Urinary and Plasma Levels of Vasohibin-1 Can Predict Renal Functional Deterioration in Patients with Renal Disorders

<div><p>Vasohibin-1 (VASH-1) is a negative feedback regulator of angiogenesis, and a small vasohibin-binding protein (SVBP) serves as its secretory chaperone and contributes to its antiangiogenic effects. In the present study, we aimed to define the clinical significance of VASH-1 and SVBP in patients with chronic kidney disease (CKD). We recruited 67 Japanese hospitalized patients with renal disorders with (n = 45) or without (n = 22) renal biopsy samples and 10 Japanese healthy controls. We evaluated the correlations between the plasma and urinary levels of VASH-1/VASH-1-SVBP complex/SVBP and the clinicopathological parameters. The plasma levels of VASH-1 were inversely correlated with age and systolic and diastolic blood pressure and positively correlated with crescent formation. Increased plasma and urinary levels of VASH-1 and VASH-1-SVBP complex were significantly correlated with worse renal outcomes. These results demonstrate an association between elevated urinary and plasma levels of VASH-1 and progressive decline of the renal function, thus suggesting a potential role for VASH-1 in predicting a worse renal prognosis in patients with renal disease, including CKD.</p></div

Correlations between the plasma and urinary levels of vasohibin-1-small vasohibin-binding protein complex and small vasohibin-binding protein, and the clinical/histological parameters and the plasma/urinary levels of vasohibin-1.

<p>Abbreviations: eGFR, estimated glomerular filtration rate; SVBP, small vasohibin-binding protein; U-Cr, urinary level of creatinine; VASH-1, vasohibin-1.</p>a<p><i>P</i><0.05.</p>b<p><i>P</i><0.01.</p

The baseline characteristics of the patients with or without renal biopsy, classified by the plasma levels of vasohibin-1.

<p>Abbreviations: eGFR, estimated glomerular filtration rate; RB, renal biopsy; SBP, systolic blood pressure; sCr, serum creatinine; VASH-1, vasohibin-1. The values are expressed as the means ± SD.</p>a<p><i>P</i><0.05 versus the Low group.</p>b<p><i>P</i><0.01 versus the Low group.</p

Characteristics of the patients with renal biopsy and the control subjects (at baseline).

<p>Abbreviations: DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; GN, glomerulonephritis; MC, minimal change; MN, membranous nephropathy; N, nephropathy; SBP, systolic blood pressure; sCr, serum creatinine. The values are expressed as the means ± SD.</p

Correlations between the plasma and urinary levels of vasohibin-1, the vasohibin-1-small vasohibin-binding protein complex and small vasohibin-binding protein, and the annual change rates in the estimated glomerular filtration rate.

<p>Abbreviations: eGFR, estimated glomerular filtration rate; SVBP, small vasohibin-binding protein; U-Cr, urinary level of creatinine; VASH-1, vasohibin-1. The annual change rates in eGFR were evaluated as follows: the annual change in eGFR was divided by the eGFR at baseline.</p>a<p><i>P</i><0.05.</p

The changes in the estimated glomerular filtration rate and the number of events in the overall patients and patients with classified renal disorders.

<p>Abbreviations: eGFR, estimated glomerular filtration rate (mL/min/1.73 m²); GN, glomerulonephritis; MC, minimal change; MN, membranous nephropathy; N, nephropathy; RB, renal biopsy; RRT, renal replacement therapy. A composite renal event was defined as a decline in the eGFR of more than 30% of the baseline value, initiation of RRT or death associated with a renal disorder. The values are expressed as the means ± SD.</p>a<p><i>P</i><0.01 versus patients with RB.</p

The changes in the estimated glomerular filtration rate and the number of events in the patients with or without renal biopsy, classified by the plasma levels of vasohibin-1.

<p>Abbreviations: eGFR, estimated glomerular filtration rate (mL/min/1.73 m²); RB, renal biopsy; RRT, renal replacement therapy; VASH-1, vasohibin-1. A composite renal event was defined as a decline in the eGFR of more than 30% of the baseline value, initiation of RRT or death associated with a renal disorder. The values are expressed as the means ± SD. The average eGFR did not include the values from the patients who received RRT or died.</p>a<p><i>P</i><0.05 versus the Low group.</p

Results of the multivariate logistic analysis of the risk of composite renal events.

<p>Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; OR, odds ratio; SVBP, small vasohibin-binding protein; U-Cr, urinary level of creatinine; VASH-1, vasohibin-1. A composite renal event was defined as a decline in the eGFR of more than 30% of the baseline value, initiation of renal replacement therapy or death associated with a renal disorder. In order to perform a multivariate logistic analysis of the plasma and urinary levels of VASH-1, the patients were stratified into two groups using the median value as the cutoff point, and the plasma levels of the VASH-1-SVBP complex, the patients were stratified into three groups.</p><p>Model 1: adjusted for age and gender.</p><p>Model 2: adjusted for age, gender and systolic blood pressure.</p

Correlations between the plasma/urinary levels of vasohibin-1 and the clinical parameters.

<p>(A) Correlations between the plasma/urinary levels of VASH-1 and age. (B) Correlation between the urinary VASH-1/Cr ratio and age. (C) Correlation between the plasma level of VASH-1 and systolic blood pressure. (D) Correlation between the urinary VASH-1/Cr ratio and systolic blood pressure. (E) Correlation between the plasma level of VASH-1 and diastolic blood pressure. (F) Correlation between the urinary VASH-1/Cr ratio and diastolic blood pressure. (G) Correlation between the plasma level of VASH-1 and eGFR. (H) Correlation between the urinary VASH-1/Cr ratio and eGFR. (I) Correlation between the plasma level of VASH-1 and proteinuria. (J) Correlation between the urinary VASH-1/Cr ratio and proteinuria. Abbreviations: BP, blood pressure; eGFR, estimated glomerular filtration rate; U-Cr, urinary level of creatinine; VASH-1, vasohibin-1.</p

The results of the Kaplan-Meier analysis of the composite renal endpoint.

<p>A composite renal event was defined as a decline in the eGFR of more than 30% of the baseline value, initiation of renal replacement therapy or death associated with a renal disorder. In order to perform a Kaplan-Meier analysis of the plasma and urinary levels of VASH-1, the patients were stratified into two groups using the median (609 fmol/mL for the plasma level and 21 fmol/mg for the urinary level of VASH-1) as the cutoff point. The log-rank test was used to compare differences between the two groups. (A and B) Increased plasma levels of VASH-1 were significantly correlated and the urinary levels of VASH-1 tended to be correlated with worse renal outcomes. (C) In order to perform a Kaplan-Meier analysis of the plasma levels of the VASH-1-SVBP complex, the patients were stratified into three groups (<316, 316 to 408 and >408 fmol/mL). The group with the highest plasma levels of the VASH-1-SVBP complex exhibited significantly worse renal outcomes than the groups with moderate or low plasma levels. Abbreviations: eGFR, estimated glomerular filtration rate; RRT, renal replacement therapy, SVBP, small vasohibin-binding protein; VASH-1, vasohibin-1.</p