Clinical Laboratory Strategies: January 27, 2011

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Assessing Risk for Acute Kidney Injury
Proteinuria Adds Prognostic Value to eGFR
By Bill Malone 

The rising prevalence of acute kidney injury has put increased emphasis on laboratory testing. While some researchers are looking for new markers for early detection, a recent retrospective study of nearly 1 million Canadians suggests that common, inexpensive tests for proteinuria can be used together with estimated glomerular filtration rate to predict risk. This issue of Strategies explores its findings.

According to the Centers for Disease Control and Prevention, acute kidney injury (AKI) affects 20 million people in the U.S. older than age 20, causing damage that raises risk for end-stage renal disease (ESRD), cardiovascular events, and death. Patients with AKI also tend to have longer and more complicated hospitalizations. Clinicians often use estimated glomerular filtration rate (eGFR) to estimate risk for AKI, but a recent study underscored the utility of proteinuria, better known for its association with diabetes, hypertension, preeclampsia, glomerular disease, and other conditions (The Lancet 2010;376: 2096-2103).

Researchers from the University of Calgary and the University of Alberta in Canada studied more than 900,000 adults without ESRD who had records of outpatient measurement of both eGFR and proteinuria by dipstick or albumin-creatinine ratio (ACR) between 2002 and 2007. Hospital admissions for AKI were identified using hospital administrative codes during a median follow-up of 35 months. The researchers used statistical regression analysis to evaluate the association between eGFR, proteinuria, and AKI, and stratified patients by baseline eGFR and normal, mild, or heavy proteinuria levels.

They found that within each eGFR stratum, heavier proteinuria conferred up to a four-fold risk for hospitalization with AKI, based on the adjusted rate ratio. They also found that an episode of AKI was significantly associated with death and progression of kidney disease. “Our findings show that proteinuria is an independent risk factor for clinically significant episodes of acute kidney injury,” said lead author Matthew James, MD, assistant professor in the department of medicine at the University of Calgary. “We also looked a step further and found that these episodes of kidney injury add further prognostic information in addition to that already known about pre-existing markers of kidney disease.”

Using proteinuria to predict risk for AKI is very practical, James emphasized. “I think this will add to our ability to identify people at high risk and then take precautions to reduce that risk,” he said. “Proteinuria can be tested in a very easy manner with a dipstick test, so it can be performed at the bedside or in a physician’s office.” Clinicians can then take steps to minimize the risk of kidney injury, by avoiding certain medications or minimizing the use of contrast agents for radiology procedures. Similarly, patients can receive fluids to improve volume status, and those who are at high risk can be followed more closely for further complications that result from AKI. “These are all aspects of patient management that can be fine-tuned,” James said.

In an editorial accompanying the study, Morgan Grams, MD and Josef Coresh, MD, PhD, noted that “although serum creatinine is commonly checked before a contrast load is administered, few think to check a urine dipstick…prevention of acute kidney injury is paramount, partly because we have little treatment to offer.”

Timothy Larson, MD, a consultant in the division of nephrology and hypertension at Mayo Clinic in Rochester, Minn., noted that he’s seen a decline in urinalysis orders over time. “I think this study could help move attention back to this simple test that can provide additional important prognostic information,” he said. “Most studies of proteinuria have focused on the implications for progressive kidney disease and cardiovascular mortality, and morbidity, and not on AKI. That’s where this study is different. Clinicians can get focused on eGFR and forget that proteinuria is also a marker of kidney injury.” Larson, who is also an associate professor of medicine and has a joint appointment in the department of laboratory medicine and pathology at Mayo, was not associated with the study.

Some possible confounding factors could impact interpretation of the findings, Larson said, in part because there are many reasons for proteinuria. Also, in absolute numbers, patients in the study with heavy proteinuria who developed kidney failure accounted for a small percentage of those who developed AKI, and there are many other factors that predispose kidney failure that were not accounted for. Another limitation of the study is that the conditions causing or associated with the proteinuria were not specified. For example, patients with urinary tract infections and other conditions can present with transient proteinuria, and from the data in the study, it’s not known whether patients’ proteinuria was persistent or not. It’s also unknown why patients had a urinalysis performed.

Despite the fact that urine dipstick tests for proteinuria are less accurate than ACR, James stressed the consistency of results with the different tests. “The dipstick is semi-quantitative and is not considered as accurate a test as ACR, particularly since it’s vulnerable to variations in urine concentration,” he said. “However, in this large study we still see very consistent effects with the results of proteinuria measured by ACR. While misclassification of proteinuria status with dipstick is possible, the information provided by either proteinuria test was valuable, despite these limitations.”

Larson would like to see further research apply the study’s findings and target strategies for using proteinuria status in the prevention and management of kidney injury. “The next step would be more specific analysis. For instance, while we try to avoid intravenous contrast agents in patients who have reduced glomerular filtration rate, it would be helpful to examine more narrowly whether patients with proteinuria are really much more predisposed to AKI with contrast,” he said. “Our radiologists use a decision support rule that every patient must have a creatinine before they receive intravenous contrast, and perhaps they ought to require a urinalysis as well.”

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Assessing Risk for Acute Kidney Injury