkers may help (i) to recognize impaired renal function at an earlier stage as compared with SCr, (ii) to identify the mechanisms involved in AKI and (iii) to improve prognostication. However, all the studies comparing ATN to other causes of AKI have been performed without histological confirmation of ATN, which is a potential source of bias. All of these markers are increased in tubular injury but none of them is specific of any part of the nephron. In addition, overlap between groups still represents a limitation. Sequential assessment and/or combinations of biomarkers should be tested [
      • Levitsky J.
      • Baker T.B.
      • Jie C.
      • Ahya S.
      • Levin M.
      • Friedewald J.
      • et al.
      Plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation.
      ] since it could help to phenotype AKI in patients with cirrhosis [
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Bhogal H.
      • Lim J.K.
      • Ansari N.
      • et al.
      Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
      ] and also to predict the outcome of AKI [
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Thiessen-Philbrook H.
      • Peixoto A.J.
      • Perazella M.A.
      • et al.
      Urinary biomarkers and progression of AKI in patients with cirrhosis.
      ], but again the gold standard of biopsy is not available. Fig. 4 shows the different phenotypes of AKI, with pathological features and potential biomarkers.
      Combinations of urinary and/or serum biomarkers may be more accurate than a single biomarker.
      Figure thumbnail gr4
      Fig. 4Kidney pathological findings in various phenotypes of AKI and correlation with potential biomarkers. Mild tubular abnormalities do not preclude the diagnosis of HRS but severe tubular lesions characterize ATN. Biomarkers of CKD may be associated with any stage of severity of kidney dysfunction. In contrast, biomarkers of functional damage appear at the stage of prerenal failure marked by kidney hypoperfusion. Biomarkers increase with the severity of AKI (HRS or ATN) whereas markers of structural damage eventually appear in HRS and are markedly increased in ATN. ∗Increase from baseline rather than absolute value; ∗∗examples: NGAL, KIM1, L-FABP, IL-18.

      Biomarkers in CKD

      Current biomarkers

      There is growing interest in the development of biomarkers to help identify patients at risk of progression to CKD, to detect extra renal complications of AKI/CKD and to predict patient and renal outcome. However, few biomarkers have been developed to determine the cause or mechanism of CKD and irrespective of the cause and the initial structural changes (glomerular, vascular or tubular), the natural history is characterized by a progressive kidney fibrosis associated with a decline of GFR. Kidney biopsy is only performed in selected patients when the cause is unclear and potentially reversible with a specific therapy.
      Patients with cirrhosis frequently have predisposing factors for the development of CKD, such as advanced age, diabetes, and hypertension. In addition, specific liver diseases may be associated with kidney disease, such as HBV/HCV-associated glomerulonephritis (membranous, membranoproliferative glomerulonephrities and cryoglobulinemia) or alcohol-related IgA nephropathy (Fig. 2B–D). Few studies have shown that several types of kidney changes involving all the parts of the nephron are frequently interconnected, even in the absence of abnormal urinalysis [
      • 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.
      ,
      • Calmus Y.
      • Conti F.
      • Cluzel P.
      • Hill G.
      • Antoine C.
      • Scatton O.
      • et al.
      Prospective assessment of renal histopathological lesions in patients with end-stage liver disease: effects on long-term renal function after liver transplantation.
      ]. However, percutaneous kidney biopsy remains challenging in patients with cirrhosis due to abnormal coagulation and thombocytopenia. Transjugular biopsy is an alternative with some limitations [
      • Jouet P.
      • Meyrier A.
      • Mal F.
      • Callard P.
      • Guettier C.
      • Stordeur D.
      • et al.
      Transjugular renal biopsy in the treatment of patients with cirrhosis and renal abnormalities.
      ,
      • Mal F.
      • Meyrier A.
      • Callard P.
      • Kleinknecht D.
      • Altmann J.J.
      • Beaugrand M.
      The diagnostic yield of transjugular renal biopsy. Experience in 200 cases.
      ]. It is technically difficult to perform in patients with kidney atrophy and/or large volume ascites, and biopsy samples are generally small. In candidates for liver transplantation and chronically impaired renal function, biomarkers of glomerulosclerosis, tubular atrophy, interstitial fibrosis and vascular changes that can be precipitated by calcineurin inhibitors after transplantation may help decide SLK transplantation rather than liver transplantation alone [
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      ]. For instance, SLK transplantation has been recommended in patients with interstitial fibrosis exceeding 30% as it is predictive of a rapid decline in GFR after transplantation [
      • Eason J.D.
      • Gonwa T.A.
      • Davis C.L.
      • Sung R.S.
      • Gerber D.
      • Bloom R.D.
      Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK).
      ].
      The role of conventional urinary markers to identify the cause and mechanisms of CKD is very limited. Albuminuria is a common finding in the general population with CKD. It is the earliest marker of glomerular diseases which usually precedes the decrease of GFR and can be used to identify patients at risk for developing CKD and/or to monitor nephroprotective measures. In patients with cirrhosis with CKD, the role of albuminuria has never been evaluated.
      CKD is also usually associated with an increase in biomarkers of tubular injury including NGAL [
      • Fagundes C.
      • Pepin M.N.
      • Guevara M.
      • Barreto R.
      • Casals G.
      • Sola E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
      ], osteopontin and TIMP-1 [
      • Xu T.Y.
      • Zhang Y.
      • Li Y.
      • Zhu D.L.
      • Gao P.J.
      The association of serum inflammatory biomarkers with chronic kidney disease in hypertensive patients.
      ].

      Other novel biomarkers

      MicroRNAs (miRNAs) are a class of short noncoding RNAs that regulate most of the important cellular processes by inhibiting gene expression through the post-transcriptional repression of their target mRNAs [
      • Ambros V.
      The functions of animal microRNAs.
      ,
      • Bartel D.P.
      MicroRNAs: genomics, biogenesis, mechanism, and function.
      ,
      • Carrington J.C.
      • Ambros V.
      Role of microRNAs in plant and animal development.
      ]. miRNAs are involved in many physiological processes but also in numerous disease states and are less complex and more stable molecules compared to mRNA. Indeed, miRNAs do not undergo post-processing modifications and they are stably expressed in plasma and urine. They are present in fluids either packaged into microvesicles and/or exosomes, or transported by RNA-binding proteins and lipoproteins, which protect them from degradation by ribonucleases [
      • Lorenzen J.M.
      • Thum T.
      Circulating and urinary microRNAs in kidney disease.
      ]. Expression of a set of tissue-specific miRNAs profiles has been identified in human kidney [
      • Landgraf P.
      • Rusu M.
      • Sheridan R.
      • Sewer A.
      • Iovino N.
      • Aravin A.
      • et al.
      A mammalian microRNA expression atlas based on small RNA library sequencing.
      ,
      • Sun Y.
      • Koo S.
      • White N.
      • Peralta E.
      • Esau C.
      • Dean N.M.
      • et al.
      Development of a micro-array to detect human and mouse microRNAs and characterization of expression in human organs.
      ]. Experimental studies have shown recently that specific profiles of miRNAs were associated with epithelial-mesenchymal transition (EMT) process, a key factor that determines fibrogenesis and progression to CKD [
      • Chandrasekaran K.
      • Karolina D.S.
      • Sepramaniam S.
      • Armugam A.
      • Wintour E.M.
      • Bertram J.F.
      • et al.
      Role of microRNAs in kidney homeostasis and disease.
      ,
      • Trionfini P.
      • Benigni A.
      • Remuzzi G.
      MicroRNAs in kidney physiology and disease.
      ].
      Transforming Growth Factor beta 1 (TGF-β1) is the main actor of kidney fibrogenic process since it stimulates the synthesis and accumulation of extracellular matrix within different parts of the nephron (glomerular, tubulointerstitial and vascular components) [
      • Boor P.
      • Floege J.
      Chronic kidney disease growth factors in renal fibrosis.
      ]. Experimental studies have shown that TGF- β1 regulates several miRNAs during renal fibrosis, including profibrotic (miR-21, miR-192, miR-433) and antifibrotic miRNAs (miR-29, miR-200 family) [
      • Chung A.C.
      • Lan H.Y.
      MicroRNAs in renal fibrosis.
      ,
      • Lan H.Y.
      • Chung A.C.
      TGF-beta/Smad signaling in kidney disease.
      ]. These experimental results suggest that specific urinary miRNAs profiles may represent non-invasive tools to assess the progression of kidney fibrosis.
      Another interesting issue is the diagnosis of specific kidney disease using miRNAs profiles. For instance, human studies have shown that in IgA nephropathy, miR-148b is upregulated in peripheral blood mononuclear cells [
      • Serino G.
      • Sallustio F.
      • Cox S.N.
      • Pesce F.
      • Schena F.P.
      Abnormal miR-148b expression promotes aberrant glycosylation of IgA1 in IgA nephropathy.
      ]. In addition, glomerular endothelial cells of patients with IgA nephropathy are characterized by reduced expression miR-223 expression, which is associated with glomerular endothelial proliferation, a pathological hallmark of IgA nephropathy [
      • Bao H.
      • Chen H.
      • Zhu X.
      • Zhang M.
      • Yao G.
      • Yu Y.
      • et al.
      MiR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin alpha4 and alpha5 in IgA nephropathy.
      ]. Low levels of miR-223 were found in circulating endothelial cells, providing a possible non-invasive method for evaluating the severity of IgA nephropathy. Among promising biomarkers tested, soluble urokinase-type plasminogen activator receptor (suPAR) may be interesting for the screening of CKD but also for predicting the decline of GFR [
      • Hayek S.S.
      • Sever S.
      • Ko Y.A.
      • Trachtman H.
      • Awad M.
      • Wadhwani S.
      • et al.
      Soluble Urokinase Receptor and Chronic Kidney Disease.
      ] and should be tested in patients with cirrhosis.

      New concepts

      An emerging concept is the close interconnection of AKI and CKD [
      • Chawla L.S.
      • Eggers P.W.
      • Star R.A.
      • Kimmel P.L.
      Acute kidney injury and chronic kidney disease as interconnected syndromes.
      ]. In the general population, both AKI and CKD are associated with similar predisposing factors including advanced age, diabetes and ethnicity [
      • Levey A.S.
      • Coresh J.
      Chronic kidney disease.
      ,
      • Chawla L.S.
      • Amdur R.L.
      • Amodeo S.
      • Kimmel P.L.
      • Palant C.E.
      The severity of acute kidney injury predicts progression to chronic kidney disease.
      ]. A central predisposing factor for AKI is preexisting CKD. Patients with underlying CKD are at 10 times higher risk of developing AKI as compared to patients without CKD [
      • Khosla N.
      • Soroko S.B.
      • Chertow G.M.
      • Himmelfarb J.
      • Ikizler T.A.
      • Paganini E.
      • et al.
      Preexisting chronic kidney disease: a potential for improved outcomes from acute kidney injury.
      ]. Conversely the risk of developing CKD is higher in patients with severe and/or repeated episodes of AKI [
      • Chawla L.S.
      • Eggers P.W.
      • Star R.A.
      • Kimmel P.L.
      Acute kidney injury and chronic kidney disease as interconnected syndromes.
      ]. The rate of CKD after one episode of AKI is as high as 8 per 100 patient years [
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Thiessen-Philbrook H.
      • Peixoto A.J.
      • Perazella M.A.
      • et al.
      Urinary biomarkers and progression of AKI in patients with cirrhosis.
      ].
      The mechanisms leading to progression from AKI to CKD involve maladaptative repair [
      • Bonventre J.V.
      Maladaptive proximal tubule repair: cell cycle arrest.
      ,
      • Ferenbach D.A.
      • Bonventre J.V.
      Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.
      ] (Fig. 5). Whichever kidney structure is initially injured, AKI is characterized by an injury phase with an acute insult of the kidney that most often results in hypoxia [
      • Thadhani R.
      • Pascual M.
      • Bonventre J.V.
      Acute renal failure.
      ]. In response to hypoxia, a second phase is characterized by endothelial activation, recruitment of leucocytes and widespread tubular cell injury with local production of nitric oxide, a number of profibrotic and proinflammatory cytokines, growth factors and reactive oxygen species. Adapatative repair which leads to resolution and return to normal kidney function is characterized by cell proliferation arising from surviving mature tubular cells [
      • Bonventre J.V.
      Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure.
      ] or, possibly, renal stem cells [
      • Cantley L.G.
      Adult stem cells in the repair of the injured renal tubule.
      ] to restore tubular cell layer. In adaptative repair, pericytes do not give rise to new myofibroblasts [
      • Ferenbach D.A.
      • Bonventre J.V.
      Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.
      ]. In some circumstances AKI is followed by maladaptative repair characterized by G2/M tubular cell cycle arrest [
      • Ferenbach D.A.
      • Bonventre J.V.
      Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.
      ] with the release of cytokines and growth factors and ongoing inflammation. Inflammation leads to pericyte dissociation from the endothelium and collagen I deposition by myofibroblasts arising from activated pericytes [
      • Ferenbach D.A.
      • Bonventre J.V.
      Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.
      ]. Maladaptative repair leads to progressive scarring with chronic kidney changes. Factors associated with a switch from adaptative to maladapatative repair include advanced age, previous AKI/CKD and DNA damage. Epigenetic changes (DNA methylation, histone modification) seem to play a central role in the initiation of maladaptative repair [
      • Ferenbach D.A.
      • Bonventre J.V.
      Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.
      ].
      Figure thumbnail gr5
      Fig. 5Adaptative or maladaptative repair after an episode of AKI, resolution or transition to CKD. AKI is characterized by tubular cell injury and death (necrosis, apoptosis) which triggers endothelial activation and inflammatory cells recruitment. In adaptative repair, tubular regeneration arises from the proliferation of surviving mature cells that dedifferentiate and proliferate to replace dead tubular cells, leading to the restoration of tubular cell layer integrity and to the recovery of baseline renal function. In maladaptative repair, dedifferentiated tubular cells are blocked in the G2/M phase of cell cycle. These blocked cells release cytokines and growth factors that recruit inflammatory cells, resulting in ongoing inflammation. These stimuli activate the production of extracellular matrix components (collagen I) by myofibroblasts that lead to CKD. Factors associated with arrest in G2/M phase are ageing, previous episodes of AKI and/or underlying CKD, DNA damage, mitochondrial dysfunction, prolonged hypoxia and oxidative stress.
      Interconnections between AKI and CKD have not been specifically investigated in cirrhosis. However, patients with end-stage cirrhosis are prone to develop repeated episodes of AKI following sepsis, hypovolemia, circulatory changes associated with large volume paracentesis, and HRS. Moreover, patients with intense renal vasoconstriction but also systemic “sterile” inflammation during HRS may have sustained kidney hypoxia, even though a progression from HRS to ATN has not been clearly demonstrated in cirrhosis. Therefore, it can be assumed that patients with repeated AKI may develop irreversible chronic kidney changes which are not accurately reflected by SCr. Differentiation of adaptative from maladaptative repair process through specific biomarkers would obviously help identify patients unlikely to recover after AKI. More data are needed to identify biomarkers of maladaptative repair.

      Practical aspects and perspectives

      Early recognition of AKI

      Early recognition of AKI in cirrhosis is important in order to avoid factors that may contribute to further deterioration of renal function and to initiate appropriate management. SCr within the normal range does not exclude markedly impaired renal function in cirrhosis [
      • Francoz C.
      • Prie D.
      • Abdelrazek W.
      • Moreau R.
      • Mandot A.
      • Belghiti J.
      • et al.
      Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: impact on the model for end-stage liver disease score.
      ]. A diagnosis of AKI in cirrhosis should no longer be solely based on an increase in SCr over 133 μmol/L (1.5 mg/dl). AKI should be considered as early as an increase in SCr ⩾26.5 μmol/L (0.3 md/dl) within 48 h and/or a percentage increase in SCr ⩾50% from baseline known or presumed to have occurred within the prior 7 days is observed [
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      ]. Studies conducted in emergency units and ICU have suggested that high circulating NGAL (>150 ng/ml) and cystatin C (>1.1 mg/L) as well as urinary NGAL may help identify AKI at an earlier stage [
      • Nickolas T.L.
      • O’Rourke M.J.
      • Yang J.
      • Sise M.E.
      • Canetta P.A.
      • Barasch N.
      • et al.
      Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury.
      ,
      • Haase-Fielitz A.
      • Bellomo R.
      • Devarajan P.
      • Story D.
      • Matalanis G.
      • Dragun D.
      • et al.
      Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery–a prospective cohort study.
      ]. In patients with cirrhosis, baseline cystatin C GFR [
      • Hoek F.J.
      • Kemperman F.A.
      • Krediet R.T.
      A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate.
      ] (cut-of <55 ml/min/1.73 m2) was predictive of AKI 48 h before its occurrence [
      • Slack A.J.
      • McPhail M.J.
      • Ostermann M.
      • Bruce M.
      • Sherwood R.
      • Musto R.
      • et al.
      Predicting the development of acute kidney injury in liver cirrhosis–an analysis of glomerular filtration rate, proteinuria and kidney injury biomarkers.
      ]. However, apart from prospective studies, systematic use of circulating NGAL, circulating cystatin C, urinary NGAL and cystatin C-based clearance are not recommended for early diagnosis of AKI in cirrhosis due to insufficient evidence.

      Differential diagnosis between type-1 HRS and ATN

      Absence of response to volume expansion is a common feature of type-1 HRS and ATN. An algorithm is proposed to differentiate type-1 HRS from ATN (Fig. 6). The cut-off value of 194 μg/g creatinine of urinary NGAL to separate type-1 HRS from ATN is derived from a large study comparing urinary NGAL in different phenotypes of AKI and CKD [
      • Fagundes C.
      • Pepin M.N.
      • Guevara M.
      • Barreto R.
      • Casals G.
      • Sola E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
      ]. However, this algorithm should be interpreted with caution due to some limitations. Urinary NGAL is not available in patients with anuria. The value of urinary NGAL in patients with extreme oliguria needs to be explored. Plasma NGAL seems to be less discriminant than urinary NGAL even if differences exist between different phenotypes. As mentioned before, there is an overlap between type-1 HRS and ATN. Finally, uNGAL increases in patients with infection [
      • Fagundes C.
      • Pepin M.N.
      • Guevara M.
      • Barreto R.
      • Casals G.
      • Sola E.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.
      ,
      • Martensson J.
      • Bellomo R.
      The rise and fall of NGAL in acute kidney injury.
      ].
      Figure thumbnail gr6
      Fig. 6Differentiation of type-1 hepatorenal syndrome, acute tubular necrosis in patients with cirrhosis and impaired renal function unresponsive to volume expansion. ∗A diagnosis of type-1 HRS should not be definitively excluded in patients with uNGAL >194 μg/g creatinine due to a possible overlap, especially in patients with infection.

      Liver transplantation vs. simultaneous liver and kidney transplantation

      In stable patients with CKD, measurement of GFR using an exogenous marker is strongly recommended in the evaluation process. Patients with measured GFR ⩽30 ml/min should be considered for SLK transplantation [
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      ]. When measured GFR is not available, estimated GFR using the MDRD-6 equation with a threshold value of <40 ml/min is considered an acceptable alternative [
      • Francoz C.
      • Nadim M.K.
      • Baron A.
      • Prie D.
      • Antoine C.
      • Belghiti J.
      • et al.
      Glomerular filtration rate equations for liver-kidney transplantation in patients with cirrhosis: validation of current recommendations.
      ,
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      ]. Whether cystatin C-based or creatinine-cystatin C-based equations are superior to MDRD-6 in cirrhosis needs to be further explored. In patients with CKD and GFR between 30 and 60 ml/min, SLK transplantation should also be considered when kidney biopsy shows glomerulosclerosis >30% and/or interstitial fibrosis >30% [
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      ,
      • Eason J.D.
      • Gonwa T.A.
      • Davis C.L.
      • Sung R.S.
      • Gerber D.
      • Bloom R.D.
      Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK).
      ]. Kidney biopsy is especially useful in patients with risk factors for CKD/decreased GFR (i.e., age over 60, diabetes, past episodes of AKI). Biomarkers of kidney fibrosis are needed. However, no such biomarkers have been clearly identified yet.
      In patients with AKI, criteria have been proposed to perform SLK transplantation rather than liver transplantation alone based on a high probability of non-renal recovery post transplantation [
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      ]. Whatever patients are on dialysis or not, these criteria rely on the progression of AKI over a period of 4 weeks or more. However, patients with a high model for end-stage liver disease (MELD) score (30-40) may be offered an organ less than 4 weeks after being placed on the waiting list. In these patients, increased baseline creatinine (before the onset of AKI), diabetes [
      • Levitsky J.
      • Baker T.B.
      • Jie C.
      • Ahya S.
      • Levin M.
      • Friedewald J.
      • et al.
      Plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation.
      ], history of hypertension, advanced age, abnormal renal imaging [
      • Levitsky J.
      • Baker T.
      • Ahya S.N.
      • Levin M.L.
      • Friedewald J.
      • Gallon L.
      • et al.
      Outcomes and native renal recovery following simultaneous liver-kidney transplantation.
      ] and proteinuria >2 g/day [
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      ] argue for SLK transplantation (Fig. 7). However, no clear-cut algorithm has been validated yet. It has been shown that several kidney biomarkers including serum osteopontin, serum TIMP-1 and urinary IL-18 may help identify patients unlikely to experience kidney recovery after liver transplantation [
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Thiessen-Philbrook H.
      • Peixoto A.J.
      • Perazella M.A.
      • et al.
      Urinary biomarkers and progression of AKI in patients with cirrhosis.
      ,
      • Levitsky J.
      • Baker T.B.
      • Jie C.
      • Ahya S.
      • Levin M.
      • Friedewald J.
      • et al.
      Plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation.
      ]. Objective markers of maladaptative repair after tubular cell injury also represent an attractive perspective [
      • Ferenbach D.A.
      • Bonventre J.V.
      Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.
      ].
      Figure thumbnail gr7
      Fig. 7Decision of simultaneous liver and kidney transplantation vs. liver transplantation alone in candidates with acute kidney injury. ∗Consider GFR before any episode of AKI, in a stable patient. AKI, acute kidney injury; HRS, hepatorenal syndrome; uNGAL, urinary neutrophilic gelatinase-associated lipocalin; ATN, acute tubular necrosis; IL-18, interleukin 18; KIM-1, kidney injury molecule 1; L-FABP, liver-type fatty acid binding protein; SCr, serum creatinine; GFR, glomerular filtration rate; eGFR, estimated glomerular filtration rate).
      Type-2 HRS is an uncommon condition with a more chronic phenotype. Renal function is difficult to assess due to fluctuations in SCr and GFR. Liver transplantation alone is generally recommended as small series have shown reversal of type-2 HRS in the majority of patients [
      • Tan H.K.
      • Marquez M.
      • Wong F.
      • Renner E.L.
      Pretransplant type 2 hepatorenal syndrome is associated with persistently impaired renal function after liver transplantation.
      ,
      • Rodriguez E.
      • Henrique Pereira G.
      • Sola E.
      • Elia C.
      • Barreto R.
      • Pose E.
      • et al.
      Treatment of type 2 hepatorenal syndrome in patients awaiting transplantation: Effects on kidney function and transplantation outcomes.
      ]. However, even if HRS reverses, more than 50-60% of patients develop stage 3 CKD during the first year after transplantation, suggesting that prolonged kidney ischemia resulted in irreversible kidney changes. In the absence of reliable kidney biomarkers of fibrosis, kidney biopsy, whenever feasible, is the only means for identifying these changes.
      In the absence of kidney biopsy, technically difficult to obtain in cirrhotic patients, kidney changes remain poorly assessed. Serum and/or urine biomarkers of kidney fibrosis may help to identify irreversible changes.

      Conclusion

      Interactions between the liver and the kidney are complex in cirrhosis. Recent biomarkers (cystatin C and NGAL in particular) may help better assess kidney function, clarify the mechanisms involved and improve prognostication. However, a number of simple or more complex kidney biomarkers still need to be explored and validated in cirrhosis. Assessment of fibrosis is a central issue to predict recovery in patients with AKI. In parallel with biomarkers, physical (transient elastography, supersonic shear imaging) and imaging (MRI) techniques should be explored [
      • Sommerer C.
      • Scharf M.
      • Seitz C.
      • Millonig G.
      • Seitz H.K.
      • Zeier M.
      • et al.
      Assessment of renal allograft fibrosis by transient elastography.
      ,
      • Grenier N.
      • Poulain S.
      • Lepreux S.
      • Gennisson J.L.
      • Dallaudiere B.
      • Lebras Y.
      • et al.
      Quantitative elastography of renal transplants using supersonic shear imaging: a pilot study.
      ]. A major difficulty is that histology which the gold standard is difficult to obtain in this population.

      Conflict of interest

      The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      Supplementary data

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