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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) levels in patients with normoalbuminuria, microalbuminuria, and overt proteinuria.Box-whisker plots indicating the median, interquartile range, and range of 24-h uVDBP per patient category: general population with normoalbuminuria, general population with microalbuminuria, chronic kidney disease with overt proteinuria treated with ACE inhibitor and liberal sodium diet, and chronic kidney disease with overt proteinuria treated with ACE inhibitor+ARB+low sodium diet. UVDBP increased with albuminuria (first three groups, p<0.001) and responded to intensification of anti-proteinuric treatment (two last groups, p<0.001).
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pone-0055887-g003: Urinary vitamin D binding protein (uVDBP) levels in patients with normoalbuminuria, microalbuminuria, and overt proteinuria.Box-whisker plots indicating the median, interquartile range, and range of 24-h uVDBP per patient category: general population with normoalbuminuria, general population with microalbuminuria, chronic kidney disease with overt proteinuria treated with ACE inhibitor and liberal sodium diet, and chronic kidney disease with overt proteinuria treated with ACE inhibitor+ARB+low sodium diet. UVDBP increased with albuminuria (first three groups, p<0.001) and responded to intensification of anti-proteinuric treatment (two last groups, p<0.001).

Mentions: We further characterized urinary VDBP excretion in the clinical setting. Table 3 shows baseline parameters at inclusion for the study groups: subjects with microalbuminuria (n = 100) and normoalbuminuric controls (n = 100), both derived from a general population cohort study, and subjects with non-diabetic chronic kidney disease (CKD) with overt proteinuria (n = 47). The CKD group was studied during two different treatment periods of 6 weeks, one period with an ACE inhibitor under a liberal sodium diet, and one period with intensified renoprotective therapy: dual renin-angiotensin-aldosterone system (RAAS) blockade (ACE inhibitor and AT1 receptor blocker) under dietary sodium restriction. As shown in Figure 3, uVDBP was low in normoalbuminuric subjects, higher in microalbuminurics, and highest in patients with established CKD (p<0.001). In CKD patients, intensification of anti-proteinuric therapy (dual RAAS blockade and dietary sodium restriction) reduced uVDBP from median 4 mg/day to 1 mg/24 h (p<0.001); however urinary VDBP was still >100-fold increased as compared to normoalbuminuric subjects (median 7 µg/24 h; p<0.001 vs CKD+ACEi+ARB+low sodium), consistent with persistent tubulointerstitial damage despite maximal therapy. When uVDBP was normalized for albuminuria, differences remained similar: patients with normoalbuminuria 0.44 [0.22–0.77] µg/mg; microalbuminuria 0.62 [0.34–1.18] µg/mg; established CKD+ACEi+liberal sodium: 2.44 [1.02–4.51] µg/mg, p<0.001; CKD+ACEi+ARB+low sodium 1.87 [0.92–2.97] µg/mg, p<0.05. Plasma VDBP levels were similar in all groups (normoalbuminuria: 31 [25–42] µg/l; microalbuminuria: 32 [24–43] µg/l; CKD+ACEi+liberal sodium: 39 [38–47] µg/l; CKD+ACEi+ARB+low sodium: 38 [34–42] µg/l; p = NS).


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) levels in patients with normoalbuminuria, microalbuminuria, and overt proteinuria.Box-whisker plots indicating the median, interquartile range, and range of 24-h uVDBP per patient category: general population with normoalbuminuria, general population with microalbuminuria, chronic kidney disease with overt proteinuria treated with ACE inhibitor and liberal sodium diet, and chronic kidney disease with overt proteinuria treated with ACE inhibitor+ARB+low sodium diet. UVDBP increased with albuminuria (first three groups, p<0.001) and responded to intensification of anti-proteinuric treatment (two last groups, p<0.001).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3569442&req=5

pone-0055887-g003: Urinary vitamin D binding protein (uVDBP) levels in patients with normoalbuminuria, microalbuminuria, and overt proteinuria.Box-whisker plots indicating the median, interquartile range, and range of 24-h uVDBP per patient category: general population with normoalbuminuria, general population with microalbuminuria, chronic kidney disease with overt proteinuria treated with ACE inhibitor and liberal sodium diet, and chronic kidney disease with overt proteinuria treated with ACE inhibitor+ARB+low sodium diet. UVDBP increased with albuminuria (first three groups, p<0.001) and responded to intensification of anti-proteinuric treatment (two last groups, p<0.001).
Mentions: We further characterized urinary VDBP excretion in the clinical setting. Table 3 shows baseline parameters at inclusion for the study groups: subjects with microalbuminuria (n = 100) and normoalbuminuric controls (n = 100), both derived from a general population cohort study, and subjects with non-diabetic chronic kidney disease (CKD) with overt proteinuria (n = 47). The CKD group was studied during two different treatment periods of 6 weeks, one period with an ACE inhibitor under a liberal sodium diet, and one period with intensified renoprotective therapy: dual renin-angiotensin-aldosterone system (RAAS) blockade (ACE inhibitor and AT1 receptor blocker) under dietary sodium restriction. As shown in Figure 3, uVDBP was low in normoalbuminuric subjects, higher in microalbuminurics, and highest in patients with established CKD (p<0.001). In CKD patients, intensification of anti-proteinuric therapy (dual RAAS blockade and dietary sodium restriction) reduced uVDBP from median 4 mg/day to 1 mg/24 h (p<0.001); however urinary VDBP was still >100-fold increased as compared to normoalbuminuric subjects (median 7 µg/24 h; p<0.001 vs CKD+ACEi+ARB+low sodium), consistent with persistent tubulointerstitial damage despite maximal therapy. When uVDBP was normalized for albuminuria, differences remained similar: patients with normoalbuminuria 0.44 [0.22–0.77] µg/mg; microalbuminuria 0.62 [0.34–1.18] µg/mg; established CKD+ACEi+liberal sodium: 2.44 [1.02–4.51] µg/mg, p<0.001; CKD+ACEi+ARB+low sodium 1.87 [0.92–2.97] µg/mg, p<0.05. Plasma VDBP levels were similar in all groups (normoalbuminuria: 31 [25–42] µg/l; microalbuminuria: 32 [24–43] µg/l; CKD+ACEi+liberal sodium: 39 [38–47] µg/l; CKD+ACEi+ARB+low sodium: 38 [34–42] µg/l; p = NS).

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