Beta Trace-Protein versus Cystatin C: Which is a Better Surrogate Marker of Renal Function versus Prognostic Indicator in Cardiovascular Diseases?

Beta trace-protein (BTP), also known as prostaglandin D2 synthase, is a low-molecular-weight glycoprotein (MW 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 non-renal 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 JACC, Manzano-Fernández et al(3), reported that in a cohort of 220 patients hospitalized with acute decompensated heart failure (ADHF), BTP and cys-C predicted risk for death and/or heart failure (HF) hospitalization, and are 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, BUN, age, New York Heart Association functional class, NT-proBNP, uric acid, troponin T and C-reactive protein, while both were negatively correlated with eGFR, serum albumin and haemoglobin. 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/HF hospitalization, whereas serum creatinine, estimated eGFR, and BUN were no longer significant. Importantly, in patients with eGFR>60mL/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 to Cys-C?

In an elegant study by Donadio et al, the authors evaluated the relationship between serum levels of BTP, GFR for comparison with Cys-C(4). 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 demonstrated that glucocorticoid therapy resulted in a dose dependent underestimation of GFR by serum cys-C, and an overestimation by BTP(5). Hence, BTP offers no advantage over cys C in this setting. The Mild and Moderate Kidney Disease (MMKD) Study Group evaluated measured GFR and the serum markers, cys-C and BTP, for diagnostic accuracy in defining the stage of kidney impairment and as risk predictors of chronic renal diseases (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, cys-C and BTP values at baseline compared with the patients who did not reach a predefined renal endpoint. Cox proportional hazard 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 maker as compared to 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 demonstrated that serum and urinary levels of BTP were increased in essential hypertension, even in normal renal function(7). The increase in serum BTP was associated with blood pressure, urinary excretions of BTP, serum creatinine, and gender. Eguchi et al 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(8). 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. In this issue of JACC, Manzano-Fernández et al, reported that using ROC analyses, the prognostic accuracy of BTP in predicting adverse clinical events survival in ADHF, was slightly superior to the more conventional measures of renal function and comparable to cys-C.

Future Research Directions

While the current evidence suggests that BTP is comparable to Cys-C as a surrogate marker to renal function, more studies are needed to define the prognostic value of BTP in various cardiovascular diseases such as coronary artery diseases, hypertension, diabetes etc. It would be very clinically relevant to determine if serial measurements of BTP has added prognostic value.