Acute kidney injury (AKI) can be deadlier than a heart attack,1 add tens of thousands of dollars to the cost of a patient’s hospital stay,2,3 increase the number of readmissions,4 and place the patient on a lifelong trajectory of renal and cardiovascular complications. The most deadly forms of AKI (moderate-severe, stage 2-3) can occur in 20 percent or more of critically ill patients.5-7 A recently published analysis identified AKI as the number-one complication associated with increased hospital length of stay and the number-two complication associated with increased in-hospital costs.8 Despite these disturbing numbers, until recently AKI was largely underappreciated as a common and often preventable driver of patient morbidity, mortality, and costs.9
The most common causes of AKI include major surgery, sepsis including severe pneumonia, circulatory shock, and nephrotoxic drugs.10 The condition is both difficult to identify and usually silent, without early warning signs or symptoms.11 Because there is no curative treatment for AKI, it is paramount to identify patients who are most at risk for AKI and to promptly apply kidney sparing management strategies that may prevent or lessen the severity of AKI, thus providing the best chance of a good outcome. The Kidney Disease Improving Global Outcomes (KDIGO) AKI guideline describes several such management strategies for patients at high risk for AKI, including discontinuing nephrotoxic drugs when possible; ensuring appropriate volume status and perfusion pressure; considering implementing functional hemodynamic monitoring and closer monitoring of serum creatinine and urine output; and considering alternatives to radio-contrast procedures.
AKI biomarkers in clinical practice
AKI manifests clinically as an abrupt (hours to days) decrease in kidney function that may be detected as an increase in serum creatinine or a decrease in urine output (oliguria). This functional change may be caused by problems outside the kidney such as low blood volume, cardiac output, or blood pressure, or can be caused by damage to the nephrons themselves resulting from nephrotoxic drugs, reactive oxygen species, inflammatory factors, or other causes.12
Serum creatinine does not indicate a significant change in kidney function until approximately 50 percent of nephrons have been compromised, significantly lagging or being insensitive to the actual injury to the kidney.13 This frequently leads to a late and inaccurate diagnosis of AKI, resulting in adverse patient outcomes. For example, one study of patients who died with a final diagnosis of AKI revealed substantial deficiencies and unacceptable delays in the recognition and management of AKI, with only 50 percent of AKI patients receiving good care.14
The KDIGO AKI guideline recommends that patients be assessed for risk of AKI to protect their kidney function. Until now, there have been very few options available to clinicians to identify which patients are at the highest risk for moderate to severe AKI. This unmet clinical need is now being addressed with the introduction of an assay measuring the urinary concentration of two proteins, tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7). The test multiplies the concentrations of the two proteins to provide a single quantitative test result that indicates risk of imminent AKI. Based on results from clinical studies, patients with a positive score (greater than the cutoff of 0.3) have seven times the risk of developing moderate or severe AKI within 12 hours of assessment, compared with patients with a negative score.15
TIMP-2 and IGFBP-7 are soluble proteins expressed in the kidney and are known to be involved in the response to a wide variety of tissue insults that can cause AKI such as inflammation, oxidative stress, drugs, and toxins.16 The two proteins are thought to be involved in several processes associated with renal tubule cell stress and injury, including a protective mechanism called G1 cell-cycle arrest, during the earliest phases of injury. This may explain why elevated levels of urinary TIMP-2 and IGFBP-7 correspond closely to the risk of imminent AKI.
These two urinary protein biomarkers and their multiplicative combination as an indicator of risk for imminent AKI were discovered in a rigorous analysis of more than 1,200 diverse ICU patients from 37 clinical sites in North America and Europe and were subsequently validated in prospective clinical trials of more than 500 diverse ICU patients from 29 clinical sites in the United States.17 Based on these clinical studies, a cut-off for the risk score of >0.3 was established to achieve high sensitivity while preserving acceptable specificity, allowing for the majority of patients who will manifest moderate to severe AKI within 12 hours to be identified rapidly. Additional studies demonstrate the performance of the test for risk assessment of AKI in specific patient populations, such as major surgery18 and cardiac surgery.19 Increased levels of TIMP-2 and IGFBP-7 are also known to be associated with poorer nine-month outcomes in critically ill patients with AKI.20
Improving quality and outcomes
The clinical laboratory is committed to demonstrating value and improving patient outcomes. Recall that the laboratory played a key role in changing the outcome of patients with myocardial infarction (MI), even before specific interventions and treatments such as stents and thrombolytic drugs existed. The cardiac clinical impact journey began with the introduction of a series of biomarkers that ultimately resulted in troponin being recognized as the gold standard for MI.
The same journey has begun with regard to early diagnosis of acute kidney injury. The recent FDA-clearance of the first urinary biomarker test for risk assessment for AKI now provides the laboratory with an opportunity to join the fight against this silent killer by providing a new objective tool to alert clinicians rapidly to which of their patients are most at risk. Also, the laboratory can demonstrate value by expanding its menu offering with new AKI biomarkers.
- Chawla LS, Amdur RL, Shaw AD, et al. Association between AKI and long-term renal and cardiovascular outcomes in United States veterans. Clin J Am Soc Nephrol. 2014;9(3):448-456.
- Dasta JF, Kane-Gill SL, Durtschi AJ, Pathak DS, Kellum JA. Costs and outcomes of acute kidney injury (AKI) following cardiac surgery. Nephrol Dial Transplant. 2008;23(6):1970-1974.
- Hobson C, Ozrazgat-Baslanti T, Kuxhausen A, et al. Cost and mortality associated with postoperative acute kidney injury. Ann Surg. 2014 May 30. [Epub ahead of print].
- Brown JR, Parikh CR, Ross CS, et al. Impact of perioperative acute kidney injury as a severity index for thirty-day readmission after cardiac surgery. Ann Thorac Surg. 2014;97(1):111-117.
- Hoste EAJ, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006;10(3):R73.
- Bagshaw SM, George C, Dinu I, Bellomo R. A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant. 2008;23:1203-1210.
- Joannidis M, Metnitz B, Bauer P, et al Acute kidney injury in critically ill patients classified by AKIN versus RIFLE using the SAPS 3 database. Int Care Med. 2009;35(10):1692-1702.
- Complications Research, a new Premier methodology for identifying hospital-wide harm associated with increased cost, length of stay and mortality in U.S. hospitals. Premier, Inc. http://ftpcontent4.worldnow.com/wtoc/web/Complications-Research-Press-Call-Slides-6-11-14.pdf. Accessed May 20, 2015.
- Lewington AJP, Certa J, Mehta RL. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int. 2013;84(3):457-467.
- Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Inter., Suppl. 2012;2:1-138.
- Ronco C, Ricci Z. The concept of risk and the value of novel markers of acute kidney injury. Crit Care. 2013;17:117-118.
- McCullough PA, Shaw AD, Haase M, et al. Diagnosis of acute kidney injury using functional and injury biomarkers: workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference. Contrib Nephrol. 2013;182:13-29.
- Martensson J, Martling CR, Bell M. Novel biomarkers of acute kidney injury and failure: clinical applicability. Brit J Anesth. 2012;109(6):843-850.
- National Confidential Enquiry into Patient Outcome and Death. Adding Insult to Injury. 2009;1-98. http://www.ncepod.org.uk/2009report1/Downloads/AKI_report.pdf, Accessed May 20, 2015.
- Bihorac A, Chawla LS, Shaw AD, et al. Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. Am J Respir Crit Care Med. 2014;189(8):932-939.
- Kashani K, Al-Khafaji A, Ardiles T, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17:R25.
- Hoste EA, McCullough PA, Kashani K, et al. Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers. Nephrol Dial Transplant. 2014;29:2054-2061.
- Gocze I, Koch M, Renner P, et al. Urinary Biomarkers TIMP-2 and IGFBP7 Early predict acute kidney injury after major surgery. PLoS ONE. 2015;10(3):e0120863.
- Meersch M, Schmidt C, Van Aken H, et al. Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery. PLoS ONE. 2014;9(3):e93460.
- Koyner JL, Shaw AD, Chawla LS, et al. Tissue inhibitor metalloproteinase-2 (TIMP-2)*IGF-binding protein-7 (IGFBP7) levels are associated with adverse long-term outcomes in patients with AKI. J Am Soc Nephrol. 2015;26. [ePub ahead of print].