Robert L. Fitzgerald

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication

RATIONALE We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. OBJECTIVES We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. METHODS We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. MEASUREMENTS AND MAIN RESULTS Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). CONCLUSIONS Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: The NGAL EvaLuation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial

Neutrophil gelatinase‐associated lipocalin (NGAL) is a measure of acute kidney injury. Renal dysfunction portends significant risk after discharge from acute heart failure (AHF). Thus, a sensitive marker of renal injury might also help to risk stratify HF patients.

Ninety-minute accelerated critical pathway for chest pain evaluation

Rapid, efficient, and accurate evaluation of chest pain patients in the emergency department optimizes patient care from public health, economic, and liability perspectives. To evaluate the performance of an accelerated critical pathway for patients with suspected coronary ischemia that utilizes clinical history, electrocardiographic findings, and triple cardiac marker testing (cardiac troponin I [cTnI], myoglobin, and creatine kinase-MB [CK-MB]), we performed an observational study of a chest pain critical pathway in the setting of a large Emergency Department at the Veterans Affairs Medical Center in 1,285 consecutive patients with signs and symptoms of cardiac ischemia. The accelerated critical pathway for chest pain evaluation was analyzed for: (1) accuracy in triaging of patients within 90 minutes of presentation, (2) sensitivity, specificity, positive predictive value, and negative predictive value of cTnI, myoglobin, and CK-MB in diagnosing acute myocardial infarction (MI) within 90 minutes, and (3) impact on Coronary Care Unit (CCU) admissions. All MIs were diagnosed within 90 minutes of presentation (sensitivity 100%, specificity 94%, positive predictive value 47%, negative predictive value 100%). CCU admissions decreased by 40%. Ninety percent of patients with negative cardiac markers and a negative electrocardiogram at 90 minutes were discharged home with 1 patient returning with an MI (0.2%) within the next 30 days. Thus, a simple, inexpensive, yet aggressive critical pathway that utilizes high-risk features from clinical history, electrocardiographic changes, and rapid point-of-care testing of 3 cardiac markers allows for accurate triaging of chest pain patients within 90 minutes of presenting to the emergency department.

Immunoassays for Testosterone in Women: Better than a Guess?

Recent developments in the field of mass spectrometry have provided the accuracy and sensitivity to evaluate very-low-abundance steroids such as testosterone in female and pediatric patients. In this issue of Clinical Chemistry , Taieb et al. (1) present the most comprehensive evaluation of automated testosterone immunoassays to date. They compared 10 commercially available immunoassays with isotope-dilution gas chromatography–mass spectrometry (ID-GC/MS) and reached the inescapable conclusion that testosterone immunoassay results for specimens from females are inaccurate. Similar data have been reported for individual testosterone immunoassays previously (2), but Taieb et al. (1) are the first to show that for every commercially available testosterone assay studied, the values are in error—by a factor of 2 on average and in some cases by a factor of almost 5. Are assays that miss target values by 200–500% meaningful? Guessing would be more accurate and additionally could provide cheaper and faster testosterone results for females—without even having to draw the patient’s blood. By limiting all guesses to a narrow range, e.g., 2.04–2.44 nmol/L, the results would rarely be off by more than a factor of 3. Using a random number generator, we generated values close to the average female concentration measured by Taieb et al. (they were kind …

Serial Sampling of ST2 Predicts 90-Day Mortality Following Destabilized Heart Failure

BACKGROUND To prospectively determine the prognostic utility of serial sampling of the interleukin-1 receptor family member, ST2, for predicting 90-day mortality in patients with heart failure (HF) admitted to a Veteran Affairs Medical Center. METHODS AND RESULTS A total 150 patients hospitalized with acutely destabilized HF were followed at the Veteran Affairs Healthcare System in San Diego, CA. Multiple cardiac-related parameters were measured including ST2, B-type natriuretic peptide (BNP), NT-proBNP, and blood urea nitrogen (BUN). Plasma samples were collected at 6 time points between admission and discharge. Biomarker concentrations were correlated to survival at 90 days. Uni- and multivariate analyses were used to identify prognostic variables. From admission to discharge, percent change in ST2 was strongly predictive of 90-day mortality: those patients whose ST2 values decreased by 15.5% or more during the study period had a 7% chance of death, whereas patients whose ST2 levels failed to decrease by 15.5% in this time interval had a 33% chance of dying. CONCLUSIONS Percent change in ST2 concentrations during acute HF treatment is predictive of 90-day mortality and was independent of BNP or NT-proBNP levels. ST2 may provide clinicians with an additional tool for guiding treatment in patients with acute destabilized HF.

Pro-B-Type Natriuretic Peptide Levels in Acute Decompensated Heart Failure

OBJECTIVES The present study sought to evaluate the clinical utility of pro-B-type natriuretic peptides (proBNP) in patients admitted with acute decompensated heart failure. BACKGROUND Plasma natriuretic peptides (BNP(1-)(32), N-terminal [NT]-proBNP(1-76)) have been demonstrated to assist in the diagnosis of patients with heart failure. However, the precursor to these polypeptides (proBNP(1-108)) circulates in plasma and may interfere with the measurement of currently used biomarkers. METHODS Plasma natriuretic peptides were assessed in 164 individuals (99% men) hospitalized with decompensated heart failure. The B-type natriuretic peptide (BNP), NT-proBNP, and proBNP levels at hospital admission and discharge were compared with the incidence of cardiac death and all-cause mortality within 90 days post-discharge. RESULTS Pro-B-type natriuretic peptides demonstrated a high degree of correlation with both BNP (R = 0.924, p < 0.001) and NT-proBNP (R = 0.802, p < 0.001) at admission. Further characterization of proBNP demonstrated little variation with changes in age, body mass index, creatinine, or systolic dysfunction. All 3 plasma natriuretic peptides were significantly elevated at admission in patients suffering a cardiac death or all-cause mortality (p < 0.05). Receiver-operating characteristic curves demonstrated that admission and discharge NT-proBNP (area under the curve [AUC] 0.788 and AUC 0.834) had superior prognostic power for all-cause mortality when compared with BNP (AUC 0.644, p < 0.01 and AUC 0.709, p < 0.01) and proBNP (AUC 0.653, p < 0.01 and AUC 0.666, p < 0.01) at the same time points. CONCLUSIONS Admission values of all natriuretic peptides can be used to predict cardiac death and all-cause mortality. A preliminary comparison suggests that discharge values of NT-proBNP have the greatest diagnostic yield for predicting these end points. Further studies should explore the synergistic prognostic potential of all natriuretic peptides.

Correlation and Prognostic Utility of B-Type Natriuretic Peptide and Its Amino-Terminal Fragment in Patients With Chronic Kidney Disease

This study compared the correlation and prognostic utility of B-type natriuretic peptide (BNP) and the N-terminal fragment of proBNP (NT-proBNP) in 171 outpatients with renal dysfunction. The NT-proBNP correlated well with BNP in all cases (r = 0.911; P pound .01), regardless of degree of renal impairment or type of left ventricular dysfunction. BNP and NT-proBNP concentrations (P < .005) and their ratios (P pound .01) increased as the glomerular filtration rate (GFR) declined, indicating a greater effect of GFR on NT-proBNP levels. Both natriuretic peptide levels were higher in patients with systolic dysfunction (P < .05) compared with patients with normal echocardiograms. In contrast, BNP and NT-proBNP levels were below the diagnostic cutoffs for congestive heart failure exacerbations in patients with normal heart function or diastolic dysfunction, with no statistical difference between these groups (P = .99). Both peptides are useful prognostic tools for predicting mortality and cardiac hospitalization in renal patients.

Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of >90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD.

Mitigation of the clinical significance of spurious elevations of cardiac troponin I in settings of coronary ischemia using serial testing of multiple cardiac markers.

The ability to differentiate between true positives, false positives, and sporadically elevated cardiac troponin levels has grown in importance as cardiac troponins assume an increasingly dominant role in the diagnosis of coronary syndromes. In a population sample of 1,000 patients who presented consecutively to a large urban hospital emergency room, 50 of 112 patients who had elevated troponin levels (> 0.6 ng/ml) during evaluation for myocardial injury were subsequently found to have had an isolated, spurious elevation of cardiac troponin, and not a diagnosed myocardial infarction. Logistic regression analysis shows that by hierarchically analyzing electrocardiographic changes with concurrent creating kinase-MB and myoglobin levels at the time of the troponin elevation, one may predict with 91% accuracy whether the troponin elevation is actually indicative of a myocardial infarction in a patient. Spurious troponin elevations may be a common occurrence, and if not detected, may result in an increased number of falsely diagnosed myocardial infarctions.

Educating medical students in laboratory medicine: a proposed curriculum.

As the 100th anniversary of the Flexner report nears, medical student education is being reviewed at many levels. One area of concern, expressed in recent reports from some national health care organizations, is the adequacy of training in the discipline of laboratory medicine (also termed clinical pathology). The Academy of Clinical Laboratory Physicians and Scientists appointed an ad hoc committee to review this topic and to develop a suggested curriculum, which was subsequently forwarded to the entire membership for review. The proposed medical student laboratory medicine curriculum defines goals and objectives for training, provides guidelines for instructional methods, and gives examples of how outcomes can be assessed. This curriculum is presented as a potentially helpful outline for use by medical school faculty and curriculum committees.