Rapid Diagnosis of Severe Kidney Damage – New Biomarkers Tested

Using tests currently available in the hospital, this question is often difficult to answer. A large multicenter study by clinicians of the Experimental and Clinical Research Center (ECRC), a joint cooperation between the Max Delbrück Center (MDC), the Charité – Universitätsmedizin Berlin, the Helios Hospital (all in Berlin, Germany), and two hospitals in the U.S. has now shown that a urine test for proteins excreted by a damaged kidney helps to swiftly identify high-risk patients (Journal of the American College of Cardiology, online, 9. January 2012)*.

“There are no typical symptoms for acute kidney injury,” said Professor Kai Schmidt-Ott. “Nevertheless it is very important for the doctor to rapidly determine whether or not a patient has acute kidney injury” stressed the nephrologist from the Charité, who leads a research group at the MDC. Jonathan Barasch, Associate Professor of Medicine and Cell Biology at Columbia University and senior author of the paper commented: “When a patient presents to the Emergency Department and a blood test identifies an abnormal creatinine value, it is difficult to know whether the patient needs to be hospitalized because of ongoing intrinsic acute kidney injury (a potentially fatal disease) or whether the patient needs to be sent home after intravenous or oral fluids and later examined at an outpatient clinic.

This study, based on earlier studies by Professor Thomas L. Nickolas and Professor Schmidt-Ott, demonstrates the strength of association of the novel biomarker neutrophil gelatinase- associated lipocalin (NGAL) with intrinsic acute kidney injury and not simple volume depletion or more indolent forms of chronic kidney disease”, Prof. Barasch said. “Furthermore, the study demonstrates that NGAL and a second biomarker, kidney-injury molecule-1 (Kim1), predict poor outcomes during hospitalization, even days after the initial measurements.”

“In the initial stage of acute kidney injury, we may have most room for improvement of our current clinical practice” Professor Schmidt-Ott points out. In cases of advanced acute kidney injury, dialysis treatment is required. Many patients with severe acute kidney injury die in the hospital. Statistics illustrate how extensive the problem is. In the U.S. alone, one million patients are diagnosed every year with severe acute kidney injury. According to data of the German Society of Nephrology, there are currently around 70 000 dialysis patients in Germany; and this number is on the increase.

Currently, only the serum creatinine level is used for the diagnosis of acute kidney injury. Creatinine is a molecule that is normally excreted via the kidney, but accumulates in the blood when kidney function is impaired. “However, an elevated creatinine level is not a direct measure of kidney damage,” Professor Schmidt-Ott explained. “Thus, a prolonged slight-hypoperfused kidney can lead to a significant increase in serum creatinine, although the kidney tissue is not damaged. This functional impairment of the kidney usually responds well to treatment. The patients receive an electrolyte solution or have to stop taking the medications that damage the kidneys. In contrast, tissue damage in the kidney has a significantly worse prognosis. Nevertheless, serum creatinine values in the emergency room are of limited value because after kidney damage, 24 to 48 hours may elapse before serum creatinine values accumulate in the blood. Thus, at-risk patients remain undetected. That is why there is an urgent need for more accurate biomarkers of tissue damage in the kidney.”

Research has indicated that damaged kidneys synthesize specific proteins. In previous smaller studies, researchers investigated whether or not these proteins could serve as biomarkers to identify high-risk patients with kidney tissue damage. During the past three years, Professor Nickolas and Professor Barasch (Columbia University) and Professor Schmidt-Ott and Professor Friedrich C. Luft (both ECRC), pursued this question in a large-scale study. The researchers in Berlin and New York took a single measure of five urinary biomarkers from almost 1700 emergency room patients upon their admission to the hospital.

The investigators found that primarily the two putative biomarkers, NGAL and KIM-1, were useful in providing an early risk assessment. If both NGAL and KIM-1 levels are low, the patient’s risk of dying in the hospital or requiring dialysis treatment is likewise low. In contrast, high levels indicate the risk of acute kidney damage. If a doctor bases the diagnosis both on these biomarker readings and the serum creatinine levels, a more exact assessment of the individual risk is possible, according to Professor Schmidt-Ott, who is also adjunct assistant professor at Columbia University. This finding could quickly help emergency room doctors to devise an adequate treatment strategy for the patient.

But it is still not clear whether or not all patients admitted to an emergency room should be tested for these biomarkers. Perhaps only certain patients, for example diabetics or patients with high blood pressure, who are at high risk for acute kidney injury should be included. Furthermore, whether or not these biomarkers actually influence the individual treatment outcome is uncertain. As Professor Schmidt-Ott concluded, further studies are needed to answer these questions.

*Diagnostic and Prognostic Stratification in the Emergency Department Using Urinary Biomarkers of Nephron Damage – A Multicenter Prospective Cohort Study

Thomas L. Nickolas*†1, Kai M. Schmidt-Ott*†2,3, Pietro Canetta1, Catherine Forster1, Eugenia Singer2,3, Meghan Sise1, Antje Elger2, Omar Maarouf4, David Antonio Sola-Del Valle1, Matthew O’Rourke1, Evan Sherman1, Peter Lee1, Abdallah Geara1, Philip Imus1, Achuta Guddati1, Allison Polland1, Wasiq Rahman1, Saban Elitok3, Nasir Malik1, James Giglio1, Suzanne El-Sayegh4, Prasad Devarajan5, Sudarshan Hebbar6, Subodh J. Saggi4, Barry Hahn4, Ralph Kettritz2,3, Friedrich C. Luft2,3, and Jonathan Barasch1

1 Columbia University College of Physicians and Surgeons, New York, NY, USA
2 Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany
3 Helios Clinics, Berlin, Germany
4 Staten Island University Hospital, Staten Island, NY, USA
5 Cincinnati Childrens Hospital, Cincinnati, OH, USA
*† Co-first and co-corresponding authors
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