Author + information
- Horng H. Chen, MB, BCh⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Horng H. Chen, Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic and Foundation, 200 First Street Southwest, Rochester, Minnesota 55905
β-trace protein (BTP), also known as prostaglandin D2 synthase, is a low-molecular-weight glycoprotein (25.2 kDa) that was initially isolated from cerebrospinal fluid and served as a marker of cerebrospinal fluid leakage (1). It is expressed in all tissues except the ovaries, with biological actions that include vasodilatation, bronchoconstriction, inhibition of platelet aggregation, and recruitment of inflammatory cells. BTP was also found to be increased in the serum of patients with renal failure. The half-life of BTP is approximately 1.2 h, and it is freely filtered through the glomerular basement membrane with minimal nonrenal elimination. Hence, it has been proposed as a new endogenous marker of glomerular filtration rate (GFR). Studies have confirmed a good correlation between serum BTP levels and the GFR measurement based on inulin clearance and nuclear medicine methods (1).
Cystatin C (cys-C) is a 122-amino acid, 13-kDa protein that is a member of a family of competitive inhibitors of cysteine proteases. cys-C is produced by all human nucleated cells, and the human cys-C gene is of the housekeeping type, which indicates a stable production rate of cys-C by most nucleated cell types. cys-C has several properties that make it a good candidate marker of GFR, including a constant production rate, free filtration at the glomerulus, complete reabsorption and catabolism by the proximal tubules with no reabsorption into the bloodstream, and no renal tubular secretion (2).
In this issue of the Journal, Manzano-Fernández et al. (3) reported that in a cohort of 220 patients hospitalized with acute decompensated heart failure, BTP and cys-C predicted risk for death and/or heart failure hospitalization and were superior to standard measures of renal function for this indication. Plasma BTP concentration was positively correlated with cys-C concentration. Both, plasma BTP and cys-C concentrations, were positively correlated with serum creatinine, blood urea nitrogen, age, New York Heart Association functional class, N-terminal pro–B-type natriuretic peptide, uric acid, troponin T, and C-reactive protein, whereas both were negatively correlated with estimated glomerular filtration rate (eGFR), serum albumin, and hemoglobin. Surprisingly, neither BTP nor cys-C was associated with worsening renal function during index hospitalization. After multivariable adjustment, both BTP and cys-C were significant predictors of death/heart failure hospitalization, whereas serum creatinine, eGFR, and blood urea nitrogen were no longer significant. Importantly, in patients with eGFR >60 ml/min, elevated concentrations of BTP and cys-C were still associated with significantly higher risk of adverse clinical events. Net reclassification index analysis suggested that BTP and cys-C had comparable information regarding prognosis.
Is BTP a better surrogate marker of renal function as compared with cys-C?
In an elegant study by Donadio et al. (4), the authors evaluated the relationship between serum levels of BTP and GFR for comparison with cys-C. Serum levels of BTP progressively increased with the reduction of GFR. A good correlation was found between GFR and serum levels of BTP (r = 0.918) and cys-C (r = 0.937). Importantly, no statistically significant difference was found between BTP and cys-C as indicators of a moderate GFR impairment. As a tool for GFR measurement, BTP may have some distinct advantages. It has been reported that serum BTP levels do not have a significant relationship with C-reactive protein and that they are unaffected by body composition. During the third trimester of pregnancy, BTP, but not cys-C, has been shown to adequately reflect the GFR. Unlike cys-C, thyroid function has not been reported to affect the concentration of BTP. Another possible advantage would be the lack of effect of corticosteroid administration on BTP concentrations. However, Abbink et al. (5) demonstrated that glucocorticoid therapy resulted in a dose-dependent underestimation of GFR by serum cys-C and an overestimation by BTP. Hence, BTP offers no advantage over cys-C in this setting. The Mild and Moderate Kidney Disease Study Group evaluated measured GFR and the serum markers cys-C and BTP for diagnostic accuracy in defining stage of kidney impairment and as risk predictors of chronic kidney disease (CKD) progression (1). They measured serum marker concentrations in 227 patients with primary nondiabetic CKD and various degrees of renal impairment and followed 177 patients prospectively for up to 7 years to assess progression of CKD. At baseline, cys-C and BTP were strongly correlated with GFR as measured by iohexol clearance. Sixty-five patients experienced progression of CKD, defined as doubling of baseline creatinine and/or terminal renal failure during prospective follow-up. These patients were older and had a lower GFR and higher cys-C and BTP values at baseline as compared with the patients who did not reach a predefined renal end point. Cox proportional hazards regression analysis revealed that both BTP and cys-C were equally strong predictors of CKD progression, even after adjustment for age, sex, GFR, and proteinuria.
Is BTP a better prognostic marker as compared with cys-C?
Several cohort and population-based studies have demonstrated that cys-C is an important prognostic indicator of cardiovascular and overall mortality (6). In comparison, the prognostic value of BTP in cardiovascular disease is less defined. Hirawa et al. (7) demonstrated that serum and urinary levels of BTP were increased in essential hypertension, even with normal renal function. The increase in serum BTP was affected by blood pressure, urinary excretions of BTP, serum creatinine, and sex. Eguchi et al. (8) demostrated that BTP is present in both endocardium and myocardium of normal subjects and at the stenotic site of patients with stable angina and is secreted into the coronary circulation. Immunoreactivity and mRNA expression of BTP confirm that BTP was definitely localized and generated in atherosclerotic plaques, especially of the human coronary artery (9). Furthermore, BTP was also found in vascular endothelial cells in the systemic atherosclerotic artery. Hence, these findings suggest that BTP may play a role in the pathophysiology for cardiovascular diseases and may therefore have prognostic value beyond being a surrogate marker of renal function. Manzano-Fernández et al. (3) reported that using receiver-operator characteristic analyses, the prognostic accuracy of BTP in predicting adverse clinical events survival in acute decompensated heart failure was slightly superior to the more conventional measures of renal function and was comparable to cys-C.
Future research directions
Although the current evidence suggests that BTP is comparable to cys-C as a surrogate marker of renal function, more studies are needed to define the prognostic value of BTP in various cardiovascular diseases such as coronary artery diseases, hypertension, diabetes, and so on. It would be very clinically relevant to determine whether serial measurements of BTP have added prognostic value.
This research was supported by grants from the National Institutes of Health (PO1 HL 76611 and R01 HL-84155) and the Mayo Foundation. Dr. Chen has reported that he has no relationships to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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