A possible role of cystatin C in adipose tissue homeostasis may impact kidney function estimation in metabolic syndrome

Abstract

The assessment of kidney function [1] serves two main purposes: one is to accurately diagnose kidney function impairment at a given—preferably early—point in time, and the other is to determine the slope of function decline by serial assessment. Kidney function is best measured as the glomerular filtration rate (GFR) by infusion of exogenous markers such as inulin, I-iothalamate or chromium–EDTA. Unfortunately, these gold standards are cumbersome, costly and often too time-consuming for clinical or epidemiological purposes. Current guidelines recommend the use of prediction equations based on a single serum creatinine concentration to estimate the GFR or to calculate the creatinine clearance from a 24-h urine sample. Many investigators have questioned the accuracy of these equations, particularly when used in the normal to elevated range of kidney function. Consequently, there has been much interest in the performance of alternative biomarkers such as cystatin C. Cystatin C, a low-molecular weight (13kD) protein and a member of the super-family of cysteine protease inhibitors, has been proposed to provide a more accurate estimation of the GFR than serum creatinine [2, 3]. In various populations, cystatin C was more sensitive in the identification of mild reductions in kidney function than serum creatinine [3]. Cystatin C is believed to be produced at a constant rate by a “housekeeping” gene that is present in all nucleated cells, and to be freely filtered across the glomerulus. Prediction equations based on serum cystatin C concentrations have been formulated [4], whereas 100/cystatin C visualizes function decline over time. Unlike creatinine, cystatin C does not undergo tubular secretion, but is catabolized by epithelial cells of the proximal tubulus, which prevents cystatin C from being used for calculating clearance. The rate of production of cystatin C was initially believed to be uninfluenced by changes in diet, muscle mass, age, gender and ethnicity. Yet various recent studies have shown that cystatin C concentrations are indeed affected by determinants other than kidney function: age, male gender, body mass index, fat mass, triglyceride concentrations, hypertension, uric acid, C-reactive protein and diabetes have all been associated with higher serum concentrations of cystatin C independent of kidney function (in some studies assessed using I-iothalamate and Chromium-EDTA) [5–7]. Intriguingly, all these factors cluster together in the metabolic syndrome [8], suggesting a yet ill-defined role of cystatin C in the pathophysiology of the metabolic syndrome. In this issue of NDT, Reutens et al. [9] report on an association between cystatin C and incident type-2 diabetes. The study involved a large cohort of participants included in the DESIR cohort, which comprises men and women of the French general population aged 36–71 years with relatively low prevalence of the metabolic syndrome (24%). The 3-year incidence of type 2 diabetes was only 2%. The authors confirmed recent literature that showed that cystatin C predicts incident diabetes independent of the estimated GFR (MDRD), waist circumference, insulin resistance and other risk factors for type-2 diabetes. More importantly, Reutens et al. showed that the impact of cystatin C on incident type-2 diabetes was dependent on the amount of adiposity. This finding sheds some interesting light on the possible role of cystatin C in obesity. Cystatin C’s main biological role is to be the endogenous inhibitor of the cysteine proteases cathepsins [10], which comprises a family of 11 human proteases (cathepsins B, C, H, F, K, L, O, S, V, W and Z) [11]. Of this family, cathepsins S, K and L have been shown to promote adipogenesis, often in conjunction with the degradation of extracellular matrix (ECM) [12–14]. Cysteinyl cathepsins, which have proteolytic activity, are known to degrade ECM components [11]. In addition, they are involved in the processing of antigen presentation [15], while inflammatory cells migrate into tissue in a cathepsin-dependent manner. In agreement, mouse models of cathepsin deficiencies typically display attenuated inflammation [16]. These are properties that may be of relevance to the remodelling of adipose tissue. Recent evidence suggests that impaired IN F O C U S