The kidneys are involved in numerous homeostatic functions that are critical for survival and proper body functioning, including regulation of fluid, electrolyte, and acid-base balance, removal of drugs and metabolism waste products, and regulation of several hormone levels.1 With its wide array of underlying causes, ranging from hypertension, to diabetes mellitus, and atherosclerotic disease, chronic kidney disease (CKD) has become a major public health problem, with rising incidence and prevalence, poor outcomes, and increasing costs.2 Evaluation of kidney function is therefore a major desideratum, and numerous laboratory parameters, such as blood urea nitrogen (BUN) and uric acid, urine protein content, blood and urine electrolyte and glucose levels, urine output, specific gravity, and osmolality, and particularly serum creatinine are routinely evaluated for estimating renal function in a wide array of clinical settings.3 Most of these parameters are, however, nonspecific for kidney disease.
The glomerular filtration rate (GFR) represents at present the single most widely used parameter for kidney function assessment and has been used in numerous studies to identify both predictors and complications of CKD.4 Inulin is an ideal filtration marker seen as gold standard for GFR assessment, although other exogenous markers, such as 51-chromium-labeled ethylenediamine tetra-acetic acid (51Cr-EDTA), diethylenetriaminepentaacetic acid, iothalamate, or iohexol can also be used.5 Although extremely useful in physiological studies and as a research tool, using exogenous markers for renal clearance assessment is, however, complex, expensive, time-consuming, and too cumbersome to be implemented as a routine clinical tool. Creatinine, an endogenous by-product of creatine phosphate that is produced at a constant rate by the body and cleared from the blood by the kidneys, has emerged as a widely available marker for GFR estimation.
Serum creatinine and serum creatinine-derived estimated GFR (eGFR) evaluation have, however, nonnegligible limitations. Creatinine production is closely related to muscle bulk, and is therefore highly variable according to age, gender, race, and bodyweight, factors that are incorporated, in various combinations, in the equations most commonly used to estimate GFR. Other factors, such as pregnancy, dietary protein intake, liver disease, muscle injury, rhabdomyolysis, or muscular dystrophy, and administration of certain drugs that block creatinine secretion in the renal tubules (e.g., cimetidine, spironolactone, trimethoprim) can also affect, however, the levels of serum creatinine and eGFR values derived from them.6 Additionally, studies evaluating the accuracy of one of the most widely used equations, Modification of Diet in Renal Disease (MDRD), in patients in whom iothalamate clearance tests were performed to measure GFR have shown that although the MDRD equation was relatively accurate in patients with CKD, it greatly underestimated GFR in healthy individuals.7 Similarly, studies assessing the Cockroft-Gault equation in patients in whom GFR was measured using 51Cr-EDTA clearance tests have shown reduced sensitivity and accuracy of this equation and overestimated GFR levels, particularly at low filtration rates, due to creatinine secretion by the renal tubules and lack of adjustment for body-surface area.8 Creatinine clearance also overestimates renal function in obese and edematous patients, and is futile in patients who are cachectic or pregnant, who have ascites or low muscle mass.6 In addition, increases in serum creatinine are late indicators of renal dysfunction, that may sometimes become apparent only when renal function has already decreased by 50–75%,6 and is therefore incapable of identifying subclinical kidney impairment.9 Serum creatinine concentrations are also not related to renal structural injury, and cannot differentiate between different causes of kidney dysfunction such as parenchymal renal injury due to nephrotoxicity, severe liquid loss, or obstructive renal disease.10
Therefore, similar to other clinical settings,11,12 measurement of biomarkers more sensitive than serum creatinine may be required to detect subtle renal changes, and to identify additional predictors and consequences of kidney injury. Among them, neutrophil gelatinase-associated lipocalin (NGAL), a glycoprotein that is rapidly released into the bloodstream in response to renal injury,13 and cystatin C, a low molecular-weight protein that accurately reflects early kidney impairment,14 appear to be extremely promising candidates. Unlike serum creatinine, which provides a rather late reflection of significant functional renal injury, NGAL is an early and highly sensitive marker of structural renal damage,15 and both NGAL and cystatin C levels are less affected by factors such as age, sex, or muscle mass than serum creatinine.14
Accordingly, in the present study, we aimed to identify predictors and consequences of subclinical renal impairment, as reflected by the levels of two biomarkers more sensitive than serum creatinine (i.e., NGAL and cystatin C), in patients with vascular (coronary or peripheral) artery disease.