Clinical Chemistry Podcast

Maintaining high ethical standards is a characteristic we expect in many professionals, but perhaps most in the field of medicine. Although biomedical ethics is a relatively new field, there have been discussions of moral issues in medicine since ancient times. The Hippocratic Oath, for instance, was written by Hippocrates at approximately 400 B.C. It requires that a new physician swear to uphold specific ethical standards. Over 2000 years later new physicians still swear by the Hippocratic or a similar oath. The December 2019 issue of Clinical Chemistry published a Review paper that provides a broad overview of ethics as it pertains to laboratory medicine.

Science is not just based on interesting findings. One of the key elements in research reports is an informative description of the methods that were used to develop the experiment, to collect the data, and to analyze them. Since this process rests on replication, reporting of methods is essential as it allows others to stage a similar experiment, to design an identical study, and to evaluate whether the findings can be replicated. If they cannot be reproduced, the outcomes from the previous experiment or trial will gradually or immediately lose credibility. A recent editorial on this topic appeared in the December 2019 issue of Clinical Chemistry.

Circular RNAs have the unique topological feature of circularity among the RNAs species. They are single-stranded, covalently closed, circular RNA molecules and are hypothesized to be generated largely through back-splicing of exons from precursor messenger RNAs. Circular RNAs were once considered as aberrant splicing by-products, which were only present in minute amounts in cells. The potential of this RNAs species as a disease biomarker is to be explored, but there are biological properties of circular RNAs which make them suitable for biomarker development. An Editorial appearing in the October 2019 issue of Clinical Chemistry by Drs. Jacky Lam and Dennis Lo discussed circular RNAs as potential urinary biomarkers.

Heart failure is a leading cause of morbidity and mortality worldwide with prevalence expected to increase over the next 20 years. Early diagnosis and optimal management of heart failure are key to reducing its impact. Because B-type natriuretic peptide, or BNP, and amino terminal proBNP, or NT-proBNP, as well as their precursor proBNP, are secreted by the heart in direct proportion to the degree of cardiac dysfunction and clinical severity, measurement of these peptides is now mandated by authoritative international guidelines for the diagnosis and risk stratification of the disease. However, circulating concentrations of both BNP and NT-proBNP are reduced by obesity, and this phenomenon is one of the key weaknesses of the diagnostic performance of the natriuretic peptides in heart failure. A paper appearing in the September 2019 issue of Clinical Chemistry shows that obesity is associated with decreased concentrations of proBNP that is not glycosylated at threonine at position 71 of the peptide. Decreased proBNP substrate amenable to processing could partially explain the lower NT-proBNP and BNP concentrations measured in obese individuals, including those presenting with heart failure.

Measurement of plasma adrenocorticotropic hormone, or ACTH, is key in the differential diagnosis of hypothalamic pituitary adrenal disorders. Two-site sandwich immunoassay dominate clinical testing of ACTH in North America. However, discordant results among different assays have been repeatedly reported. To help resolve this discrepancy, a multicenter effort developed a liquid chromatography tandem mass spectrometry assay for the intended measurand, that is the biologically active intact ACTH. A report on that initiative appears in the November 2019 issue of Clinical Chemistry. We are pleased to have the senior author of that paper , Dr. Mari DeMarcoas our guest in this podcast.

Obesity is on the rise worldwide and it's a risk factor for systemic hypertension, hyperlipidemia, diabetes mellitus, and left ventricular hypertrophy, all of which are conditions associated with an increased prevalence of heart failure. However, the applications of BNP and NT-proBNP as biomarkers in obese patients are limited, as the relationship between their levels and myocardial stiffness is complex. An Editorial appearing in the September 2019 issue of Clinical Chemistry examines the interrelationship between obesity and BNP and NT-proBNP measurements.

A paper appearing in the October 2019 issue of Clinical Chemistry found that fragments of proCNP could be measured in urine from subjects with diabetes mellitus. The urinary NT-proCNP to creatinine ratio was also more reproduceable than the now commonly used albumin to creatinine ratio and strongly associated with the presence of chronic kidney disease.

Sacubitril/Valsartan, known as Entresto, is a new dual drug therapy that includes an angiotensin receptor inhibitor and is indicated to reduce the risk of cardiovascular death and hospitalization in patients with chronic heart failure. Since its approval for the treatment of chronic heart failure with reduced injection fraction, a commonly raised question is whether treatment with this drug challenges the use of B-type natriuretic peptide, or BNP, testing compared to the N terminal proBNP assay because Sacubitril may interfere with BNP clearance. The clinical and analytical studies addressing this issue are limited, along with the fact the diversity of both BNP and NT-proBNP assays used in clinical laboratory practice have not been adequately evaluated in clinical trials or studies to provide an evidenced-based on final decision as to what assay or assays should be used or eliminated from use when a patient is on Entresto. In the September 2019 issue of Clinical Chemistry, a Q&A feature titled, "Role of BNP vs NT-proBNP Testing in the Age of New Drug Therapies" asked five experts with different roles in this field to discuss this issue.

Overutilization of laboratory services is an important unresolved issue in health care. A recent study that appears in the September 2019 issue of Clinical Chemistry attempts to address this issue. That paper titled " Once-Per-Visit Alerts: A Means to Study Alert Compliance and Reduce Repeat Laboratory Testing," examined reorders of a laboratory test within the same admission.

B-type natriuretic peptides, or BNP, and N-terminal proBNP, or NT-proBNP, are peptides produced in the heart in response to increased wall stretch and volume overload. Their production and secretion increases in the heart with the progression of heart failure and they have emerged as useful heart failure biomarkers. Since the discovery of BNPs in the 1980s, much effort has been made to precisely determine the BNP and NT-proBNP levels via immunoassays for reliable heart failure diagnostics. Entresto™ is a new heart failure therapy that includes sacubitril as one of its components. Sacubitril is a specific inhibitor of neprilysin. This is a zinc-dependent metalloproteinase that cleaves various peptides including BNP. In fact, augmentation of circulating BNP due to neprilysin inhibition is considered as a possible mechanism of Entresto's positive effects. A paper appearing in the October 2019 issue of Clinical Chemistry examines the circulating products of BNP proteolysis by neprilysin and how they might reflect impact on the metabolism of active BNP.

In the August 2019 issue of Clinical Chemistry, a Q&A feature titled "Optimal Use of Biomarker for Chronic Kidney Disease" asked five experts in laboratory medicine and nephrology to examine laboratory ordering, testing, and reporting practices, and recommend how those practices should be optimized to better serve patients with CKD. In this podcast, Dr. Greg Miller from the Department of Pathology at Virginia Commonwealth University in Richmond who moderated the Q&A will summarize the expert advice from his colleagues.