NephroCheck is an assay to assess the risk of developing acute kidney injury. The laboratory test was developed by Astute Medical, in San Diego, California, in collaboration with clinical investigators. It was notable for being the first test of its kind for determining whether certain critically ill hospitalized patients were at risk of developing moderate to severe acute kidney injury (AKI) in the next 12 hours. Early knowledge that a patient is likely to develop AKI may prompt closer patient monitoring and help prevent permanent kidney damage or death. A randomized control trial led by Alexander Zarbock, M.D., at University Hospital Muenster, Germany has indicated that using Astute Medical’s NephroCheck Test to identify patients at high risk for acute kidney injury (AKI) after open-heart surgery and providing them treatment recommended by globally-recognized care guidelines significantly improved outcomes by reducing the occurrence of moderate to severe AKI more than 33 percent.
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History
Nephrocheck took six years to be developed. The development included a discovery effort that tested over 300 possible biomarkers in clinical samples, an immunoassay cartridge and meter, clinical validation of the test in a series of extensive trials in the United States and Europe, CE mark in European countries and FDA-clearance to market it in the United States. It cost approximately $100,000,000 to develop and is intended for patients who are admitted to the hospital. The cost of the test is covered by a diagnostic related group (DRG) payment. The list price of the test to a hospital in the United States is $85. The price of the meter is approximately $5,000. Nephrocheck uses two urinary cell-cycle arrest biomarkers (e.g., TIMP-2 and IGFBP7) to determine if a person is at increased risk for developing moderate to severe acute kidney injury (AKI) in the next 12 hours.
Knowing this information earlier theoretically may improve patient outcomes by allowing clinicians to focus on high risk patients and prevent further injury. Diagnosis of AKI is often difficult, and delays in diagnosis are common. Acute kidney injury is common in critically ill patients, and AKI is a major cause of death and long-term morbidity in these patients. Common functional markers, such as serum creatinine, have been used, yet they are late indicators of AKI.
Pre-NephroCheck
Serum creatinine (sCr), the most widely used marker of kidney function, is a component of the definition of AKI, and as a single measurement is unhelpful in differentiating acute from chronic kidney disease. While sCr is an adequate marker of renal function (GFR), sCr itself does not correlate with hospital survival whether measured at the time of presentation or the start of dialysis. sCR is insensitive and slow to change after kidney injury, leading to a late and inaccurate diagnosis of AKI with adverse outcomes. The more predictive changes in sCr require several hours to days before they reach steady state following an injury to the kidney. The change in sCr is a tool for defining when a change in kidney function has occurred, but not good for detecting that which is presently occurring (or about to occur). Regardless of the advanced technologies available, AKI remains a common disorder that complicates the hospital course for many patients. Unlike a myocardial infarction, AKI is usually silent, and does not cause any physical symptoms. Given the financial and human costs associated with AKI, there is a critical need for better identification and assessment of those patients at risk. The need for better assessment tools prompted the development of the NephroCheck test, which included the discovery and identification of AKI biomarkers.
Utilization of novel biomarkers
For risk assessment for moderate to severe AKI, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) were found to be significantly superior to all previously described markers of AKI (p<0.002) including LCN2 (NGAL) and kidney injury molecule (KIM)-1. During sensitivity analyses TIMP-2 and IGFBP7 remained significant and superior to all other markers regardless of changes in reference creatinine method. Both TIMP2 and IGFBP7 have been associated with the G1 cell cycle arrest phase noted to occur during the very early phases of kidney injury. Cell cycle arrest is a protective mechanism that cells use to avoid cell division when injured and induces the release of TIMP2 and IGFBP7 which is beneficial. Remote ischemic conditioning was used in a study to induce protection in the kidney prior to cardiac surgery. The study results indicate that remote ischemic preconditioning was effective in patients with increased NephroCheck levels prior to surgery. Increase levels during surgery predict development of acute kidney injury showing a potential use for NephroCheck, in conjunction with other therapies, to prevent or treat acute kidney injury in addition to assessing risk. In addition, TIMP-2 and IGFBP7 have been associated with death or renal replacement therapy only in subjects who developed AKI.
Application of TIMP-2 and IGFBP7 via NephroCheck
The NephroCheck test (e.g., urinary TIMP-2 and IGFBP7) assesses risk for AKI. As with other diagnostic tests, it does not take the place of clinical judgment. The test was designed to assess risk for stage 2-3 AKI, yet the biomarker concentrations correspond to severity of AKI across all three stages. The markers appear to be short-lived in the urine after AKI has occurred. This may be normal in patients who have already manifested AKI by functional criteria (e.g., serum creatinine). An international Clinical Practice Guideline for AKI recommends risk assessment but acknowledges the lack of tools available to perform risk assessment. The clinical application of NephroCheck is to aid in risk assessment so that the KDIGO bundle can be applied.