Serum cystatin C is an independent biomarker associated with the renal resistive index in patients with chronic kidney disease

<div><p>Cystatin C is a cysteine protease inhibitor that is produced by nearly all human cells. The serum level of cystatin C is a stronger predictor of the renal outcome and the risk of cardiovascular events than the creatinine level. The resistive index (RI) on renal Doppler ultrasonography is a good indicator of vascular resistance as well as the renal outcomes in patients with chronic kidney disease (CKD). However, it is unclear whether serum cystatin C is associated with signs of vascular dysfunction, such as the renal RI. We measured the serum cystatin C levels in 101 CKD patients and investigated the relationships between cystatin C and markers of vascular dysfunction, including the renal RI, ankle-brachial pulse wave velocity (baPWV), intima-media thickness (IMT), and cardiac function. The renal RI was significantly correlated with the serum cystatin C level (p < 0.0001, r = 0.6920). The serum cystatin C level was found to be a significant determinant of the renal RI (p < 0.0001), but not the baPWV, in a multivariate regression analysis. The multivariate odds ratio of the serum cystatin C level for a renal RI of more than 0.66 was statistically significant (2.92, p = 0.0106). The area under the receiver-operating characteristic curve comparing the sensitivity and specificity of cystatin C for predicting an RI of more than 0.66 was 0.882 (cutoff value: 2.04 mg/L). In conclusion, the serum cystatin C level is an independent biomarker associated with the renal RI in patients with CKD.</p></div

The correlation between the resistive index (RI) and various parameters.

<p>The relationships between the RI and patient age (years) (A), estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) (B), albuminuria (mg/day) (C), cystatin C (mg/L) (D) and markers of systemic atherosclerosis, including the ankle-brachial pulse wave velocity (baPWV) (E) and maximum intima-media thickness (IMT) (F), are shown. The RI was positively correlated with age, albuminuria, and cystatin C, and inversely correlated with eGFR (A-D). Regarding the markers of systemic atherosclerosis, baPWV and maximum IMT were positively correlated with RI (E, F).</p

The multivariate odds ratios for the resistive index (RI: 0.66) among patients with CKD.

<p>The values are displayed as the odds ratio (OR) (solid boxes) with 95% confidence intervals (CIs) (horizontal limit lines). For continuous variables, the unit of change is given in parentheses. Adjusted for age and eGFR. SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate.</p

Serum cystatin C is an independent biomarker associated with the renal resistive index in patients with chronic kidney disease - Fig 3

<p><b>The ROC curves comparing the sensitivity and specificity of cystatin C (A), albuminuria (B), BNP (C) and e’ (D) for predicting a resistive index (RI) 0.66.</b> The AUC values for the ROC curve when cystatin C, albuminuria, BNP and e’ were used to detect an RI of 0.66 were 0.882 (p < 0.0001), 0.705 (p = 0.0012), 0.865 (p < 0.0001) and 0.722 (p = 0.0007), respectively.</p

Baseline characteristics of the study subjects.

<p>Baseline characteristics of the study subjects.</p

A multiple logistic regression analysis of predictors of PWV≥1400 cm/sec.

<p>Adjusted for age, gender, mean blood pressure, antihypertensive drug use, drinking and current smoking. CKD, chronic kidney disease; 1,25D, 1,25-dihydroxyvitamin D; eGFR, estimated glomerular filtration rate; FGF23, fibroblast growth factor 23; HDL, high density lipoprotein; MBD, mineral and bone disorder; NGSP, national glycohemoglobin standardization program.</p

Correlation between the serum Klotho levels (pg/mL) and various parameters.

<p>The relationships between the serum Klotho levels and patient age (years) (A), estimated glomerular filtration rate (eGFR) (mL/min/1.73 m²) (B) and markers of chronic kidney disease-mineral and bone disorder (CKD-MBD), including 1,25-dihydroxyvitamin D (1,25D) (pg/mL) (C), log intact parathyroid hormone (PTH) (pg/mL) (D), fractional excretion of phosphate (FEPi) (%) (E) and fractional excretion of calcium (FECa) (%) (F) are shown. The serum Klotho levels were inversely correlated with age and positively correlated with eGFR (<b>A, B</b>). Regarding CKD-MBD markers, the serum Klotho levels were significantly correlated with 1,25D and negatively correlated with log intact PTH and FEPi; however, no significant correlation was observed with FECa (<b>C–F</b>). (<b>A–F</b>) N = 114.</p

Baseline characteristics of the study subjects.

<p>ACEI, angiotensin converting enzyme inhibitor; ACI, abdominal aortic calcification index; ARB, angiotensin receptor blocker; baPWV, brachial-ankle pulse wave velocity; CRP, C-reactive protein; 1,25D, 1,25-dihydroxyvitamin D; 25D, 25-hydroxyvitamin D; eGFR, estimated glomerular filtration rate; FECa, fractional excretion of calcium; FEPi, fractional excretion of phosphate; FGF23, fibroblast growth factor 23; FMD, flow-mediated dilatation, HDL, high density lipoprotein; IMT, intima-media thickness; LDL, low density lipoprotein; MBP, mean blood pressure; NGSP, national glycohemoglobin standardization program.</p

Multivariate odds ratio for ankle-brachial pulse wave velocity (baPWV) among patients with CKD displayed as the odds ratio (OR) (solid boxes) with 95% confidence intervals (CIs) (horizontal limit lines).

<p>For continuous variables, the unit of change is given in parenthesis based on the multivariate model described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056695#pone-0056695-t002" target="_blank">Table 2</a>. MBP, mean blood pressure; eGFR, estimated glomerular filtration rate; PTH, parathyroid hormone; 1,25D, 1,25-dihydroxyvitamin D; FGF23, fibroblast growth factor 23.</p