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通讯作者:

曹长春,E⁃mail:caochangchun@njmu.edu.cn

中图分类号:R692.5

文献标识码:A

文章编号:1007-4368(2021)05-690-06

DOI:10.7655/NYDXBNS20210509

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参考文献 10
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参考文献 12
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参考文献 13
AGGARWAL A,YADAV A K,RAMACHANDRAN R,et al.Bioavailable vitamin D levels are reduced and corre⁃ late with bone mineral density and markers of mineral me⁃ tabolism in adults with nephrotic syndrome[J].Nephrolo⁃ gy(Carlton),2016,21(6):483-489
参考文献 14
DOORENBOS C R,DE CUBA M M,VOGT L,et al.Anti⁃ proteinuric treatment reduces urinary loss of vitamin D ⁃ binding protein but does not affect vitamin D status in pa⁃ tients with chronic kidney disease[J].J Steroid Biochem Mol Biol,2012,128(1⁃2):56-61
参考文献 15
TAGLIABUE E,RAIMONDI S,GANDINI S.Meta⁃analy⁃ sis of vitamin D⁃binding protein and cancer risk[J].Can⁃ cer Epidemiol Biomarkers Prev,2015,24(11):1758-1765
参考文献 16
WANG X,SHENG Z,MENG L,et al.25⁃Hydroxyvitamin D and Vitamin D Binding Protein Levels in Patients With Primary Hyperparathyroidism Before and After Parathy⁃ roidectomy[J].Front Endocrinol(Lausanne),2019,10:171
参考文献 17
FERNANDO M,ELLERY S J,MARQUINA C,et al.Vita⁃ min D ⁃ binding protein in pregnancy and reproductive health[J].Nutrients,2020,12(5):1489
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周苗,夏同耀,孙爱玲,等.健康管理人群慢性肾脏病风险预测模型[J].山东大学学报(医学版),2017,55(6):98-103
参考文献 19
SHROFF R,AITKENHEAD H,COSTA N,et al.Normal 25⁃ hydroxyvitamin D levels are associated with less pro⁃ teinuria and attenuate renal failure progression in chil⁃ dren with CKD[J].J Am Soc Nephrol,2016,27(1):314-322
参考文献 20
DOYON A,SCHMIEDCHEN B,SANDER A,et al.Genet⁃ ic,environmental,and disease ⁃ associated correlates of vitamin D status in children with CKD[J].Clin J Am Soc Nephrol,2016,11(7):1145-1153
参考文献 21
BROWN A J,COYNE D W.Bioavailable vitamin D in chronic kidney disease[J].Kidney Int,2012,82(1):5-7
目录contents

    摘要

    目的:探讨血清维生素D结合蛋白(vitamin D binding protein,DBP)水平与慢性肾脏病(chronic kidney disease,CKD) 发生的相关性。进一步建立CKD的临床风险预测模型,并评估其对CKD的预测效能。方法:选取2020年3—9月肾内科住院的患者,酶联免疫吸附法检测患者血清DBP水平,分析血清DBP与CKD相关指标的关系,比较高DBP组和低DBP组患者的临床资料。构建包含DBP的临床风险预测模型并评估其预测CKD发生的效能。结果:与正常对照组和CKD 3期患者相比,CKD 4期和CKD 5期患者血清DBP水平显著降低。血清DBP与CKD相关临床指标及干预措施具有明显的相关性。与综合临床风险预测模型A(年龄、性别、尿酸、是否合并瓣膜钙化、高血压、糖尿病)[受试者工作特征曲线的曲线下面积(area under curve,AUC)= 0.917,95% CI:0.849~0.985,P<0.001]相比,综合临床风险预测模型B(年龄、性别、尿酸、DBP、是否合并瓣膜钙化、高血压、糖尿病)(AUC=0.942,95% CI:0.894~0.991,P<0.001)增加了血清DBP这一预测变量,显著改善了预测CKD的受试者工作特征曲线的 AUC和特异度。结论:血清DBP水平与CKD的发生具有相关性。增加血清DBP这一预测变量,可显著改善模型预测CKD的效能,有助于筛查CKD的高危患者。

    Abstract

    Objective:This study aims to explore the relationship between serum vitamin D binding protein(DBP)level and the occurrence of chronic kidney disease(CKD),further establish a clinical risk prediction model for CKD and evaluate its predictive power for CKD. Methods:The patients who were hospitalized in the department of nephrology between March 2020 and September 2020 were selected. The serum DBP levels of the patients were detected by the ELISA method. The relationship between serum DBP and CKD related indicators was anacyzed. And the clinical data of the high DBP group and low DBP group were compared. A clinical risk prediction model including DBP was construct and its effectiveness was evaluated in predicting the occurrence of CKD. Results: Compared with the normal control group and CKD stage 3 patients,the serum DBP levels of patients with CKD stage 4 and CKD stage 5 were significantly lower. Serum DBP and CKD related indicators and interventions have obvious correlation. Compared with the comprehensive clinical risk prediction model A(AUC=0.917,95% CI:0.849~0.985,P<0.001),the comprehensive clinical risk prediction model B(AUC=0.942,95% CI:0.894~0.991,P<0.001)increased the serum DBP as a predictor variable,and significantly improved the AUC and,specificity for predicting CKD. Conclusion:Serum DBP decreases significantly in CKD 4⁃5 stages,which are correlated with the occurrence of CKD. The addition of the predictive variable of serum DBP significantly improves the predictive performance of the model in predicting CKD and helps to screen high⁃risk patients with CKD.

  • 慢性肾脏病(chronic kidney disease,CKD)是由各种原因引起的进行性和不可逆的肾脏结构或功能异常[1-2],患病率高达8%~16%,已成为全球范围内的公共卫生问题[3-4]。人类维生素D结合蛋白基因是白蛋白多基因家族中的一员,该基因家族还包括白蛋白和甲胎蛋白基因[5],维生素D结合蛋白(Vitamin D binding protein,DBP),也称为Gc⁃球蛋白(GC⁃Glob⁃ ulin),是一种糖基化的α⁃球蛋白,大小为58kDa。DBP不仅可以运输维生素D及其代谢产物,还具有抗炎、免疫调节以及清除坏死细胞外G⁃肌动蛋白等功能[6]

  • CKD时普遍存在维生素D的缺乏[7-8],DBP作为维生素D的主要载体蛋白,在CKD时是否会受到影响,目前并没有系统的相关研究。已有研究发现在肿瘤[9]、糖尿病[10-11] 等终末期疾病中血清DBP水平发生变化[12],有理由推测DBP和CKD可能存在相关性。本研究通过分析正常对照组和CKD1~5期患者血清DBP水平的差异,探讨血清DBP水平与CKD相关指标的相关性,初步建立包含DBP的CKD临床风险预测模型,并对其预测效能进行评估,为CKD的临床诊疗提供参考。

  • 1 对象和方法

  • 1.1 对象

  • 选取2020年3—9月南京医科大学附属逸夫医院肾内科住院的患者110例。入选标准:①年龄18~75岁;②签订知情同意书。排除标准:①急性肾损伤(acute kidney injury,AKI);②服用活性维生素D制剂、西那卡塞、磷结合剂;③恶性肿瘤;④严重感染;⑤肾脏移植;⑥系统性淀粉样变;⑦严重的肝脏疾病;⑧身体一般情况较差者。排除27例后,本研究共纳入符合入组标准的患者83例,用酶联免疫吸附(enzyme linked immunosorbent assay,ELISA)法检测患者血清DBP水平,收集患者的临床和实验室指标,分析DBP与CKD相关指标的关系,绘制DBP诊断CKD的受试者工作特征曲线(receiver operating characteristic curve,ROC曲线),根据ROC曲线的最佳临界值将患者分为高DBP组和低DBP组,比较高DBP组和低DBP组患者的临床资料。构建包含DBP的临床风险预测模型并评估其预测CKD发生的效能。本研究经南京医科大学附属逸夫医院伦理委员会批准(2019⁃SR⁃022)。

  • 1.2 方法

  • 记录患者一般信息及临床资料:年龄,性别,是否贫血,近期是否服用铁剂,重组人促红细胞生成素等药物,是否存在血管钙化,心脏瓣膜钙化。肾功能相关评价指标:血清肌酐(serum creatinine, Scr),血尿素氮(blood urea nitrogen,BUN),β2微球蛋白(β2⁃microglobulin,β2⁃MG),肾小球滤过率(glo⁃ merular filtration rate,GFR),尿酸(uric acid,UA),甲状旁腺激素(parathyroid hormone,PTH)。肝功能相关评价指标:丙氨酸氨基转移酶(alanine aminotrans⁃ ferase,ALT),天门冬氨酸氨基转移酶(aspartate ami⁃ notransferase,AST)。其他评价指标:血钙,血磷。

  • CKD是由于各种原因引起的进行性和不可逆的肾脏结构或功能异常。依据“肾脏疾病·改善全球预后”组织2012年颁布的“慢性肾脏疾病评估和管理的临床实践诊疗指南”(KDIGO 2012指南),本研究分为:①正常对照组,GFR≥90mL/(min·1.73m2)且肾脏结构和功能正常;②CKD组,包括CKD 1~5期患者;其中①CKD 1期,GFR≥90mL/(min·1.73m2) 伴有肾脏结构和功能异常,持续时间>3个月;② CKD 2期,GFR为60~89mL/(min·1.73m2);③ CKD 3期,GFR为30~59mL/(min·1.73m2);④ CKD 4期, GFR为15~29mL/(min · 1.73m2);⑤ CKD 5期, GFR<15mL/(min·1.73m2)。本研究共采用3种分组标准:①83例患者分为两组,正常对照组和CKD组。②83例患者分为3组,正常对照+CKD 1期组, CKD 2~3期组,CKD 4~5期组。③83例患者分为6组,正常对照组,CKD 1期组,CKD 2期组,CKD 3期组,CKD 4期组和CKD 5期组。GFR的计算采用慢性肾脏病流行病学协作(chronic kidney disease epi⁃ demiology collaboration,CKD⁃EPI)方程。高尿酸血症诊断标准:男性血清UA水平>420 μmol/L,女性>357 μmol/L。

  • 入院第2天早晨收集入选者静脉血标本。标本收集后30min内离心(2 500r/min,10min),分装于1mL EP管中,-80℃冻存备用。采用ELISA法测定血清DBP,试剂盒(Catalog Number DVDBP0B)购自美国的R&D SYSTEMS公司。按照试剂盒说明书操作。

  • 1.3 统计学方法

  • 本研究统计分析采用SPSS21.0软件。服从正态分布的连续变量采用均数±标准差(x- ± s)表示,两组间比较采用独立样本 t 检验,多组资料间的比较采用方差分析。计数资料或等级资料采用频率或百分比表示,两组间比较采用Pearson卡方检验或校正卡方检验。对于双变量正态分布的资料采用Pearson相关分析,对于总体分布未知的资料和原始数据用等级表示的资料采用Spearman秩相关分析。多因素Logistic回归构建临床风险预测模型,用ROC曲线下面积(area under curve,AUC)评估临床风险预测模型的预测效能。P <0.05为差异有统计学意义。

  • 2 结果

  • 2.1 血清DBP水平的比较

  • 本研究共纳入83例患者,正常对照组15例 (18.1%);CKD组68例(81.9%):其中CKD 1期4例 (4.8%),CKD 2期6例(7.2%),CKD 3期15例(18.1%), CKD 4期4例(4.8%),CKD 5期39例(47.0%)。83例患者血清DBP平均值为(170.69±52.87)μg/mL,正常对照组和CKD各期患者血清DBP水平分别为:正常对照组(205.84±24.45)μg/mL;CKD 1期(209.88± 7.66)μg/mL;CKD 2期(183.76 ± 21.90)μg/mL; CKD 3期(193.83 ± 52.57)μg/mL;CKD 4期(133.31 ± 15.84)μg/mL;CKD 5期(146.07±55.21)μg/mL。与正常对照组相比,CKD 1~3期无显著统计学差异, CKD 4期和CKD 5期患者血清DBP水平显著降低 (P <0.05);与CKD 3期相比,CKD 4期和CKD 5期患者血清DBP水平显著降低(P <0.05,图1)。

  • 图1 CKD1~5期血清DBP水平

  • Fig.1 Serum DBP levels in 1~5stages of CKD

  • 2.2 相关分析结果

  • 血清DBP水平分别与患者的年龄、血清Scr、BUN,是否伴有贫血、高血压、瓣膜钙化,是否使用重组人促红细胞生成素、铁剂等药物呈负相关,与GFR、ALT、AST和血钙水平呈正相关(表1)。

  • 2.3 以血清DBP水平预测CKD发生的价值

  • 通过绘制ROC曲线明确血清DBP对CKD的影响程度,结果发现,血清DBP预测CKD发生的AUC为0.752(95%CI:0.635~0.870,P=0.002),灵敏度为0.632,特异度为0.733,约登指数为0.365。血清DBP预测CKD的最佳临界值(cut⁃off值)为161.40 μg/mL,提示血清DBP水平低于161.40 μg/mL的患者更易发生CKD(图2)。

  • 2.4 CKD不同分期DBP水平百分条图

  • 根据血清DBP预测CKD发生的最佳临界值分为高DBP组和低DBP组。83例中正常对照组和CKD1期共19例,且全部患者均为高DBP组;CKD 2~3期21例,其中17例(81%)为高DBP组,4例 (19%)为低DBP组;CKD 4~5期共43例,其中18例 (42%)为高DBP组,25例(58%)为低DBP组。随着CKD的进展,高DBP组患者所占比例减少,低DBP组患者所占比例增多(图3)。

  • 表1 血清DBP与临床指标的相关性分析

  • Table1 Correlation analysis of serum DBP and clinical indicators

  • 图2 DBP诊断CKD发生的ROC曲线

  • Fig.2 ROC curve of DBP diagnosis of CKD

  • 2.5 血清高DBP组与低DBP组患者临床资料的比较

  • 根据血清DBP预测CKD发生的最佳临界值分为高DBP组和低DBP组。与高DBP组相比,低DBP组血清Scr、BUN增高,使用重组人促红细胞生成素的患者增多,而血清GFR降低(均P <0.05,表2)。

  • 图3 CKD不同分期DBP水平百分条图

  • Fig.3 Percentage bar graph of DBP levels in different stages of CKD

  • 2.6 血清DBP水平与CKD的发生具有相关性

  • 将单因素Logistic回归分析P< 0.2的指标以及与CKD相关的临床指标纳入二元Logistic回归模型中,结果显示在校正了年龄(P=0.111)、性别(P=0.487)、高血压(P=0.055)、糖尿病(P=0.515)、瓣膜钙化(P=0.520)等因素后发现,UA(OR:1.009,95%CI: 1.003~1.015,P=0.006)是CKD的主要危险因素,而血清DBP(OR:0.981,95%CI:0.964~0.998,P=0.030) 则是预防CKD的保护性因素(表3)。

  • 将单因素Logistic回归模型中P <0.2以及与CKD相关的临床指标用进入法纳入多因素Logistic回归模型进行分析,拟合优度Hosmer⁃ Lemeshow检验,卡方值15.807,P=0.045。

  • 2.7 临床风险预测模型预测CKD发生的效能

  • 综合临床风险预测模型A纳入年龄、性别、UA、是否合并瓣膜钙化、高血压、糖尿病,该回归模型预测CKD发生的AUC为0.917(95%CI:0.849~0.985, P <0.001),灵敏度为0.956,特异度为0.733,约登指数为0.689;综合临床风险预测模型B纳入年龄、性别、UA、DBP、是否合并瓣膜钙化、高血压、糖尿病,该回归模型预测CKD发生的AUC为0.942(95%CI: 0.894~0.991,P <0.001),灵敏度为0.868,特异度为1,约登指数为0.868;与模型A相比,模型B增加了血清DBP这一预测变量,显著改善了预测CKD的AUC、特异度和约登指数(图4)。

  • 表2 血清高DBP组和低DBP组患者临床资料的比较

  • Table2 Comparison of clinical data of patients with serum high DBP group and low DBP group

  • 表3 CKD多因素logistic回归分析

  • Table3 Multivariate logistic regression analysis of CKD

  • 图4 临床风险预测模型诊断CKD发生的ROC曲线

  • Fig.4 The ROC curve of the clinical risk prediction model to diagnose the occurrence of CKD

  • 3 讨论

  • Aggarwal等[13] 研究发现肾病综合征患者组和对照组的血清DBP水平相似。在该研究中,肾病综合征患者的血清肌酐水平和肾小球滤过率水平与对照组相比差异没有统计学意义,说明在肾功能不受损的肾病综合征患者中,血清DBP水平保持正常。这支持了我们的研究结论:在CKD 1~2期时,血清DBP水平正常。本研究还提示在肾功能严重降低时[GFR<30mL/(min·1.73m2)],血清DBP水平显著降低。Doorenbos等[14] 研究发现,与健康对照组相比,CKD患者的尿DBP排泄显著增加,这可能是CKD 4~5期患者血清DBP水平降低的重要原因。

  • Tagliabue等[15] 研究发现,与低DBP水平的受试者比较,高DBP水平的受试者患癌症的危险性降低;Wang等[16] 的研究发现,与对照组相比,原发性甲状旁腺功能亢进症患者的DBP水平较低(P<0.01);Fernando等[17] 的研究发现,孕妇血清DBP浓度低与不育,子宫内膜异位,多囊卵巢综合征,自然流产以及不良妊娠结局(包括妊娠期糖尿病、先兆子痫、早产和胎儿生长受限)有关。本研究发现在CKD 4~5期血清DBP水平降低,进一步在肾脏病领域证实了疾病状态时,DBP的水平偏低,DBP可能作为一种保护性因子存在于各组织器官中。

  • 目前国内未有CKD与血清DBP相关关系的报道,国外研究多集中于血清DBP的单核苷酸多态性的研究,本研究首先发现了血清DBP水平与患者的年龄、血清Scr、BUN,是否伴有贫血、高血压、瓣膜钙化,是否使用重组人促红细胞生成素、铁剂等药物呈负相关,与GFR、ALT、AST和血钙水平呈正相关。更加确切地说,本研究发现了在肾功能严重受损时,血清DBP水平降低。与综合临床风险预测模型A(AUC=0.917,95%CI:0.849~0.985,P <0.001)相比,综合临床风险预测模型B(AUC=0.942,95%CI: 0.894~0.991,P <0.001)增加了血清DBP这一预测变量,显著改善了预测CKD的AUC、特异度和约登指数。周苗等[18] 构建模型的预测因子有年龄、性别、高血压、糖尿病、血肌酐、血尿素氮、血尿酸、嗜碱性粒细胞百分比,模型AUC为0.685(95%CI: 0.678~0.692),灵敏度和特异度分别为70.220%和55.580%。与周苗的预测模型相比,本研究构建的预测模型的灵敏度、特异度更好,更具有预测潜力。

  • 虽然维生素D结合蛋白是维生素D及其代谢物运输过程中重要的载体蛋白,但Shroff等[19] 的研究表明CKD儿童患者25⁃羟维生素D和血清DBP无相关性,而Doyon等[20] 的研究表明,肾小球病患者由于DBP的丧失,继发25⁃羟维生素D降解加速。Brown等[21] 研究进一步表明,DBP通过近端小管的重吸收机制维持维生素D的水平,过滤后的DBP与巨蛋白结合,并由近端肾小管细胞通过内吞作用吸收,因此蛋白尿会导致DBP丧失,并可能导致维生素D缺乏症。

  • 但本研究也存在局限性,如没有检测血清维生素D,以便进一步分析维生素D与DBP的关系;研究样本数不够大,研究对象仅随访了其住院期间的临床资料及实验室指标,随访时间不够长。后期需加大样本量进行多中心前瞻性研究,进一步验证临床风险预测模型的预测效能。

  • 总之,本研究发现,血清DBP在CKD 4~5期水平下降,与CKD的发生具有相关性。综合临床风险预测模型增加了血清DBP这一预测变量,显著改善了预测CKD的AUC、特异度和约登指数。综合临床风险预测模型对CKD发生的预测效能较高,有助于筛查CKD的高危患者,但仍需进一步探索血清维生素D结合蛋白在CKD中的具体机制。

  • 参考文献

    • [1] WEBSTER A C,NAGLER E V,MORTON R L,et al.Chronic kidney disease[J].Lancet,2017,389(10075):1238-1252

    • [2] ROMAGNANI P,REMUZZI G,GLASSOCK R,et al.Chronic kidney disease[J].Nat Rev Dis Primers,2017,3:17088

    • [3] ROMANOWSKI K,CLARK E G,LEVIN A,et al.Tuber⁃ culosis and chronic kidney disease:an emerging global syndemic[J].Kidney Int,2016,90(1):34-40

    • [4] 孙连芹,聂广燕,左晨艳,等.慢性肾脏病患者尿电解质相关临床因素分析[J].南京医科大学学报(自然科学版),2020,40(8):1163-1169

    • [5] BOUILLON R,SCHUIT F,ANTONIO L,et al.Vitamin D binding protein:a historic overview[J].Front Endocrinol(Lausanne),2019,10:910

    • [6] KEW R R.The Vitamin D binding protein and inflamma⁃ tory injury:a mediator or sentinel of tissue damage?[J].Front Endocrinol(Lausanne),2019,10:470

    • [7] JEAN G,SOUBERBIELLE J C,CHAZOT C.Vitamin D in chronic kidney disease and dialysis patients[J].Nutri⁃ ents,2017,9(4).

    • [8] CHEN T K,KNICELY D H,GRAMS M E.Chronic kid⁃ ney disease diagnosis and management:a review[J].JA⁃ MA,2019,322(13):1294-1304

    • [9] HUANG Y F,WU Y H,CHENG W F,et al.Vitamin D ⁃ binding protein enhances epithelial ovarian cancer pro⁃ gression by regulating the insulin⁃like growth factor⁃1/Akt pathway and Vitamin D receptor transcription[J].Clin Cancer Res,2018,24(13):3217-3228

    • [10] KELLY C B,WAGNER C L,SHARY J R,et al.Vitamin D metabolites and binding protein predict preeclampsia in women with type 1 diabetes[J].Nutrients,2020,12(7):2048

    • [11] VILORIA K,NASTESKA D,BRIANT L J B,et al.Vita⁃ min ⁃D ⁃binding protein contributes to the maintenance of α cell function and glucagon secretion[J].Cell Rep,2020,31(11):107761

    • [12] 刘舒颖,盛志峰,王湘兵.维生素D结合球蛋白临床研究[J].中华骨质疏松和骨矿盐疾病杂志,2018,11(3):296⁃304

    • [13] AGGARWAL A,YADAV A K,RAMACHANDRAN R,et al.Bioavailable vitamin D levels are reduced and corre⁃ late with bone mineral density and markers of mineral me⁃ tabolism in adults with nephrotic syndrome[J].Nephrolo⁃ gy(Carlton),2016,21(6):483-489

    • [14] DOORENBOS C R,DE CUBA M M,VOGT L,et al.Anti⁃ proteinuric treatment reduces urinary loss of vitamin D ⁃ binding protein but does not affect vitamin D status in pa⁃ tients with chronic kidney disease[J].J Steroid Biochem Mol Biol,2012,128(1⁃2):56-61

    • [15] TAGLIABUE E,RAIMONDI S,GANDINI S.Meta⁃analy⁃ sis of vitamin D⁃binding protein and cancer risk[J].Can⁃ cer Epidemiol Biomarkers Prev,2015,24(11):1758-1765

    • [16] WANG X,SHENG Z,MENG L,et al.25⁃Hydroxyvitamin D and Vitamin D Binding Protein Levels in Patients With Primary Hyperparathyroidism Before and After Parathy⁃ roidectomy[J].Front Endocrinol(Lausanne),2019,10:171

    • [17] FERNANDO M,ELLERY S J,MARQUINA C,et al.Vita⁃ min D ⁃ binding protein in pregnancy and reproductive health[J].Nutrients,2020,12(5):1489

    • [18] 周苗,夏同耀,孙爱玲,等.健康管理人群慢性肾脏病风险预测模型[J].山东大学学报(医学版),2017,55(6):98-103

    • [19] SHROFF R,AITKENHEAD H,COSTA N,et al.Normal 25⁃ hydroxyvitamin D levels are associated with less pro⁃ teinuria and attenuate renal failure progression in chil⁃ dren with CKD[J].J Am Soc Nephrol,2016,27(1):314-322

    • [20] DOYON A,SCHMIEDCHEN B,SANDER A,et al.Genet⁃ ic,environmental,and disease ⁃ associated correlates of vitamin D status in children with CKD[J].Clin J Am Soc Nephrol,2016,11(7):1145-1153

    • [21] BROWN A J,COYNE D W.Bioavailable vitamin D in chronic kidney disease[J].Kidney Int,2012,82(1):5-7

  • 参考文献

    • [1] WEBSTER A C,NAGLER E V,MORTON R L,et al.Chronic kidney disease[J].Lancet,2017,389(10075):1238-1252

    • [2] ROMAGNANI P,REMUZZI G,GLASSOCK R,et al.Chronic kidney disease[J].Nat Rev Dis Primers,2017,3:17088

    • [3] ROMANOWSKI K,CLARK E G,LEVIN A,et al.Tuber⁃ culosis and chronic kidney disease:an emerging global syndemic[J].Kidney Int,2016,90(1):34-40

    • [4] 孙连芹,聂广燕,左晨艳,等.慢性肾脏病患者尿电解质相关临床因素分析[J].南京医科大学学报(自然科学版),2020,40(8):1163-1169

    • [5] BOUILLON R,SCHUIT F,ANTONIO L,et al.Vitamin D binding protein:a historic overview[J].Front Endocrinol(Lausanne),2019,10:910

    • [6] KEW R R.The Vitamin D binding protein and inflamma⁃ tory injury:a mediator or sentinel of tissue damage?[J].Front Endocrinol(Lausanne),2019,10:470

    • [7] JEAN G,SOUBERBIELLE J C,CHAZOT C.Vitamin D in chronic kidney disease and dialysis patients[J].Nutri⁃ ents,2017,9(4).

    • [8] CHEN T K,KNICELY D H,GRAMS M E.Chronic kid⁃ ney disease diagnosis and management:a review[J].JA⁃ MA,2019,322(13):1294-1304

    • [9] HUANG Y F,WU Y H,CHENG W F,et al.Vitamin D ⁃ binding protein enhances epithelial ovarian cancer pro⁃ gression by regulating the insulin⁃like growth factor⁃1/Akt pathway and Vitamin D receptor transcription[J].Clin Cancer Res,2018,24(13):3217-3228

    • [10] KELLY C B,WAGNER C L,SHARY J R,et al.Vitamin D metabolites and binding protein predict preeclampsia in women with type 1 diabetes[J].Nutrients,2020,12(7):2048

    • [11] VILORIA K,NASTESKA D,BRIANT L J B,et al.Vita⁃ min ⁃D ⁃binding protein contributes to the maintenance of α cell function and glucagon secretion[J].Cell Rep,2020,31(11):107761

    • [12] 刘舒颖,盛志峰,王湘兵.维生素D结合球蛋白临床研究[J].中华骨质疏松和骨矿盐疾病杂志,2018,11(3):296⁃304

    • [13] AGGARWAL A,YADAV A K,RAMACHANDRAN R,et al.Bioavailable vitamin D levels are reduced and corre⁃ late with bone mineral density and markers of mineral me⁃ tabolism in adults with nephrotic syndrome[J].Nephrolo⁃ gy(Carlton),2016,21(6):483-489

    • [14] DOORENBOS C R,DE CUBA M M,VOGT L,et al.Anti⁃ proteinuric treatment reduces urinary loss of vitamin D ⁃ binding protein but does not affect vitamin D status in pa⁃ tients with chronic kidney disease[J].J Steroid Biochem Mol Biol,2012,128(1⁃2):56-61

    • [15] TAGLIABUE E,RAIMONDI S,GANDINI S.Meta⁃analy⁃ sis of vitamin D⁃binding protein and cancer risk[J].Can⁃ cer Epidemiol Biomarkers Prev,2015,24(11):1758-1765

    • [16] WANG X,SHENG Z,MENG L,et al.25⁃Hydroxyvitamin D and Vitamin D Binding Protein Levels in Patients With Primary Hyperparathyroidism Before and After Parathy⁃ roidectomy[J].Front Endocrinol(Lausanne),2019,10:171

    • [17] FERNANDO M,ELLERY S J,MARQUINA C,et al.Vita⁃ min D ⁃ binding protein in pregnancy and reproductive health[J].Nutrients,2020,12(5):1489

    • [18] 周苗,夏同耀,孙爱玲,等.健康管理人群慢性肾脏病风险预测模型[J].山东大学学报(医学版),2017,55(6):98-103

    • [19] SHROFF R,AITKENHEAD H,COSTA N,et al.Normal 25⁃ hydroxyvitamin D levels are associated with less pro⁃ teinuria and attenuate renal failure progression in chil⁃ dren with CKD[J].J Am Soc Nephrol,2016,27(1):314-322

    • [20] DOYON A,SCHMIEDCHEN B,SANDER A,et al.Genet⁃ ic,environmental,and disease ⁃ associated correlates of vitamin D status in children with CKD[J].Clin J Am Soc Nephrol,2016,11(7):1145-1153

    • [21] BROWN A J,COYNE D W.Bioavailable vitamin D in chronic kidney disease[J].Kidney Int,2012,82(1):5-7