Renal angina: right concept...Wrong name?

AKI is the loss of kidney function over a period of hours to days. Although the definition is easily stated, operationalizing it in a form that can be readily applied in clinical practice and in research settings has been a challenge. Markers of glomerular filtration, including serum creatinine and urine output, generally lag behind the actual onset of parenchymal kidney injury and reliance on these functional parameters for early detectionofkidneydamagemaydelaydiagnosis.Although some might argue that this has minimal clinical consequence given the absence of effective pharmacologic interventions, the inability to rapidly diagnose AKI has been one of the barriers to developing effective pharmacologic therapies tomitigate parenchymal damage in the minutes to hours after an inciting insult (1). AKI is not a homogeneous syndrome, which further complicates the situation. Patients may sustain a reduction in kidney function from fluctuations in renal perfusion or obstruction to urine flow without sustaining significant parenchymal damage. Thus, a major focus in AKI research over the past decade has been the identification and validation of novel biomarkers of kidney damage to facilitate rapid identification of patientswith intrinsicAKI (2). By analogy with cardiology, this quest for biomarkers has been characterized as a search for a “renal troponin” that will allow transformation of the management of AKI from the current paradigm of supportive care, as characterized the management of acute myocardial infarction before the current era of lytic therapy and percutaneous coronary intervention, to a new paradigm of biomarker-guided targeted intervention (3). Although multiple candidate urine and plasma biomarkers have been identified, including kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, IL-18, liver fatty acid binding protein, and several others, to date, none has been demonstrated to have sufficient diagnostic discrimination to transform the management of AKI as cardiac troponin and other biomarkers transformed the management of acute myocardial infarction. One of the potential reasons for the disappointing performance of these biomarkers has been difficulty in identifying the correct population for their application. Simply stated, unlike acute myocardial infarction, AKI does not hurt. Although cardiac troponin has high sensitivity and specificity for the diagnosis of acute myocardial infarction when assayed in patients with retrosternal chest pain and shortness of breath, it has poor diagnostic discrimination when measured in patients with atypical or absent symptoms. Prompted by recognition of the need to identify patients at high risk for AKI in order to effectively utilize kidney injury biomarkers in clinical practice, Goldstein andChawla proposed the concept of “renal angina” in a commentary published in CJASN nearly 4 years ago (4). In their conceptual model, renal angina is defined by a combination of risk factors (e.g., age, diabetes, CKD, sepsis, cirrhosis, postsurgical state, and critical illness) and clinical context. They proposed that among high-risk patients, the development of oliguria, any increase in serum creatinine, or development of fluid overload constitutes a “renal anginal equivalent” and should prompt immediate evaluation for evidence of impaired renal perfusion and should trigger more frequent monitoring of serum creatinine and urine output and assessment of biomarkers to facilitate the diagnosis of AKI. Over the past 4 years, Goldstein, Chawla, and colleagues have published a series of articles attempting to operationalizethisconceptofrenalangina, includingtwo articles in this issue of CJASN (7,8). Basu and colleagues developed a pediatric renal angina index (RAI), calculated as the product of scores for risk of AKI (very high risk: 5 points; high risk: 3 points; moderate risk: 1 point) and clinical signs of injury (no decrease in estimated creatinine clearance [eCCl] or,5% fluid overload [FO]: 1 point; 0%– 25% decrease in eCCl or 5%–10% FO: 2 points; 25%–50% decrease in eCClor 10%–15%FO: 4points;$50%decrease in eCCl or $15% FO: 8 points). They defined a RAI score$8 as renal angina and reported that its presence on admission to the intensive care unit predicted the development of severe AKI (defined as a.200% increase in serum creatinine 72 hours after intensive care unit admission), with a C-statistic of 0.74–0.81, a positive predictive value of 18%–40%, and a negative predictive value of 92%–99% (6). In this issue of CJASN, Basu and colleagues report on the combination of the RAI and three candidate biomarkers— neutrophil gelatinase-associated lipocalin, matrix metalloproteinase-8, and neutrophil elastase-2— in a cohort of 214 children with severe sepsis or septic shock (7). Although individually the biomarkers provided less diagnostic discrimination for AKI than the RAI, when they were combined with the RAI, either individually or in pairs, the overall predictive performance for diagnosis of AKI improved, albeit modestly. Also in this issue of CJASN, Cruz and colleagues report on a different model for operationalizing renal angina in adults (8). Using recognized acute (hypotension, high-risk surgery, nephrotoxin exposure, and sepsis) and major (advanced age, diabetes mellitus, Renal Section, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; and Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania