Creatinine and Cystatin C
2018; Lippincott Williams & Wilkins; Volume: 137; Issue: 19 Linguagem: Inglês
10.1161/circulationaha.118.033343
ISSN1524-4539
AutoresMaria Rosa Costanzo, Jonathan Barasch,
Tópico(s)Folate and B Vitamins Research
ResumoHomeCirculationVol. 137, No. 19Creatinine and Cystatin C Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCreatinine and Cystatin CNot the Troponin of the Kidney Maria Rosa Costanzo, MD and Jonathan Barasch, MD, PhD Maria Rosa CostanzoMaria Rosa Costanzo Advocate Heart Institute, Naperville, IL (M.R.C.). and Jonathan BaraschJonathan Barasch Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY (J.B.). Originally published18 Jun 2018https://doi.org/10.1161/CIRCULATIONAHA.118.033343Circulation. 2018;137:2029–2031Article, see p 2016The current perception, based on data from earlier studies, is that worsening renal function (WRF) during diuresis of patients with acute heart failure (HF) means that the therapy is overzealous and exposes the patients to permanent kidney injury and increased mortality.1 Underlying this view is the assumption that increased serum creatinine (sCr)/cystatin C and acute kidney injury (AKI) are interchangeable terms.1 Recent findings, however, suggest that transient increases in sCr may instead reflect a benign and potentially reversible hemodynamically driven reduction in glomerular filtration rate (GFR), reflective of effective decongestion that is associated with improved outcomes.2 Thus, serious harm continues to be perpetrated against patients with acute illnesses, including HF, by referring to increased sCr/cystatin C, WRF, and AKI as if they were merely different names of the same pathological entity. Ahmad and colleagues in this issue of Circulation, while attempting to determine if renal tubular injury is the primary mechanism for WRF resulting from aggressive diuresis, came face-to-face with the reality that increases in either sCr or markers of tubular damage are, at best, poorly correlated with each other and with the diuretic effect and, at worse, may worsen outcomes because of the premature cessation of decongestive therapies.3For myocardial infarction, cardiac troponins (I and T) are widely considered adequate diagnostic biomarkers based on their myocardial tissue specificity and their association with important clinical outcomes.4 In contrast, assessment of renal status by sCr is not straightforward, because defective excretion of sCr can result from extrarenal hypovolemia, impaired blood perfusion, intrinsic kidney causes (attributable to sepsis, ischemia, drugs, toxins, interstitial or glomerular causes, or a combination of these conditions), or postrenal disease.5 It is implausible, therefore, that creatinine, an end-product of muscle catabolism freely filtered by the glomerulus and secreted by the tubule, can discriminate between causes of renal dysfunction. Although measurement of sCr is cheap, widely available, and standardized, its disadvantages include not only the many inducers of elevated sCr, but also the large number of conditions affecting its non-GFR determinants, including renal reserve, muscle metabolism, protein intake, volume of distribution, medications, and extrarenal degradation. In fact, equations estimating GFR using sCr have variable bias across populations, and are imprecise despite standardization of sCr assays and inclusion of age, sex, race, and body size as surrogates for creatinine generation.5 These equations assume that sCr is a steady-state marker of creatinine production and disposal, conditions that do not apply to AKI. An alternative to creatinine, cystatin C, is a protein produced in all nucleated cells and distributed in extracellular fluid. It is freely filtered and mostly reabsorbed and catabolized by the proximal tubule. Cystatin C is not affected by muscle mass or diet and is less strongly associated with age, sex, and race than creatinine, but smoking, inflammation, adiposity, thyroid diseases, malignancy, and glucocorticoids influence cystatin C levels, diminishing their value as a measure of renal excretory performance.5 In addition, international standardization of the cystatin C assay is not finalized.5 Estimation of GFR using creatinine, cystatin C, or both has not been validated in acutely ill patients, in whom these estimates appear to be inaccurate in comparison with 4-hour urinary creatinine clearance for detection of renal function changes.6 It is disappointing, therefore, that the severity of AKI is predominantly classified according to sCr changes or cystatin changes.5,7 This is because, in the absence of steady state, a patient may have florid tubular damage at presentation without significant changes in sCr attributable to renal reserve and consequent delay in achievement of detectable changes in this analyte. Conversely, the correlation of an increase in sCr levels with better outcomes during the treatment of HF suggests that elevation of this analyte identifies physiological, volume-sensitive responses to diuretics, rather than tubular damage.2Ahmad and colleagues expand the evidence that, in the context of aggressive diuresis of fluid-overloaded patients with HF, WRF, as defined by creatinine-based estimation of GFR, occurs without obvious renal tubular injury.3 These findings support the notion that sCr-based AKI stages inaccurately describe the severity of excretory dysfunction and fail to provide information on whether tubular damage, if it occurs at all, is reabsorptive or excretory.7,8 Advances in kidney transcriptomics and urinary proteomics suggest that kidney genes and their encoded proteins can be specific for certain stimuli and cellular targets. Serum creatinine is not in this category because it can be elevated to similar extents in different experimental and clinical situations. Xu and colleagues9 have found that different genetic signatures are activated by renal ischemia versus volume depletion. Differential gene expression was also shown in thousands of patients presenting with a broad range of illnesses.10 Hence, the dissociation between kidney cell lines transcriptomics/urinary proteomics and sCr identified by Ahmad and colleagues is likely attributable to differences in the intrinsic characteristics of sCr (delayed, insensitive, not specific to tubular damage) and the genetic responses of the kidney (rapid, sensitive, cell-specific, stimulus-specific).8,9,11 Then why are biomarkers of tubular injury, such as those measured by Ahmad and colleagues, not widely used in patients with decompensated HF to distinguish true tubular injury from changes in renal clearance function because of diuresis-driven hemoconcentration? Waikar and colleagues11 observed that in predictive modeling, the performance of biomarkers as measures of tubular injury is undermined by both use of sCr as the gold standard comparator and a lack of consideration of disease prevalence in the target population. Assuming that, at a certain cutoff value, sCr is 90% sensitive and 90% specific and disease prevalence is 20%, a new biomarker with 100% sensitivity and 100% specificity may seem to have only 69% sensitivity and 97% specificity in comparison with the imperfect gold standard.11 Therefore, changes in therapy of patients with acute HF based only on sCr increases rather than on biomarker and clinical data are problematic because of the kinetics and non-GFR determinants of creatinine, and because they may trigger adjustments in or discontinuation of symptom-improving and lifesaving antineurohormomal drugs and prevent effective decongestion.1,8,9,11,12Unfortunately, this fact is still viewed with skepticism despite the emerging evidence that unresolved congestion is strongly associated with poor outcomes.2,12 In comparison with healthy subjects, even asymptomatic patients with HF have decreased sodium excretion in response to volume expansion.1 Abnormal fluid handling is associated with physiological abnormalities in multiple organ systems. Increased myocardial water can lead to ischemia and decreased contractility in animals and humans.1 Deranged hemodynamics, neurohormonal activation, excessive tubular sodium reabsorption, inflammation, oxidative stress, and nephrotoxic medications are important drivers of harmful cardiorenal interactions in patients with HF.1 Elevation of central venous pressure is rapidly transmitted to the renal veins, causing increased interstitial and tubular hydrostatic pressure, which decreases net glomerular filtration.1 Increased central venous pressure is independently associated with renal dysfunction and unfavorable outcomes in both acute and chronic HF.1 Venous congestion itself can produce endothelial activation, upregulation of inflammatory cytokines, hepatic dysfunction, and intestinal villi ischemia. Bacterial endotoxins can then enter the circulation, magnifying the inflammatory milieu created by venous congestion and neurohormonal activity.1 Thus, the foremost goal in managing patients with decompensated HF is to effectively resolve fluid overload.1,12 If a decrease in intravascular volume by fluid removal causes small transient increases in sCr, effective decongestion may still be essential to protect the kidney in the long term.1,12Although there were no consistent changes in neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-d-glucosaminidase, and kidney injury molecule–1, suggesting that gross tubular injury cannot account for WRF (in particular, because these 3 biomarkers map to different parts of the nephron and display different mechanisms of activation), Ahmad et al found that a small subset of patients demonstrated increases in biomarker urinary concentrations in the range of tubular damage seen in previous studies (eg, the patients with delta NGAL>115 ng/mg urinary concentration).3,10 Yet even in these patients, an increase in biomarkers of tubular injury did not worsen outcomes, suggesting that fluid overload was a greater evil than some degree of renal tubular injury.1,3,12 In addition, NGAL, N-acetyl-β-d-glucosaminidase, and kidney injury molecule–1 levels in the cohort analyzed by Ahmad et al may have been magnified because they were indexed to urine creatinine (the denominator), which decreases with excretory abnormalities.13 Hence, it seems premature to equate changes in NGAL, N-acetyl-β-d-glucosaminidase, and kidney injury molecule–1 to injury even in the subset of patients with higher biomarker levels until thorough molecular and histological characterization is available for all renal cell types. Finally, is there a possibility that NGAL and kidney injury molecule–1 may be protective during AKI by, respectively, delivering iron and mediating phagocytosis?14,15Unquestionably, Ahmad and colleagues accomplish 2 important goals: they confirm that congestion is associated with poor outcomes in acute HF and shed light on the knowledge gaps in the identification of AKI and the assessment of its severity, because hemodynamically driven changes in sCr were not generally accompanied by changes in biomarkers of tubular damage. Although the absence of consistent changes in biomarkers supports continuation of decongestive treatments, increased confidence in these therapies will require documentation of WRF reversibility.DisclosuresDr Costanzo served as principal investigator for the AVOID-HF trial (Aquapheresis Versus Intravenous Diuretics and Hospitalization for Heart Failure); has received research support through her institution for the AVOID-HF trial; and served as a consultant for Axon Therapies and CHF Solutions. Columbia University is the assignee for biomarker patents developed by Dr Barasch.Footnoteshttp://circ.ahajournals.orgThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Maria Rosa Costanzo, MD, Advocate Heart Institute, Edward Heart Hospital, 4th Floor, 801 South Washington St, PO Box 3226, Naperville, IL 60566. E-mail [email protected]References1. Costanzo MR, Ronco C, Abraham WT, Agostoni P, Barasch J, Fonarow GC, Gottlieb SS, Jaski BE, Kazory A, Levin AP, Levin HR, Marenzi G, Mullens W, Negoianu D, Redfield MM, Tang WHW, Testani JM, Voors AA. Extracorporeal ultrafiltration for fluid overload in heart failure: current status and prospects for further research.J Am Coll Cardiol. 2017; 69:2428–2445. doi: 10.1016/j.jacc.2017.03.528.CrossrefMedlineGoogle Scholar2. Brisco MA, Zile MR, Hanberg JS, Wilson FP, Parikh CR, Coca SG, Tang WH, Testani JM. Relevance of changes in serum creatinine during a heart failure trial of decongestive strategies: insights from the DOSE trial.J Card Fail. 2016; 22:753–760. doi: 10.1016/j.cardfail.2016.06.423.CrossrefMedlineGoogle Scholar3. Ahmad T, Jackson K, Rao VS, Tang WHW, Brisco-Bacik MA, Chen HH, Felker GM, Hernandez AF, O'Connor CM, Sabbisetti VS, Bonventre JV, Wilson FP, Coca SG, Testani JM. 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Unique transcriptional programs identify subtypes of AKI.J Am Soc Nephrol. 2017; 28:1729–1740. doi: 10.1681/ASN.2016090974.CrossrefMedlineGoogle Scholar10. Nickolas TL, Schmidt-Ott KM, Canetta P, Forster C, Singer E, Sise M, Elger A, Maarouf O, Sola-Del Valle DA, O'Rourke M, Sherman E, Lee P, Geara A, Imus P, Guddati A, Polland A, Rahman W, Elitok S, Malik N, Giglio J, El-Sayegh S, Devarajan P, Hebbar S, Saggi SJ, Hahn B, Kettritz R, Luft FC, Barasch J. Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study.J Am Coll Cardiol. 2012; 59:246–255. doi: 10.1016/j.jacc.2011.10.854.CrossrefMedlineGoogle Scholar11. Waikar SS, Betensky RA, Emerson SC, Bonventre JV. Imperfect gold standards for kidney injury biomarker evaluation.J Am Soc Nephrol. 2012; 23:13–21. doi: 10.1681/ASN.2010111124.CrossrefMedlineGoogle Scholar12. Costanzo MR. Verdict in: congestion guilty!JACC Heart Fail. 2015; 3:762–764. doi: 10.1016/j.jchf.2015.06.004.CrossrefMedlineGoogle Scholar13. Waikar SS, Sabbisetti VS, Bonventre JV. Normalization of urinary biomarkers to creatinine during changes in glomerular filtration rate.Kidney Int. 2010; 78:486–494. doi: 10.1038/ki.2010.165.CrossrefMedlineGoogle Scholar14. Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, Schmidt-Ott KM, Chen X, Li JY, Weiss S, Mishra J, Cheema FH, Markowitz G, Suganami T, Sawai K, Mukoyama M, Kunis C, D'Agati V, Devarajan P, Barasch J. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115:610–621. doi: 10.1172/JCI23056.CrossrefMedlineGoogle Scholar15. Yang L, Brooks CR, Xiao S, Sabbisetti V, Yeung MY, Hsiao LL, Ichimura T, Kuchroo V, Bonventre JV. KIM-1-mediated phagocytosis reduces acute injury to the kidney.J Clin Invest. 2015; 125:1620–1636. doi: 10.1172/JCI75417.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zhang Q, Cai Z, Lin H, Han L, Yan J, Wang J, Ke P, Zhuang J and Huang X (2021) Expression, purification and identification of isotope-labeled recombinant cystatin C protein in Escheichia coli intended for absolute quantification using isotope dilution mass spectrometry, Protein Expression and Purification, 10.1016/j.pep.2020.105785, 178, (105785), Online publication date: 1-Feb-2021. Costanzo M (2021) Methods to Assess Intra- and Extravascular Volume Status in Heart Failure Patients Textbook of Cardiorenal Medicine, 10.1007/978-3-030-57460-4_15, (177-206), . Rocha N and McCullough P (2021) Type 2 Cardiorenal Syndrome Textbook of Cardiorenal Medicine, 10.1007/978-3-030-57460-4_8, (75-94), . Han X, Zhang S, Chen Z, Adhikari B, Zhang Y, Zhang J, Sun J and Wang Y (2020) Cardiac biomarkers of heart failure in chronic kidney disease, Clinica Chimica Acta, 10.1016/j.cca.2020.07.040, 510, (298-310), Online publication date: 1-Nov-2020. Zdanowicz A, Urban S, Ponikowska B, Iwanek G, Zymliński R, Ponikowski P and Biegus J (2022) Novel Biomarkers of Renal Dysfunction and Congestion in Heart Failure, Journal of Personalized Medicine, 10.3390/jpm12060898, 12:6, (898) May 8, 2018Vol 137, Issue 19 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.033343PMID: 29735590 Originally publishedJune 18, 2018 Keywordsdiuresisheart failurecreatinineglomerular filtration rateacute kidney injuryEditorialsPDF download Advertisement SubjectsCardiorenal Syndrome
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