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The ischemic/nephrotoxic acute kidney injury and the use of renal biomarkers in clinical practice

Published:December 22, 2016DOI:https://doi.org/10.1016/j.ejim.2016.12.001

      Highlights

      • The term ARF due to ischemic/nephrotoxic injury should be replaced by AKI.
      • Most studies on AKI are still using serum creatinine as indicator of kidney injury.
      • Serum creatinine is not adequate for an early identification of GFR reduction.
      • Renal tubular biomarkers are better and earlier indicators of ischemic/toxic AKI.
      • The renal tubular biomarkers are listed and described.

      Abstract

      The term Acute Renal Failure (ARF) has been replaced by the term Acute Kidney Injury (AKI). AKI indicates an abrupt (within 24–48 h) decrease in Glomerular Filtraton Rate, due to renal damage, that causes fluid and metabolic waste retention and alteration of electrolyte and acid-base balance. The renal biomarkers of AKI are substances or processes that are indicators of normal or impaired function of the kidney. The most used renal biomarker is still serum creatinine that is inadequate for several reasons, one of which is its inability to differentiate between hemodynamic changes of renal function (“prerenal azotemia”) from intrinsic renal failure or obstructive nephropathy. Cystatin C is no better in this respect. After the description of the pathophysiology of “prerenal azotemia” and of Acute Kidney Injury (AKI) due to ischemia or nephrotoxicity, the renal biomarkers are listed and described: urinary NAG, urinary and serum KIM-1, serum and urinary NGAL, urinary IL-18, urinary L-FABP, serum Midkine, urinary IGFBP7 and TIMP2, urinary α-GST and π-GST, urinary ɣGT and AP, urinary β2M, urinary RBP, serum and urinary miRNA. All have been shown to appear much earlier than the rise of serum Creatinine. Some of them have been demonstrated to predict the clinical outcomes of AKI, such as the need for initiation of dialysis and mortality.

      Keywords

      The term Acute Renal Failure (ARF) secondary to ischemic/nephrotoxic injury should no longer be used, but replaced by the term Acute Kidney Injury (AKI) indicating an abrupt (within 24–48 h) decrease in Glomerular Filtraton Rate (GFR) that causes fluid and metabolic waste retention and alteration of electrolyte and acid-base balance [
      • Mehta R.L.
      • Kellum J.A.
      • Shah S.V.
      • Molitoris B.A.
      • Ronco C.
      • Warnock D.G.
      • et al.
      Acute Kidney Injury Network, Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.
      ,
      • Dirkes S.
      Acute kidney injury: not just acute renal failure anymore?.
      ,
      • Schrier R.W.
      ARF, AKI, or ATN?.
      ]. The word “injury” includes the entire range of renal impairment from small changes of serum creatinine (SCr) to the complete loss of renal function [
      • Schrier R.W.
      ARF, AKI, or ATN?.
      ]. The term ARF is limited to patients with a decrease in GFR so severe to require renal replacement therapy [
      • Lattanzio M.R.
      • Kopyt N.P.
      Acute kidney injury: new concepts in definition, diagnosis, pathophysiology, and treatment.
      ].

      1. Severities of AKI

      Two groups of nephrologists have defined the different severities of AKI. According to the RIFLE (acronym of “Risk of injury, Injury, Failure, Loss of function, and End-stage renal failure”) classification [
      • Bellomo R.
      • Ronco C.
      • Kellum J.A.
      • Mehta R.L.
      • Palevsky P.
      Acute dialysis quality initiative w: 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.
      ] the increase in SCr over 7 days correlates with the severity of AKI. The lowest degree of severity of AKI was defined as risk: an increase of SCr 1.5 times the normal level with urine output <0.5 mL/Kg for 6 h; injury: an increase in SCr 2 times the normal level with urine output <0.5 mL/Kg for 12 h; failure: an increase in SCr 3 times the normal level with urine output <0.5 mL/Kg for 12 h or anuria for 12 h; loss: the complete loss of renal function for >4 weeks; end-stage kidney disease: the need for dialysis for >3 months [
      • 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.
      ]. The other group suggested the AKIN (acronym of Acute Kidney Injury Network) classification that eliminated the last 2 degrees of RIFLE, calling the first 3 degrees (Risk, Injury and Failure) stages I, II and III respectively and defining AKI as an increase in SCr over 48 h [
      • Mehta R.L.
      • Kellum J.A.
      • Shah S.V.
      • Molitoris B.A.
      • Ronco C.
      • Warnock D.G.
      • et al.
      Acute Kidney Injury Network, Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.
      ,
      • Schrier R.W.
      ARF, AKI, or ATN?.
      ].
      AKI has to be differentiated from “Prerenal azotemia”.

      1.1 Pathophysiology of “Prerenal azotemia” (“functional” renal failure)

      The normal kidney has a peculiar property, called “renal autoregulation”: it can face wide changes in renal perfusion pressure without modifying renal blood flow (RBF) and GFR. In any condition of hypovolemia, the renal perfusion pressure falls. Should it fall below the lower limit of the autoregulation (this occurs when blood pressure < 80 mmHg), RBF and glomerular capillary pressure will decrease causing a fall in GFR. Furthermore, hypovolemia may stimulate the adrenergic nervous system with a subsequent release of vasoconstricting hormones which cause renal vasoconstriction aggravating the renal hypoperfusion. Under such circumstances, the kidney is not damaged despite a rise in SCr [
      • Andreucci V.E.
      • Fuiano G.
      • Russo D.
      • Andreucci M.
      Vasomotor nephropathy in the elderly.
      ].
      The same phenomenon is realized in cases of contraction of the “effective” circulating blood volume (relative fullness of the arterial tree, as determined by cardiac output, peripheral vascular resistances and total blood volume), as it occurs in congestive heart failure [
      • Pascual J.
      • Liano F.
      • Ortuno J.
      The elderly patient with acute renal failure.
      ], in cirrhosis with ascites and in nephrotic syndrome [
      • Andreucci V.E.
      • Fuiano G.
      • Russo D.
      • Andreucci M.
      Vasomotor nephropathy in the elderly.
      ,
      • Pascual J.
      • Liano F.
      • Ortuno J.
      The elderly patient with acute renal failure.
      ,
      • Andreucci V.E.
      • Russo D.
      • Cianciaruso B.
      • Andreucci M.
      Some sodium, potassium and water changes in the elderly and their treatment.
      ,
      • Brun C.
      • Knudsen E.O.
      • Raaschou F.
      The influence of posture on the kidney function; glomerular dynamics in the passive erect posture.
      ].
      “Prerenal azotemia” is the fall in GFR due to renal hypoperfusion caused by an ischemic insult, associated with an increase in SCr and retention of nitrogenous metabolic waste, as a consequence of a major hemorrhage or a severe ExtraCellular Volume (ECV) depletion, due to extrarenal losses of fluid (by vomiting and/or diarrhea, by gastric, enteric or biliary drainage, by enterostomy, by abuse of laxatives or loss through sweating) or to losses of fluid with urine (by glucose or salt-losing nephritis or by abuse of diuretics) or to losses in the “third-space” (by pancreatitis or intestinal obstruction). In the “functional” renal impairment the renal tubules are intact, not damaged, perfectly functioning; thus, the fractional excretion of sodium (FENa = [UNa × PCr/PNa × UCr] × 100) is <1.0%, indicating that the tubules are reabsorbing avidly the tubular fluid with the aim to normalize the contracted ECV: the result is oliguria with concentrated urine and low urinary sodium (usually <20 mEq/L) and normal urinary sediment. This condition is usually reversed by adequate treatement. However, it is the most frequent cause of renal impairment in aged patients [
      • Andreucci V.E.
      • Fuiano G.
      • Russo D.
      • Andreucci M.
      Vasomotor nephropathy in the elderly.
      ,
      • Huh W.S.
      • Kim Y.S.
      • Ahn C.
      • Han J.S.
      • Kim S.
      • Lee J.S.
      Acute renal failure in the elderly; analysis of 101 patients referred to neprhologists..
      ,
      • Macias-Nunez J.F.
      • Lopez-Novoa J.M.
      • Martinez-Maldonado M.
      Acute renal failure in the aged.
      ,
      • Andreucci M.
      • Faga T.
      • Pisani A.
      • Sabbatini M.
      • Michael A.
      Pathogenesis of acute renal failure induced by iodinated radiographic contrast media.
      ].
      Clinical signs of salt depletion and ECV contraction will be postural hypotension associated with tachycardia and decrease in central venous pressure.

      1.2 Pathophysiology of Acute Kidney Injury (AKI) due to ischemia or nephrotoxicity

      AKI may represent an evolution of untreated “Prerenal azotemia” if renal damage occurs. However, even a severe salt depletion caused in normal subjects by diuretics plus low salt intake is not followed by AKI. Thus, some factor(s) is(are) associated with the salt depletion in causing “intrinsic” renal failure. Anyhow, in ischemic/nephrotoxic AKI the lesions occur primarily in the renal tubular epithelium [
      • Andreucci M.
      Contrast media and nephrotoxicity: a molecular conundrum.
      ,
      • Andreucci M.
      • Fuiano G.
      • Presta P.
      • Esposito P.
      • Faga T.
      • Bisesti V.
      • et al.
      Radiocontrast media cause dephosphorylation of Akt and downstream signaling targets in human renal proximal tubular cells.
      ,
      • Andreucci M.
      • Faga T.
      • Lucisano G.
      • Uccello F.
      • Pisani A.
      • Memoli B.
      • et al.
      Mycophenolic acid inhibits the phosphorylation of NF-kappaB and JNKs and causes a decrease in IL-8 release in H2O2-treated human renal proximal tubular cells.
      ,
      • Sabbatini M.
      • Santillo M.
      • Pisani A.
      • Paterno R.
      • Uccello F.
      • Seru R.
      • et al.
      Inhibition of Ras/ERK1/2 signaling protects against postischemic renal injury.
      ,
      • Pisani A.
      • Riccio E.
      • Andreucci M.
      • Faga T.
      • Ashour M.
      • Di Nuzzi A.
      • et al.
      Role of reactive oxygen species in pathogenesis of radiocontrast-induced nephropathy.
      ,
      • Pisani A.
      • Sabbatini M.
      • Riccio E.
      • Rossano R.
      • Andreucci M.
      • Capasso C.
      • et al.
      Effect of a recombinant manganese superoxide dismutase on prevention of contrast-induced acute kidney injury.
      ,
      • Andreucci M.
      • Faga T.
      • Russo D.
      • Bertucci B.
      • Tamburrini O.
      • Pisani A.
      • et al.
      Differential activation of signaling pathways by low-osmolar and iso-osmolar radiocontrast agents in human renal tubular cells.
      ,
      • Andreucci M.
      • Michael A.
      • Kramers C.
      • Park K.M.
      • Chen A.
      • Matthaeus T.
      • et al.
      Renal ischemia/reperfusion and ATP depletion/repletion in LLC-PK(1) cells result in phosphorylation of FKHR and FKHRL1.
      ,
      • Michael A.
      • Faga T.
      • Pisani A.
      • Riccio E.
      • Bramanti P.
      • Sabbatini M.
      • et al.
      Molecular mechanisms of renal cellular nephrotoxicity due to radiocontrast media.
      ,
      • Andreucci M.
      • Fuiano G.
      • Presta P.
      • Lucisano G.
      • Leone F.
      • Fuiano L.
      • et al.
      Downregulation of cell survival signalling pathways and increased cell damage in hydrogen peroxide-treated human renal proximal tubular cells by alpha-erythropoietin.
      ,
      • Andreucci M.
      • Lucisano G.
      • Faga T.
      • Bertucci B.
      • Tamburrini O.
      • Pisani A.
      • et al.
      Differential activation of signaling pathways involved in cell death, survival and inflammation by radiocontrast media in human renal proximal tubular cells.
      ,
      • Andreucci M.
      Radiographic contrast nephropathy.
      ]. Upon renal biopsy, the tubular lesions are, in fact, the first variable phenomenon in extension and severity, initially seen only under electron microscopy (degeneration of nuclei, swelling of mitochondria, distortion of the cristae), then visible also under light microscopy. But, before these microscopic changes become visible in the tubules, a loss of some enzymes and/or molecules takes place in the tubules, representing an early phenomenon; thus, the substances lost in the urine may be used as renal biomarkers.
      Clinical signs of severe ischemic/nephrotoxic AKI include oliguria (secondary to the fall in GFR) until a complete anuria, hyponatremia (that may be due to water overload because of anuria), metabolic acidosis, hyperkalemia, hypocalcemia, hyperphosphatemia, anemia, frequently associated with nausea, vomiting leading to chronic dialysis requirement (ischemic/nephrotoxic ARF), sometimes gastrointestinal bleeding, enterocolitis, infection, that is usually the cause of death [
      • Andreucci V.E.
      • Fuiano G.
      • Stanziale P.
      • Andreucci M.
      Role of renal biopsy in the diagnosis and prognosis of acute renal failure.
      ,
      • Andreucci M.
      • Faga T.
      • Pisani A.
      • Sabbatini M.
      • Michael A.
      Acute kidney injury by radiographic contrast media: pathogenesis and prevention.
      ,
      • Andreucci M.
      • Federico S.
      • Andreucci V.E.
      Edema and acute renal failure.
      ].
      What is peculiar about ischemic/nephrotoxic AKI is the high urinary sodium concentration (>40 mEq/L) due to the reduced capacity of the renal tubular epithelium to reabsorb sodium, despite the frequent presence of salt depletion with hypovolemia. Thus, FENa is >2% in the absence of glucosuria or the use of diuretics.

      1.3 The most used renal biomarkers: SCr and serum Cystatin C (Cys-C)

      We may define the renal biomarkers of AKI substances or processes that are indicators of normal or impaired function of the kidney.
      Most studies on AKI are still using SCr as indicator of kidney injury despite its poor sensitivity and specificity and poor accuracy of renal damage [
      • Lattanzio M.R.
      • Kopyt N.P.
      Acute kidney injury: new concepts in definition, diagnosis, pathophysiology, and treatment.
      ,
      • Andreucci M.
      • Faga T.
      • Pisani A.
      • Sabbatini M.
      • Russo D.
      • Mattivi F.
      • et al.
      Reversal of radiocontrast medium toxicity in human renal proximal tubular cells by white grape juice extract.
      ,
      • Andreucci M.
      • Faga T.
      • Pisani A.
      • Sabbatini M.
      • Russo D.
      • Michael A.
      Prevention of contrast-induced nephropathy through a knowledge of its pathogenesis and risk factors.
      ]. SCr is not adequate for an early identification of GFR reduction: it does not allow differentiation between hemodynamically mediated changes in renal function (“prerenal azotemia”) and intrinsic renal failure or obstructive nephropathy; SCr may not rise until a marked decrease of GFR has occurred, thus, it takes several hours or days for SCr to reach a new steady state; SCr reflects the real value of GFR under steady state conditions, but not when renal function is decreasing; important fluctuations occurs, during the day in creatinine production from the creatine of muscles, even in normal subjects; SCr varies with age, gender, race and weight. The last problem is overcome by using the estimated glomerular filtration rate (eGFR), i.e. the Creatinine Clearance (CrCl) calculated either by the MDRD (Modification of Diet in Renal Disease) formula or by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation or by the Cockcroft-Gault formula. Undoubtedly, in our opinion both, the MDRD and the CKD-EPI formulas, are more accurate than the Cockcroft-Gault formula [
      • 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.
      ,
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • Zhang Y.L.
      • Castro III, A.F.
      • Feldman H.I.
      • et al.
      A new equation to estimate glomerular filtration rate.
      ,
      • Cockcroft D.W.
      • Gault M.H.
      Prediction of creatinine clearance from serum creatinine.
      ]. However, we prefer using the latter in clinical practice, at the bed side, when we do not need an extremely precise value of eGFR, because it is easy to memorize and simple to calculate without the need of a calculator: (140 − number years of age) × Kg body weight/72/mg/dL of serum creatinine; in females the result has to be multiplied by 0.85. Obviously, in the case of a medical research setting, either MDRD or CKD-EPI would be preferred. Creatinine is not only filtered by the glomerulus, but also secreted by the renal tubule and the secreted component may vary when the kidney is damaged and when other drugs (cimetidine, trimethoprim, and salicylates) modify its tubular secretion [
      • Andreucci M.
      • Solomon R.
      • Tasanarong A.
      Side effects of radiographic contrast media: pathogenesis, risk factors, and prevention.
      ,
      • Andreucci M.
      • Faga T.
      • Riccio E.
      • Sabbatini M.
      • Pisani A.
      • Michael A.
      The potential use of biomarkers in predicting contrast-induced acute kidney injury.
      ]. In this respect, Cystatin C is better than creatinine.
      Cystatin C is another biomarker of GFR produced at a constant rate by all nucleated cells, is not bound to plasma proteins and, therefore, is freely filtered by the glomerulus and reabsorbed by the proximal tubule where it is degraded by megalin [
      • Kaseda R.
      • Iino N.
      • Hosojima M.
      • Takeda T.
      • Hosaka K.
      • Kobayashi A.
      • et al.
      Megalin-mediated endocytosis of cystatin C in proximal tubule cells.
      ]. It is not secreted by renal tubules and does not vary with gender, race, weight, changes of muscle mass, and nutrition. The half-life of Cystatin C (1.5 h) is three times shorter than that of Creatinine; thus, its serum concentration will rise more rapidly than SCr when GFR decreases [
      • Sjostrom P.
      • Tidman M.
      • Jones I.
      The shorter T1/2 of cystatin C explains the earlier change of its serum level compared to serum creatinine.
      ,
      • Briguori C.
      • Quintavalle C.
      • Donnarumma E.
      • Condorelli G.
      Novel biomarkers for contrast-induced acute kidney injury.
      ,
      • Nejat M.
      • Hill J.V.
      • Pickering J.W.
      • Edelstein C.L.
      • Devarajan P.
      • Endre Z.H.
      Albuminuria increases cystatin C excretion: implications for urinary biomarkers.
      ,
      • Lima R.M.
      • Navarro L.H.
      • Nakamura G.
      • Solanki D.R.
      • Castiglia Y.M.
      • Vianna P.T.
      • et al.
      Serum cystatin C is a sensitive early marker for changes in the glomerular filtration rate in patients undergoing laparoscopic surgery.
      ,
      • Conti M.
      • Moutereau S.
      • Zater M.
      • Lallali K.
      • Durrbach A.
      • Manivet P.
      • et al.
      Urinary cystatin C as a specific marker of tubular dysfunction.
      ]. But marked albuminuria decreases tubular reabsorption of Cystatin C because albumin is also reabsorbed by megalin-facilitated endocytosis thereby competing with its tubular reabsorption. This makes Cystatin C an unreliable marker of GFR when proteinuria is present [
      • Andreucci M.
      • Faga T.
      • Riccio E.
      • Sabbatini M.
      • Pisani A.
      • Michael A.
      The potential use of biomarkers in predicting contrast-induced acute kidney injury.
      ,
      • Kaseda R.
      • Iino N.
      • Hosojima M.
      • Takeda T.
      • Hosaka K.
      • Kobayashi A.
      • et al.
      Megalin-mediated endocytosis of cystatin C in proximal tubule cells.
      ,
      • Nejat M.
      • Hill J.V.
      • Pickering J.W.
      • Edelstein C.L.
      • Devarajan P.
      • Endre Z.H.
      Albuminuria increases cystatin C excretion: implications for urinary biomarkers.
      ,
      • Amsellem S.
      • Gburek J.
      • Hamard G.
      • Nielsen R.
      • Willnow T.E.
      • Devuyst O.
      • et al.
      Cubilin is essential for albumin reabsorption in the renal proximal tubule.
      ,
      • Charlton J.R.
      • Portilla D.
      • Okusa M.D.
      A basic science view of acute kidney injury biomarkers.
      ].

      1.4 The renal biomarkers of ischemic/toxic AKI

      We need new biomarkers for an earlier diagnosis of ischemic/nephrotoxic AKI.
      A good biomarker (a) should theoretically be easy and simple to be measured; (b) should have earlier detectability than the rise of SCr, in order to allow the diagnosis of AKI as early as possible; (c) should allow the distinction of AKI from “prerenal azotemia” and from chronic kidney disease; (d) should identify type and location of the cause of AKI; (e) should indicate the severity of incoming AKI and some estimate as to the timing of its onset; (f) should allow the prediction of the patient's outcome (recovery, dialysis and mortality) [
      • Andreucci M.
      • Faga T.
      • Riccio E.
      • Sabbatini M.
      • Pisani A.
      • Michael A.
      The potential use of biomarkers in predicting contrast-induced acute kidney injury.
      ,
      • Charlton J.R.
      • Portilla D.
      • Okusa M.D.
      A basic science view of acute kidney injury biomarkers.
      ,
      • Endre Z.H.
      • Walker R.J.
      • Pickering J.W.
      • Shaw G.M.
      • Frampton C.M.
      • Henderson S.J.
      • et al.
      Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).
      ,
      • Ostermann M.
      • Forni L.G.
      Measuring biomarkers of acute kidney injury during renal replacement therapy: wisdom or folly?.
      ]; (g) should allow monitoring of pharmacological responses to therapy. [
      • Strimbu K.
      • Tavel J.A.
      What are biomarkers?.
      ,
      • WHO
      Biomarkers in risk assessment: validity and validation.
      ]

      2. NAG

      N-acetyl-β-D-glucosamininidase (NAG) is an enzyme produced by the lysosomes of the renal proximal tubular cells. It can be found in the urine of normal subjects in very small amounts. Because of its high molecular weight, it cannot be filtered by glomeruli; thus, its increase in the urine derives from tubular damage [
      • de Geus H.R.
      • Betjes M.G.
      • Bakker J.
      Biomarkers for the prediction of acute kidney injury: a narrative review on current status and future challenges.
      ,
      • Waring W.S.
      • Moonie A.
      Earlier recognition of nephrotoxicity using novel biomarkers of acute kidney injury.
      ]. It occurs in AKI between 12 h and 4 days before the rise in SCr. Westhuyzen et al. [
      • Westhuyzen J.
      • Endre Z.H.
      • Reece G.
      • Reith D.M.
      • Saltissi D.
      • Morgan T.J.
      Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit.
      ] have carried out a study on 26 consecutive patients admitted to the Intensive-Care Unit (ICU); 4 patients had ARF (the authors do not use the term AKI as yet) (ARF group). At the time of admission the urine of the control group (n. 22) had a low concentration of NAG (15.1 U/L) that remained about the same after 12 and 24 h. The urine of the ARF group (n. 4) had very high concentrations of NAG (20.7 U/L) on admission to the ICU that increased significantly after 12 h (43.6 U/L) and 24 h (69.1 U/L).
      According to Ren et al. [
      • Ren L.
      • Ji J.
      • Fang Y.
      • Jiang S.H.
      • Lin Y.M.
      • Bo J.
      • et al.
      Assessment of urinary N-acetyl-beta-glucosaminidase as an early marker of contrast-induced nephropathy.
      ] the urinary NAG is a useful, non-invasive, simple, inexpensive and sensitive and early marker of contrast induced-AKI in patients undergoing coronary angiography and/or therapeutic percutaneous coronary intervention. Its high urinary levels are correlated with a poor outcome of AKI [
      • Chew S.L.
      • Lins R.L.
      • Daelemans R.
      • Nuyts G.D.
      • De Broe M.E.
      Urinary enzymes in acute renal failure.
      ].

      3. KIM-1

      KIM-1 (Kidney Injury Molecule-1) is a type 1 cell membrane glycoprotein [
      • Ichimura T.
      • Asseldonk E.J.
      • Humphreys B.D.
      • Gunaratnam L.
      • Duffield J.S.
      • Bonventre J.V.
      Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells.
      ]. It is not present in the urine of normal subjects [
      • Hayashi M.
      • Izawa H.
      Recent prophylactic strategies and novel biomarkers for contrast-induced acute kidney injury.
      ,
      • Bonventre J.V.
      Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more.
      ], found following an ischemic or toxic injury of the renal proximal tubule [
      • 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.
      ]. KIM-1 seems an ideal biomarker of kidney injury, because of the absence of KIM-1 expression in the normal kidney and its marked upregulation and its insertion into the apical membrane of the renal proximal tubular cells after injury, its persistence in the renal epithelial tubular cell until the cell has recovered and the rapid cleavage of the ectodomain [
      • Bonventre J.V.
      Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more.
      ]. It has been suggested that KIM-1 plays an important role in regenerating damaged epithelial cells and in removal of dead cells fom the tubular lumen by phagocytosis [
      • Ichimura T.
      • Asseldonk E.J.
      • Humphreys B.D.
      • Gunaratnam L.
      • Duffield J.S.
      • Bonventre J.V.
      Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells.
      ,
      • Bonventre J.V.
      Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more.
      ]. KIM-1 is found in the urine as early as 24 h after coronary angiography (using the iso-osmolar contrast medium iodixanol or the low-osmolar contrast medium iopromide), while eGFR (based on SCr) did not change significantly during the first 48 h after contrast administration [
      • Vijayasimha M.
      • Padma V.V.
      • Mujumdar S.K.D.
      • Satyanarayana P.V.V.
      Kidney injury molecule-1: a urinary biomarker for contrast induced acute kidney injury.
      ]. In adult patients undergoing cardiac surgery, urinary KIM-1 could predict the development of AKI much more than NGAL [
      • Koyner J.L.
      • Vaidya V.S.
      • Bennett M.R.
      • Ma Q.
      • Worcester E.
      • Akhter S.A.
      • et al.
      Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury.
      ,
      • Han W.K.
      • Wagener G.
      • Zhu Y.
      • Wang S.
      • Lee H.T.
      Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery.
      ]. In a cohort of 201 patients with AKI of multiple causes, urinary KIM-1 and NAG levels were able to predict patients' adverse clinical outcomes, such as dialysis and mortality [
      • Liangos O.
      • Perianayagam M.C.
      • Vaidya V.S.
      • Han W.K.
      • Wald R.
      • Tighiouart H.
      • et al.
      Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure.
      ]. Apparently, even plasma KIM-1 was higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI; in patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (p < 0.01) [
      • Sabbisetti V.S.
      • Waikar S.S.
      • Antoine D.J.
      • Smiles A.
      • Wang C.
      • Ravisankar A.
      • et al.
      Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes.
      ].

      4. NGAL

      NGAL (Neutrophil Gelatinase-Associated Lipocalin) is a reliable diagnostic and prognostic biomarker for AKI, as its serum and urinary levels rise much earlier (2 h after the injury [
      • 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.
      ,
      • Parikh C.R.
      • Mishra J.
      • Thiessen-Philbrook H.
      • Dursun B.
      • Ma Q.
      • Kelly C.
      • et al.
      Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.
      ,
      • Portilla D.
      • Dent C.
      • Sugaya T.
      • Nagothu K.K.
      • Kundi I.
      • Moore P.
      • et al.
      Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery.
      ,
      • Dent C.L.
      • Ma Q.
      • Dastrala S.
      • Bennett M.
      • Mitsnefes M.M.
      • Barasch J.
      • et al.
      Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study.
      ,
      • Bennett M.
      • Dent C.L.
      • Ma Q.
      • Dastrala S.
      • Grenier F.
      • Workman R.
      • et al.
      Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study.
      ,
      • Devarajan P.
      Biomarkers for the early detection of acute kidney injury.
      ,
      • Fadel F.I.
      • Abdel Rahman A.M.
      • Mohamed M.F.
      • Habib S.A.
      • Ibrahim M.H.
      • Sleem Z.S.
      • et al.
      Plasma neutrophil gelatinase-associated lipocalin as an early biomarker for prediction of acute kidney injury after cardio-pulmonary bypass in pediatric cardiac surgery.
      ,
      • Krawczeski C.D.
      • Woo J.G.
      • Wang Y.
      • Bennett M.R.
      • Ma Q.
      • Devarajan P.
      Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass.
      ]) and exhibit better sensitivity than SCr [
      • Hayashi M.
      • Izawa H.
      Recent prophylactic strategies and novel biomarkers for contrast-induced acute kidney injury.
      ,
      • 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.
      ,
      • Paragas N.
      • Qiu A.
      • Hollmen M.
      • Nickolas T.L.
      • Devarajan P.
      • Barasch J.
      NGAL-siderocalin in kidney disease.
      ,
      • Haase M.
      • Bellomo R.
      • Devarajan P.
      • Schlattmann P.
      • Haase-Fielitz A.
      Group NM-aI: accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis.
      ,
      • Ronco C.
      Biomarkers for acute kidney injury: is NGAL ready for clinical use?.
      ,
      • 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.
      ,
      • 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.
      ,
      • Haase M.
      • Bellomo R.
      • Matalanis G.
      • Calzavacca P.
      • Dragun D.
      • Haase-Fielitz A.
      A comparison of the RIFLE and acute kidney injury network classifications for cardiac surgery-associated acute kidney injury: a prospective cohort study.
      ,
      • Haase-Fielitz A.
      • Bellomo R.
      • Devarajan P.
      • Bennett M.
      • Story D.
      • Matalanis G.
      • et al.
      The predictive performance of plasma neutrophil gelatinase-associated lipocalin (NGAL) increases with grade of acute kidney injury.
      ] in patients with ischemic AKI, as well as in AKI due to nephrotoxic drugs, such as tacrolimus, cisplatin, cyclosporine A and radiographic contrast media [
      • Fadel F.I.
      • Abdel Rahman A.M.
      • Mohamed M.F.
      • Habib S.A.
      • Ibrahim M.H.
      • Sleem Z.S.
      • et al.
      Plasma neutrophil gelatinase-associated lipocalin as an early biomarker for prediction of acute kidney injury after cardio-pulmonary bypass in pediatric cardiac surgery.
      ,
      • Krawczeski C.D.
      • Woo J.G.
      • Wang Y.
      • Bennett M.R.
      • Ma Q.
      • Devarajan P.
      Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass.
      ,
      • 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.
      ,
      • Tsuchimoto A.
      • Shinke H.
      • Uesugi M.
      • Kikuchi M.
      • Hashimoto E.
      • Sato T.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin: a useful biomarker for tacrolimus-induced acute kidney injury in liver transplant patients.
      ,
      • Gaspari F.
      • Cravedi P.
      • Mandala M.
      • Perico N.
      • de Leon F.R.
      • Stucchi N.
      • et al.
      Predicting cisplatin-induced acute kidney injury by urinary neutrophil gelatinase-associated lipocalin excretion: a pilot prospective case-control study.
      ,
      • Wasilewska A.
      • Zoch-Zwierz W.
      • Taranta-Janusz K.
      • Michaluk-Skutnik J.
      Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of cyclosporine nephrotoxicity?.
      ,
      • Hirsch R.
      • Dent C.
      • Pfriem H.
      • Allen J.
      • Beekman III, R.H.
      • Ma Q.
      • et al.
      NGAL is an early predictive biomarker of contrast-induced nephropathy in children.
      ,
      • Ling W.
      • Zhaohui N.
      • Ben H.
      • Leyi G.
      • Jianping L.
      • Huili D.
      • et al.
      Urinary IL-18 and NGAL as early predictive biomarkers in contrast-induced nephropathy after coronary angiography.
      ,
      • Shaker O.G.
      • El-Shehaby A.
      • El-Khatib M.
      Early diagnostic markers for contrast nephropathy in patients undergoing coronary angiography.
      ,
      • Bachorzewska-Gajewska H.
      • Poniatowski B.
      • Dobrzycki S.
      NGAL (neutrophil gelatinase-associated lipocalin) and L-FABP after percutaneous coronary interventions due to unstable angina in patients with normal serum creatinine.
      ,
      • Bachorzewska-Gajewska H.
      • Malyszko J.
      • Sitniewska E.
      • Malyszko J.S.
      • Dobrzycki S.
      Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.
      ].
      NGAL is a small protein associated with human neutrophil gelatinase in specific granules; its homodimeric form is produced by neutrophils, while the monomeric and the heterodimeric forms are produced by proximal tubular epithelial cells [
      • Cai L.
      • Rubin J.
      • Han W.
      • Venge P.
      • Xu S.
      The origin of multiple molecular forms in urine of HNL/NGAL.
      ]. It is stimulator of epithelial growth and epithelial protector againt ischemia [
      • 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.
      ,
      • Yang H.N.
      • Boo C.S.
      • Kim M.G.
      • Jo S.K.
      • Cho W.Y.
      • Kim H.K.
      Urine neutrophil gelatinase-associated lipocalin: an independent predictor of adverse outcomes in acute kidney injury.
      ].
      Serum NGAL in a normal subject is around 20 ng/mL, deriving mainly from neutrophils. NGAL is freely filtered by the glomerulus and reabsorbed by the renal proximal tubule, where it is degraded by megalin; it is in part excreted in the urine. The urine concentration of NGAL in a normal subject is around 20 ng/mL. Albuminuria may increase the excretion of NGAL [
      • Andreucci M.
      • Faga T.
      • Riccio E.
      • Sabbatini M.
      • Pisani A.
      • Michael A.
      The potential use of biomarkers in predicting contrast-induced acute kidney injury.
      ].
      After an ischemic/toxic injury the renal tubular epithelial cells will be damaged; under these conditions NGAL is upregulated and released into the plasma and the urine; this will increase its plasma and urinary concentration, much earlier than the occurrence of the rise in serum creatinine [
      • Charlton J.R.
      • Portilla D.
      • Okusa M.D.
      A basic science view of acute kidney injury biomarkers.
      ]. Apparently, the serum NGAL in AKI would mainly arise from the injured thick ascending renal tubules and the renal collecting ducts by back-leak [
      • Paragas N.
      • Qiu A.
      • Zhang Q.
      • Samstein B.
      • Deng S.X.
      • Schmidt-Ott K.M.
      • et al.
      The Ngal reporter mouse detects the response of the kidney to injury in real time.
      ,
      • Haase M.
      • Devarajan P.
      • Haase-Fielitz A.
      • Bellomo R.
      • Cruz D.N.
      • Wagener G.
      • et al.
      The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies.
      ]. Some authors [
      • Schmidt-Ott K.M.
      • Mori K.
      • Li J.Y.
      • Kalandadze A.
      • Cohen D.J.
      • Devarajan P.
      • et al.
      Dual action of neutrophil gelatinase-associated lipocalin.
      ] believe that in renal injury, urinary NGAL derives from the distal parts of the nephron within few hours after the insult, while renal proximal tubule NGAL derives from the circulating NGAL. The increase of urinary NGAL seems to be more specific than the rise in its serum concentration for the early detection of AKI [
      • Hayashi M.
      • Izawa H.
      Recent prophylactic strategies and novel biomarkers for contrast-induced acute kidney injury.
      ,
      • Haase M.
      • Bellomo R.
      • Devarajan P.
      • Schlattmann P.
      • Haase-Fielitz A.
      Group NM-aI: accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis.
      ].
      Urinary NGAL has been shown to be useful in predicting AKI also in patients with septic shock, as the levels are not elevated in septic patients without AKI [
      • 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.
      ,
      • Martensson J.
      • Bell M.
      • Oldner A.
      • Xu S.
      • Venge P.
      • Martling C.R.
      Neutrophil gelatinase-associated lipocalin in adult septic patients with and without acute kidney injury.
      ,
      • Simsek A.
      • Tugcu V.
      • Tasci A.I.
      New biomarkers for the quick detection of acute kidney injury.
      ,
      • Constantin J.M.
      • Futier E.
      • Perbet S.
      • Roszyk L.
      • Lautrette A.
      • Gillart T.
      • et al.
      Plasma neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: a prospective study.
      ,
      • 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.
      ].
      NGAL predicts impairment of renal function following transplantation. Thus Niemann et al. [
      • Niemann C.U.
      • Walia A.
      • Waldman J.
      • Davio M.
      • Roberts J.P.
      • Hirose R.
      • et al.
      Acute kidney injury during liver transplantation as determined by neutrophil gelatinase-associated lipocalin.
      ] have studied the behavior of NGAL in liver transplant patients; serum NGAL increased 2 h after reperfusion and was predictive of AKI in all patients. Li et al. [
      • Li Y.
      • Zhu M.
      • Xia Q.
      • Wang S.
      • Qian J.
      • Lu R.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin and L-type fatty acid binding protein as diagnostic markers of early acute kidney injury after liver transplantation.
      ] have found an increase of urinary NGAL in liver transplant recipients at 2 h after reperfusion only in patients who did have AKI; they concluded that NGAL is a sensitive and specific marker of AKI in liver transplant recipients.
      According to Devarajan [
      • Devarajan P.
      Biomarkers for the early detection of acute kidney injury.
      ], NGAL is an excellent biomarker in urine and plasma also for the prognosis of AKI. The serum and urine levels of NGAL, in fact, have been demonstrated to predict the clinical outcomes of AKI, such as the need for initiation of dialysis and mortality [
      • Haase M.
      • Bellomo R.
      • Devarajan P.
      • Schlattmann P.
      • Haase-Fielitz A.
      Group NM-aI: accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis.
      ,
      • Endre Z.H.
      • Pickering J.W.
      • Walker R.J.
      • Devarajan P.
      • Edelstein C.L.
      • Bonventre J.V.
      • et al.
      Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function.
      ].
      Urinary NGAL and urinary IL-18 represent early, predictive biomarkers of delayed graft function after kidney transplantation [
      • Parikh C.R.
      • Jani A.
      • Mishra J.
      • Ma Q.
      • Kelly C.
      • Barasch J.
      • et al.
      Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation.
      ]. After kidney transplantation from deceased kidney donors, in the recipients who had delayed graft function (defined as dialysis requirement within the first week after transplantation) because of tubule cell injury, while peak SCr was observed 2 to 4 days after transplant, urinary NGAL and urinary IL-18 were high on the day of the transplantation. Thus, urinary NGAL and IL-18 are early, non-invasive, accurate predictors of dialysis [
      • Hall I.E.
      • Yarlagadda S.G.
      • Coca S.G.
      • Wang Z.
      • Doshi M.
      • Devarajan P.
      • et al.
      IL-18 and urinary NGAL predict dialysis and graft recovery after kidney transplantation.
      ].
      In conclusion urinary NGAL represents also an early sign for predicting the patients' clinical outcomes (dialysis and mortality) [
      • Devarajan P.
      Biomarkers for the early detection of acute kidney injury.
      ,
      • Yang H.N.
      • Boo C.S.
      • Kim M.G.
      • Jo S.K.
      • Cho W.Y.
      • Kim H.K.
      Urine neutrophil gelatinase-associated lipocalin: an independent predictor of adverse outcomes in acute kidney injury.
      ,
      • Constantin J.M.
      • Futier E.
      • Perbet S.
      • Roszyk L.
      • Lautrette A.
      • Gillart T.
      • et al.
      Plasma neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: a prospective study.
      ,
      • Niemann C.U.
      • Walia A.
      • Waldman J.
      • Davio M.
      • Roberts J.P.
      • Hirose R.
      • et al.
      Acute kidney injury during liver transplantation as determined by neutrophil gelatinase-associated lipocalin.
      ,
      • de Geus H.R.
      • Bakker J.
      • Lesaffre E.M.
      • le Noble J.L.
      Neutrophil gelatinase-associated lipocalin at ICU admission predicts for acute kidney injury in adult patients.
      ,
      • Siew E.D.
      • Ware L.B.
      • Gebretsadik T.
      • Shintani A.
      • Moons K.G.
      • Wickersham N.
      • et al.
      Urine neutrophil gelatinase-associated lipocalin moderately predicts acute kidney injury in critically ill adults.
      ,
      • Cruz D.N.
      • de Cal M.
      • Garzotto F.
      • Perazella M.A.
      • Lentini P.
      • Corradi V.
      • et al.
      Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population.
      ,
      • Bagshaw S.M.
      • Bennett M.
      • Haase M.
      • Haase-Fielitz A.
      • Egi M.
      • Morimatsu H.
      • et al.
      Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness.
      ].
      Haase et al. [
      • Haase M.
      • Devarajan P.
      • Haase-Fielitz A.
      • Bellomo R.
      • Cruz D.N.
      • Wagener G.
      • et al.
      The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies.
      ] identified a new category of patients with “subclinical AKI”, in whom urinary NGAL is present without an increase in SCr.

      5. IL-18

      Cytokine IL-18 (Interleukin-18), known as an interferon-γ (IFN-γ)-inducing factor is an important mediator of acute ischemic AKI. Its level in the kidneys more than doubles following AKI; its conversion from the IL-18 precursor requires caspase-1 [
      • Melnikov V.Y.
      • Ecder T.
      • Fantuzzi G.
      • Siegmund B.
      • Lucia M.S.
      • Dinarello C.A.
      • et al.
      Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure.
      ] and occurs in the renal proximal tubule [
      • Andreucci M.
      • Faga T.
      • Riccio E.
      • Sabbatini M.
      • Pisani A.
      • Michael A.
      The potential use of biomarkers in predicting contrast-induced acute kidney injury.
      ,
      • Edelstein C.L.
      • Hoke T.S.
      • Somerset H.
      • Fang W.
      • Klein C.L.
      • Dinarello C.A.
      • et al.
      Proximal tubules from caspase-1-deficient mice are protected against hypoxia-induced membrane injury.
      ].
      Urinary levels of IL-18 are greatly increased both in ischemic and in toxic AKI compared with “Prerenal azotemia”, urinary tract infection, chronic renal failure and nephrotic syndrome; it has a sensitivity and specificity of >90% for the diagnosis of AKI [
      • Parikh C.R.
      • Jani A.
      • Melnikov V.Y.
      • Faubel S.
      • Edelstein C.L.
      Urinary interleukin-18 is a marker of human acute tubular necrosis.
      ].
      A recent meta-analysis of 23 studies with 4512 patients has demonstrated that urinary IL-18 was predictive of AKI in cardiac surgery patients, in patients in Intensive-Care Units and in patients of coronary care units [
      • 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.
      ].
      Also in patients following cardiopulmonary bypass, the increase of urinary IL-18 was already present from 4 to 6 h after cardiopulmonary bypass while the rise of SCr occurred from 48 to 72 h after the bypass [
      • Parikh C.R.
      • Mishra J.
      • Thiessen-Philbrook H.
      • Dursun B.
      • Ma Q.
      • Kelly C.
      • et al.
      Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.
      ]. Also in patients with Acute Respiratory Distress Syndrome (ARDS) in Intensive Care Units urinary IL-18 predicted not only the development of AKI within 24 and 48 h, but also mortality [
      • Parikh C.R.
      • Abraham E.
      • Ancukiewicz M.
      • Edelstein C.L.
      Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit.
      ].
      Urinary IL-18 and urinary NGAL can also be used for detection of AKI in children undergoing surgical treatment for congenital cardiac lesions [
      • Parikh C.R.
      • Coca S.G.
      • Thiessen-Philbrook H.
      • Shlipak M.G.
      • Koyner J.L.
      • Wang Z.
      • et al.
      Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery.
      ].
      Urinary IL-18 can predict a delayed graft function after kidney transplantation from deceased kidney donors, even on the day of the transplantation [
      • Parikh C.R.
      • Jani A.
      • Mishra J.
      • Ma Q.
      • Kelly C.
      • Barasch J.
      • et al.
      Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation.
      ,
      • Hall I.E.
      • Yarlagadda S.G.
      • Coca S.G.
      • Wang Z.
      • Doshi M.
      • Devarajan P.
      • et al.
      IL-18 and urinary NGAL predict dialysis and graft recovery after kidney transplantation.
      ].
      Washburn et al. [
      • Washburn K.K.
      • Zappitelli M.
      • Arikan A.A.
      • Loftis L.
      • Yalavarthy R.
      • Parikh C.R.
      • et al.
      Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children.
      ] have demonstrated that urinary IL-18 not only rises prior to SCr in non-septic critically ill children with AKI, but also predicts the severity of AKI and mortality [
      • Washburn K.K.
      • Zappitelli M.
      • Arikan A.A.
      • Loftis L.
      • Yalavarthy R.
      • Parikh C.R.
      • et al.
      Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children.
      ]. According to Siew et al. [
      • 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.
      ], on the contrary, urinary IL-18 did not reliably predict AKI development, but did predict poor clinical outcomes in critically ill adult populations in Intensive-Care Units.
      Urinary IL-18 increased significantly at 6 and 12 h after the injection of the radiocontrast agent in the contrast induced-AKI patients [
      • Ling W.
      • Zhaohui N.
      • Ben H.
      • Leyi G.
      • Jianping L.
      • Huili D.
      • et al.
      Urinary IL-18 and NGAL as early predictive biomarkers in contrast-induced nephropathy after coronary angiography.
      ,
      • He H.
      • Li W.
      • Qian W.
      • Zhao X.
      • Wang L.
      • Yu Y.
      • et al.
      Urinary interleukin-18 as an early indicator to predict contrast-induced nephropathy in patients undergoing percutaneous coronary intervention.
      ]. Other authors disagree on these results [
      • Hayashi M.
      • Izawa H.
      Recent prophylactic strategies and novel biomarkers for contrast-induced acute kidney injury.
      ,
      • Bulent Gul C.B.
      • Gullulu M.
      • Oral B.
      • Aydinlar A.
      • Oz O.
      • Budak F.
      • et al.
      Urinary IL-18: a marker of contrast-induced nephropathy following percutaneous coronary intervention?.
      ].

      6. L-FABP

      FABP, acronym of Fatty Acid-Binding Protein, is a cytoplasmic protein found in all tissues with fatty acid metabolism. In the kidney there are 2 types of FABP: Liver-type (L-)FABP in the renal proximal tubule and heart type (H-)FABP in the renal distal tubule. In normal conditions, L-FABP is present in the lysosomal compartment of the proximal convoluted tubules and of the renal proximal straight tubules [
      • Kamijo A.
      • Sugaya T.
      • Hikawa A.
      • Okada M.
      • Okumura F.
      • Yamanouchi M.
      • et al.
      Urinary excretion of fatty acid-binding protein reflects stress overload on the proximal tubules.
      ,
      • 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.
      ].
      Urinary L-FABP is undetectable in the urine of healthy subjects.
      Experimental studies have demonstrated that the appearance of urinary L-FABP is a useful biomarker in ischemic and nephrotoxin-induced AKI [
      • 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.
      ,
      • Negishi K.
      • Noiri E.
      • Doi K.
      • Maeda-Mamiya R.
      • Sugaya T.
      • Portilla D.
      • et al.
      Monitoring of urinary L-type fatty acid-binding protein predicts histological severity of acute kidney injury.
      ,
      • Negishi K.
      • Noiri E.
      • Sugaya T.
      • Li S.
      • Megyesi J.
      • Nagothu K.
      • et al.
      A role of liver fatty acid-binding protein in cisplatin-induced acute renal failure.
      ].
      In clinical practice, urinary L-FABP is a good biomarker for AKI in cisplatin-induced nephrotoxicity [
      • Negishi K.
      • Noiri E.
      • Sugaya T.
      • Li S.
      • Megyesi J.
      • Nagothu K.
      • et al.
      A role of liver fatty acid-binding protein in cisplatin-induced acute renal failure.
      ], in septic shock induced AKI [
      • Tsuchimoto A.
      • Shinke H.
      • Uesugi M.
      • Kikuchi M.
      • Hashimoto E.
      • Sato T.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin: a useful biomarker for tacrolimus-induced acute kidney injury in liver transplant patients.
      ,
      • Nakamura T.
      • Sugaya T.
      • Koide H.
      Urinary liver-type fatty acid-binding protein in septic shock: effect of polymyxin B-immobilized fiber hemoperfusion.
      ], in contrast-induced AKI [
      • Manabe K.
      • Kamihata H.
      • Motohiro M.
      • Senoo T.
      • Yoshida S.
      • Iwasaka T.
      Urinary liver-type fatty acid-binding protein level as a predictive biomarker of contrast-induced acute kidney injury.
      ,
      • Thurman J.M.
      • Parikh C.R.
      Peeking into the black box: new biomarkers for acute kidney injury.
      ,
      • Nakamura T.
      • Sugaya T.
      • Node K.
      • Ueda Y.
      • Koide H.
      Urinary excretion of liver-type fatty acid-binding protein in contrast medium-induced nephropathy.
      ,
      • Kato K.
      • Sato N.
      • Yamamoto T.
      • Iwasaki Y.K.
      • Tanaka K.
      • Mizuno K.
      Valuable markers for contrast-induced nephropathy in patients undergoing cardiac catheterization.
      ,
      • Vijayasimha M.
      • Padma P.V.
      • Majumdar S.K.D.
      • Satyanarayana P.V.V.
      • Yadav A.
      Kidney injury molecule-1: a urinary biomarker for contrast induced acute kidney injury.
      ,
      • Nozue T.
      • Nozue T.
      • Michishita I.
      • Mizuguchi I.
      Predictive value of serum cystatin C, β2-microglobulin, and urinary liver-type fatty acid-binding protein on the development of contrast-induced nephropathy.
      ], in AKI occurring in patients undergoing percutaneous coronary intervention due to unstable angina [
      • Bachorzewska-Gajewska H.
      • Poniatowski B.
      • Dobrzycki S.
      NGAL (neutrophil gelatinase-associated lipocalin) and L-FABP after percutaneous coronary interventions due to unstable angina in patients with normal serum creatinine.
      ], in AKI following cardiac surgery [
      • Negishi K.
      • Noiri E.
      • Sugaya T.
      • Li S.
      • Megyesi J.
      • Nagothu K.
      • et al.
      A role of liver fatty acid-binding protein in cisplatin-induced acute renal failure.
      ,
      • Katagiri D.
      • Doi K.
      • Honda K.
      • Negishi K.
      • Fujita T.
      • Hisagi M.
      • et al.
      Combination of two urinary biomarkers predicts acute kidney injury after adult cardiac surgery.
      ], in AKI of patients admitted to the Intensive-Care Unit with sepsis [
      • 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 AKI occurring in pediatric patients following cardiopulmonary bypass surgery [
      • Portilla D.
      • Dent C.
      • Sugaya T.
      • Nagothu K.K.
      • Kundi I.
      • Moore P.
      • et al.
      Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery.
      ], in AKI of human kidney transplant patients from living-related donors [
      • Andreucci M.
      • Faga T.
      • Riccio E.
      • Sabbatini M.
      • Pisani A.
      • Michael A.
      The potential use of biomarkers in predicting contrast-induced acute kidney injury.
      ,
      • 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.
      ]. Under these conditions, urinary L-FABP is detected much earlier than the rise in SCr.
      L-FABP may be useful in patients whose SCr is unlikely to increase for mild insults to the kidney. For instance, in patients with liver disease, urinary L-FABP might help verify whether there is normal kidney function, thereby helping to decide between combined kidney–liver transplantation or liver transplantation alone [
      • Thurman J.M.
      • Parikh C.R.
      Peeking into the black box: new biomarkers for acute kidney injury.
      ].
      According to other Authors, the predictive value of L-FABP for contrast induced-AKI has not been established [
      • Hayashi M.
      • Izawa H.
      Recent prophylactic strategies and novel biomarkers for contrast-induced acute kidney injury.
      ], particularly in liver transplant recipients [
      • Li Y.
      • Zhu M.
      • Xia Q.
      • Wang S.
      • Qian J.
      • Lu R.
      • et al.
      Urinary neutrophil gelatinase-associated lipocalin and L-type fatty acid binding protein as diagnostic markers of early acute kidney injury after liver transplantation.
      ].

      7. Midkine

      Midkine (MK) is a multifunctional heparin-binding growth factor, induced by oxidative stress through activation of hypoxia-inducible factor-1a, and has been implicated in the pathogenesis of AKI and diabetic nephropathy. Investigation of MK as a renal biomarker has been undertaken with respect to contrast induced-AKI in patients undergoing percutaneous coronary intervention due to stable angina, using the iso-osmolar contrast agent iodixanol [
      • Malyszko J.
      • Bachorzewska-Gajewska H.
      • Koc-Zorawska E.
      • Malyszko J.S.
      • Kobus G.
      • Dobrzycki S.
      Midkine: a novel and early biomarker of contrast-induced acute kidney injury in patients undergoing percutaneous coronary interventions.
      ]. It was observed that MK was significantly higher in patients with CI-AKI. However more studies are necessary to affirm the potential of this molecule.

      8. Cell cycle arrest markers: IGFBP7 and TIMP2

      The IGFBP7 is the acronym of Insulin-like Growth factor-Binding Protein 7, while the TIMP2 is the acronym of Tissue Inhibitor of MetalloProteinases-2, both of which have been implicated in cell cycle arrest [
      • Kashani K.
      • Al-Khafaji A.
      • Ardiles T.
      • Artigas A.
      • Bagshaw S.M.
      • Bell M.
      • et al.
      Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.
      ,
      • Brew K.
      • Nagase H.
      The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity.
      ,
      • Verhagen H.J.
      • de Leeuw D.C.
      • Roemer M.G.
      • Denkers F.
      • Pouwels W.
      • Rutten A.
      • et al.
      IGFBP7 induces apoptosis of acute myeloid leukemia cells and synergizes with chemotherapy in suppression of leukemia cell survival.
      ].
      In a prospective, multicenter investigation the Urine IGFBP7 and TIMP2, two new biomarkers for AKI were discovered and validated in about 1000 critically ill adult patients from 35 Intensive-Care Units at high risk of AKI from multiple causes. The two new markers were compared with 340 other markers including Urine KIM-1, Urine and Plasma NGAL, plasma Cystatin C, urine IL-18, urine π-GST (Glutathione S-Transferase, another biomarker. See later), and L-FABP. All biomarkers were evaluated in their capability to predict the occurrence of AKI within 12–36 h. AKI occurred in 14% of the subjects. Urine IGFBP7 and TIMP-2 together demonstrated an AUC of 0.80 (0.76 and 0.79 alone), significantly superior to all previously described markers of AKI (KIM-1, NGAL, Cystatin-C, IL-18, π-GST, L-FABP; p < 0.002) The authors concluded that both new markers - IGFBP7 and TIMP-2 - are superior to existing markers for AKI [
      • Kashani K.
      • Al-Khafaji A.
      • Ardiles T.
      • Artigas A.
      • Bagshaw S.M.
      • Bell M.
      • et al.
      Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.
      ].
      However, whilst TIMP-2 and IGFBP7 have been confirmed to be useful biomarkers of AKI by some authors [
      • Wetz A.J.
      • Richardt E.M.
      • Wand S.
      • Kunze N.
      • Schotola H.
      • Quintel M.
      • et al.
      Quantification of urinary TIMP-2 and IGFBP-7: an adequate diagnostic test to predict acute kidney injury after cardiac surgery?.
      ,
      • Yamashita T.
      • Doi K.
      • Hamasaki Y.
      • Matsubara T.
      • Ishii T.
      • Yahagi N.
      • et al.
      Evaluation of urinary tissue inhibitor of metalloproteinase-2 in acute kidney injury: a prospective observational study.
      ,
      • Meersch M.
      • Schmidt C.
      • Van Aken H.
      • Martens S.
      • Rossaint J.
      • Singbartl K.
      • et al.
      Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery.
      ,
      • Bihorac A.
      • Chawla L.S.
      • Shaw A.D.
      • Al-Khafaji A.
      • Davison D.L.
      • Demuth G.E.
      • et al.
      Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.
      ,
      • Gocze I.
      • Koch M.
      • Renner P.
      • Zeman F.
      • Graf B.M.
      • Dahlke M.H.
      • et al.
      Urinary biomarkers TIMP-2 and IGFBP7 early predict acute kidney injury after major surgery.
      ], one study has questioned their accuracy as predictors of AKI, since in urine samples (obtained upon admission) from 94 ICU patients, the admission levels of these biomarkers did not differ between patients who developed AKI and those who did not [
      • Bell M.
      • Larsson A.
      • Venge P.
      • Bellomo R.
      • Martensson J.
      Assessment of cell-cycle arrest biomarkers to predict early and delayed acute kidney injury.
      ].

      9. α-GST and π-GST

      α-Glutathione S-Transferase (α-GST) and π-Glutathione S-Transferase (π-GST) are 2 enzymes of a multigene family of detoxification enzymes that are present in the kidney and in many other organs. They are usually not found in the urine of normal subjects, even though sometimes they can be detected in very small amounts (see Table 1).
      Table 1Summary of the activity and efficacy of major renal biomarkers.
      N.NameIndicator of change in GFRIndicator of proximal tubule damageIndicator of distal tubule damagePresence/levels in urine of healthy individualsPresence/effect on levels in urine of individual with AKI
      the arrow denotes an increase.
      Time period within which changes occurAdverse outcome predictionSuggested by the authors
      +++ = strongly recommended, ++- = recommended with some reservations.
      Molecular weight/kDa
      1Serum creatinine
      The values have been omitted for the reasons mentioned in the main body of the text.
      Yes2–5 days0.113
      2Serum Cystatin C
      The values have been omitted for the reasons mentioned in the main body of the text.
      Yes12–24 h13
      3NAG (N-acetyl-β-D-glucosaminidase)Yes15.1 U/L
      Data from Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ: Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrology, dialysis, transplantation 2003, 18(3): 543–551).
      12 hYes+++̴200
      4KIM-1 (Kidney Injury Molecule-1)YesNoYes24 hYes+++104
      KIM-1 has an estimated molecular weight of 104kDa, although the 90kDa ectodomain is shed in the plasma and urine.
      5NGAL (Neutrophil Gelatinase-Associated Lipocalin)YesYes20 ng/mL2 hYes+++25
      6IL-18 (Interleukin-18)YesYes4–6 hYes++−18
      7L-FABP (l-fatty acid binding protein)YesYesNoYes2 hYes+++15
      8IGFBP7 (insulin-like growth factor binding protein 7)Yes[TIMP-2] × [IGFBP7] ≤ 0.3 (ng/mL)2/1000
      Kashani et al. (ref. 129) identified IGFBP7 and TIMP-2 as the best biomarkers of AKI and found that they had additive predictive value together; they observed that the risk of AKI rose sharply above a value of 0.3 (ng/mL)2/1000 for the multiplied values of the concentrations of these 2 biomarkers.
      - see legend for explanation
      12–36 h++−29
      9TIMP-2 (Tissue inhibitor of metalloproteinases-2)Yes12–36 h++−21
      10α-GST (α-glutathione-S-transferase)Yes4 μg/L
      Data from Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ: Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrology, dialysis, transplantation 2003, 18(3): 543–551).
      24 h+++̴50
      11π-GST (π-glutathione-S-transferase)Yes5.9 μg/L
      Data from Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ: Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrology, dialysis, transplantation 2003, 18(3): 543–551).
      24 h+++̴50
      12ɣGT (ɣGlutamyl Transpeptidase)Yes39 mmol/L
      Data from Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ: Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrology, dialysis, transplantation 2003, 18(3): 543–551).
      24 h+++84
      13AP (Alkaline phosphatase)Yes5 U/L
      Data from Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ: Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrology, dialysis, transplantation 2003, 18(3): 543–551).
      24 hUnstable in acidic urine100–200
      Alkaline phosphatase may exist in an active dimeric or tetrameric form with the molecular weight ranging from 100 to 200kDa.
      14β2M (β2-microglobulin)Yes<311 μg/L
      The upper limit of normal, defined as the mean+2SD of the urinary concentrations observed in a group of 100 healthy subjects. (data from Bernard AM, Vyskocil AA, Mahieu P, Lauwerys RR: Assessment of urinary retinol-binding protein as an index of proximal tubular injury. Clinical chemistry 1987, 33(6): 775–779).
      12 h
      The upper limit of normal, defined as the mean+2SD of the urinary concentrations observed in a group of 100 healthy subjects. (data from Bernard AM, Vyskocil AA, Mahieu P, Lauwerys RR: Assessment of urinary retinol-binding protein as an index of proximal tubular injury. Clinical chemistry 1987, 33(6): 775–779).
      Unstable in acidic urine11.8
      15RBP (Retinol Binding Protein)Yes<308 μg/L
      The upper limit of normal, defined as the mean+2SD of the urinary concentrations observed in a group of 100 healthy subjects. (data from Bernard AM, Vyskocil AA, Mahieu P, Lauwerys RR: Assessment of urinary retinol-binding protein as an index of proximal tubular injury. Clinical chemistry 1987, 33(6): 775–779).
      12 h
      The upper limit of normal, defined as the mean+2SD of the urinary concentrations observed in a group of 100 healthy subjects. (data from Bernard AM, Vyskocil AA, Mahieu P, Lauwerys RR: Assessment of urinary retinol-binding protein as an index of proximal tubular injury. Clinical chemistry 1987, 33(6): 775–779).
      +++21
      a The values have been omitted for the reasons mentioned in the main body of the text.
      b The upper limit of normal, defined as the mean + 2SD of the urinary concentrations observed in a group of 100 healthy subjects. (data from Bernard AM, Vyskocil AA, Mahieu P, Lauwerys RR: Assessment of urinary retinol-binding protein as an index of proximal tubular injury. Clinical chemistry 1987, 33(6): 775–779).
      c Data from Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ: Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrology, dialysis, transplantation 2003, 18(3): 543–551).
      d Alkaline phosphatase may exist in an active dimeric or tetrameric form with the molecular weight ranging from 100 to 200 kDa.
      e KIM-1 has an estimated molecular weight of 104 kDa, although the 90 kDa ectodomain is shed in the plasma and urine.
      f Kashani et al. (ref.
      • Kashani K.
      • Al-Khafaji A.
      • Ardiles T.
      • Artigas A.
      • Bagshaw S.M.
      • Bell M.
      • et al.
      Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.
      ) identified IGFBP7 and TIMP-2 as the best biomarkers of AKI and found that they had additive predictive value together; they observed that the risk of AKI rose sharply above a value of 0.3 (ng/mL)2/1000 for the multiplied values of the concentrations of these 2 biomarkers.
      g the arrow denotes an increase.
      h +++ = strongly recommended, ++- = recommended with some reservations.
      After a renal injury, α-GST is detected mainly in the tubular proximal cells, while π-GST is observed in the distal tubular cells [
      • de Geus H.R.
      • Betjes M.G.
      • Bakker J.
      Biomarkers for the prediction of acute kidney injury: a narrative review on current status and future challenges.
      ]. Thus the increased excretion with urine of α-GST implies epithelial necrosis in the proximal tubules, while the increased excretion with urine of π-GST implies epithelial necrosis in the distal tubules
      In the prospective pilot study of Westhuyzen et al. on 26 consecutive patients who were admitted to the ICU to evaluate the utility of combined measurements of the 2 urinary tubular enzymes in predicting AKI in critically ill patients, 4 patients had ARF (15,4%). At the time of admission of these patients in the ICU, α-GST and π-GST indexed to urine creatinine provided AUC of 0.893 and 0.929 respectively. The urine of control group (n. 22) had very low concentrations of α-GST (4 μg/L) and π-GST (5.9 μ/L) on admission to the ICU and remained around the same low values after 12 and 24 h. The urine of the ARF group (n. 4) had very high concentrations of α-GST (28.1 μg/L) and π-GST (18.5 μ/L) on admission to the ICU and increased significantly after 12 h (α-GST 40.6 μg/L and π-GST 69.0 μ/L) and 24 h (α-GST 51.0 μg/L). As far as the sensitivity (true positives) for detecting ARF is concerned, it was very high for π-GST (100%) and for α-GST [
      • Haase M.
      • Bellomo R.
      • Matalanis G.
      • Calzavacca P.
      • Dragun D.
      • Haase-Fielitz A.
      A comparison of the RIFLE and acute kidney injury network classifications for cardiac surgery-associated acute kidney injury: a prospective cohort study.
      ]. The authors concluded that tubular excretion with urine of enzymes α-GST and π-GST on admission to the ICU is useful in predicting AKI [
      • Westhuyzen J.
      • Endre Z.H.
      • Reece G.
      • Reith D.M.
      • Saltissi D.
      • Morgan T.J.
      Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit.
      ]. This loss of cytoplasmic enzymes is an expression of the severe damage of epithelial cells that is responsible for decreased tubular reabsorption and consequently increased urinary excretion also of filtered low-molecular weight proteins like β2-microglobulin and Retinol Binding Protein [
      • Ad-hoc working group of E
      • Fliser D.
      • Laville M.
      • Covic A.
      • Fouque D.
      • Vanholder R.
      • et al.
      A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines on acute kidney injury: part 1: definitions, conservative management and contrast-induced nephropathy.
      ], two other renal biomarkers.

      10. ɣGT and AP

      ɣGT is the acronym of ɣGlutamyl Transpeptidase and AP is the acronym of alkaline phosphatase.
      ɣGT and AP are 2 enzymes of the proximal tubular brush border that are released into the urine when the brush border is damaged with loss of the microvillus structures [
      • de Geus H.R.
      • Betjes M.G.
      • Bakker J.
      Biomarkers for the prediction of acute kidney injury: a narrative review on current status and future challenges.
      ]. AP is also a marker of vascular injury in subjects with normal renal function [
      • Perticone F.
      • Perticone M.
      • Maio R.
      • Sciacqua A.
      • Andreucci M.
      • Tripepi G.
      • et al.
      Serum alkaline phosphatase negatively affects endothelium-dependent vasodilation in naive hypertensive patients.
      ].
      There are not many data on these two renal biomarkers.
      In the same study of Westhuyzen et al. mentioned above in which several biomarkers have been evaluated in the urine of 26 patients admitted to ICU and 4 of them had ARF (or AKI), urinary ɣGT, AP, NAG, αGST and π-GST were all very high in the ARF group on admission (p < 0.05), while the increase in SCr occurred 12 h to 4 days later. In the control group (n. 22), Urinary ɣGT was 39 mmol/L and remained the same after 12 and 24 h. In the ARF group (n. 4), Urinary ɣGT was 81 mmol/L and increased significantly after 12 h (113 mmol/L) and after 24 h (226 mmol/L). In the control group (n. 22), Urinary AP was 5 U/L and remained the same after 12 and 24 h. In the ARF group (n. 4), Urinary AP was 10 mmol/L and increased after 12 h (12 mmol/L) [
      • Westhuyzen J.
      • Endre Z.H.
      • Reece G.
      • Reith D.M.
      • Saltissi D.
      • Morgan T.J.
      Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit.
      ].
      Increased excretion of ɣGT and AP implies a damage of the epithelium of the proximal tubule [
      • Westhuyzen J.
      • Endre Z.H.
      • Reece G.
      • Reith D.M.
      • Saltissi D.
      • Morgan T.J.
      Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit.
      ].
      Urinary levels of ɣGT were significantly increased in patients 24 h after the injection of the high osmolality contrast medium diatrizoate and in patients 24 h after the injection of the low osmolality contrast medium iohexol, whereas SCr did not show any change [
      • Parvez Z.
      • Ramamurthy S.
      • Patel N.B.
      • Moncada R.
      Enzyme markers of contrast media-induced renal failure.
      ].

      11. β2-microglobulin

      The β2-microglobulin (β2M) is the light chain component of the major histocompatibility class I molecule. Under normal conditions, it is synthesized and shed during cellular turnover, dissociating from the heavy chain; then it enters the circulation, is filtered by the glomerulus and absorbed and metabolized by the renal proximal tubule [
      • Bernier G.M.
      Beta 2-microglobulin: structure, function and significance.
      ].
      To evaluate whether a proximal tubular damage has occurred in a patient, we may look for the presence in high concentration in the urine of low-molecular weight (<40.000 kDa) proteins, like β2M: this indicates a reduced proximal tubular reabsorption. The increase in urinary excretion of β2M is probably a significant specific index of tubular damage only when GFR is normal or only slightly reduced. A drawback of β2M is its instability in acid urine [
      • Bernard A.M.
      • Vyskocil A.A.
      • Mahieu P.
      • Lauwerys R.R.
      Assessment of urinary retinol-binding protein as an index of proximal tubular injury.
      ].
      Under conditions of tubular damage secondary to rhabdomyolysis, therapy with nephrotoxic antibiotics or analgesics, poisoning by solvents, heavy metals, or pesticides β2-microglobulin has been proved to be a sensitive biomarker of renal tubular damage [
      • Bernard A.M.
      • Vyskocil A.A.
      • Mahieu P.
      • Lauwerys R.R.
      Assessment of urinary retinol-binding protein as an index of proximal tubular injury.
      ].
      The β2M is present both in serum and urine of normal subjects. The serum β2M in a normal subject is 2 (0.6–2.8) mg/L. The urinary concentration of β2M in a normal subject is 80 (3.6–320) μg/L [
      • Latt D.
      • Weiss J.B.
      • Jayson M.I.
      Beta 2-microglobulin levels in serum and urine of rheumatoid arthritis patients on gold therapy.
      ].

      12. RBP

      RBP, acronym of Retinol Binding Protein is a protein synthesized in the liver and involved in vitamin A transport from the liver to other tissues. It is filtered by the glomerulus and reabsorbed and metabolized by the renal proximal tubule.
      Urinary RBP is a sensitive marker of tubular injury. Its sensitivity is slightly lower than that of β2M, but much higher than that of NAG. In contrast to β2M, RBP is stable in acid urine. Like urinary β2M, its increase has probably a significant specific index of tubular damage only when GFR is normal or only slightly reduced. This, for instance, has been observed after i.v. high doses of oxacilline antibiotic: urinary excretion of both, RBP and β2M, drastically (in <24 h) increased [
      • Bernard A.M.
      • Vyskocil A.A.
      • Mahieu P.
      • Lauwerys R.R.
      Assessment of urinary retinol-binding protein as an index of proximal tubular injury.
      ]. Urinary RBP has been used as a marker in assessing prophylactic treatments for contrast induced-AKI [
      • Sadat U.
      • Walsh S.R.
      • Norden A.G.
      • Gillard J.H.
      • Boyle J.R.
      Does oral N-acetylcysteine reduce contrast-induced renal injury in patients with peripheral arterial disease undergoing peripheral angiography? A randomized-controlled study.
      ].
      The excretion of RBP with the urine indicates a reduced capacity of proximal tubular reabsorption only when GFR is normal, since the tubular uptake of proteins is a saturable process. In this case the urinary RBP is the ideal marker for an early detection of proximal tubule damage when GFR is not yet reduced [
      • Bernard A.M.
      • Vyskocil A.A.
      • Mahieu P.
      • Lauwerys R.R.
      Assessment of urinary retinol-binding protein as an index of proximal tubular injury.
      ].

      13. MicroRNA

      MicroRNA (miRNA) molecules are short non-coding sequences of RNA. They have been implicated in cellular proliferation, differentiation, death (apoptosis) as well as inflammation and have been implicated in injury due to ischemia and toxic stresses. It is therefore feasible that miRNAs play a role in the pathogenesis of AKI due to ischemic/nephrotoxic factors [
      • Li Y.F.
      • Jing Y.
      • Hao J.
      • Frankfort N.C.
      • Zhou X.
      • Shen B.
      • et al.
      MicroRNA-21 in the pathogenesis of acute kidney injury.
      ,
      • Du J.
      • Cao X.
      • Zou L.
      • Chen Y.
      • Guo J.
      • Chen Z.
      • et al.
      MicroRNA-21 and risk of severe acute kidney injury and poor outcomes after adult cardiac surgery.
      ,
      • Wei Q.
      • Mi Q.S.
      • Dong Z.
      The regulation and function of microRNAs in kidney diseases.
      ].
      Several specific miRNAs are involved in the pathogenesis of AKI: miR-687, miR-489, miR-494, miR-24, miR-21, and miR-126 [
      • Li Y.F.
      • Jing Y.
      • Hao J.
      • Frankfort N.C.
      • Zhou X.
      • Shen B.
      • et al.
      MicroRNA-21 in the pathogenesis of acute kidney injury.
      ,
      • Wei Q.
      • Bhatt K.
      • He H.Z.
      • Mi Q.S.
      • Haase V.H.
      • Dong Z.
      Targeted deletion of Dicer from proximal tubules protects against renal ischemia-reperfusion injury.
      ,
      • Liu Z.
      • Wang S.
      • Mi Q.S.
      • Dong Z.
      MicroRNAs in pathogenesis of acute kidney injury.
      ]. Serum and urine levels of miR21 (the most studied molecule) have been shown to predict severe AKI progression in patients undergoing cardiac surgery [
      • Aguado-Fraile E.
      • Ramos E.
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      • et al.
      A pilot study identifying a set of microRNAs as precise diagnostic biomarkers of acute kidney injury.
      ].
      A study of Intensive-Care Unit and cardiac surgery patients suggested that some of these miRNA molecules could predict AKI after cardiac surgery [
      • Du J.
      • Cao X.
      • Zou L.
      • Chen Y.
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      • Chen Z.
      • et al.
      MicroRNA-21 and risk of severe acute kidney injury and poor outcomes after adult cardiac surgery.
      ].
      One study has recently identified several miRNAs, whose levels increased in sera obtained from patients with contrast induced-AKI: miR-30a, miR-30c and miR-30e showed two-fold increases in contrast induced-AKI patients [
      • Gutierrez-Escolano A.
      • Santacruz-Vazquez E.
      • Gomez-Perez F.
      Dysregulated microRNAs involved in contrast-induced acute kidney injury in rat and human.
      ]. In another study miR-30a, miR-30e and miR-188 also were upregulated between 2 and 3 fold [
      • Sun S.
      • Zhang T.
      • Cai Z.
      • Sun Z.
      • Hu L.
      • Nie P.
      • et al.
      Circulating miRNA-30a, -30e,-188 as early biomarkers for CI-AKI.
      ].

      14. Conclusion

      We have examined the renal biomarkers nowadays available for an early diagnosis of ischemic/nephrotoxic AKI. Early injury to the proximal tubule is difficult to detect. The two low-molecular weight biomarkers, β2M and RBP, are important to figure out proximal tubular damage when GFR is normal or slightly reduced. Under these conditions, their increased excretion with urine indicates proximal tubular impairment. They are also useful to detect possible toxic effects of antibiotics on the tubules, by measuring their concentration in the urine before, during and after the administration of these drugs. In Table 1 we have summarized the activity and the efficacy of all biomarkers available today. Besides the conditions in which GFR is normal or almost normal, in our opinion the urinary NAG, KIM-1 and NGAL are three useful, non-invasive, sensitive, early markers of tubular damage in ischemic/nephrotoxic AKI. Urinary NGAL is also an early, predictive biomarker of delayed graft function after kidney transplantation and represents also an early sign for predicting the patients' clinical outcomes (dialysis and mortality). Undoubtedly, a further validation in large, multi-centre prospective studies with well-defined values for each biomarker is still required.
      It may well be that a combination of biomarkers may be needed to evaluate and/or predict the extent of renal injury, which may require equipment that can make rapid measurements with greater sensitivity. This itself would present challenges in the clinical setting with respect to costs and technical expertise needed, but in the long term these will be offset by the benefits to patient healthcare.

      Funding sources

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Conflict of interest statement

      Authors report no conflicts of interest in this work.

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