Acute kidney injury

Cell cycle arrest biomarkers win race for AKI diagnosis

FDA approval of the first device to use novel biomarkers of kidney damage to assess risk of acute kidney injury (AKI) potentially brings forward diagnosis of moderate-to-severe AKI to a time frame that could enable early intervention. Although the device awaits greater scrutiny, its approval marks the beginning of a new era.

Acute kidney injury (AKI) is a major global health concern. However, despite enormous efforts, biomarkers to facilitate early diagnosis and treatment of AKI have not yet transitioned to clinical practice. In a historic decision,1 the FDA has now permitted marketing of NephroCheck® (Astute Medical, Inc., USA), the first point-of-care device to use biomarkers of kidney damage to detect early AKI. NephroCheck® uses a fluorescence immunoassay to measure urinary levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7). Concentrations of these biomarkers are used to assess the risk of developing moderate-to-severe AKI, defined as stage 2 or 3 AKI by KDIGO consensus criteria,2 within 12 hours following testing. The early identification of patients at risk of AKI is an important milestone in the AKI–biomarker saga; this test is the first of its kind to be approved for AKI diagnosis since the hunt for diagnostic AKI biomarkers began over a decade ago.

The FDA approved NephroCheck® on the basis of data from two prospective multicentre studies, Opal3 and Topaz,4 which assessed 154 and 420 critically ill patients, respectively. However, the diagnostic performance of TIMP-2 and IGFBP7 as biomarkers of AKI was first described in the Sapphire study, which included 744 patients across 20 North American and 15 European centres. In Sapphire, TIMP-2 and IGFBP7 outperformed seven other biomarkers of AKI damage; the product of the two biomarkers also marginally outperformed either one alone.5 The cut-off to diagnose AKI with NephroCheck® derived from the Sapphire study (0.3 [ng/ml]2/1,000), was prospectively verified in Opal,3 where the positive predictive value of the threshold was 49% (69% after prevalence adjustment) and the negative predictive value was 97% (96% after prevalence adjustment). In the Topaz study, the same cut-off had an area under the curve of 0.82 (95% CI 0.76–0.88) with a sensitivity of 92% (95% CI 85–98%) and a negative likelihood ratio of 0.18 (95% CI 0.06–0.33).

“Damage biomarkers currently provide our only real insight into the enormity of the changes that occur in early AKI”

FDA approval of NephroCheck® overcomes many of the laboratory standardization issues that confront competing biomarkers, including serum creatinine level. This approval will also promote use of TIMP-2 and IGFBP7 over other potential biomarkers of AKI, some of which are used in point-of-care devices in other settings. It will accelerate NephroCheck® use globally, which clearly is good news for individuals at risk of developing AKI. Robust thresholds for AKI diagnosis and intervention have long been awaited. A well-validated cut-off will enable implementation of the Acute Dialysis Quality Initiative's recently proposed matrix approach to the definition of AKI, which combines functional and damage biomarkers,6 and should facilitate a more robust approach to early diagnosis of AKI. Whether the threshold used in Nephrocheck®, which is based on a creatinine-dependent definition of AKI, will also identify 'biomarker-positive, creatinine-negative' individuals at high risk of dialysis and death, as does urinary neutrophil gelatinase-associated lipocalin (NGAL) or kidney injury molecule 1 (KIM-1), remains uncertain.7 Ideally, creatinine-independent methods of validating damage biomarkers are needed for the AKI diagnostic matrix.8

The results of the multicentre Opal and Topaz studies and the multinational Sapphire study seem readily transferable to critically ill patients in other settings; but, before getting too excited, we must pause to ask some important questions. Is this device the long-awaited 'renal troponin'? Can it alone triage patients to intervention? What is the false positive rate? Although the performance of the recommended cut-off may be comparable to some commonly used biomarkers of cardiac injury, this comparison is a weak argument for changing the definition of AKI.3 Having taken years to gain consensus on AKI definitions, it remains highly desirable that we persist with and refine the existing definitions rather than create new ones, specified by the cut-off threshold of a particular biomarker, which presumably reflects only one specific aspect of the injury pathway.

Credit: Photodisc/Getty

The combined Opal and Sapphire study data3 show that, as the time window for detection of AKI increased to 48 h (the consensus KDIGO window for diagnosis), the positive predictive value increased and negative predictive value decreased. This finding is expected and the changes are not dramatic; however, information is lacking on whether, in this wider time window, the product of TIMP-2 and IGFBP7 concentration continued to outperform competitor biomarkers in the Sapphire study, such as urinary and plasma NGAL, urinary KIM-1, IL-18, and plasma cystatin C.5

The type and severity of AKI that is diagnosed by Nephrocheck® must be qualified. As cogently stated by the authors, “biomarkers are not 'crystal balls' and cannot forecast future events that have not yet taken place when the biomarkers were sampled”.3 Thus, it is important to understand the severity of AKI that is being diagnosed and not 'predicted' by Nephrocheck®. Assuming a single renal insult, we can use creatinine kinetics (ignoring changes in production) to calculate that a 55% decrease in glomerular filtration rate (GFR) is needed to produce stage 2 AKI within 12 h; this minimum doubling of serum creatinine level will lead to a 220% plateau increase in creatinine level by 27 h. Similarly, the 71% decrease in GFR required to achieve a threefold increase in creatinine level by 12 h will plateau at 344% by 37 h, with both equilibria achieved within the 48 h KDIGO reference framework. These estimations explain the FDA's justification that “early knowledge that a patient is likely to develop AKI may prompt closer patient monitoring and help prevent permanent kidney damage or death.”1 The value of Nephrocheck®, therefore, is that it reflects, in near real-time, a significant loss of GFR that later manifests as a change in creatinine level.

Is bringing AKI diagnosis forward by 12 h worthwhile? Absolutely. 12 h is a long time in the life of an injured renal cell. Provided the risk assessment is valid, this time course is a dramatic improvement, which will facilitate clinical trials in AKI and alert clinicians to adopt renoprotective strategies including avoidance of nephrotoxins, and maintainance of volume status and perfusion pressure as appropriate.2

What increases in biomarker levels tell us about the kidney is even more profound. In AKI, residual renal function, facilitated by hyperfiltering intact nephrons, effectively masks most of the functional changes that might be revealed in the future by real-time GFR measurements. Damage biomarkers currently provide our only real insight into the enormity of the changes that occur in early AKI. The Nephrocheck® team have revealed the importance of cell cycle arrest in AKI development; clearly such arrest is a critical step in the injury pathway, but only one of many defining events in the syndrome of AKI.

Much about these biomarkers remains unknown, however. Until the temporal profiles of these and other damage biomarkers are known and compared in the same injury and comorbidity contexts, uncertainties about the precise phase of renal injury to which they correspond, and the most appropriate intervention strategies, will remain. How easily the findings from Opal and Topaz can be extrapolated outside the boundaries of the intensive care unit remains uncertain. The specific cut-off validated in NephroCheck® is untested in other contexts. Although diagnostic performance seems intact in sepsis, no information exists about the performance of these or other cell cycle arrest markers in patients with impaired baseline renal function, the strongest risk factor for AKI and for which context-specific nomograms may be needed to optimize biomarker selection and for differing durations of exposure to harm.9 Finally, approval of NephroCheck® is unlikely to dampen investigations into competing damage biomarkers, such as NGAL and KIM-1. The performance of cell cycle arrest markers in predicting risk of AKI has not yet been subjected to the same degree of scrutiny as NGAL and KIM-1. Similar initial enthusiasm for these earlier novel biomarkers led to disillusionment,10 from which we have only now surfaced through a better understanding of the context in which to refine biomarker selection and utilization. Until further data are available, we should celebrate this milestone.

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Correspondence to Zoltán H. Endre.

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Endre, Z., Pickering, J. Cell cycle arrest biomarkers win race for AKI diagnosis. Nat Rev Nephrol 10, 683–685 (2014). https://doi.org/10.1038/nrneph.2014.198

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