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Urinary vitamin D binding protein: a potential novel marker of renal interstitial inflammation and fibrosis.

Mirković K, Doorenbos CR, Dam WA, Lambers Heerspink HJ, Slagman MC, Nauta FL, Kramer AB, Gansevoort RT, van den Born J, Navis G, de Borst MH - PLoS ONE (2013)

Bottom Line: In multivariate regression analysis, uVDBP was associated with tubulointerstitial macrophage accumulation (standardized beta = 0.47, p = 0.01) and collagen III expression (standardized beta = 0.44, p = 0.02) independently of albuminuria.In humans, uVDBP was increased in 100 microalbuminuric subjects (44±93 µg/d) and in 47 CKD patients with overt proteinuria (9.2±13.0 mg/d) compared to 100 normoalbuminuric subjects (12±12 µg/d, p<0.001).Prospectively designed studies are required to validate our findings and confirm its relevance in the clinical setting.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

ABSTRACT
Non-invasive tubulointerstitial damage markers may allow better titration and monitoring of renoprotective therapy. We investigated the value of urinary vitamin D binding protein excretion (uVDBP) as a tubulointerstitial inflammation and fibrosis marker in adriamycin rats, and tested whether uVDBP parallels renal damage and responds to therapy intensification in humans. In adriamycin (ADR) rats, uVDBP was strongly elevated vs controls (CON) already 6 wks after nephrosis induction (ADR: 727±674 [mean±SD] vs CON: 9±12 µg/d, p<0.01), i.e. before onset of pre-fibrotic and inflammatory tubulointerstitial damage, and at all following 6-wk time points until end of follow up at 30 wks (ADR: 1403±1026 vs CON: 206±132 µg/d, p<0.01). In multivariate regression analysis, uVDBP was associated with tubulointerstitial macrophage accumulation (standardized beta = 0.47, p = 0.01) and collagen III expression (standardized beta = 0.44, p = 0.02) independently of albuminuria. In humans, uVDBP was increased in 100 microalbuminuric subjects (44±93 µg/d) and in 47 CKD patients with overt proteinuria (9.2±13.0 mg/d) compared to 100 normoalbuminuric subjects (12±12 µg/d, p<0.001). In CKD patients, uVDBP responded to intensification of renoprotective therapy (ACEi+liberal sodium: 9.2±13.0 mg/d vs dual RAAS blockade+low sodium: 2747±4013, p<0.001), but remained still >100-fold increased during maximal therapy vs normoalbuminurics (p<0.001), consistent with persisting tubulointerstitial damage. UVDBP was associated with tubular and inflammatory damage markers KIM-1 (standardized beta = 0.52, p<0.001), beta-2-microglobuline (st.beta = 0.45, p<0.001), cystatin C (st.beta = 0.40, p<0.001), MCP-1 (st.beta = 0.31, p<0.001) and NGAL (st.beta = 0.20, p = 0.005), independently of albuminuria. UVDBP may be a novel urinary biomarker of tubulointerstitial damage. Prospectively designed studies are required to validate our findings and confirm its relevance in the clinical setting.

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Urinary vitamin D binding protein (uVDBP) and established renal tubular damage markers in patients with renal damage.Box-whisker plots illustrating the relation between uVDBP and established renal tubular damage markers kidney injury molecule-1 (KIM-1) (A), beta-2-microglobulin (B2M) (B), Cystatin C (CysC) (C) and monocyte chemoattractant protein-1 (MCP-1) (D) in normo- and microalbuminuric subjects (both n = 100). The uVDBP is presented per quartile of the established renal damage marker studied. In all panels (A-D), the left four box whisker plots represent the unadjusted VDBP excretion, and the right four box whisker plots represent the uVDBP adjusted for albuminuria. All biomarkers are positively associated with uVDBP, also when VDBP was adjusted for albuminuria (p<0.001, Kruskal Wallis).
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pone-0055887-g004: Urinary vitamin D binding protein (uVDBP) and established renal tubular damage markers in patients with renal damage.Box-whisker plots illustrating the relation between uVDBP and established renal tubular damage markers kidney injury molecule-1 (KIM-1) (A), beta-2-microglobulin (B2M) (B), Cystatin C (CysC) (C) and monocyte chemoattractant protein-1 (MCP-1) (D) in normo- and microalbuminuric subjects (both n = 100). The uVDBP is presented per quartile of the established renal damage marker studied. In all panels (A-D), the left four box whisker plots represent the unadjusted VDBP excretion, and the right four box whisker plots represent the uVDBP adjusted for albuminuria. All biomarkers are positively associated with uVDBP, also when VDBP was adjusted for albuminuria (p<0.001, Kruskal Wallis).

Mentions: The relation between uVDBP and established markers of proximal tubular damage and renal inflammation was further addressed in normo- and microalbuminuric subjects (n = 200). UVDBP was strongly associated with urinary KIM-1, beta-2-microglobulin and cystatin C (Table 4 and Figure 4). Of interest, urinary VDBP was also associated with urinary excretion of the inflammation markers MCP-1 and NGAL. These associations were independent of albuminuria (Table 4, Figure 4). Accordingly, the VDBP/albuminuria ratio was associated with KIM-1 (r = 0.50, p<0.001), beta-2-microglobulin (r = 0.26, p<0.001), cystatin C (r = 0.26, p = 0.001), MCP-1 (r = 0.19, p = 0.009) and NGAL (r = 0.16, p = 0.01). Using VDBP/proteinuria ratios yielded similar results. None of the urinary biomarker levels were associated with their plasma levels (data not shown). Neither urinary VDBP excretion nor albuminuria was associated with eGFR.


Urinary vitamin D binding protein: a potential novel marker of renal interstitial inflammation and fibrosis.

Mirković K, Doorenbos CR, Dam WA, Lambers Heerspink HJ, Slagman MC, Nauta FL, Kramer AB, Gansevoort RT, van den Born J, Navis G, de Borst MH - PLoS ONE (2013)

Urinary vitamin D binding protein (uVDBP) and established renal tubular damage markers in patients with renal damage.Box-whisker plots illustrating the relation between uVDBP and established renal tubular damage markers kidney injury molecule-1 (KIM-1) (A), beta-2-microglobulin (B2M) (B), Cystatin C (CysC) (C) and monocyte chemoattractant protein-1 (MCP-1) (D) in normo- and microalbuminuric subjects (both n = 100). The uVDBP is presented per quartile of the established renal damage marker studied. In all panels (A-D), the left four box whisker plots represent the unadjusted VDBP excretion, and the right four box whisker plots represent the uVDBP adjusted for albuminuria. All biomarkers are positively associated with uVDBP, also when VDBP was adjusted for albuminuria (p<0.001, Kruskal Wallis).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569442&req=5

pone-0055887-g004: Urinary vitamin D binding protein (uVDBP) and established renal tubular damage markers in patients with renal damage.Box-whisker plots illustrating the relation between uVDBP and established renal tubular damage markers kidney injury molecule-1 (KIM-1) (A), beta-2-microglobulin (B2M) (B), Cystatin C (CysC) (C) and monocyte chemoattractant protein-1 (MCP-1) (D) in normo- and microalbuminuric subjects (both n = 100). The uVDBP is presented per quartile of the established renal damage marker studied. In all panels (A-D), the left four box whisker plots represent the unadjusted VDBP excretion, and the right four box whisker plots represent the uVDBP adjusted for albuminuria. All biomarkers are positively associated with uVDBP, also when VDBP was adjusted for albuminuria (p<0.001, Kruskal Wallis).
Mentions: The relation between uVDBP and established markers of proximal tubular damage and renal inflammation was further addressed in normo- and microalbuminuric subjects (n = 200). UVDBP was strongly associated with urinary KIM-1, beta-2-microglobulin and cystatin C (Table 4 and Figure 4). Of interest, urinary VDBP was also associated with urinary excretion of the inflammation markers MCP-1 and NGAL. These associations were independent of albuminuria (Table 4, Figure 4). Accordingly, the VDBP/albuminuria ratio was associated with KIM-1 (r = 0.50, p<0.001), beta-2-microglobulin (r = 0.26, p<0.001), cystatin C (r = 0.26, p = 0.001), MCP-1 (r = 0.19, p = 0.009) and NGAL (r = 0.16, p = 0.01). Using VDBP/proteinuria ratios yielded similar results. None of the urinary biomarker levels were associated with their plasma levels (data not shown). Neither urinary VDBP excretion nor albuminuria was associated with eGFR.

Bottom Line: In multivariate regression analysis, uVDBP was associated with tubulointerstitial macrophage accumulation (standardized beta = 0.47, p = 0.01) and collagen III expression (standardized beta = 0.44, p = 0.02) independently of albuminuria.In humans, uVDBP was increased in 100 microalbuminuric subjects (44±93 µg/d) and in 47 CKD patients with overt proteinuria (9.2±13.0 mg/d) compared to 100 normoalbuminuric subjects (12±12 µg/d, p<0.001).Prospectively designed studies are required to validate our findings and confirm its relevance in the clinical setting.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

ABSTRACT
Non-invasive tubulointerstitial damage markers may allow better titration and monitoring of renoprotective therapy. We investigated the value of urinary vitamin D binding protein excretion (uVDBP) as a tubulointerstitial inflammation and fibrosis marker in adriamycin rats, and tested whether uVDBP parallels renal damage and responds to therapy intensification in humans. In adriamycin (ADR) rats, uVDBP was strongly elevated vs controls (CON) already 6 wks after nephrosis induction (ADR: 727±674 [mean±SD] vs CON: 9±12 µg/d, p<0.01), i.e. before onset of pre-fibrotic and inflammatory tubulointerstitial damage, and at all following 6-wk time points until end of follow up at 30 wks (ADR: 1403±1026 vs CON: 206±132 µg/d, p<0.01). In multivariate regression analysis, uVDBP was associated with tubulointerstitial macrophage accumulation (standardized beta = 0.47, p = 0.01) and collagen III expression (standardized beta = 0.44, p = 0.02) independently of albuminuria. In humans, uVDBP was increased in 100 microalbuminuric subjects (44±93 µg/d) and in 47 CKD patients with overt proteinuria (9.2±13.0 mg/d) compared to 100 normoalbuminuric subjects (12±12 µg/d, p<0.001). In CKD patients, uVDBP responded to intensification of renoprotective therapy (ACEi+liberal sodium: 9.2±13.0 mg/d vs dual RAAS blockade+low sodium: 2747±4013, p<0.001), but remained still >100-fold increased during maximal therapy vs normoalbuminurics (p<0.001), consistent with persisting tubulointerstitial damage. UVDBP was associated with tubular and inflammatory damage markers KIM-1 (standardized beta = 0.52, p<0.001), beta-2-microglobuline (st.beta = 0.45, p<0.001), cystatin C (st.beta = 0.40, p<0.001), MCP-1 (st.beta = 0.31, p<0.001) and NGAL (st.beta = 0.20, p = 0.005), independently of albuminuria. UVDBP may be a novel urinary biomarker of tubulointerstitial damage. Prospectively designed studies are required to validate our findings and confirm its relevance in the clinical setting.

Show MeSH
Related in: MedlinePlus