An inside view of human kidneys in red color, in front of a blue background.

New guidance document on laboratory investigation of acute kidney injury (AKI) released by the AACC Academy aims to better guide clinicians and laboratorians in their evaluations of AKI, with the goal of promoting best practices to improve patient outcomes.

The evidence-based guidance, compiled by a multidisciplinary group of laboratory scientists and nephrologists and published in May (J Appl Lab Med 2021;jfab020. doi:10.1093/jalm/jfab020), features 13 findings and recommendations regarding monitoring for AKI, traditional and new biomarkers affiliated with the condition, and the potential value of instituting automated alerts and eliminating unnecessary testing. Notably, these recommendations include a proposal to use new diagnostic thresholds, called the 20/20 AACC AKI criteria, when determining whether a patient has AKI with creatinine testing.

New Biomarkers Lead to New Challenges

AKI is defined as a sudden episode of kidney damage or failure. It affects up to 15% of hospitalized patients and can lead to serious complications or death. It is essential that clinicians are aware of the clinical presentation of AKI and that laboratorians provide them with the right tools to aid in early diagnosing and staging, the guidance authors said.

“Recent literature provides strong evidence that AKI is independently associated with higher risk of cardiovascular events after hospital discharge, affects short- and long-term outcomes in liver failure patients, and is associated with higher 60-day mortality in patients with septic shock,” the authors wrote. Moreover, the 72-hour period immediately after AKI can impact kidney-specific outcomes such as progressive chronic kidney disease or need for long-term dialysis, they said.

AKI traditionally has been identified in hospitalized patients through a rise in blood creatinine and/or a fall in urine output, as recommended by the 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines, said Joe El-Khoury, PhD, DABCC, FADLM, chair of the guidance writing committee and director of the Clinical Chemistry Laboratory at Yale-New Haven Health in Connecticut.

However, there have been significant developments over the last decade in this space, he said.

New biomarkers and electronic tools have emerged that potentially can help predict which patients are at greater risk for developing AKI or identify early changes. This includes a Food and Drug Administration-approved test (NephroCheck) that detects the presence of the urinary biomarkers tissue inhibitor metalloproteinases 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7). But literature studies and access to these technologies have been variable, leading to some disparities in the identification and management of AKI among medical centers, El-Khoury said.

“I hope this document will stimulate a conversation between laboratorians and clinical care providers to redefine AKI based on biological and analytical variability, and based on the studies we’ve looked at and recommend,” he said. “We also hope they have a conversation about the role of emerging markers and try to talk them out of using those without the strong evidence needed to show an effect on clinical outcomes,” as inappropriate use of these markers can add costs and yield false-positive results.

Detecting AKI With Greater Precision

One of the guidance’s major recommendations is to implement new thresholds for diagnosing AKI, called the 20/20 AACC AKI criteria. The authors noted that studies have shown using the KDIGO guidelines of a +0.3 mg/dL change in baseline creatinine as a sign of AKI can lead to high false-positive rates (CJASN 2015;10:1723-31) in as many as 30.5% of those with chronic kidney disease. The new AACC guidance instead recommends using a +0.20 mg/dL (~20 μmol/L) change in creatinine when baseline is less than 1.00 mg/dL (~90 μmol/L), or a +20% change when baseline blood creatinine is greater than 1.00 mg/dL. This could improve sensitivity for AKI detection, the authors said, and is supported by results of a recent study of nearly 15,000 patients demonstrating same-day changes of 0.20 mg/dL or 20% are associated with all-cause mortality (Sci Rep 2020;10:6552).

The new criteria aim to make AKI diagnosis more precise, explained coauthor Chirag Parikh, MD, PhD, director of nephrology for the Johns Hopkins University School of Medicine, in Baltimore. If baseline creatinine is low, around 0.5 mg/dL (seen in older adults and young children), it can take longer to achieve a 0.3 absolute increase, he said, whereas if baseline creatinine is high, around 4 mg/dL, a 0.3 absolute change is “meaningless,” so the percentage change makes more sense.

“We suspect moving to these new criteria will help us detect AKI earlier, and act more appropriately, because right now nephrologists who know about the KDIGO guidelines know its limitations and use clinical experience to make decisions for these patients,” El-Khoury said. “This addresses that in a big way, and helps them have a solid, evidence-based reference to make a decision.”

Other Recommendations on Testing for AKI

The guidance also recommends clinicians and laboratories only employ creatinine assays with intralaboratory analytical variability of 3.4% or less; eliminate testing for urine eosinophils to confirm or exclude acute interstitial nephritis; and be cautious when using measures of the protein cystatin C in predicting renal recovery. And it states that more evidence is needed to fully endorse TIMP-2/IGFBP7 measures as part of routine risk assessment of AKI, and to assess the value of automated electronic record alerts to notify providers of patients with creatinine changes.

“I see this as a reflection of all the guidelines, and bringing nephrologists and laboratorians together—which has not been done enough—to highlight where the low-hanging fruits are in terms of eliminating some wasteful testing and thinking appropriately about AKI diagnoses and what the future holds,” Parikh said.

The document is timely, and is a good reminder when trying to determine a patient’s baseline creatinine that if you are treating someone who came from another hospital, to be aware of potential differences or biases among methods to measure creatinine, commented KT Jerry Yeo, PhD, DABCC, FADLM, medical director of the Clinical Chemistry, Clinical Pharmacogenomics, and Translational Mass Spectrometry Laboratories, and professor of pathology, at the University of Chicago.

“The summary table is good in that it goes through some classic, traditional biomarkers including the use of fractional excretion of sodium (FENa),” Yeo added. “Mainly what I like is it tells someone like myself that I need to work with a clinician, because some of this information like analytical and intra-individual variability for creatinine can ultimately affect the interpretation of what constitutes a real change in creatinine over baseline, and not just by chance. It’s very helpful, and it tells us what is ready for prime time and what maybe still needs to be sorted out.”

Diagnosing AKI is particularly tricky. Creatinine is not produced by the kidney but by the muscle, Parikh said. The accumulation of creatinine is used as an indirect measure that kidney filtration has decreased. It’s not as direct as measures of cardiac troponin, for example, where a rising level strongly indicates heart damage, added El-Khoury. The way kidney injury is conceptualized is if filtration decreases abruptly.

“At some point, if there is a lot of injury, the filtration function will fail, but there is frequently a disconnect when the two are not going together, so you can have decreased filtration but no injury, or a little injury but no decrease in filtration,” Parikh said. “This compounds to make a difficult definition.”

There are often fluctuations in kidney function when patients are acutely ill, said John Lieske, MD, a nephrologist with the Mayo Clinic in Rochester, Minnesota. Sometimes that’s reversible and mostly hemodynamic, and sometimes it progresses and it’s not, so patients will need dialysis, he said, adding that “differentiating between those possibilities can be quite challenging."

Diagnosing AKI by changes in creatinine or urine output alone relies on “antiquated, functional markers of the kidney,” said nephrologist Jay Koyner, MD, a professor of medicine at the University of Chicago. “Creatinine has been around and known to be associated with kidney function for 160 years plus, so it is ubiquitous. It’s cheap, it’s easy, and like most things that have been around for that long, it’s imperfect. It’s delayed, it’s not always sensitive, and it is a bronze standard from my perspective.”

Likewise, urine output is easy to measure—if a patient is catheterized. But that’s less common now with hospitals targeting reduced catheter use as one way to reduce infection. “There are pitfalls in the tools we use, and there has been a movement for more than the past two decades to try to find better ways to diagnose patients,” Koyner said.

Looking to the Future

So what does the future hold as AKI diagnosis continues to evolve?

“I definitely think there is a role for automated alerts, and decision support around the care of patients with AKI,” Koyner said, “but the data around it is a little bit muddied, and there are studies that have shown if you don’t provide guidance, you can do harm. We need to be thoughtful about it. It’s not a yes or no, one-box flowsheet. It’s a complicated thing that takes expertise and varies from patient to patient.”

Koyner’s group is studying machine learning to see if they can predict who is at risk for AKI, using data in their electronic health record. It’s possible that combining these technologies with urine output or biomarker measures could identify a high-risk population who may benefit from early nephrology consults and intensive, kidney-focused care, or from novel prophylactic or therapeutic treatments for AKI, he said. Additional biomarkers such as NGAL (neutrophil gelatinase-associated lipocalin), LFABP (liver fatty acid binding protein) or proenkephalin used in other countries also may prove helpful, he said.

But to be effective, Yeo cautioned, any new tests would have to be automated or have a short turnaround time, and there shouldn’t be special handling requirements for samples.

Good evidence and a concerted effort by working groups may be needed to effect significant change, Lieske said.

“We know a lot more about AKI now than we did 10 years ago, but practically speaking, what’s going to be the big advance is probably more going to relate to recognizing people at risk and intervening early and trying to resuscitate people very quickly,” he said.

Koyner is a consultant for and receives research funding from Astute Medical and BioPorto Diagnostics A/S.

Karen Blum is a freelance medical/science writer in Owings Mills, Maryland. +EMAIL: [email protected]