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【摘要】 目的:探讨尿毒清颗粒对慢性肾脏病(CKD)3~5期钙、磷代谢及成纤维生长因子23(FGF23)水平的影响。方法:选择符合美国2002年K/DOQI CKD诊断标准3~5期患者54例,随机分为治疗组(尿毒清颗粒)和对照组,同时选取正常组20例。测定外周血中FGF23、全段甲状旁腺激素(iPTH)、尿素氮(BUN)、血肌酐(Scr)、Ca、P水平,以及尿肌酐水平;根据MDRD公式计算肾小球滤过率(GFR)。结果:随着GFR的下降,CKD3~5期患者的血P、FGF23、BUN、Scr较正常组均显著升高,血Ca较正常组显著下降,差异均有统计学意义(P<0.01)。CKD3~4期:与治疗前比较,治疗组Scr下降显著(P<0.05),P、FGF23均显著下降(P<0.01),GFR显著提高(P<0.01),BUN下降但无显著差异(P>0.05);对照组FGF23显著下降(P<0.05),Scr下降、GFR提高,但均无显著差异(P>0.05);两组Ca均提高,无统计学意义(P>0.05);与对照组比较,治疗组的P、FGF23均显著下降(P<0.05或P<0.01)。CKD5期:与治疗前比较,治疗组GFR显著提高(P<0.01),Ca提高(P<0.05),两组的FGF23也下降(P<0.05或P<0.01),BUN、Scr、P也下降,但无明显差异(P>0.05),对照组GFR提高,但无明显差异(P>0.05)。结论:尿毒清颗粒具有改善患者钙、磷代谢以及FGF23水平的作用,且其可能通过改善血中钙、磷代谢水平,降低PTH、FGF23等因子的表达,从而延缓CKD-MBD的进展。
【关键词】 尿毒清颗粒; 慢性肾脏病; 钙、磷代谢; 成纤维细胞生长因子23; 甲状旁腺激素
The Influence of Niaoduqing Particle on the Calcium and Phosphorus Metabolism and FGF23 in Patients with Chronic Kidney Disease/YE Min-yuan,ZHENG Jing,ZHANG Juan,et al.//Medical Innovation of China,2015,12(23):016-018
【Abstract】 Objective:To explore the influence of Niaoduqing(NDQ) Particle on the calcium,phosphorus and fibroblast growth factor 23(FGF23) in patients with CKD stage 3-5.Method:According to the standard of NKF-K/DOQI proposed,fifty-four CKD patients were randomly divided into the treatment group(Niaoduqing Particle) and the control group,at the same time,20 cases were selected as the normal group.FGF23,iPTH,BUN,Scr,Ca,P levels and Ucr were determined,then GFR was calculated based on MDRD equation.Result:Compared with normal group,with the decline of GFR,the level of P,FGF23,BUN,Scr in the serum of the patients with CKD stage 3-5 were significantly increased,the level of Ca was significantly decreased,the differences were statistically significant(P<0.01).CKD stage 3-4:compared with the pretherapy,serum P,FGF23,Scr level were decreased(P<0.01 or P<0.05),GFR was increased(P<0.01) in the treatment group,there was no significant difference in BUN(P>0.05).In the control group,FGF23 level was decreased(P<0.05),Scr decreased and GFR increased,but there were no statistically significant differences(P>0.05).Ca of the two groups were increased,but there had no statistical significances(P>0.05).Compared with the control group,the P and FGF23 level of the treatment group were decreased significantly(P<0.05 or P<0.01).CKD stage 5:compared with the pretherapy,GFR and Ca of the treatment group were significantly increased(P<0.01 or P<0.05),FGF23 of the two groups were decreased(P<0.05 or P<0.01),BUN,Scr,P decreased,but there were no statistically significant differences(P>0.05).GFR of the control group was decreased,but there had no statistical significances(P>0.05).Conclusion:Niaoduqing Particle can improve the levels of calcium,phosphorus and FGF23 of the patients,and it may play an important role to delay the progression of CKD-MBD by improving the calcium and phosphorus metabolism,reducing the expression of PTH,FGF23 and other factors. 【Key words】 Niaoduqing Particle; Chronic kidney disease; Calcium and phosphorus metabolism; Fibroblast growth factor 23; Parathyroid hormone
First-author’s address:Fujian University of Traditional Chinese Medicine,Fuzhou 350100,China
doi:10.3969/j.issn.1674-4985.2015.23.006
慢性肾脏病-矿物质和骨代谢紊乱(CKD-MBD)是指CKD患者中系统性矿物质和骨代谢紊乱[1]。而钙、磷代谢紊乱是主因[2]。CKD-MBD可发生于CKD早期,而在CKD4~5期会出现显著的高磷、高PTH和高FGF23血症,透析患者几乎都受影响[3]。CKD-MBD可导致骨骼系统、心血管疾病(CVD)等[4]。流行病调查显示,低血钙、血磷,FGF23水平升高与肾性骨病、CVD有直接关系[5]。尿毒清颗粒是肾科常用药,对降低BUN、Scr以及延缓CKD进展均有明显效果[6-7]。那么尿毒清颗粒能否对CKD-MBD发挥治疗作用及能否改善CKD患者血清中钙、磷代谢紊乱以及FGF23的水平值得进一步探讨。
1 资料与方法
1.1 一般资料 选择2012年7月-2013年7月福建省人民医院肾内科病房符合诊断标准的CKD3~5期患者54例,CKD3期19例,CKD4期17例,CKD5期18例。利用随机数字表法将所有患者分为治疗组28例和对照组26例,两组患者的性别、年龄等一般资料比较差异均无统计学意义(P>0.05),具有可比性。正常组:来自福建中医药大学附属人民医院健康志愿者,符合纳入标准者共20例,男12例,女8例,年龄36~77岁,平均(55.10±10.49)岁。
1.2 诊断标准 (1)西医诊断标准:依据美国2002年NKF-
K/DOQI CKD临床实践指南进行定义及分期[8];(2)中医辨证分型标准:依照中华中医药学会肾病分会慢性肾衰竭的诊断、辨证分型及疗效评定(试行方案)的脾肾气虚证辨证分型[9]。
1.3 纳入标准 (1)符合上述诊断标准的CKD3~5期患者;(2)年龄35~80岁。
1.4 排除标准 (1)纳入前1个月内有创伤、手术或肿瘤病史;(2)已服其他中药者;(3)感染、妊娠期、哺乳期患者,精神病者和拒绝加入本临床试验者;(4)严重的CVD;(5)急性肾衰竭患者;(6)肾脏替代治疗患者;(7)医从性差者。
1.5 治疗方法
1.5.1 对照组 (1)严格控制饮食;(2)改善患者钙、磷代谢,给予口服钙尔奇D、阿法骨化醇;(3)控制血压、血糖;(4)纠正代谢紊乱;(5)肾性贫血者予EPO(益比奥6000 U,每周分2~3次)。
1.5.2 治疗组 治疗组在对照组治疗的基础上联合尿毒清颗粒(康臣药业有限公司)。温水冲服。4次/d,三餐前各服一袋,睡前服2袋。停用其他中药治疗。疗程1个月。
1.6 观察指标及检测方法 用ELISA方法检测FGF23,免疫放射法测定iPTH,反相高效液相色谱法检测尿Cr,利用BECKMAN-C800全自动生化分析仪测定血Ca、P、BUN、Scr,按照MDRD公式算出GFR。
1.7 统计学处理 采用SPSS 16.0进行统计分析,计量资料以(x±s)表示,多组组间差异采用方差LSD法,t检验使用两个独立样本t检验,不符合正态的使用秩和检验,使用Spearman分析进行相关分析,以P<0.05为差异有统计学意义。
2 结果
2.1 CKD患者与正常组血清各指标比较 随着GFR的下降,CKD3~5期患者的血P、FGF23、BUN、Scr较正常组均显著升高,血Ca较正常组显著下降,差异均有统计学意义(P<0.01),见表1。
2.2 治疗组及对照组治疗前后各指标水平比较
2.2.1 CKD3~4期 与治疗前比较,治疗组Scr下降显著(P<0.05),P、FGF23均显著下降(P<0.01),GFR显著提高(P<0.01),BUN下降但无显著差异(P>0.05);对照组FGF23显著下降(P<0.05),Scr下降、GFR提高,但均无显著差异(P>0.05);两组Ca均提高,无统计学意义(P>0.05);与对照组比较,治疗组的P、FGF23均显著下降(P<0.05或P<0.01),见表2。
2.2.2 CKD5期 与治疗前比较,治疗组GFR显著提高(P<0.01),Ca提高(P<0.05),两组的FGF23也下降(P<0.05或P<0.01),BUN、Scr、P也下降,但无明显差异(P>0.05),对照组GFR提高,但无明显差异(P>0.05),见表3。
2.3 相关分析结果 CKD患者治疗前后血PTH与BUN、Scr、P、FGF23呈正相关(P<0.05或P<0.01),与GFR、Ca呈负相关(P<0.01)。血P与BUN、Scr、FGF23呈正相关(P<0.01),与GFR呈负相关(P<0.01),血Ca与Scr、FGF23呈负相关(P<0.01),与GFR呈正相关(P<0.01),P、Ca和Ca、BUN均无相关性。
3 讨论
CKD-MBD的病机分为:(1)Ca-PTH-维生素D轴;(2)P-FGF23-肾轴[10-11]。FGF23与血磷呈正相关[12]。当GFR下降时血磷、FGF23清除减少,肾脏Klotho蛋白表达下降进一步刺激了FGF23的过度分泌[11]。有研究提出,FGF23升高是CKD患者预后不良的重要危险因素,也会造成组织器官的损害,与CVD等相关[13-14]。 尿毒清颗粒是由大黄、黄芪、姜半夏、何首乌、茯苓、丹参、白术、川芎等组成的,具有通腑泄浊、活血化瘀等功效。现代药理表明,黄芪能促进小管上皮细胞修复、增加白蛋白合成;大黄可提高尿磷排泄,改善肾功能;党参具有抗血小板聚集等作用[6-7]。李相友等[15]发现它能改善CRF患者主动脉瓣膜钙化氧化应激。
从本研究可看出,CKD患者治疗前后血P与FGF23呈正相关,进一步说明高血磷刺激FGF23表达升高,而血P的改善使FGF23表达下降,FGF23水平下降将会对延缓CKD-MBD的进展发挥重要作用。笔者在研究中同时发现,CKD患者治疗前后血PTH与P呈正相关,与Ca呈负相关,说明低血钙、高血磷均刺激了PTH的升高,与文献[15]报道一致。
综上所述,尿毒清颗粒具有改善患者钙、磷代谢以及FGF23的作用,可能通过改善血中钙、磷代谢水平,降低PTH、FGF23等因子的表达,达到延缓CKD-MBD进展的作用。
参考文献
[1] Kidney Disease:Improving Global Outcomes (KDIGO) CKD-MBD Work Group.KDIGO clinical practice guideline for the diagnosis,evaluation,prevention,and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)[J].Kidney International Supplement,2009,76(Suppl 113):S1-S2.
[2]陈孜瑾,陈楠.从KDOQI到KDIGO指南解读慢性肾脏病矿物质和骨异常[J].中国实用内科杂志,2011,31(12):927-929.
[3]中国血液净化编辑部.慢性肾脏病骨代谢及其疾病的临床实践指南[J].中国血液净化,2006,5(2):95-97.
[4] Moe S,Eke T,Cunningham J,et al.Definition,evaluation,and classification of renal osteodystrophy:a position statement from Kidney Disease:Improving Global Outcomes(KDIGO)[J].Kidney International,2006,69(11):1945-1953.
[5] Gutiérrez O M,Michael M,Tamara I,et al.Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis[J].N Engl J Med,2008,359(6):584-592.
[6]黎君君,梁正林.尿毒清颗粒治疗慢性肾衰竭39例的临床研究[J].广西医学,2009,31(10):1450-1451.
[7]谢志华,董建华.尿毒清颗粒延缓慢性肾衰竭的临床研究[J].中国中西医结合肾病杂志,2009,10(3):238-239.
[8] National Kidney Foundation.K/DOQI.Clinical practice guidelines for chronic kidney disease:evaluation,classification,and stratification[J].Am J Kidney Dis,2002,39(2 suppl 1):S1-S266.
[9]中华中医药学会肾病分会.慢性肾衰竭的诊断、辨证分型及疗效评定(试行方案)[J].上海中医药杂志,2006,40(8):8-9.
[10]汤婷,邢昌赢.成纤维细胞生长因子-23介导的骨-肾调节轴在慢性肾脏病中的作用[J].国际泌尿系统杂志,2008,28(6):833-837.
[11] Liu S,Quarles L D.How fibroblast growth factor 23 works[J].Journal of the American Society of Nephrology:JASN,2007,18(6):1637-1647.
[12] Yu X,White K E.FGF23 and disorders of phosphate homeostasis[J].Cytokine Growth Factor Rev,2005,16(2):221-232.
[13] Gutierrez O,Isakova T,Rhee E,et al.Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease[J].J Am Soc Nephr,2005,16(7):2205-2215.
[14] Ibrahin S,Rashed L.Serum fibroblast growth factor-23 levels in chronic haemodialysis patients[J].Int Urol Nephrol,2009,41(1):163-169.
[15]李相友,夏瑗瑜,张素华,等.尿毒清颗粒对慢性肾衰竭主动脉瓣膜钙化患者中氧化应激状态的影响[J].中国中西医结合肾病杂志,2011,12(5):438-439.
(收稿日期:2015-03-05) (本文编辑:欧丽)
【关键词】 尿毒清颗粒; 慢性肾脏病; 钙、磷代谢; 成纤维细胞生长因子23; 甲状旁腺激素
The Influence of Niaoduqing Particle on the Calcium and Phosphorus Metabolism and FGF23 in Patients with Chronic Kidney Disease/YE Min-yuan,ZHENG Jing,ZHANG Juan,et al.//Medical Innovation of China,2015,12(23):016-018
【Abstract】 Objective:To explore the influence of Niaoduqing(NDQ) Particle on the calcium,phosphorus and fibroblast growth factor 23(FGF23) in patients with CKD stage 3-5.Method:According to the standard of NKF-K/DOQI proposed,fifty-four CKD patients were randomly divided into the treatment group(Niaoduqing Particle) and the control group,at the same time,20 cases were selected as the normal group.FGF23,iPTH,BUN,Scr,Ca,P levels and Ucr were determined,then GFR was calculated based on MDRD equation.Result:Compared with normal group,with the decline of GFR,the level of P,FGF23,BUN,Scr in the serum of the patients with CKD stage 3-5 were significantly increased,the level of Ca was significantly decreased,the differences were statistically significant(P<0.01).CKD stage 3-4:compared with the pretherapy,serum P,FGF23,Scr level were decreased(P<0.01 or P<0.05),GFR was increased(P<0.01) in the treatment group,there was no significant difference in BUN(P>0.05).In the control group,FGF23 level was decreased(P<0.05),Scr decreased and GFR increased,but there were no statistically significant differences(P>0.05).Ca of the two groups were increased,but there had no statistical significances(P>0.05).Compared with the control group,the P and FGF23 level of the treatment group were decreased significantly(P<0.05 or P<0.01).CKD stage 5:compared with the pretherapy,GFR and Ca of the treatment group were significantly increased(P<0.01 or P<0.05),FGF23 of the two groups were decreased(P<0.05 or P<0.01),BUN,Scr,P decreased,but there were no statistically significant differences(P>0.05).GFR of the control group was decreased,but there had no statistical significances(P>0.05).Conclusion:Niaoduqing Particle can improve the levels of calcium,phosphorus and FGF23 of the patients,and it may play an important role to delay the progression of CKD-MBD by improving the calcium and phosphorus metabolism,reducing the expression of PTH,FGF23 and other factors. 【Key words】 Niaoduqing Particle; Chronic kidney disease; Calcium and phosphorus metabolism; Fibroblast growth factor 23; Parathyroid hormone
First-author’s address:Fujian University of Traditional Chinese Medicine,Fuzhou 350100,China
doi:10.3969/j.issn.1674-4985.2015.23.006
慢性肾脏病-矿物质和骨代谢紊乱(CKD-MBD)是指CKD患者中系统性矿物质和骨代谢紊乱[1]。而钙、磷代谢紊乱是主因[2]。CKD-MBD可发生于CKD早期,而在CKD4~5期会出现显著的高磷、高PTH和高FGF23血症,透析患者几乎都受影响[3]。CKD-MBD可导致骨骼系统、心血管疾病(CVD)等[4]。流行病调查显示,低血钙、血磷,FGF23水平升高与肾性骨病、CVD有直接关系[5]。尿毒清颗粒是肾科常用药,对降低BUN、Scr以及延缓CKD进展均有明显效果[6-7]。那么尿毒清颗粒能否对CKD-MBD发挥治疗作用及能否改善CKD患者血清中钙、磷代谢紊乱以及FGF23的水平值得进一步探讨。
1 资料与方法
1.1 一般资料 选择2012年7月-2013年7月福建省人民医院肾内科病房符合诊断标准的CKD3~5期患者54例,CKD3期19例,CKD4期17例,CKD5期18例。利用随机数字表法将所有患者分为治疗组28例和对照组26例,两组患者的性别、年龄等一般资料比较差异均无统计学意义(P>0.05),具有可比性。正常组:来自福建中医药大学附属人民医院健康志愿者,符合纳入标准者共20例,男12例,女8例,年龄36~77岁,平均(55.10±10.49)岁。
1.2 诊断标准 (1)西医诊断标准:依据美国2002年NKF-
K/DOQI CKD临床实践指南进行定义及分期[8];(2)中医辨证分型标准:依照中华中医药学会肾病分会慢性肾衰竭的诊断、辨证分型及疗效评定(试行方案)的脾肾气虚证辨证分型[9]。
1.3 纳入标准 (1)符合上述诊断标准的CKD3~5期患者;(2)年龄35~80岁。
1.4 排除标准 (1)纳入前1个月内有创伤、手术或肿瘤病史;(2)已服其他中药者;(3)感染、妊娠期、哺乳期患者,精神病者和拒绝加入本临床试验者;(4)严重的CVD;(5)急性肾衰竭患者;(6)肾脏替代治疗患者;(7)医从性差者。
1.5 治疗方法
1.5.1 对照组 (1)严格控制饮食;(2)改善患者钙、磷代谢,给予口服钙尔奇D、阿法骨化醇;(3)控制血压、血糖;(4)纠正代谢紊乱;(5)肾性贫血者予EPO(益比奥6000 U,每周分2~3次)。
1.5.2 治疗组 治疗组在对照组治疗的基础上联合尿毒清颗粒(康臣药业有限公司)。温水冲服。4次/d,三餐前各服一袋,睡前服2袋。停用其他中药治疗。疗程1个月。
1.6 观察指标及检测方法 用ELISA方法检测FGF23,免疫放射法测定iPTH,反相高效液相色谱法检测尿Cr,利用BECKMAN-C800全自动生化分析仪测定血Ca、P、BUN、Scr,按照MDRD公式算出GFR。
1.7 统计学处理 采用SPSS 16.0进行统计分析,计量资料以(x±s)表示,多组组间差异采用方差LSD法,t检验使用两个独立样本t检验,不符合正态的使用秩和检验,使用Spearman分析进行相关分析,以P<0.05为差异有统计学意义。
2 结果
2.1 CKD患者与正常组血清各指标比较 随着GFR的下降,CKD3~5期患者的血P、FGF23、BUN、Scr较正常组均显著升高,血Ca较正常组显著下降,差异均有统计学意义(P<0.01),见表1。
2.2 治疗组及对照组治疗前后各指标水平比较
2.2.1 CKD3~4期 与治疗前比较,治疗组Scr下降显著(P<0.05),P、FGF23均显著下降(P<0.01),GFR显著提高(P<0.01),BUN下降但无显著差异(P>0.05);对照组FGF23显著下降(P<0.05),Scr下降、GFR提高,但均无显著差异(P>0.05);两组Ca均提高,无统计学意义(P>0.05);与对照组比较,治疗组的P、FGF23均显著下降(P<0.05或P<0.01),见表2。
2.2.2 CKD5期 与治疗前比较,治疗组GFR显著提高(P<0.01),Ca提高(P<0.05),两组的FGF23也下降(P<0.05或P<0.01),BUN、Scr、P也下降,但无明显差异(P>0.05),对照组GFR提高,但无明显差异(P>0.05),见表3。
2.3 相关分析结果 CKD患者治疗前后血PTH与BUN、Scr、P、FGF23呈正相关(P<0.05或P<0.01),与GFR、Ca呈负相关(P<0.01)。血P与BUN、Scr、FGF23呈正相关(P<0.01),与GFR呈负相关(P<0.01),血Ca与Scr、FGF23呈负相关(P<0.01),与GFR呈正相关(P<0.01),P、Ca和Ca、BUN均无相关性。
3 讨论
CKD-MBD的病机分为:(1)Ca-PTH-维生素D轴;(2)P-FGF23-肾轴[10-11]。FGF23与血磷呈正相关[12]。当GFR下降时血磷、FGF23清除减少,肾脏Klotho蛋白表达下降进一步刺激了FGF23的过度分泌[11]。有研究提出,FGF23升高是CKD患者预后不良的重要危险因素,也会造成组织器官的损害,与CVD等相关[13-14]。 尿毒清颗粒是由大黄、黄芪、姜半夏、何首乌、茯苓、丹参、白术、川芎等组成的,具有通腑泄浊、活血化瘀等功效。现代药理表明,黄芪能促进小管上皮细胞修复、增加白蛋白合成;大黄可提高尿磷排泄,改善肾功能;党参具有抗血小板聚集等作用[6-7]。李相友等[15]发现它能改善CRF患者主动脉瓣膜钙化氧化应激。
从本研究可看出,CKD患者治疗前后血P与FGF23呈正相关,进一步说明高血磷刺激FGF23表达升高,而血P的改善使FGF23表达下降,FGF23水平下降将会对延缓CKD-MBD的进展发挥重要作用。笔者在研究中同时发现,CKD患者治疗前后血PTH与P呈正相关,与Ca呈负相关,说明低血钙、高血磷均刺激了PTH的升高,与文献[15]报道一致。
综上所述,尿毒清颗粒具有改善患者钙、磷代谢以及FGF23的作用,可能通过改善血中钙、磷代谢水平,降低PTH、FGF23等因子的表达,达到延缓CKD-MBD进展的作用。
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(收稿日期:2015-03-05) (本文编辑:欧丽)