Renal angina

Renal angina is a clinical methodology to risk stratify patients for the development of persistent and severe acute kidney injury (AKI). The composite of risk factors and early signs of injury for AKI, renal angina is used as a clinical adjunct to help optimize the use of novel AKI biomarker testing. The term angina from Latin (“infection of the throat”) and from the Greek ẚnkhone (“strangling”) are utilized in the context of AKI to denote the development of injury and the choking off of kidney function. Unlike angina pectoris, commonly caused due to ischemia of the heart muscle secondary to coronary artery occlusion or vasospasm, renal angina carries no obvious physical symptomatology (i.e., flank tenderness, suprapubic tenderness, pain with voiding or micturition). Renal angina was derived as a conceptual framework to identify evolving AKI. Like acute coronary syndrome which precedes or is a sign of a heart attack, renal angina is used as a herald sign for a kidney attack. Detection of renal angina is performed by calculating the renal angina index. Renal angina is a clinical methodology to risk stratify patients for the development of persistent and severe acute kidney injury (AKI). The composite of risk factors and early signs of injury for AKI, renal angina is used as a clinical adjunct to help optimize the use of novel AKI biomarker testing. The term angina from Latin (“infection of the throat”) and from the Greek ẚnkhone (“strangling”) are utilized in the context of AKI to denote the development of injury and the choking off of kidney function. Unlike angina pectoris, commonly caused due to ischemia of the heart muscle secondary to coronary artery occlusion or vasospasm, renal angina carries no obvious physical symptomatology (i.e., flank tenderness, suprapubic tenderness, pain with voiding or micturition). Renal angina was derived as a conceptual framework to identify evolving AKI. Like acute coronary syndrome which precedes or is a sign of a heart attack, renal angina is used as a herald sign for a kidney attack. Detection of renal angina is performed by calculating the renal angina index. Acute kidney injury (AKI) has been extensively associated with worsened morbidity and is an independent risk factor for mortality in adult and pediatric patients. AKI in the developed world occurs most commonly as a secondary injury to numerous disease processes. Sepsis and cardiopulmonary bypass (CPB) are the most oft recognized and reported “causative” injuries leading to AKI. The pathophysiology of AKI can be broadly categorized into four main categories: ischemic injury – manifest by low glomerular blood flow or perfusion pressure to the renal capillary system, hypoxic injury to the renal interstitium, inflammation of the renal tubules, or necrosis and apoptosis of the renal parenchyma. There is increasing recognition that people are not just dying with AKI, but from AKI. The epidemiology of AKI has changed dramatically in the past 20–25 years. Advances made in the treatment of other diseases (e.g., sepsis and bone marrow transplant (BMT)) have placed more patients at risk of nephrotoxic therapies and medication leading to a spike in secondary AKI (mentioned above). Additionally, diagnostic criteria have become more standardized (mentioned below). Discharge coding data from a sample of United States Medicare beneficiaries demonstrated in increase in AKI prevalence from 14.2 to 34.6 AKI cases per 100 patient discharges and increase from 0.5 to 9.9 per 1,000 hospitalized children. In 49,518 patients, 11% had AKI. Two recent cohorts of critically ill children reported a 17.9% incidence in 2106 admissions and 10% of 3396 admissions. Incidence data for AKI is also commonly reported by association to the inciting disease processes or the use of continuous renal replacement therapy (CRRT), otherwise known as continuous dialysis. An estimated 30-50% of all patients with sepsis suffer AKI while 20-40% of all patients after CPB suffer AKI. Other populations with high incidence of AKI include burn victims, trauma patients, and patients after BMT. Mortality for patients on CRRT exceeds 50% for adults and is 33-50% in children. Unfortunately, no singular therapy for AKI exists and trials of CRRT for AKI, even at varying doses, have proven to be ineffective at reducing AKI associated morbidity or mortality. The diagnosis of AKI encompasses tests of the blood, urine, and imaging of the kidneys. The glomerular filtration rate (GFR) is used as an index of kidney function and the most frequently used diagnostic test to calculate GFR is the serum creatinine level. GFR also factors in urine and plasma solute concentration. Unfortunately, serum creatinine is highly variable depending on age, sex, metabolic state, body composition (muscle mass), and rate of excretion by the kidney itself. The rate of urine production (i.e., urine output) is also interpreted as a marker of kidney function but the definitions of low urine output (oliguria) also vary by age. Urinalysis often provides clues about kidney health – hematuria, tubular casts, and proteinuria have been used as markers of injury. Unfortunately, the multiple ways used by different practitioners to diagnose AKI have made large scale population analysis difficult (Table 1 - Previous Diagnostic Tests for AKI) In 2004, the Acute Dialysis Quality Initiative group standardized the definition of AKI using the “RIFLE” criteria. Based on GFR, serum creatinine values, and urine output plotted against time of admission, RIFLE, a mnemonic for three levels of severity – Risk, Injury, and Failure, and two outcomes, Loss and End-stage kidney disease, marks progressive degrees of injury in both ICU and non-ICU adult patients. In 2007, the Acute Kidney Injury Network (AKIN) devised strata which defined AKI based on time in relation to absolute creatinine increase, percentage increase, or documented oliguria, broadening the window for time of AKI diagnosis and creating an automatic “failure” designation for any patient placed on renal replacement therapy. In 2007, a pediatric RIFLE (pRIFLE) stratification system was established with weight based – pediatric specific cut-offs for estimated GFR and urine output. Most recently, the Kidney Diseases Improving Global Outcomes (KDIGO) collaborative issued newer severity based AKI stages (Table 2 - Staging Criteria for AKI). Since 2005, numerous studies in both adult and pediatric patient populations have demonstrated that, retrospectively, escalating severity of AKI stratified by these criteria are associated with increased in-hospital morbidity, hospital length of stay, persistence of kidney disease to chronic kidney disease, and mortality. AKI researchers have sought novel early, sensitive, and specific biomarkers for AKI. A number of biochemical markers are currently under study for established AKI, early detection of AKI, and prognosis of AKI. The most frequently studied new biomarkers include Cystatin C (CysC), neutrophil gelatinase associated lipocalin (NGAL), interleukin-18, liver-fatty acid binding protein (l-FABP), and kidney injury molecule-1 (KIM-1). Children following cardiopulmonary bypass are often used to derive biomarker performance and validate optimal cut-off values given a known timing and duration of insult, relative homogeneity, and freedom from co-morbidities. Unfortunately, when these and other biomarkers are applied to a more heterogeneous patient population (the general intensive care unit, non-critically ill patients, patients in the emergency department), they demonstrate less robust predictive performance. The inability to detect AKI in the early stages of injury may be a reason for the poor outcomes associated with the disease processes. The quest for the ideal biomarker(s) for early detection of injury has been dubbed “the search for the renal troponin I”. An apt analogy to the diagnosis of heart attack, or myocardial infarction, the discovery of serum troponin as a confirmatory biomarker for injury in patients with known risk factors and signs of injury (e.g., pain, chest tightness) revolutionized the survival for acute coronary syndrome (ACS). Without correct context, the performance of troponin for detection of a heart attack is marginal. Renal angina was proposed as an empiric concept to create a threshold of AKI risk to identify patients who would most benefit from a confirmatory AKI biomarker test. Used to predict the development of severe and persistent AKI, defined as RIFLE Stage I or F three days after admission, renal angina is an easy to use, AKI predictive tool. Renal angina manages the heterogeneity of patient populations, directing biomarker testing only for patients who fulfill a combination of illness severity and changes in kidney function. Renal angina can be thought of in terms of a simple equation: Renal angina threshold = risk of AKI x evidence of AKI