Investigational biomarkers and the evaluation of acute tubular necrosis
- Uta Erdbruegger, MD
Uta Erdbruegger, MD
- Assistant Professor of Medicine
- University of Virginia
- Mark D Okusa, MD
Mark D Okusa, MD
- Professor of Medicine
- University of Virginia Health System
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a common clinical problem [1-7]. Although measurement of the serum creatinine concentration is widely used for the detection of AKI, it does not permit early diagnosis of acute tubular necrosis (ATN), since tubular injury precedes a significant rise in serum creatinine. Investigational biomarkers have been evaluated in patients with possible ATN in an attempt to detect tubular injury at an earlier stage. The US Food and Drug Administration (FDA) has approved use of the first platform measuring tissue-inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) to assess for the development of AKI.
We discuss here biomarkers that are being studied for the diagnosis of ATN. The pathophysiology, etiology, clinical presentation, and evaluation and diagnosis of prerenal disease and ATN are discussed elsewhere. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury (acute renal failure)".)
The diagnostic approach to patients with acute or chronic kidney disease (CKD), the possible prevention and management of ATN, and renal and patient outcomes after ATN are also discussed elsewhere. (See "Diagnostic approach to the patient with subacute kidney injury in an outpatient setting" and "Possible prevention and therapy of ischemic acute tubular necrosis" and "Renal and patient outcomes after acute tubular necrosis".)
The loss of kidney function in acute kidney injury (AKI) is most easily detected by measurement of the serum creatinine, which is used to estimate the glomerular filtration rate (GFR). Although the serum creatinine is widely used in diagnosing the presence of AKI, it is a suboptimal biomarker. It is a lagging marker of change in kidney function; therefore, it has poor sensitivity for the early diagnosis of AKI, and, as a marker of glomerular filtration, it is unable to differentiate among the various causes of AKI . As an example, the rise in serum creatinine is slow following the onset of AKI. By the time a change is observed in the serum creatinine, a critical therapeutic window may have been missed, particularly among those with acute tubular necrosis (ATN). (See "Assessment of kidney function".)
Thus, different urinary and serum proteins have been intensively investigated as possible biomarkers for the early diagnosis of ATN. There are promising candidate biomarkers that report on kidney and tubule function, detect an early and graded increase in tubular epithelial cell injury, and distinguish prerenal disease from ATN [8-11]. These novel biomarkers have therefore the potential to reflect physiologic and pathophysiologic processes of the injured kidney. Some biomarkers are detected in the urine of patients without a diagnostic increase in serum creatinine, which defines a group of patients with "subclinical AKI," who are at risk for adverse outcomes . Biomarkers are used in clinical investigation to facilitate early randomization to different treatment arms . These vanguard studies using biomarkers may lead to the identification of new therapies and the practical use of biomarkers in routine patient care [8,9,14-16]. Future studies are also needed to investigate whether biomarker profiles can be matched to unique injuries. For instance, sepsis-associated AKI may have a biomarker profile that is distinctly different from that of nephrotoxin-associated AKI.
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- DIAGNOSTIC BIOMARKERS
- Urinary tubular enzymes
- Urinary low-molecular-weight proteins
- Neutrophil gelatinase-associated lipocalin (NGAL)
- Urinary kidney injury molecule-1
- Urinary interleukin-18
- Urinary liver-type fatty acid-binding protein in acute kidney injury
- Panel of biomarkers
- Combination of functional and damage biomarkers
- PROGNOSTIC BIOMARKERS
- Urinary renin and angiotensinogen
- Plasma NGAL
- Urinary insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP2)