Cystatin C as a Marker of Acute Kidney Injury in the Emergency Department

Department of Nephrology, Hospital Fernando Fonseca, Lisbon, Portugal.
Clinical Journal of the American Society of Nephrology (Impact Factor: 4.61). 10/2010; 5(10):1745-54. DOI: 10.2215/CJN.00690110
Source: PubMed


The diagnosis of acute kidney injury (AKI) is usually based on changes in serum creatinine, which is a poor marker of early renal dysfunction. The discriminative and predictive abilities of serum and urinary cystatin C were examined for the prediction of AKI.
In this prospective cohort study, serum and urinary cystatin C were serially measured in a heterogeneous group of patients (n = 616) presenting to a tertiary care emergency department. The primary outcome was AKI, classified according to RIFLE and AKIN criteria. The secondary outcome was an adjudication based on clinical criteria to AKI, prerenal azotemia, chronic kidney disease (CKD), and normal kidney function.
Patients were adjudicated to have AKI in 21.1%, prerenal azotemia in 25.8%, CKD in 2.4%, and normal kidney function in 50.7%. For the diagnosis of AKI, the discriminatory ability of urinary creatinine and cystatin C was marginal. Both serum cystatin C and serum creatinine (at presentation and 6 hours later) showed high discriminatory ability for the diagnosis of AKI. However, only serum cystatin C attained a significant early predictive power (Hosmer-Lemeshow P value > 0.05). Serum cystatin C could differentiate between AKI and prerenal azotemia, but not between AKI and CKD.
Serum cystatin C is an early, predictive biomarker of AKI, which outperforms serum creatinine in the heterogeneous emergency department setting. However, neither biomarker discriminated between AKI and CKD. Additional biomarkers continue to be needed for improved specificity in the diagnosis of community-acquired AKI.

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    • "Some maintain that attempting to clinically distinguish PRA from intrinsic kidney injury is not feasible and likely unnecessary as all AKI lies on a spectrum [18]. A limited number of non-cardiac surgery studies have had varying success in attempting to adjudicate AKI events and tease out the ability of novel biomarkers to distinguish PRA from direct tubular injury [10,14,15]. "
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    ABSTRACT: Adjudication of patient outcomes is a common practice in medical research and clinical trials. However minimal data exists on the adjudication process in the setting of Acute Kidney Injury (AKI) as well as the ability to judge different etiologies (e.g. Acute Tubular Necrosis (ATN), Pre-renal Azotemia (PRA)). We enrolled 475 consecutive patients undergoing cardiac surgery at four sites of the Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) study. Three expert nephrologists performed independent chart review, utilizing clinical variables and retrospective case report forms with pre intra and post-operative data, and then adjudicated all cases of AKI (n = 67). AKI was defined as a > 50% increase in serum creatinine for baseline (RIFLE Risk). We examined the patterns of AKI diagnoses made by the adjudication panel as well as association of these diagnoses with pre and postoperative kidney injury biomarkers. There was poor agreement across the panel of reviewers with their adjudicated diagnoses being independent of each other (Fleiss’ Kappa = 0.046). Based on the agreement of the two out of three reviewers, ATN was the adjudicated diagnosis in 41 cases (61%) while PRA occurred in 13 (19%). Neither serum creatinine or any other biomarker of AKI (urine or serum), was associated with an adjudicated diagnosis of ATN within the first 24 post-operative hours. The etiology of AKI after cardiac surgery is probably multi-factorial and pure forms of AKI etiologies, such as ATN and PRA may not exist. Biomarkers did not appear to correlate with the adjudicated etiology of AKI; however the lack of agreement among the adjudicators impacted these results. Trial registration NCT00774137
    BMC Nephrology 07/2014; 15(1):105. DOI:10.1186/1471-2369-15-105 · 1.69 Impact Factor
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    • "Given that filtered cystatin C is not normally present in the urine, urinary cystatin C may be also considered as a biomarker for early renal (proximal tubule) dysfunction/injury. Elevated urinary cystatin C levels have been demonstrated to differentiate intrinsic AKI from prerenal AKI and have a graded association with AKI severity (Park et al. 2013b), whilst serum cystatin C can better distinguish between AKI and non-AKI (Soto et al. 2010). Among biomarkers of intrinsic AKI, KIM-1 appears to be the only biomarker solely originating from renal proximal tubular cells whilst cystatin C originates from all nucleated cells; however, filtered cystatin C is reabsorbed by tubular cells as previously mentioned. "
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    ABSTRACT: Cardiovascular disease (CVD) and kidney disease are closely interrelated. Disease of one organ can induce dysfunction of the other, ultimately leading to failure of both. Clinical awareness of synergistic adverse clinical outcomes in patients with coexisting CVD and kidney disease or 'cardiorenal syndrome (CRS)' has existed. Renal dysfunction, even mild, is a strong independent predictor for adverse clinical outcomes in CVD patients. Developing therapeutic interventions targeting acute kidney injury (AKI) has been limited due mainly to lack of effective tools to accurately detect AKI in a timely manner. Neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 have been recently demonstrated to be potential candidate biomarkers in patients undergoing cardiac surgery. However, further validating AKI biomarkers is needed especially in the setting of acute decompensated heart failure and acute myocardial infarction where AKI commonly occurs. The other concern with regard to understanding the pathogenesis of renal complications in CVD is that mechanistically-oriented study has been relatively rare. Pre-clininal studies have shown that activation of renal inflammation-fibrosis processes, likely triggered by hemodynamic derangement, underlies CVD-associated renal dysfunction. On the other hand, it is postulated that there still are likely missing links in the heart-kidney connection in CRS patients with significant renal dysfunction. At present, nondialyzable protein-bound uremic toxins (PBUTs) appear to be the main focus in this regard. Evidence of the causal role of PBUTs in CRS has been increasingly demonstrated, mainly focusing on indoxyl sulfate (IS) and p-cresyl sulfate (pCS). Both IS and pCS are derived from colonic microbiotic metabolism of dietary amino acids, hence the colon has become a target of treatment in addition to efforts in improving dialysis techniques for better removal of PBUTs. Novel therapy targeting site of toxin production has led to new prospects in early intervention for predialysis patients with chronic kidney disease. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 06/2014; 592(18). DOI:10.1113/jphysiol.2014.273078 · 5.04 Impact Factor
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    • "Over the short term, however, early in the course of AKI, creatinine changes need not reflect trends in renal function and thus show poor association with outcomes when not coupled with similar changes in cystatin C levels. Cystatin C strongly associates with outcomes in multiple settings of AKI including ICU 9 , emergency room [7], and transplant [28]. Intriguingly, changes in cystatin C may be more specific to outcomes than creatinine. "
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    ABSTRACT: Background. Acute kidney injury (AKI) is a common and severe complication in patients with cirrhosis. Progression of AKI to a higher stage associates with increased mortality. Intervening early in AKI when renal dysfunction is worsening may improve outcomes. However, serum creatinine correlates poorly with glomerular filtration in patients with cirrhosis and fluctuations may mask progression early in the course of AKI. Cystatin C, a low-molecular-weight cysteine proteinase inhibitor, is a potentially more accurate marker of glomerular filtration. Methods. We conducted a prospective multicenter study in patients with cirrhosis comparing changes in cystatin and creatinine immediately following onset of AKI as predictors of a composite endpoint of dialysis or mortality. Results. Of 106 patients, 37 (35%) met the endpoint. Cystatin demonstrated less variability between samples than creatinine. Patients were stratified into four groups reflecting changes in creatinine and cystatin: both unchanged or decreased 38 (36%) (Scr-/CysC-); only cystatin increased 25 (24%) (Scr-/CysC+); only creatinine increased 15 (14%) (Scr+/CysC-); and both increased 28 (26%) (Scr+/CysC+). With Scr-/CysC- as the reference, in both instances where cystatin rose, Scr-/CysC+ and Scr+/CysC+, the primary outcome was significantly more frequent in multivariate analysis, P = 0.02 and 0.03, respectively. However, when only creatinine rose, outcomes were similar to the reference group. Conclusions. Changes in cystatin levels early in AKI are more closely associated with eventual dialysis or mortality than creatinine and may allow more rapid identification of patients at risk for adverse outcomes.
    International Journal of Nephrology 03/2014; 2014:708585. DOI:10.1155/2014/708585
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