Creatinine as the gold standard for kidney injury biomarker studies?

Abstract

Before 2005, when the Acute Dialysis Quality Initiative proposed a consensus definition [1], acute kidney injury (formerly known as ‘acute renal failure’) was identified by most clinicians in the way that Justice Potter Stewart identified obscenity: they knew it when they saw it. Epidemiologists and clinical researchers, who needed an objective criterion, seemed to devise a different definition for every new study; indeed, over 35 definitions have been used to define AKI in the nephrology literature [2]. For Homer Smith, who introduced the term ‘acute renal failure’ in his textbook, The Kidney: Structure and Function in Disease and Health [3], a specific definition did not seem to matter: nowhere in his textbook does he propose a way to define AKI. We know that definitions do matter in modern clinical medicine. The consensus definition of acute myocardial infarction, which has evolved over the years and now requires biochemical evidence of myocardial tissue injury, has facilitated the design and execution of studies that have led to revolutionary changes in the treatment and outcome of patients with acute myocardial infarction around the world. The consensus definitions of sepsis and acute lung injury similarly permitted the critical care community to study and advance the clinical science and management of critically ill patients, with some clear success stories [4,5]. Within nephrology, the new consensus definition of chronic kidney disease, while controversial, has focused attention on early recognition and staging of the clinical syndrome, influenced clinical trial design as well as referral patterns to nephrologists [6], and hopefully will provide a tangible benefit for our patients. Defining AKI is clearly of paramount importance as nephrology struggles to translate a host of steady advances in the understanding of the pathobiology of AKI into clinical benefit for patients. Unfortunately, however, we face a challenge not faced by cardiologists and pulmonologists: the uncertain relationship between our ‘gold standard’ biomarkers [serum creatinine (SCr) and urine output] and our disease process. In cardiology, the relationship between the defining biomarker (troponin) and the disease process (myocardial infarction) is direct: injured myocardial cells release troponin into the circulation, where it can be measured and used to diagnose a clinical condition. In pulmonology, one of the biomarkers used is the partial pressure of oxygen: acute lung injury and acute respiratory distress syndrome are defined by the difference between the alveolar and arterial concentration of oxygen. This biomarker reflects the critical life sustaining function of the organ: delivery of oxygen to the circulation to support aerobic metabolism. What is curious about our universally used biomarker (SCr) is that we do not trust it; it is not an injury marker but rather a functional marker (and a poor one at that, especially in the acute setting). A rise in SCr may not define kidney injury at all: for example, the syndrome ‘pre-renal azotaemia’ may look biochemically just like ‘acute tubular necrosis’ by changes in SCr, but differs markedly in underlying pathophysiology, treatment implications and prognosis. All nephrologists know that SCr can be deceptively normal: consider lupus nephritis, in which severe parenchymal injury can coexist with preserved glomerular filtration rate and maintenance of a normal SCr. The ability of SCr to reliably identify AKI is particularly impaired when we try to define relatively milder forms of the disease. Using mathematical models of creatinine kinetics, we have argued [7] that the prevailing consensus definitions of AKI, which largely use percentage changes in SCr, are misinformed because they will lead to a delay in the diagnosis in patients with elevated baseline SCr levels—precisely the population in which AKI is most common. Any definition of AKI, however, which is based on SCr—whether absolute increases over a defined time period, as we have proposed, or percentage rises over baseline—will be bound to misclassify patients. (The inclusion of urine output criteria present in the RIFLE [1] and AKIN [8] definitions may add even more confusion: oliguria can be masked by diuretics, and can denote simple mechanical obstruction of Foley catheters.) It is interesting in this context to observe the evolution of the kidney injury biomarker field, where several proteins and urinary enzymes have been studied as potential