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Clinical Laboratory Strategies: May 28, 2009

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Assessing Risk for Pancreatic Necrosis
Serum Creatinine Found to be Highly Specific Marker
By Gina Rollins  

Pancreatic necrosis is a serious, even life-threatening complication of acute pancreatitis that requires aggressive treatment to forestall or limit its effects. Several algorithms predict risk for developing the condition, but they are cumbersome to use and some require physiologic measurements that are not performed routinely. An elevated hematocrit has been associated with development of pancreatic necrosis, but the authors of a new study hypothesize that serum creatinine, another analyte affected by plasma volume, might be predictive of the condition. This issue of Strategies examines those findings.

Acute pancreatitis (AP) is a common but serious disorder that results in about 210,000 hospitalizations in the U.S. each year. An estimated 15% of AP patients subsequently develop pancreatic necrosis (PN), a complex process that causes an intense inflammatory response, a variety of complications, longer hospitalization, and significant morbidity and mortality, particularly when the necrotic area becomes infected. PN is associated with severely diminished blood flow to the pancreas, and typically is detected via contrast-enhanced computed tomography (CECT) or magnetic resonance imaging. Some studies have determined that PN occurs within 2 to 4 days of an AP episode, while others have found that the condition develops later, even after hospital discharge.

In Search of Better Markers

Previous research has demonstrated that a hematocrit ≥44% is associated with development of PN, but the test has a relatively low positive predictive value, ranging from 21% to 62%. Urea nitrogen (BUN) is a component of one of the algorithms for determining the severity of AP, but tends to be sensitive to mild intravascular volume changes. The various pancreatitis severity algorithms, such as Ranson’s Criteria for Pancreatitis Mortality, tend not to be used in everyday clinical practice and some of the measures the algorithms use to determine a patient’s risk, such as lactate dehydrogenase, are not ordered routinely. A variety of other analytes have been examined as potential biomarkers of PN, but most have been employed for research purposes only. The authors of the new study hypothesized that since renal function is impacted by the same severe intravascular blood volume depletion and associated stress response that leads to PN, elevated serum creatinine levels, a marker of kidney injury, would likewise be an indicator of risk for PN (Am J Gastroenterol 2009;104:164-172). Their prospective study of 185 patients was aimed at discerning the association between routine lab tests like serum creatinine, BUN, and hematocrit, and development of PN in patients with AP.

"We wanted to find a simple marker that would identify patients at risk for PN," explained lead author Venkata Muddana, MD, a gastroenterology fellow at the University of Pittsburgh School of Medicine. "Hematocrit, BUN, and creatinine are routine lab markers that are checked every day in hospitalized patients, but hematocrit has poor positive predictive value, and once the blood supply is restored to the kidneys, BUN reverts to normal. But creatinine only goes up when kidney tubules are necrosed or at risk for necrosis because of prolonged hypoperfusion. So we have two organs that are getting hit by this

volume depletion, and we thought that this measure of kidney injury would be directly showing us what was happening in the pancreas too."

Early identification and treatment of patients likely to develop PN is essential in mitigating the serious problems associated the disorder, according to Mark DeLegge, MD, professor of medicine and director of the Digestive Disease Center at the Medical College of South Carolina in Charleston. "The interventions have to be done early-on. You want these patients in the ICU, on antibiotics and intravenous fluids, and you want to be ready to take them to surgery if things go south. They need a tremendous amount of treatment rapidly," he explained. DeLegge was not involved in the study.

All patients enrolled in the study were recruited within 24 hours of admission and had a diagnosis of AP based on the presence of two of three criteria, including abdominal pain characteristic of AP, serum amylase and/or lipase ≥3 times the upper limit of normal, and characteristic findings of AP based on CT scan. Only the 135 patients who underwent CECT during their admission were included in the final analysis, and CECT was used to diagnose PN.

Receiver operating characteristic curves had an area under the curve of 0.79 for admission hematocrit, 0.78 for peak hematocrit, 0.72 for admission creatinine, 0.77 for peak creatinine within 48 hours, 0.60 for admission BUN and 0.72 for peak BUN within 48 hours, respectively. Admission hematocrit, peak creatinine, and peak BUN all were significantly higher in patients with PN than without. A multivariate logistic regression step-up model assessing these three criteria as continuous measures confirmed statistical significance for admission hematocrit and peak creatinine but not for peak BUN. In univariate analysis, admission hematocrit ≥44.8% resulted in a high negative predictive value of 88.5%, while peak creatinine >1.8mg/dL within 48 hours had both high specificity (98.9%) and positive predictive value (93.3%) as indicators for the development of PN. Significantly, 14 out of 15 patients with peak creatinine >1.8mg/dL within 48 hours developed PN.

If confirmed in larger, multi-institutional trials, the study could have a significant impact on the diagnosis and management of PN, according to DeLegge. "The negative predictive value of hematocrit and positive predictive value of serum creatinine were very tight; much better than any scoring system I’ve seen," he observed. "We’re used to using increased hematocrit as a marker of AP patients in trouble, but in this study it paled in comparison to serum creatinine. It’s a very interesting finding."

Muddana agreed that the findings need to validated in a larger study, and reported that his colleagues at the University of Pittsburgh are currently seeking grant funding for such a trial. He also cautioned that while elevated serum creatinine was quite specific for risk of developing PN, it had a relatively low sensitivity of 41%, with only 14 out of 34 patients who ultimately developed PN having increased creatinine levels. Still, the findings potentially have significant import in the identification and management of patients at risk for PN.

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