Reply to: “A cut-off serum creatinine value of 1.5 mg/dl for AKI – To be or not to be”
Authors: Salvatore Piano, Marta Tonon, Marta Cavallin, Filippo Morando, Antonietta Romano, Elisabetta Gola, Silvano Fasolato, Paolo Angeli
Journal: Journal of Hepatology (2014)

Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascitesJournal of HepatologyVol. 59Issue 3PreviewFor several years hepatologists have defined acute renal failure in patients with cirrhosis as an increase in serum creatinine (sCr) ⩾50% to a final value of sCr >1.5 mg/dl (conventional criterion). Recently, the Acute Kidney Injury Network (AKIN) defined acute renal failure as acute kidney injury (AKI) on the basis of an absolute increase in sCr of 0.3 mg/dl or a percentage increase in sCr ⩾50% providing also a staging from 1 to 3. AKIN stage 1 was defined as an increase in sCr ⩾0.3 mg/dl or increase in sCr ⩾1.5-fold to 2-fold from baseline. Full-Text PDF A cut-off serum creatinine value of 1.5 mg/dl for AKI – To be or not to beJournal of HepatologyVol. 62Issue 3PreviewAcute renal failure (ARF) is a common problem in patients with decompensated cirrhosis and ascites [1]. Traditionally, the diagnosis of ARF is made using the conventional criteria of a 50% increase in serum creatinine with the final serum creatinine reaching ⩾1.5 mg/dl [2]. More recently, it has been recognized in non-cirrhotic patients that smaller increases in serum creatinine also have a negative impact on survival [3]. This has led various learned societies to re-define ARF as acute kidney injury (AKI), incorporating even small changes in serum creatinine either in absolute or percentage terms in the diagnostic criteria [4–6]. Full-Text PDF Open Access A cut-off creatinine value of 1.5mg/dl for AKI: sometimes "the question" does not concern "the being", but "the meaning"To the Editor: We want to thank Wong et al. for their interest in our study published in 2013 in the Journal of Hepatology regarding the application of acute kidney injury network (AKIN) criteria in the diagnosis of acute kidney injury (AKI) in patients with cirrhosis and ascites [[1]Piano S. Rosi S. Maresio G. Fasolato S. Cavallin M. Romano A. et al.Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.J Hepatol. 2013; 59: 482-489Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar]. In their letter Wong et al. express their concern about the use of a cut off serum creatinine (sCr) of 1.5 mg/dl in the diagnosis of AKI in patients with cirrhosis, in particular in women. They reported that in hospitalized patients with cirrhosis and bacterial infections, patients with AKI and a peak sCr <1.5 mg/dl had a poor survival than patients without AKI. These results are interesting and emphasize that in the setting of bacterial infections mild impairment of renal function may be associated with poor short-term outcome. However, let us summarize the development of the application of AKI criteria in patients with cirrhosis. After the appearance of the AKIN criteria, a working party of specialists from multiple disciplines proposed summary statements for the classification of renal dysfunction in cirrhosis, including the AKIN classification [[2]Wong F. Nadim M.K. Kellum J.A. Salerno F. Bellomo R. Gerbes A. et al.Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.Gut. 2011; 60: 702-709Crossref PubMed Scopus (324) Google Scholar]. However, as hepatologists, we have used for several years our own definition of acute renal failure, achieving relevant results in its prevention and treatment [[3]Arroyo V. Acute kidney injury (AKI) in cirrhosis: should we change current definition and diagnostic criteria of renal failure in cirrhosis?.J Hepatol. 2013; 59: 415-417Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. Thus, the International Club of Ascites proposed to compare our own diagnostic criteria of acute renal failure with the AKIN criteria in terms of prognostic accuracy, rather than to accept uncritically the latter [[4]Angeli P. Sanyal A. Moller S. Alessandria C. Gadano A. Kim R. et al.Current limits and future challenges in the management of renal dysfunction in patients with cirrhosis: report from the International Club of Ascites.Liver Int. 2013; 33: 16-23Crossref PubMed Scopus (56) Google Scholar]. Thus, our prospective clinical study was specifically aimed to address this relevant issue. Now, let us to explain better the main observations reported in our manuscript, since it appears they have been misunderstood. First of all we want to highlight that we have never suggested maintaining the cut-off sCr of 1.5 mg/dl for the diagnosis of AKI in patients with cirrhosis. We clearly stated that the AKIN criteria and the AKIN staging of AKI should be accepted and used in patients with cirrhosis. Then, we suggested using two parameters, namely a cut-off sCr of 1.5 mg/dl and/or AKI stage progression, in order to titrate the intensity of treatment in patients with initial AKI stage 1. In fact, our data showed that, in this subgroup of patients, a sCr <1.5 mg/dl was able to predict both an low probability of AKI progression (<10%) to a higher stage and a high probability of AKI resolution (>70%) by simple therapeutic measures that we will mention later on. Conversely, in patients with an initial AKI stage 1, a value of sCr ⩾1.5 mg/dl was found to be a predictor of both progression of the AKI stage and poor in hospital survival [[1]Piano S. Rosi S. Maresio G. Fasolato S. Cavallin M. Romano A. et al.Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.J Hepatol. 2013; 59: 482-489Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar]. Fagundes et al. reported similar results in the same issue of the Journal [[5]Fagundes C. Barreto R. Guevara M. Garcia E. Sola E. Rodriguez E. et al.A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis.J Hepatol. 2013; 59: 474-481Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. According to these data, Fagundes et al. proposed a new classification of AKI dividing patients with peak stage 1 AKI in 2 groups according to sCr >or ⩽1.5 mg/dl [[5]Fagundes C. Barreto R. Guevara M. Garcia E. Sola E. Rodriguez E. et al.A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis.J Hepatol. 2013; 59: 474-481Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. Moving to the management of AKI stage 1 and sCr <1.5 mg/dl, nowhere in our paper is reported that AKI stage 1 with sCr <1.5 mg/dl should be considered a benign condition. In fact, specific interventions were suggested for these patients, namely withdrawal of nephrotoxic drugs, tapering or withdrawal of diuretics, treatment of bacterial infections and plasma volume expansion, according to clinical scenario. These measures are similar to those suggested by Kidney Disease Improving Global Outcome (KDIGO) practice guidelines for the management of AKI in the general population [[6]Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO Clinical Practice Guideline for Acute Kidney Injury.Kidney Int. 2012; 2: 113-138Google Scholar] and they were applied both in our study and in Fagundes' study. These treatments led to resolution of AKI in 70.6% of patients with AKI stage 1 and serum creatinine <1.5 mg/dl [[1]Piano S. Rosi S. Maresio G. Fasolato S. Cavallin M. Romano A. et al.Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.J Hepatol. 2013; 59: 482-489Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar]. Finally, we proposed a close follow up of these patients in spite of the resolution of AKI just relying this recommendation on the data of Tsien et al. [[7]Tsien C.D. Rabie R. Wong F. Acute kidney injury in decompensated cirrhosis.Gut. 2013; 62: 131-137Crossref PubMed Scopus (184) Google Scholar]. We do not think that we have underestimated this clinical condition. Moving now to patients with initial AKI stage with sCr ⩾1.5 mg/dl and/or progression of AKI stage, we suggested applying the same intensive treatment provided for patients with initial AKI stage 2 or 3. This treatment includes plasma volume expansion with the maximal provided doses of albumin (i.e., 1 g/kg of body weight for two consecutive days) and, in case of fulfillment of all the other diagnostic criteria for hepatorenal syndrome (HRS), vasoconstrictors plus albumin. Thus, definitively, we proposed to maintain a sCr cut off value of 1.5 mg/dl mainly in order to avoid a risky and unjustified use of vasoconstrictors, and in particular of terlipressin in patients with AKI-HRS stage 1 without progression. To be clearer we propose two brief questions about two clinical cases of cirrhosis with AKI stage 1 without progression, that is peak AKI stage 1. Would you treat with vasoconstrictors and albumin a patient with a value of sCr going up from 0.6 to 1.0 mg/dl (AKI stage 1 with sCr <1.5 mg/dl) who fulfills all the other diagnostic criteria for AKI-HRS? Would you treat with vasoconstrictors and albumin a patient with a value of sCr going up from 1.3 to 1.7 mg/dl (AKI stage 1 with sCr ⩾1.5 mg/dl) who fulfills all the other diagnostic criteria for AKI-HRS? We think that there is no need to hire the Gallup pool to state that most of the experts would answer no to the first and yes to the second question. Why? Because only in the second case the impairment of renal function would be considered large enough to justify in terms of risk/benefit the treatment with vasoconstrictors and albumin. In order to complete the discussion, please note that in patients with initial AKI stage 2 and 3, no cut-off was provided for the management of AKI in our algorithm, giving the possibility to treat intensively a patient with baseline sCr level of 0.6 mg/dl who develops AKI with an initial sCr even below 1.5 mg/dl (e.g. 1.3 mg/dl) because we proved he/she, having an initial AKI stage 2, has a high risk of short term mortality. In this regard it would be interesting to know how many patients with AKI and sCr <1.5 mg/dl had AKI stage 1 and how many had AKI stage >1 in the cohort of Wong et al., since these data were not reported. Thus, in our view, the use of the threshold sCr of 1.5 mg/dl is not detrimental. Nevertheless, as we stated in the manuscript, our algorithm is a simple working hypothesis, and we are fully agree with Wong et al. that large prospective controlled interventional studies are needed to clarify this issue. As far as a possible discrimination against women is concerned, we fully agree that the assessment of glomerular filtration rate (GFR) with sCr is a relevant problem in female, both in the general population and in those with cirrhosis. However, this is a limitation of the use of sCr as a marker of GFR more than of AKIN criteria. Furthermore these limits are shared with all the scores in which sCr is included, such as MELD score. In fact, beyond its amazing merits, the use of MELD score in the assessment of prognosis and in priority allocation for liver transplantation penalizes females [[8]Moylan C.A. Brady C.W. Johnson J.L. Smith A.D. Tuttle-Newhall J.E. Muir A.J. Disparities in liver transplantation before and after introduction of the MELD score.JAMA. 2008; 300: 2371-2378Crossref PubMed Scopus (257) Google Scholar]. Furthermore, in the calculation of MELD score all sCr values below 1 mg/dl are bounded to 1 mg/dl. This is a serious limitation since patients with cirrhosis and sCr below 1 mg/dl may have wide variations in measured GFR [[9]Francoz C. Prié 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.Liver Transpl. 2010; 16: 1169-1177Crossref PubMed Scopus (141) Google Scholar]. Thus, this point raised by Wong et al. looks a little bit like what we define, in soccer, an own goal. Thus, joke aside, we would like to invite the authors to direct the value of their observation on discrimination against women also to the liver transplant setting, where it is probably more relevant that in the management of AKI. We would be very interested to investigate these issues in collaborative prospective studies. The last point raised by Wong et al., is the prognostic impact of failure of organs other than the kidney in patients with cirrhosis. Wong et al. seem to suggest that AKI has a deeper negative impact on prognosis than other organ failures. There is no doubt about the negative effect of renal failure on prognosis of patients with cirrhosis and bacterial infections. As hepatologists, we know it from several years [10Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (482) Google Scholar, 11Fasolato 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.Hepatology. 2007; 45: 223-229Crossref PubMed Scopus (248) Google Scholar]. Nevertheless, it has recently been shown that a classification based on the acute-on-chronic liver failure (ACLF) stages, which was recently proposed by the Canonic study [[12]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (2021) Google Scholar], has a higher accuracy than that based on AKI stages in the prediction of short term mortality in patients who were admitted to the hospital for an acute decompensation of cirrhosis [[13]Angeli P. Rodríguez E. Piano S. Ariza X. Morando F. Solà E. et al.Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis.Gut. 2014; https://doi.org/10.1136/gutjnl-2014-307526Crossref PubMed Scopus (84) Google Scholar]. These data suggest that the prognostic evaluation of patients with an acute decompensation of cirrhosis cannot ignore the failures of organs other than the kidney. Once we have clarified all of this, we share the conclusions of Wong et al. that prospective clinical trials are needed on several steps of the management of AKI in patients with cirrhosis considering all the possible clinical scenarios. We also agree that we should work together to achieve shared criteria in the management of AKI in cirrhosis. Wong et al. well know we are already doing it all together, because we all strongly believe that, in science, the different opinions should always create an opportunity for a worldwide growth of knowledge and never a reason for disputes or for something even worse, that is a harmful division in the scientific community. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.