March 2010 Clinical Laboratory News: Diagnostic Profiles

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March 2010: Volume 36, Number 3

NT-proBNP, CRP Add to Risk Prediction for Perioperative Cardiovascular Events

New research indicates that both N-terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) are strong and independent predictors of perioperative major cardiovascular events (PMCE) in non-cardiac surgery. The findings suggest that the two biomarkers could add significantly to the predictive value of current clinical risk evaluation methods, such as the revised cardiac risk index (RCRI) (Heart 2010; 96:56–62).

The study involved 2,054 prospectively enrolled patients who were referred to a consulting cardiologist for evaluation of preoperative cardiovascular risk. The patients were scheduled for elective non-cardiac surgery but had at least one cardiovascular risk factor such as hypertension or diabetes, or abnormal electrocardiography (ECG). NT-proBNP and CRP levels were measured within 2 weeks of surgery, and preoperative cardiovascular risk was assessed using RCRI, which assigns points to risk factors such as history of ischemic heart disease and pulmonary edema. Prior research had shown that RCRI scores of 0 to ≥3 corresponded to a 0.4% to 11% risk of a major cardiac event, including myocardial infarction (MI) and pulmonary edema.

The study’s primary endpoint was PMCE, defined as any single or combined event of secondary endpoints including MI, onset of pulmonary edema, or primary cardiovascular death. Ultimately, PMCE developed in 14.1% of patients.

The researchers evaluated increasing RCRI score, and increasing quartiles of NT-proBNP and CRP as risk predictors of PMCE, and found that all three were associated with greater risk of PMCE. They also discovered that each variable was related to clinical outcomes independently of each other. Each standard deviation increase in RCRI, log CRP, or log NT-proBNP was associated with a 1.3–2.2-fold increased rate of PMCE after adjustment for other risk predictors and risk factors. The researchers also found that adding NT-proBNP and CRP to RCRI increased the adjusted relative risk from 1.5 to 4.55, suggesting that the predictive power of RCRI could be strengthened significantly when used with the two biomarkers.

Low Blood Lead Levels in Adolescents Linked to Reduced Kidney Function

According to a newly published study, blood lead levels below the current CDC-designated level of concern in children are associated with lower estimated glomerular filtration rate (GFR) in adolescents (Arch Intern Med 2010;170:75–82). This analysis, which is one of the largest examining the association between lead levels and kidney function in children, suggests that more attention should be paid to the effects of low-level environmental lead exposure, even in young populations generally free of comorbidities that typical contribute to chronic kidney disease (CKD).

The study builds on a growing body of evidence in adults exploring the link between low-level lead exposure and kidney function. In 1991, CDC lowered the blood lead level of concern for children from 30 to 10 µg/dL based on studies linking blood lead levels as low as 10 µg/dL to neurodevelopmental effects. While subsequent research has bolstered the premise that chronic lead exposure <10 µg/dL negatively impacts cognitive and cardiovascular function in children and adolescents, the same type of analysis involving kidney function has been challenging due to the high variability and low sensitivity of serum creatinine measurements used to estimate GFR. Investigators in this study had the advantage of being able to use a pediatric-specific cystatin C-based eGFR equation, with serum cystatin C levels measured as part of the Third National Health and Nutrition Examination Study (NHANES III). The study population included 769 adolescents between the ages of 12 and 20 who participated in NHANES III.

The researchers found that nearly all the participants had blood lead levels <10 µg/dL, with the median level being 1.5 µg/dL, and median cystatin C-eGFR of 112.9 mL/min/1.73m2. Linear regression analysis showed that higher blood lead levels were consistently associated with lower eGFR, and that participants with lead levels in the highest quartile had a 6.6 mL/min/1.73m2 eGFR compared with those in the lowest quartile. In a model adjusted fully for factors such as age, sex, and race, doubling of blood lead levels was associated with a 2.9 mL/min/1.73m2-lower eGFR. The investigators also used a creatinine-based eGFR equation, which also showed an inverse, albeit weaker, association between blood lead level and eGFR.

Combined Use of H-FABP, cTn T Leads to Misclassification of Patients with Suspected MI

An analysis comparing the usefulness of heart-type fatty acid binding protein (H-FABP) in comparison with and in addition to cardiac troponin T (cTn T) in patients with suspected acute myocardial infarction (AMI) revealed that while H-FABP had higher sensitivity than cTn T during the first 4 hours of symptoms, it had poor specificity (Am J Cardiol 2010; 105:1–9). Using both H-FABP and cTn T results also improved sensitivity and negative predictive value in detecting AMI within the first 4 hours of symptom onset, but with specificity significantly lower than for cTn T alone. The latter finding resulted in a lower combined overall test accuracy and greater misclassification of patients than when cTn T alone was used, particularly in patients with non-ST elevation MI.

Although both cTn I and T dramatically changed the workup for patients presenting with suspected AMI and lead to a redefinition of MI in 2000, a number of studies have reported low sensitivity for these biomarkers within the first 6–12 hours of symptom onset. H-FABP has been proposed as a timelier marker for AMI diagnosis because of its high sensitivity shortly after symptom onset, and studies in selected study populations have shown favorable diagnostic results with H-FABP. However, there has not been an extensive analysis of H-FABP in the setting of complex diagnostic decision-making involving unselected patients, so the researchers designed their study to evaluate the use of H-FABP in 97 consecutive unselected patients presenting to the emergency department with ischemic-type chest pain.

As expected, cTn T sensitivity for diagnosing AMI was lowest when symptom duration was <4 hours, but increased to 100% when symptom duration was >4 hours. H-FABP sensitivity was higher than cTn T among patients admitted within 4 hours of symptom onset, and was greatest between 2–4 hours. However, H-FABP sensitivity declined after 8 hours, and the specificity for H-FABP was significantly lower than cTn T in all subgroups and for all periods. When evaluating use of the markers together, the researchers found a significantly greater early sensitivity compared with cTn T alone, but a much lower specificity. Consequently they concluded that “greater sensitivity for an early diagnosis of AMI using a combined test can only be achieved with a marked loss in overall diagnostic test efficiency and a greater misclassification rate.”

Serum Calcium Levels Linked to Higher Mortality in Non-Dialysis-Dependent Chronic Kidney Disease

New research indicates that both chronic hypercalcemia and acute hypocalcemia are associated with increased mortality in patients with moderate or advanced non-dialysis-dependent chronic kidney disease (NDD CKD) (Clin J Am Soc Nephrol 2010; doi:10.2215/CJN.06040809).The findings, among the first to examine the relationship between abnormal calcium levels and mortality in NDD CKD patients, suggest that while lower calcium levels can have short-term harmful effects, abnormally high levels also can be injurious over longer periods of time.

The results illustrate “calcium’s complex pathophysiologic role in humans, which varies from that of a rapidly fluctuating intracellular messenger to that of a stable component of skeletal structure,” according to the authors.

The study involved 1,259 male patients evaluated for NDD CKD with a medium of 18 calcium measurements taken during a medium follow-up of 3.2 years. The primary outcome measure was overall all-cause mortality. Baseline, time-varying, and time-averaged serum calcium levels were associated with all-cause mortality using Cox models adjusted for a variety of factors. Higher baseline calcium and time-average calcium were associated with higher mortality. However, in time-varying analyses, lower calcium levels were associated with increased mortality.

The researchers concluded that maintaining normal serum calcium levels may be beneficial in patients with NDD CKD, although they emphasized that prospective studies would be needed to determine a target range for serum calcium and how this target should be achieved to realize the greatest therapeutic potential.

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