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Progress in prediction and prevention of acute kidney injury.

Acute kidney injury (AKI) affects up to half of ICU patients (1) and progresses to moderate-severe stages in more than 20 percent. (2,4) Causes include major surgery, trauma, sepsis, pneumonia, circulatory shock, and treatments and diagnostic procedures such as nephrotoxic drugs and imaging using contrast media. (5) AKI has higher mortality than heart attack, (6) adds tens of thousands of dollars to the cost of a hospital stay, (7-8) increases readmission rates, (9) and puts patients at risk for lifelong renal and cardiovascular complications. (6)

Because AKI has no cure, identification of patients at risk, coupled with prompt application of kidney sparing management strategies to prevent or lessen the severity of AKI, is paramount. (5) The Kidney Disease Improving Global Outcomes (KDIGO) AKI guideline describes strategies for high-risk patients. These include discontinuing nephrotoxic drugs when possible, avoiding hyperglycemia, ensuring appropriate volume status and perfusion pressure, and considering functional hemodynamic monitoring and alternatives to radio-contrast procedures. (5) However, identification of patients at risk who could benefit from these interventions is problematic, because the earliest stages of AKI are silent--without reliable warning signs or symptoms. (10)

In 2014, the U.S. Food and Drug Administration (FDA) took an important step to address this deficiency by clearing the first in-vitro diagnostic test for risk assessment. (11) The test measures two urinary proteins, tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7), to identify patients at increased risk of developing moderate-severe AKI in the next 12 hours. In 2017, the first randomized controlled outcomes trial (PrevAKI) was published, (12) showing that use of the test to identify high-risk patients coupled with application of KDIGO-recommended interventions significantly reduced the occurrence and the severity of AKI.

In this article, we briefly review the diagnosis of AKI, the FDA-cleared test for risk assessment, and the PrevAKI trial.

Diagnosis of AKI

AKI typically manifests as an abrupt (hours to days) decrease in kidney function that is detected as an increase in serum creatinine or a decrease in urine output (oliguria) as defined by the KDIGO global consensus criteria for AKI. (5) AKI may start with problems outside the kidney that compromise organ perfusion such as low blood volume, cardiac output, or blood pressure, or be caused by direct injury of kidney nephrons associated with nephrotoxic drugs, reactive oxygen species, inflammatory factors, or other causes. (5,13) Although the KDIGO diagnostic criteria led to significant advances in understanding AKI, application of the criteria at the bedside can be challenging, and AKI is often a clinical diagnosis in practice. (14)

Serum creatinine does not elevate until approximately 50 percent of nephrons have been compromised, significantly lagging or being insensitive to the actual injury to the kidney. (15) This frequently leads to a late and inaccurate diagnosis of AKI, resulting in adverse patient outcomes. (5) 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. (16)

The importance of oliguria in the AKI definition was recently highlighted in a study of more than 30,000 adult ICU patients in which moderate-severe AKI manifesting only as oliguria was as clinically significant as that manifesting only by serum-creatinine criteria. (17) Similar results were reported in pediatric patients in which up to two-thirds of the AKI defined by oliguria criteria would have been missed using serum creatinine alone--yet these patients had significantly higher mortality than patients without AKI. (18) However, oliguria can be non-specific and a late indicator, and it requires careful monitoring of hourly urine output with an indwelling urinary catheter over an extended period of time. Current initiatives to reduce healthcare-acquired infections mandate the earliest possible removal of urinary catheters, hindering the effective use of oliguria criteria even in closely monitored ICU patients.

[TIMP-2]*[IGFBP7] for early risk detection

TIMP-2 and IGFBP-7 are soluble proteins expressed in the kidney that are known to participate in the response to a variety of tissue insults that cause AKI such as inflammation, oxidative stress, drugs, and toxins. (19) The proteins are thought to be involved in several processes associated with renal tubule cell stress, including a protective mechanism known as G1 cell-cycle arrest, during the earliest phases of injury. (19) This may explain why elevated levels of urinary TIMP-2 and IGFBP-7 indicate risk of AKI. Recent work revealed that secretion from renal tubule epithelial cells occurs primarily from the distal tubule for TIMP-2 and the proximal tubule for IGFBP7. (20) Both tubules are sites of injury in AKI.

The discovery and validation of urinary TIMP-2 and IGFBP7 as AKI biomarkers have been reviewed. (21) While both proteins elevate in urine during tubule cell stress associated with risk of AKI, the multiplicative combination [TIMP-2]*[IGFBP7] provided the best prediction across different patient cohorts such as sepsis or major surgery. This combination is reported by the test as a quantitative number that is proportional to the degree of risk for AKI. A high sensitivity cutoff (0.3) was validated to identify the majority of patients at risk. Analytical characteristics of the test have been reported. (22)

Importantly, the test elevates relative to established reference ranges (23) only when acute risk (stress) for AKI develops. Chronic comorbidities (24) and acute conditions such as sepsis (25) or surgery (26) do not cause test elevations in patients without acute risk. In patients who develop AKI (over several days) from a kidney exposure such as cardiac surgery, the test can elevate within several hours of the precipitating exposure. (27)

Can early detection of risk for imminent AKI (kidney stress) using the [TIMP-2]*[IGFBP7] test coupled with a KDIGO bundle of preventative care alter the course of AKI? This was the question addressed by the PrevAKI trial. (12) In this randomized controlled single-center trial, surgery patients undergoing cardiac pulmonary bypass (CPB) were tested four hours after CPB ended. The patients with a [TIMP2]*[IGFBP7] test result >0.3 (high risk for AKI) were randomized to either the hospital's standard of care (control group, N = 138) or an enhanced "KDIGO bundle" of care (intervention group, N = 138). The KDIGO bundle included advanced hemodynamic monitoring with pre-specified targets to guide fluid, inotrope, and vasopressor administration. Additional interventions included control of hyperglycemia and avoidance of nephrotoxic drugs.

Patients in the intervention group had significantly less AKI (p = 0.004, absolute risk reduction (ARR) = 16.6%, relative risk reduction (RRR) = 23.2%) and less moderate-severe AKI (p = 0.009, ARR = 15.2%, RRR = 33.9%) compared with those in the control group. This study shattered the myth that AKI is inevitable in critically ill patients and provides a starting point for improving care for patients determined to be at high risk for AKI. (28)

Improving quality and outcomes

As was demonstrated when the clinical 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 laboratory is committed to demonstrating value and improving patient outcomes. 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 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 AKI, providing a new objective tool to alert clinicians rapidly as to which of their patients are most at risk for one of the most unrecognized, but deadliest and costly, conditions challenging healthcare today.


(1.) Mandelbaum T, Scott D, Lee J, et al. Outcome of critically ill patients with acute kidney injury using the AKIN criteria. Crit Care Med. 2011;39(12):2659-2664.

(2.) Hoste EAJ, Clermont 6, 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.

(3.) 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(4):1203-1210.

(4.) 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):1692-702.

(5.) Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter. 2012;Suppl.2:1-138.

(6.) 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.

(7.) 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.

(8.) Hobson C, Ozrazgat-Baslanti T, Kuxhausen A, et al. Cost and mortality associated with postoperative acute kidney injury. Ann Surg. Ann Surg. 2015;261(6):1207-1214.

(9.) 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.

(10.) Ronco C, Ricci Z. The concept of risk and the value of novel markers of acute kidney injury. Crit Care. 2013;17(1):117-118.

(11.) Endre ZH, Pickering JW. Acute kidney injury: Cell cycle arrest biomarkers win race for AKI diagnosis. Nat Rev Nephrol. 2014;10(12):683-685

(12.) Meersch M, Schmidt C, Hoffmeier A, et al. Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial. Intensive Care Med. Open access online 2017.

(13.) 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.

(14.) Lui KD, Vijayan A, Rosner MH, Shi J, Chawla LS, Kellum JA. Clinical adjudication in acute kidney injury studies: findings from the pivotal TIMP-2*IGFBP7 biomarker study. Nephrol Dial Transplant. 2016;31(10):1641-1646.

(15.) Martensson J, Martling CR, Bell M. Novel biomarkers of acute kidney injury and failure: clinical applicability. Brit J Anesth. 2012;109(6):843-850.

(16.) National Confidential Enquiry into Patient Outcome and Death. Acute kidney injury: adding insult to injury,

(17.) Kellum JA, Sileanu FE, Murugan R, Lucko N, Shaw AD, Clermont G. Classifying AKI by urine output versus serum creatinine level. J Am Soc Nephrol. 2015;26(9):2231-2238.

(18.) Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL for the AWARE Investigators. Epidemiology of acute kidney injury in critically ill children and young adults. NEJM.j 2017;376(1):11-20.

(19.) 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(1):R25.

(20.) Emlet DR, Pastor-Soler N, Marciszyn A, et al. Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells. Am J Physiol Renal Physiol. 2017;312(2):F284-F296.

(21.) Kellum JA, Chawla LS. Cell-cycle arrest and acute kidney injury: the light and dark sides. Nephrol Dial Transplant. 2016;31(10):1641-1646.

(22.) Uettwiller-Geiger DL, Vijayendran R, Kellum JA, et al. Analytical characteristics of a biomarker-based risk assessment test for acute kidney injury (AKI). Clin Chim Acta. 2016;455:93-98

(23.) Chindarkar NS, Chawla LS, Straseski JA, et al. Reference intervals of urinary acute kidney injury (AKI) markers [IGFBP7] [TIMP2] in apparently healthy subjects and chronic comorbid subjects without AKI. Clin Chim Acta. 2016;452:32-37.

(24.) Heung M, Ortega LM, Chawla LS, et al. Common chronic conditions do not affect performance of cell cycle arrest biomarkers for risk stratification of acute kidney injury. Nephrol Dial Transplant. 2016;31(10):1633-1640.

(25.) Honore PM, Nguyen HB, Gong M, et al. Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 for risk stratification of acute kidney injury in patients with sepsis. Crit Care Med. 2016;44(10):1851-1860.

(26.) Gunnerson KJ, Shaw AD, Chawla LS, et al. TIMP2*IGFBP7 biomarker panel accurately predicts acute kidney injury in high-risk surgical patients. J Trauma Acute Care Surg. 2016;80(2):243-9.

(27.) 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.

(28.) Kellum JA. AKI: the myth of inevitability is finally shattered. Nat Rev Nephrol. 2017;13(3):140-141.

By Denise L. Uettwiller-Geiger, PhD, DLM(ASCP), and Paul McPherson, PhD

Denise L. Uettwiller-Geiger, PhD, DLM(ASCP), serves as Clinical Chemist and Director of Clinical Trials at John T. Mather Memorial Hospital in Port Jefferson, NY.

Paul McPherson, PhD, is co-founder and serves as Chief Scientific Officer of Astute Medical, Inc., developer of the NephroCheckTest, which measures urinary TIMP-2 and IGFBP-7.
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Author:Uettwiller-Geiger, Denise L.; McPherson, Paul
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:Jul 1, 2017
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