慢性肾脏病患者成纤维细胞生长因子23与肾功能及钙磷代谢的关系

目的 探讨慢性肾脏病（CKD）患者随着肾功能的变化,其成纤维细胞生长因子23（FGF23）与钙磷代谢的关系。 方法 研究对象为2008年8月至2009年4月在上海交通大学附属第一人民医院肾内科住院的初诊CKD患者72例,按照肾小球滤过率（GFR）水平分为5组,另设健康对照组20例。抽取受试者静脉血并分离血清,以酶联免疫法检测FGF23、25（OH）VitD3、1,25（OH）2VitD3;全自动生化分析仪测量钙（Ca）、磷（P）、血肌酐（Scr）、尿素氮（BUN）、白蛋白（Alb）水平;免疫放射法测定全段甲状旁腺激素（iPTH）。 结果 CKD患者血清FGF23水平随GFR降低逐渐升高,在CKD4期和5期时,血FGF23、P、iPTH上升明显,1,25（OH）2VitD3显著下降,与CKD1期差异有统计学意义（均P < 0.05）。CKD2~3期与CKD1期的FGF23、P、Ca、iPTH、活性维生素D水平差异均无统计学意义。血Ca、25（OH）VitD3随着肾功能下降有降低趋势,但各期间差异均无统计学意义。Pearson相关分析显示,CKD1~5期logFGF23与P、logiPTH呈正相关（r = 0.653,P < 0.01;r = 0.800,P < 0.01）,与GFR、1,25（OH）2VitD3呈负相关（r = -0.753,P < 0.01;r = -0.265,P < 0.05),与Ca、25（OH）VitD3无相关。CKD1~3期logFGF23与logiPTH呈正相关(r = 0.374,P < 0.05),而与Ca、P、25（OH）VitD3、1,25（OH）2VitD3、GFR均无相关。CKD4~5期log FGF23与P、logiPTH呈正相关（r = 0.381,P < 0.05;r = 0.515,P < 0.01）,与GFR呈负相关（r = -0.654,P < 0.01）,与Ca、25（OH）VitD3、1,25（OH）2VitD3无相关。 结论 随着肾功能减退,血清FGF23、P、iPTH水平逐渐升高,活性维生素D水平逐渐下降,尤以CKD4~5期明显。在肾脏病早期阶段（CKD1~3期）血iPTH水平与FGF23有关。当GFR<30 ml/min时,肾功能状态、血磷、血iPTH均可影响血FGF23水平。     

血清FGF-23与维持性血液透析患者透中低血压发生的关系

目的：探讨维持性血液透析（ maintenance hemodialysis,MHD）患者发生透中低血压（ intradialytic hypotension, IDH）与血清中可溶性klotho（soluble klotho,sKl）和成纤维细胞生长因子23（fibroblast growth factor23,FGF23）之间的关系。方法：横断面收集MHD患者病情资料,根据最近1个月内透析记录,将MHD患者分成无透中低血压组（ N-IDH）和透析中低血压组（ IDH）。收集患者同期实验室检查结果,并采集患者血清样本,检测血清FGF23与sKl水平。比较N-IDH与IDH患者之间生化指标差异。结果：共收集临床信息完整及血清标本完整患者80例,其中IDH发生率为77.5%,独立样本t检验分析结果提示五个指标在N-IDH和IDH组之间差异存在统计学意义,血铁蛋白（P=0.046）、血三酰甘油（P=0.045）、血iPTH （P=0.047）、钙磷乘积（P=0.042）和血清FGF23（P〈0.001）。而sKl在两组间差异无统计学意义（P=0.747）。相关性检验提示IDH组的患者IDH发生频率与血清FGF23浓度的相关关系分析显示两者呈正相关（r=0.722,P〈0.001）。结论：本组病例提示血清FGF23的水平与MHD患者透析中低血压的发生密切相关。     

维持性血液透析患者骨钙素和矿物质与骨代谢紊乱指标的相关性分析

目的探讨维持性血液透析(maintenance hemodialysis,MHD)患者骨钙素(bone glaprotein,BGP)水平和矿物质与骨代谢紊乱指标的相关性。方法选择2015年2月至2015年5月在济南军区总医院血液净化中心并发慢性肾脏病-矿物质与骨代谢紊乱(chronic kidney disease mineral and bone disorder,CKD-MBD)的MHD患者36例,抽取透析前空腹血进行常规实验室检查,同时检测血钙、血磷、总碱性磷酸酶。用化学发光法检测全段甲状旁腺素(immunoreactive parathyroid hormone,iPTH),酶联免疫法检测成纤维细胞生长因子23(fibroblast growth factor23,FGF23)、BGP。用Pearson相关及Logistic回归分析相关研究数据。结果36例MHD患者BGP平均水平为(193.59±87.38)μg/L,与血磷(r=0.529)、FGF23(r=0.492)、iPTH(r=0.601)正相关;与年龄(r=-0.346)负相关;与血钙(r=0.003)、总碱性磷酸酶(r=0.170)、患者透析时间(r=0.097)不相关。根据iPTH水平将患者分为低iPTH组、iPTH达标组和高iPTH组,统计分析发现组间BGP(F=21.365,P=0.0001)、FGF23(F=5.824,P=0.007)、血磷(F=7.739,P=0.002)存在差异,而血清钙、总碱性磷酸酶、年龄和透析时间之间无显著性差异。根据BGP水平将患者分为高于均值组和低于均值组,进行多因素Logistics回归分析,发现高iPTH(OR=3.49,P=0.042)、高FGF23(OR=3.221,P=0.043)、高血磷(OR=3.103,P=0.038)是BGP高于均值的独立危险因素。结论 BGP在MHD患者中明显升高,且与iPTH、血磷和FGF23正相关。     

不同血液净化模式对慢性肾衰竭患者成纤维细胞生长因子23清除的相关研究

目的：通过检测HD、HDF、HD联合HP三种透析模式下血清FGF23、PTH、1，25（OH）2D3、BUN、Scr、Ca2＋、P3-等相关指标的变化，以及FGF23与其他检测指标的相关关系，探讨FGF23与MHD患者骨和矿物质代谢紊乱的关系及血液净化治疗对FGF23水平的影响。方法：选取年龄大于18岁，规律血液透析大于3个月的患者61例（男35例，女26例）。根据单次血液净化治疗模式的不同随机分为HD、HDF、HD＋HP三组，对照组来自健康体检者。所有患者均于血液净化治疗前、治疗后空腹各抽取静脉血5ml，测定治疗前后血清Scr、BUN、Ca2＋、P3-、FGF23、PTH、1，25（OH）2D3浓度。结果：MHD患者血清FGF23、PTH、Ser、BUN、P3-较健康对照组明显升高；1，25（OH）2D3明显降低。FGF23与PTH、BUN、Scr、P3-水平及透析龄呈正相关关系，而与1，25（OH）2D3、Ca2＋、年龄无相关关系；多元线性回归分析显示：FGF23与PTH、P3-、BUN有显著相关性。HD组患者透析后血BUN、Scr、P下降；HDF及HD＋HP两组患者透析后FGF23，PTH、BUN、Scr、P3-有明显降低，差异具有统计学意义。HDF组及HD＋HP组治疗后FGF23的下降与P3-及PTH的下降均未见有相关关系。结论：MHD患者体内FGF23水平明显升高，其水平与PTH、BUN、Scr、P3-、透析龄呈正相关关系，与1，25（OH）2D3、ca2＋、年龄无明显相关关系。HDF、HD＋HP两种治疗模式可有效清除FGF23和咖。HDF组及HD＋HP组治疗后FGF23的下降与P、PrH的下降均无相关关系。     

慢性肾脏病患者甲状旁腺激素水平对肾性贫血的影响

目的 探讨慢性肾脏病（CKD）患者甲状旁腺激素（PTH）升高致红细胞寿命缩短的机制。 方法 以住院初治的CKD患者75例（按eGFR分为1～2期、3～4期和5期）和健康对照组30例为对象。免疫发光法测全段甲状旁腺激素（iPTH）;流式细胞术测红细胞表面磷脂酰丝氨酸（PS）外翻水平及红细胞内钙离子浓度（[Ca2+]i）。 结果 （1）随着肾功能的减退,CKD3～4期及5期患者 iPTH、[Ca2+]i及红细胞表面PS外翻水平逐渐升高、贫血逐渐加重,明显高于CKD1～2期和对照组（均P < 0.05）。（2）CKD3～4期或5期患者Hb与iPTH和红细胞表面PS外翻水平呈负相关（r = -0.830和-0.791,均P < 0.01）;iPTH与 [Ca2+]i和红细胞表面PS外翻水平呈正相关（r = 0.882和0.924,均P < 0.01）,与血钙浓度呈负相关（r = -0.544, P < 0.01）;红细胞表面PS外翻水平与 [Ca2+]i呈正相关（r = 0.923,P < 0.01）,与血钙浓度无相关（r = -0.138,P = 0.365）。（3）[Ca2+]i（Y）对iPTH（X）的直线回归方程：Y=3.327+0.213X（F=21.529,P < 0.05）;红细胞表面PS外翻水平（Y）对iPTH（X1）及[Ca2+]i（X2）的多元线性回归方程：Y=-0.303+0.283X2+0.139X1（F = 6.59,P < 0.01）。 结论 iPTH增加红细胞内钙离子浓度,引起红细胞表面PS外翻增多,致红细胞寿命缩短而加重肾性贫血。     

慢性肾脏病患者血管钙化与成纤维细胞生长因子23-Klotho轴的关系

目的 阐明成纤维细胞生长因子FGF23-Klotho轴与慢性肾脏病(chronic kidneydisease,CKD)患者血管钙化之间的关系,以及CKD患者成纤维细胞生长因子-23 (FGF-23)、Klotho的检测及差异.方法 应用酶联免疫分析(ELISA)法检测65例CKD 3～5期未透析患者与15名健康对照组全段FGF-23、Klotho和1,25二羟基维生素D3[1,25(OH)2-VitD3]的水平,同时测定血清肌酐(creatinine,CREA)、钙(calcium,Ca)、磷(phosphate,P)、碱性磷酸酶(alkaline phosphatese,ALP)、尿酸(uric acid,UA)、全段甲状旁腺激素(parathyroid hormone,iPTH)等指标,分析FGF-23与各指标的关系.结果 CKD患者血清FGF-23水平随肾功能下降而逐渐升高,CKD各期与对照组相比、各期组间相比差异存在统计学意义(P＜0.05).Klotho与FGF-23存在显著正相关,1,25(OH)2-VitD3随肾功能损害的程度加重而下降.相关分析结果显示:CKD 3～5期患者血清FGF-23与血清Klotho、CREA、P、Ca×P、iPrH存在显著正相关(r分别为0.338、0.542、0.402、0.423、0.342,均P＜0.01),与eGFR存在显著负相关(r为-0.627,P＜0.01).多元回归分析显示:CREA、eGFR、P、Ca×P、iPTH、Klotho是血清FGF-23水平的独立影响因素.Ca、CREA、iPTH、Klotho、1,25(OH)2-VitD3、eGFR等指标无明显差异(P＞0.05).无血管钙化组和血管钙化组比较,患者的FGF-23、年龄、Ca×P、P、ALP水平有显著性差异(P＜0.05).血管钙化的危险因素采用多因素Logistic回归分析:年龄、P可能是发生血管钙化的主要危险因素(r值分别为-1.446、-1.454,P值分别为0.011、0.029).结论 CKD 3～5期患者血清FGF-23显著升高,CREA、eGFR、P、Ca×P、iPTH、Klotho可能是血清FGF-23水平的影响因素.年龄、P可能为血管钙化的危险因素.     

61例尿毒症患者甲状旁腺全切加前臂移植术后低钙血症的发生与处理

目的针对内科治疗无效的继发性甲状旁腺功能亢进（sHPT）的尿毒症患者行甲状旁腺全切加前臂移植术,分析术后患者低钙血症的发生与处理。方法61例患者术后立即监测血钙浓度,并静脉补充葡萄糖酸钙,使血钙维持在1．8～2．2mmol／L之间,统计手术前、后患者的全段甲状旁腺激素（iPTH）、血清钙磷乘积和碱性磷酸酶（AKP）水平以及手术切除的总的腺体质量。结果56例患者（占91．7％）术后12-24h即出现血钙低于1．8mmol／L,静脉立即补充葡萄糖酸钙,约合元素钙（18±6）g,补钙剂量与术前血iPTH（r=0．621,P〈0．01）、钙磷乘积（r=0．719,P〈0．01）、AKP（r=0．606,P〈0．01）及总的切除腺体质量（r=0．716,P〈0．01）相关。结论低钙血症是患者甲状旁腺术后的常见表现,与SHPT的严重程度有关,术后及早监测血钙和静脉补钙可有效、安全预防严重低钙血症的发生。     

甲状旁腺切除术对血液透析患者合并继发性甲状旁腺功能亢进骨代谢及骨密度的影响

目的 观察甲状旁腺切除术(parathyroidectomy,PTX)对继发性甲状旁腺功能亢进(secondary hyperparathyroidism,SHPT)的维持性血液透析患者骨代谢及骨密度(BMD)的影响.方法 26例SHPT患者行PTX.术前及术后1、3、6、12、18、24个月时常规检测血钙、血磷、血清碱性磷酸酶,化学发光法检测血清全段甲状旁腺素(intact parathyroid,iPTH)、骨钙素(OC)、Ⅰ型前胶原氨基末端前肽(PINP)、β胶原蛋白(β-C TX),术前及术后24个月时双能X线法测定腰椎、股骨颈、骨盆各部位骨密度,观察患者甲状旁腺切除术前、术后骨代谢指标及骨密度变化.结果 (1)与术前比较,血清OC水平[(104.49±25.42) μg/L比(695.46±355.62) μg/L,P＜ 0.01]、PINP水平[(248.36±159.38) μg/L比(809.28±283.50) μg/L,P＜0.01]于手术3个月后明显降低,β-CTX水平于手术1个月后明显降低[(1.60±0.64) μg/L比(3.37±1.34) μg/L,P＜0.01].(2)与术前比较,术后24个月时腰椎BMD[(0.88±0.23) g/cm2比(0.78±0.23) g/cm2,P＜0.01]、股骨颈BMD[(0.96±0.19) g/cm2比(0.84±0.24) g/cm2,P＜ 0.01]及腰椎Z评分[(-1.24±0.55)比(-1.66±0.24),P＜0.01]、股骨颈Z评分[(-1.51±0.72)比(-1.93±0.40),P＜0.01]均升高.(3)相关分析显示,术前血清iPTH水平与⊿腰椎Z评分(r=0.584,P=0.002)、⊿股骨颈Z评分(r=0.400,P=0.043)呈正相关,术前血清OC水平与⊿腰椎Z评分(r=0.651,P＜0.001)、⊿股骨颈Z评分(r=0.509,P=0.008)呈正相关.结论 PTX术可以降低患者升高的iPTH、OC、PINP及β-CTX水平,增加骨密度,同时改善多项生化指标,提高患者生活质量.     

21例尿毒症患者甲状旁腺全切加前臂移植对改善透析患者肾性贫血的临床观察

目的探讨甲状旁腺全切除加部分前臂自体移植术（parathyroidectomy＋forearyauto—transplantation,PTX＋FAT）纠正重度继发性甲状旁腺功能亢进（secondaryhyperparathyroidism,SHPT）对维持性透析（maintenancehemodialysis,MHD）患者并发难治性肾性贫血的影响。方法选择MHD并发重度SHPT及难治性肾性贫血患者21例,均为经规范的药物治疗无效者行PTX＋FAT治疗,观察术前、术后第3、6、12个月时患者的血清全段甲状旁腺素（intactparathyroidhormone,i盯H）、钙（Ca）、磷（P）、血红蛋白（Hb）、红细胞压积（Hct）、血清铁蛋白（SF）、转铁蛋白饱和度（TSAT）、血清白蛋白（Alb）、KT／V等指标变化,同时记录患者的促红细胞生成素（recombinanthu—manerythropoietin,rHuEPO）用量。结果所有患者与术前相比血清iPTH、Ca、P迅速下降,从术后第3个月开始贫血得到逐步改善,术后第12个月Hb和Hct较术前显著升高（P〈0．05）,术后第6个月rHuEPO用量减少,与术前相比差异显著（P〈0．01）,术后第12个月rHuEPO用量大幅减少,与术前相比有显著性差异（P〈O．01）。手术前、后SF、TSAT、Alb、KT／V等指标差异无统计学意义（P〉0．05）。结论重度SHPT维持性血液透析患者在PTX＋FAT术后可迅速降低iPTH水平并显著改善MHD患者的难治性肾性贫血,减少rHuEPO用量,提示重度SHPT是影响肾性贫血的一个重要因素,其作用可能部分与rHuEPO抵抗有关。     

严重继发性甲状旁腺功能亢进症临床分析

目的调查血液透析患者全段甲状旁腺激素（iPTH）、血清钙和血清磷的水平，了解严重的继发性甲状旁腺功能亢进症（SHPT）的发病情况。方法选择血液透析治疗超过1年，行3次以上iPTH、Ca和P检查的患者，以血iPTH〉800ng／ml为界定点，分析严重的SHPT发病率与年龄、性别、透析龄、原发病（糖尿病或非糖尿病）、血清钙和血清磷的关系。结果139例患者中有27例是严重的SHPT患者，发病率为19．4％（27／139），它们拥有较长的透析龄（P〈0．05）；其糖尿病的发生率明显低于非糖尿病（P〈0．05），而且存在明显的高磷血症和高钙磷乘积（P〈0．05）。Logistic回归分析显示，年龄、高钙磷乘积是严重的SHPT的独立危险因素（P〈0．05）。结论严重的SHPT的发病率与年龄、高钙磷乘积有关。因此，临床上必须早治疗，严格控制高磷血症。     

Parathyroidectomy in patients with chronic kidney disease: Impacts of different techniques on the biochemical and clinical evolution of secondary hyperparathyroidism

Background

Parathyroidectomy (PTx) decreases the mortality rate of refractory secondary hyperparathyroidism (rSHP) due to chronic kidney disease. A consensus regarding which techniques of PTx are associated with better outcomes is not available. The aims of this study are to evaluate the clinical and laboratory evolution of 49 hemodialysis patients with rSHP who underwent PTx using different techniques.

Fibroblast Growth Factor 23 (FGF23) and Alpha-Klotho Stimulate Osteoblastic MC3T3.E1 Cell Proliferation and Inhibit Mineralization

Elevated serum levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) are found in patients with phosphate wasting diseases and chronic kidney disease-mineral and bone disorder (CKD-MBD). These diseases are associated with rickets and renal osteodystrophy, respectively. FGF23 is secreted from osteoblastic cells and signals through FGFRs, membrane coreceptor alpha-Klotho (Klotho), and, possibly, a circulating form of Klotho. Despite the absence of detectable Klotho on osteoblastic cells, studies have suggested that forced FGF23 expression in osteoblasts inhibited mineralization. Thus, we examined the effects of exogenously applied FGF23 on osteoblastic MC3T3.E1 cell proliferation and differentiation, with and without soluble Klotho. MC3T3.E1 cells were cultured in osteoblast differentiation medium, supplemented with FGF23 (0.1–1,000 ng/mL), Klotho (50 ng/mL), the combination FGF23 + Klotho, and FGF2 (100 ng/mL) as a control. Neither FGF23 nor Klotho exposure affected proliferation of day 4 growth phase cells or mineralization of day 14 cultures. In contrast, FGF23 + Klotho resulted in inhibition of mineralization and osteoblast activity markers at day 14, and a slight, reproducible induction of proliferation. Inhibition of FGFR1, but not FGFR2 or FGFR3, completely restored FGF23 + Klotho-induced inhibition of alkaline phosphatase (ALP) activity at day 7. ALP activity was partially restored by the MAPK inhibitor U0126 but not inhibitors p38 and P13K. Thus, soluble Klotho enables FGF23 signaling in MC3T3.E1 cells, likely through FGFR 1(IIIc). Elevated FGF23 actions, in part, appear to parallel FGF2 with lower potency. In addition to affecting bone via indirect phosphate wasting pathways, supraphysiological FGF23 and soluble Klotho may directly impact bone in diseases with elevated FGF23 levels.     

Association of FGF23 and Klotho protein with bone mineral density in maintenance hemodialysis patients

Objective To explore the association between serum FGF23 and Klotho protein, and bone mineral density in maintenance hemodialysis (MHD) patients. Methods A total of 125 MHD patients admitted in the Hospital between January 2015 and November 2015 was enrolled. Their bone mineral densities of femur neck and lumbar spine were studied by dual-energy X-ray absorptiometry. These patients were divided into three groups as normal, osteopenic and osteoporotic, according to World Health Organization criteria based on bone mineral density T scores. Levels of serum FGF23, Klotho protein and 1,25(OH)2VitD3 were measured by ELISA. The parameters including calcium, phosphorus, and parathyroid hormone were assessed. Results The incidences of osteopenia and osteoporosis at the femur neck and lumbar spine in MHD patients were 82.40% and 56.00% respectively. No significant difference was found in the levels of serum FGF23 among normal, osteopenic and osteoporotic groups on the basis of femur neck and lumbar spine bone mineral density (P﹥0.05). No correlation was found between FGF23 and bone mineral density. There however were significant differences in the levels of serum Klotho protein among three groups on the basis of femoral neck bone mineral density (P＜0.05). And the levels of Klotho protein in the osteoporotic group [(387.172±54.137) ng/L] were significantly decreased than those in normal group [(429.883±41.776) ng/L] and osteopenic group [(410.598±61.056) ng/L] (P＜0.05). There were also significant differences in the levels of serum Klotho protein among three groups in terms of lumbar spine bone mineral density (P＜0.05), while the levels of Klotho protein in the osteopenic group [(387.263±53.255) ng/L] were significantly decreased than those in normal group [(417.108±56.179) ng/L] (P＜0.05). A positive correlation was found between Klotho protein and bone mineral densities of femur neck and lumbar spine. Multiple linear regression analysis showed that one of the main factors influencing the degree of bone mineral density in MHD patients was Klotho protein. Conclusions CKD-MBD with low BMD is common and widespread in hemodialysis patients. FGF23 has no direct effect on bone mineral density in MHD patients; while Klotho protein is correlated with the severity of bone mineral density. High-level Klotho protein may reduce the severity of CKD-MBD with low BMD in MHD patients.     

FGF23 Fails to Inhibit Uremic Parathyroid Glands

Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D₃. FGF23 decreases parathyroid hormone (PTH) mRNA and secretion, but despite a marked elevation in FGF23 in uremia, PTH production increases. Here, we investigated the effect of FGF23 on parathyroid function in normal and uremic hyperplastic parathyroid glands in rats. In normal parathyroid glands, FGF23 decreased PTH production, increased expression of both the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduced cell proliferation. Furthermore, FGF23 induced phosphorylation of extracellular signal–regulated kinase 1/2, which mediates the action of FGF23. In contrast, in hyperplastic parathyroid glands, FGF23 did not reduce PTH production, did not affect expression of the calcium-sensing receptor or vitamin D receptor, and did not affect cell proliferation. In addition, FGF23 failed to activate the extracellular signal–regulated kinase 1/2–mitogen-activated protein kinase pathway in hyperplastic parathyroid glands. We observed very low expression of the FGF23 receptor 1 and the co-receptor Klotho in uremic hyperplastic parathyroid glands, which may explain the lack of response to FGF23 in this tissue. In conclusion, in hyperparathyroidism secondary to renal failure, the parathyroid cells resist the inhibitory effects of FGF23, perhaps as a result of the low expression of FGF23 receptor 1 and Klotho in this condition.Fibroblast growth factor 23 (FGF23) is produced by bone cells and plays a fundamental role in the regulation of mineral metabolism. FGF23 inhibits tubular resorption of phosphate and decreases 1α hydroxylase activity, which limits 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] production. Both phosphate excess and high 1,25(OH)₂D₃ stimulate the production of FGF23.¹ FGF23 signals through a widely expressed receptor (FGFR) that becomes functional only in cells expressing the Klotho protein.^2,3 Klotho, which is expressed in the parathyroid cell, converts FGFR1(IIIc), a canonical receptor for various FGFs, into a specific receptor for FGF23. The tissue-specific unique biological activity of FGF23 is likely to be regulated by the limited local distribution of Klotho. In renal failure, the decrease in glomerular filtration causes phosphate retention, which stimulates the production of FGF23. This elevation in FGF23 levels should help to control phosphate in patients with renal failure.⁴Klotho and FGFR are abundantly expressed in parathyroid cells. Some studies^5,6 showed that FGF23 decreases parathyroid hormone (PTH) secretion and PTH mRNA. In dialysis patients, FGF23 levels can reach extremely high values^4,7 but PTH is not reduced; in fact, the highest PTH values correspond to patients with a marked increase in FGF23 levels.⁸ Thus, it is not clear whether FGF23 is capable of reducing PTH production in uremia. Our hypothesis is that there may be a resistance to the action of FGF23 in patients with uremia.This study was designed to evaluate the effect of FGF23 on parathyroid function in normal and hyperplastic parathyroid glands. The study was performed in vivo and in vitro using intact rat parathyroid glands from normal and uremic animals with parathyroid hyperplasia.     

甲状旁腺切除术后维持性血液透析患者腹主动脉钙化的改变

目的 观察维持性血液透析(maintenance hemodialysis,MHD)合并继发性甲状旁腺功能亢进(secondary hyperparathyroidism,SHPT)患者行甲状旁腺切除术(parathyroidectomy,PTX)后腹主动脉钙化及生化指标的发展变化.方法 回顾性分析完成2年随访的严重SHPT患者,按是否行PTX分成PTX手术组和非手术组,观察术后2年腹主动脉钙化评分(abdominal aortic calcification score,AACS)、血清全段甲状旁腺素(iPTH)、血钙、血磷等变化.PTX手术组按照术后2年腹主动脉钙化有无进展分为进展组和非进展组,对比两组的年龄、透析龄、iPTH、血钙、血磷、钙磷乘积等指标,分析腹主动脉钙化进展的相关因素.结果 共纳入44例MHD合并SHPT患者,PTX手术组26例,非手术组18例.PTX手术组与非手术组基线资料比较,透析龄差异有统计学意义(P<0.05),而性别、年龄、高血压史等差异均无统计学意义.与术前比较,PTX手术组患者术后2年血iPTH、血钙、血磷均降低(均P<0.05),AACS前后差异无统计学意义.患者术后2年有8例(30.77%)腹主动脉钙化加速进展,8例(30.77%)腹主动脉钙化好转,10例(38.46%)腹主动脉钙化稳定.患者术后2年腹主动脉钙化非进展组iPTH值低于进展组[(20.62+6.44) ng/L比(132.72±76.83) ng/L,P<0.05],而非进展组术前AACS高于进展组[(13.11±2.71)分比(2.00±1.41)分,P<0.05].非手术组患者2年后AACS高于基线水平[(10.44±1.65)分比(8.05±1.26)分,P<0.05],血磷及钙磷乘积显著下降(均P<0.05),iPTH、血钙等水平无明显变化(均P>0.05).Pearson相关分析结果显示,PTX手术组术后2年AACS相对于术前的下降值与iPTH下降值(r=0.534,P=0.012)、血钙下降值(r=0.643,P=0.004)、血磷下降值(r=0.897,P<0.001)、钙磷乘积的下降值(r=0.568,P=0.021)呈正相关,与术前AACS值呈负相关(r=-0.647,P=0.014).结论 小样本资料显示,相比非手术治疗,PTX可长期纠正甲状旁腺素、钙、磷代谢紊乱,并有阻止腹主动脉钙化进展甚至逆转血管钙化的可能,而腹主动脉钙化逆转可能与iPTH、血Ca、血P、钙磷乘积的下降程度相关.     

FGFR3 and FGFR4 do not mediate renal effects of FGF23

Fibroblast growth factor 23 (FGF23) is a phosphaturic factor that suppresses both sodium-dependent phosphate transport and production of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] in the proximal tubule. In vitro studies suggest that FGFR3 is the physiologically relevant receptor for FGF23 in the kidney, but this has not been established in vivo. Here, immunohistochemical analysis of the mouse kidney revealed that the proximal tubule expresses FGF receptor 3 (FGFR3) but not FGFR1, FGFR2, or FGFR4. Compared with wild-type mice, Hyp mice, which have elevated circulating levels of FGF23, exhibited low levels of serum phosphate and 1,25(OH)(2)D, reduced expression of the sodium-dependent phosphate transporter NPT2a in the proximal tubules, and low bone mineral density as a result of osteomalacia. In contrast, neither the serum phosphate nor 1,25(OH)(2)D levels were altered in FGFR3-null mice. For examination of the role of FGFR3 in mediating the effects of FGF23, Hyp mice were crossed with FGFR3-null mice; interestingly, this failed to correct the aforementioned metabolic abnormalities of Hyp mice. Ablation of FGFR4 also failed to correct hypophosphatemia in Hyp mice. Because the ablation of neither FGFR3 nor FGFR4 inhibited the renal effects of excess FGF23, the kidney localization of FGFR1 was investigated. FGFR1 co-localized with Klotho, the co-factor required for FGF23-dependent FGFR activation, in the distal tubule. In summary, neither FGFR3 nor FGFR4 is the principal mediator of FGF23 effects in the proximal tubule, and co-localization of FGFR1 and Klotho suggests that the distal tubule may be an effector site of FGF23.     

Effects of parathyroidectomy on blood bone markers and heart rate variability in patients with stage 5 chronic kidney disease

Purpose

Decreased heart rate variability (HRV) is closely related to abnormal cardiac autonomic nervous function, especially sympathetic hyperactivity, which intensifies the risk of cardiovascular events and sudden death. HRV parameters are lower in chronic kidney disease (CKD) and parathyroidectomy (PTX) can improve these abnormalities in severe secondary hyperparathyroidism (SHPT) patients. However, few studies have evaluated correlations between circulating bone markers and HRV in CKD patients.

Methods

We conducted a cross-sectional study including 134 stage 5 CKD patients with 100 controls and a prospective study of 29 PTX patients with follow-up. Circulating bone biomarkers included: (1) intact parathyroid hormone (iPTH) as bone remodeling regulator; (2) bone-specific alkaline phosphatase (BAP), representing bone formation; (3) tartrate-resistant acid phosphatase 5b (TRACP-5b), indicating bone resorption; and (4) bone-derived hormone, fibroblast growth factor 23 (FGF23).

Results

Stage 5 CKD patients had higher circulating iPTH, BAP, TRACP-5b, and FGF23 than controls and these bone markers were significantly elevated in SHPT patients. Baseline iPTH, BAP, and lnFGF23 were independently associated with HRV in CKD patients. After PTX with a follow-up (median interval: 6.7 months), high blood iPTH, BAP, TRACP-5b, FGF23, and attenuated HRV were ameliorated. Furthermore, improved HRV indices were associated with reduced iPTH, BAP, TRACP-5b, and FGF23.

Conclusions

Circulating bone markers are correlated with HRV in CKD 5 patients and PTX can improve decreased HRV, which are associated with corrected bone markers in severe SHPT patients. Thus, we propose that PTH increases sympathetic tone and both high circulating PTH levels and sympathetic hyperactivity increase bone turnover, and that the products of bone turnover influence HRV.

     

血液透析患者血清FGF23水平的影响因素及其与矿物质骨代谢异常的关系研究

目的分析维持性血液透析患者血清成纤维细胞生长因子23(FGF23)水平的影响因素,并探究其与矿物质骨代谢异常及血管钙化的关系。 方法2018年1月至2月期间纳入在南方医科大学附属东莞市人民医院进行维持性血液透析3个月以上患者380例,记录其性别、年龄、透析龄、透析充分性及降磷药物使用情况。透析前抽取血清检查钙、磷、全段甲状旁腺素(iPTH)及碱性磷酸酶等矿物质骨代谢指标,以及血红蛋白、白蛋白、血糖、血脂、血清超敏C反应蛋白(hs-CRP)、血清β2微球蛋白等指标。使用酶联免疫吸附法(ELISA)检测血清FGF23,多层螺旋CT进行冠状动脉钙化评分(MSCT)。采用t检验和卡方检验对维持性血液透析患者FGF23的影响因素进行单因素分析,之后使用多元线性逐步回归方法进行多因素分析。 结果本中心维持性血液透析患者血清FGF23中位数水平为8 905.3 ng/L,根据患者的FGF23水平50%中位数将患者分为低水平组(组1)和高水平组(组2)两组。单因素分析结果表明,透析龄、每次透析时间、透析超滤量及使用非含钙降磷药物和透析频次为FGF23水平的影响因素。透析龄更大,每次透析时间长,每周透析次数多、透析超滤量大的患者FGF23水平更高(均P<0.05)。在FGF23水平高于中位数的患者中,尿素氮、血肌酐和血清β2微球蛋白水平更高(均P<0.05)。多元线性回归分析显示,透析龄长和血肌酐升高是FGF23升高的危险因素(均P<0.001)。同时,高FGF23水平与血清钙、血清磷、iPTH水平和高冠状动脉钙化评分相关。 结论透析龄、每次透析时间、透析超滤量、透析频次、尿素氮、血肌酐、血清β2微球蛋白水平与维持血液透析患者FGF23升高有关。透析龄长和血肌酐高是FGF23升高的危险因素。FGF23与维持性血液透析患者矿物质骨代谢和冠状动脉钙化明显相关。