Measurement of AKI biomarkers in the ICU: still striving for appropriate clinical indications

Excerpt

Compared to other organ systems, diagnostic criteria for acute kidney injury (AKI) using serum creatinine and urine output are well established [1]. Despite this, there is little evidence to support any specific interventions to improve outcomes after AKI diagnosis. Delayed and imprecise identification of early AKI by conventional diagnostic criteria may explain these failures. Consequently, numerous plasma and urinary biomarkers for renal injury or renal dysfunction have been the subject of intense study for well over 10 years with the aim of earlier and more precise recognition of incipient AKI [2]. Despite this activity, only a few AKI biomarkers have been commercially marketed for clinical use. The most well-known plasma or urinary neutrophil gelatinase-associated lipocalin (NGAL) [3] has been available for over 5 years, but has failed to demonstrate clear clinical utility [4‐6] or gain widespread uptake in the ICU. More recently, a promising combination of two cell cycle arrest markers (TIMP-2 and IGFBP-7) [7, 8] has been licenced for the early detection of AKI; however, it is as yet uncertain what clinical impact this assay will have. Importantly, while proving a statistical association with the development of AKI is relatively easy, demonstrating that a biomarker measurement meaningfully alters practice, let alone clinical outcomes, is much trickier [9]. AKI complicating critical illness is highly heterogeneous in severity, aetiology and timing [10], all of which may variably affect biomarker results. In turn, candidate biomarkers are judged by their ability to predict later AKI defined by serum creatinine—the imperfect diagnostic test that we are trying to improve. Thus, defining the appropriate timing and frequency of biomarker measurement and interpreting these results in individual patients are extremely difficult. As a consequence there are, as yet, no positive prospective randomised studies of biomarker-driven interventions for AKI, nor have any novel biomarkers been considered ready for incorporation into AKI diagnostic systems [11]. Importantly, one of the key features of successful clinical introduction of biomarkers for other clinical conditions (such as venous thrombo-embolism or coronary thrombosis) has been to restrict measurement to patients with a reasonable pre-test probability of the specific disease. Thus, in order to establish a role for AKI biomarkers we may need to better identify clinical indications for their measurement. …