Acute Kidney Injury and Sepsis

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Study finds two urine biomarkers strongly linked to AKI in septic patients.

MOLECULAR DIAGNOSTICS

A recently published study shows the elevation of two urine biomarkers, TIMP-2 and IGFBP-7, is strongly associated with the onset of acute kidney injury (AKI) in septic patients within 12 hours. The study also demonstrates that the performance of the markers remained similar in patients with or without multiple non-renal infectious comorbidities.1 These findings are part of a growing body of evidence defining the utility of these biomarkers and fueling an increased interest in using them to help identify patients at risk for AKI.

The lethal combination of sepsis and AKI is a significant issue for hospitals. Sepsis, one of the most common conditions encountered in the intensive care unit and a contributing factor to about 50% of all hospital deaths, is the most common cause of AKI in critically ill patients (47.5%). Without warning or visible signs, the kidney function of sepsis patients can begin to falter. The current standard for measuring kidney function, creatinine level, does not decrease significantly until approximately 50% of kidney function is lost.2 As a result, AKI often goes undetected for hours to days, sometimes causing irreparable damage.

Further worsening the prognosis for AKI is the lack of a specific therapy. Treatment involves implementing kidney-supportive measures, such as stopping the use of nephrotoxic agents. Since these treatments are often initiated when renal injury has already been established, it has been difficult to show the benefits of preventive and therapeutic measures for AKI.

The community began to tackle the issue of AKI by validating and adopting global clinical standards for its staging and assessment. The results were the establishment of the Acute Kidney Injury Network (AKIN), Risk, Injury, Function and End-stage (RIFLE) classification, and Kidney Disease: Improving Global Outcomes (KDIGO) criteria. While these standardized the categorization of kidney injury, all three measurements are suboptimal in stratifying risk in the acute patient care setting because they rely upon measurement of a patient’s urine output and serum creatinine levels, which do not change until hours after injury has occurred and can be altered by medications. Adding to the frustration of AKI is that it may be preventable if measures are undertaken soon after kidney insult.3

The hunt for reliable serum or urine biomarkers specific to AKI has proved challenging because it is heterogeneous, with many different etiologies. Previous to TIMP-2 and IGFBP-7, several markers emerged to assist in risk stratification in AKI. While initially considered promising, they have not seen widespread adoption for various reasons.

The hunt for reliable serum or urine biomarkers specific to AKI has proved challenging because it is heterogeneous, with many different etiologies.

Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker produced by neutrophils and shed in urine soon after AKI. However, NGAL is also elevated in other inflammatory conditions and thus has poor specificity.

KIM-1 and IL-18 are markers shed early in AKI from the proximal tubule and are more specific to the kidney when detected in urine. However, they may not have adequate sensitivity. 4

Calculating creatinine clearance after two hours of urine collection instead of waiting for the standard 24-hour collection has also been explored as a tool for measuring risk. However, this measure is limited by the overall lack of experience with reference ranges for the two-hour time period versus 24 hours.5

Overall, each biomarker has shortcomings when used in isolation.

Predictive Value

TIMP-2 and IGFBP-7 emerged when researchers undertook a discovery trial of 340 possible biomarkers (including NGAL and KIM-1) and validated the results in an international, multicenter study of 728 patients (SAPPHIRE) to identify those at risk of developing moderate to severe AKI within 12 hours of sample collection.6 TIMP-2 and IGFBP-7, when used in combination, performed better than all other biomarker combinations. These biomarkers were later validated for sensitivity and specificity in a clinically-adjudicated study (TOPAZ). 7

TIMP-2 and IGFBP-7 are associated with G1 cell cycle arrest during the very early phases of cell injury. AKI engages a series of extremely complex cellular and molecular pathways involving endothelial, epithelial, inflammatory and interstitial cells. These mechanisms include cell cycle, immunity, inflammation and apoptosis pathways.

The current study used a subset of patients from the SAPPHIRE and TOPAZ studies. It adds further evidence that TIMP-2 and IGFBP-7 ratio scores are significantly increased in patients with AKI within 12 hours of testing versus those without AKI. It also demonstrates a quantitative relationship between the test score and risk for AKI, with higher score indicating higher risk. In addition, it shows the predictive value was not affected by non-renal inflammatory events, unlike previous assays such as NGAL. Negative predictive value was shown to be high at all cutoffs (>91%), however positive predictive value remained below 54% even at the highest cutoff (2.0), at which the specificity was 89% and sensitivity 60%. Laboratorians should ensure physicians understand where the utility of this test is strongest when they order this test.

Adoption of the FDA-approved test using TIMP-2 and IGFBP-7—the only approved test to identify patients at risk for AKI—has been increasing but slowly. The widespread adoption of these biomarkers ultimately will be dependent on studies showing that their use improves clinical outcomes through reduction of AKI, reduced rates of complications, and decreased length of hospital stay. These studies are ongoing and hopefully will be published soon.


References

  1. 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. Critical Care Medicine. 2016; 44(10):1851-60
  2. Honore PM, Joannes-Boyau O, Boer P. The early biomarker of acute kidney injury: in search of the Holy Grail. Intensive Care Medicine. Nov. 2007.
  3. Schrier RW, Wang W. Acute renal failure and sepsis. The New England Journal of Medicine. 2004; 351(2):159-69.
  4. Henry’s Clinical Diagnosis and Management by Laboratory Methods: Edition 22. R. McPherson, M. Pincus. Sept. 6, 2011. Elsevier Health Sciences.
  5. Herrera-Gutiérrez ME, Seller-Pérez G, Banderas-Bravo E, et al. Replacement of 24-h creatinine clearance by 2-h creatinine clearance in intensive care unit patients: a single center study. Intensive Care Medicine. Nov. 2007. 1900-06.
  6. Kashani K, Al-Khafaji A, Ardiles T, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Critical Care 2013; 17:R25.
  7. Bihorac A, Chawla LS, Shaw AD, et al. Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. American Journal of Respiratory and Critical Care Medicine 2014; 189: 932-939.
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About Author

Raul Benavides, MD
Raul Benavides, MD

Raul Benavides, MD, is medical director of the core lab at Baylor University Medical Center, Dallas.

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