suPAR: Long-Sought Early Warning Indicator of CKD?
In a prospective study of more than 3,600 participants, soluble urokinase-type plasminogen activator receptor (suPAR) was independently associated with development of chronic kidney disease (CKD) and accelerated decline in estimated glomerular filtration rate (eGFR) (N Engl J Med 2015;373: 1916–25).
The findings suggest suPAR—the circulating form of a protein involved in regulating cell adhesion and migration through binding of integrins—could be the long-sought early warning indicator for CKD, according to senior author Jochen Reiser, MD, PhD. “SuPAR promises to do for kidney disease what cholesterol has done for cardiovascular disease,” he said in a prepared statement.
Reiser and his colleagues previously found suPAR to be implicated in the pathogenesis of focal segmental glomerulosclerosis and diabetic nephropathy. They further investigated suPAR’s association with CKD as part of the Emory Cardiovascular Biobank, a prospective registry of patients undergoing cardiac catheterization, and in a subgroup of participants in the Women’s Interagency HIV Study.
The researchers measured suPAR and serum creatinine at baseline and in follow-up assessments and calculated eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation. They divided patients into four quartiles based on baseline suPAR levels, ranging from lowest (< 2,373 pg/mL) to highest (> 4,020 pg/mL). The authors found that higher baseline suPAR levels were associated with greater declines in eGFR during follow-up. The annual change in eGFR was -0.9 mL per minute per 1.73 m2 among participants in the lowest baseline quartile of suPAR levels, compared with -4.2 mL per minute per 1.73 m2 among those in the highest quartile. Higher baseline suPAR levels had the greatest effect on patients with normal eGFR. In fact, 40% of participants with high suPAR levels but healthy eGFR at baseline went on to develop CKD within 5 years, whereas just 10% of those with low baseline suPAR levels did so. In sensitivity analysis suPAR level remained independently associated with eGFR decline regardless of race or diabetes status.
Based on these findings the researchers suggested that suPAR meets important requirements as a biomarker of CKD, including that: suPAR levels are relatively stable in plasma; suPAR adds prognostic value in all patients; it is associated with CKD in both blacks and whites despite the “marked differences” in their respective likelihood of CKD; and measuring suPAR enables risk stratification early in the course of CKD, thereby enabling treatment and/or prevention strategies.
Pancreatic Cancer Treatment Based on CA 19-9 Levels Could Improve Outcomes
In an abstract presented at the Western Surgical Association 2015 Annual Scientific Sessions, Mayo Clinic researchers reported that changing the standard sequence of treatment for pancreatic ductal adenomacarcinoma (PDAC) based on CA 19-9 levels could improve survival for some patients. The common practice for PDAC involves surgical removal of the tumor, followed by chemotherapy.
In their analysis of more than 90,000 cases in the National Cancer Database, the researchers found that patients with elevated CA 19-9 levels > 37 U/mL had poorer outcomes at 1, 2, and 3 years versus those with CA 19-9 levels < 37 U/mL, whether they had surgery alone or surgical resection followed by chemotherapy. However, when patients had chemotherapy first followed by surgical resection, the risk associated with elevated CA 19-9 was mitigated.
“This is another argument for giving chemotherapy before surgery in all pancreatic cancer patients and ending the old practice of surgery followed by chemo,” said senior author Mark Truty, MD. “The study answers an important clinical question and applies to every pancreatic cancer patient being considered for surgery.”
Truty and his colleagues also found that elevated CA 19-9 had the most detrimental effect on outcomes in patients diagnosed with Stage 1 disease. Among these patients, 9.5% did not have measurable CA 19-9 levels, 22.5% had normal levels, and 68% had elevated levels.
In addition, the investigators discovered that just 19% of patients had CA 19-9 levels measured at the time of diagnosis, and they argued that it should be a standard part of the work-up for PDAC. “Our conclusion is that every patient should have a CA 19-9 test at diagnosis. This is a simple, cheap, and widely available test that allows personalization of pancreatic cancer treatment,” said Truty.
Wide Variability in TPO Autoantibody Immunoassays
Despite efforts by manufacturers towards harmonization, researchers seeking to establish upper reference limits (URLs) for thyroid peroxidase autoantibodies (TPOAbs) with six immunoassays found a wide intra-assay dispersion of values and URLs lower than those recommended by the manufacturers (Clin Chem Acta 2016;452:61–5). The findings suggest the need for further studies looking at TPO antigen preparations as the potential source of variability among the assays.
TPOAbs are important in diagnosing autoimmune thyroid diseases, (AITDs) especially Hashimoto’s thyroiditis. Third-generation, automated quantitative immunoassays to measure TPOAbs have higher sensitivity and specificity than predecessor assays and have been adopted widely in clinical practice. However, questions have been raised about recommended procedures and rationale for establishing URLs. For example, National Academy of Clinical Biochemistry (NACB) guidelines recommend establishing URLs based on a reference group of healthy young men, when AITDs primarily affect women.
This led the investigators to determine URLs for 120 males and 120 females meeting recommended NACB characteristics using six different immunoassays. With the exception of one assay, the researchers found URLs lower than those recommended by the manufacturers, with differences ranging from 2.5% to 71.4%. They also found statistically significant differences between median and URL male and female values for two assays; however, further analysis determined these variances were not important clinically. The latter confirms the NACB recommendations for establishing URLs for TPOAbs, according to the authors.
GFAP Detects Traumatic Brain Injury in Children
New research indicates that glial fibrillary acidic protein (GFAP) measured within 6 hours of injury is a promising traumatic brain injury (TBI) marker in children, and if validated in other studies, could help reduce the number of computed tomography (CT) scans in pediatric patients (Acad Emerg Med 2015;22:1274–82).
“This could ultimately change the way we diagnose concussions, not only in children, but in anyone who sustains a head injury,” said lead author Linda Papa, MD, MSC, in a prepared statement. “We have so many diagnostic blood tests for different parts of the body, like the heart, liver, and kidneys, but there’s never been a reliable blood test to identify trauma in the brain. We think this test could change that.”
Prior research has shown GFAP as a potential brain-specific biomarker for mild and moderate TBI. Interest has mounted in finding a sensitive and specific TBI marker for children as evidence has surfaced about the potential risks of diagnostic imaging in children.
The prospective study involved 257 children who presented to participating emergency departments following blunt head trauma, as well as healthy controls. Patients had CT scans and blood samples taken within 6 hours of injury. In all, 11% of patients showed traumatic intracranial lesions on CT, and their GFAP levels were significantly higher than those without lesions. At a cutoff of 0.15 ng/mL, GFAP had a sensitivity of 94% and specificity of 47% in detecting intracranial lesions on CT, and a negative-predictive value of 98%.