Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
PLoS One. 2013;8(2):e55887. doi: 10.1371/journal.pone.0055887. Epub 2013 Feb 11.
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.
非侵入性肾小管间质损伤标志物可更好地滴定和监测肾保护治疗。我们研究了尿维生素 D 结合蛋白（uVDBP）排泄作为阿霉素大鼠肾小管间质炎症和纤维化标志物的价值，并测试了 uVDBP 是否与肾脏损伤平行，并对人类的治疗强化做出反应。在阿霉素（ADR）大鼠中，uVDBP 与对照组（CON）相比明显升高（ADR：727±674[均值±SD] vs CON：9±12 µg/d，p<0.01），即在出现前纤维化和炎症性肾小管间质损伤之前，并且在接下来的所有 6 周时间点直至 30 周的随访结束时（ADR：1403±1026 vs CON：206±132 µg/d，p<0.01）。在多变量回归分析中，uVDBP 与肾小管间质巨噬细胞积聚（标准化β=0.47，p=0.01）和胶原 III 表达（标准化β=0.44，p=0.02）相关，与蛋白尿无关。在人类中，100 名微量白蛋白尿患者（44±93 µg/d）和 47 名显性蛋白尿的 CKD 患者（9.2±13.0 mg/d）的 uVDBP 高于 100 名正常白蛋白尿患者（12±12 µg/d，p<0.001）。在 CKD 患者中，uVDBP 对肾保护治疗的强化（ACEi+宽松钠：9.2±13.0 mg/d vs 双重 RAAS 阻断+低钠：2747±4013，p<0.001）有反应，但在最大治疗期间仍比正常白蛋白尿患者高>100 倍（p<0.001），与持续的肾小管间质损伤一致。UVDBP 与肾小管和炎症损伤标志物 KIM-1（标准化β=0.52，p<0.001）、β-2-微球蛋白（st.beta=0.45，p<0.001）、胱抑素 C（st.beta=0.40，p<0.001）、MCP-1（st.beta=0.31，p<0.001）和 NGAL（st.beta=0.20，p=0.005）相关，与蛋白尿无关。UVDBP 可能是肾小管间质损伤的新型尿生物标志物。需要前瞻性设计的研究来验证我们的发现并确认其在临床环境中的相关性。
