慢性肾脏病患者血管钙化的病理机制研究进展
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摘要
在慢性肾脏病(chronickidney disease,CKD)患者中,肾功能的进行性降低导致矿物质代谢紊乱、酸中毒、营养不良、炎症和尿毒症毒素积累等症状,可引起继发性甲状旁腺功能亢进、血清钙升高、磷酸盐水平升高和血清成纤维细胞生长因子-23(fibroblastgrowthfactor-23,FGF-23)升高,由此产生CKD相关的矿物质和骨代谢紊乱,循环中过量的钙和磷酸盐也可以促进蛋白质-矿物质复合物的形成,称为钙蛋白颗粒(calpainparticles,CPPs),在CKD中,这些CPPs含有较少的钙化抑制剂,诱发炎症,并促进血管平滑肌细胞的钙化。由此促进血管钙化的发生。诸多横断面观察研究表明,血清FGF-23水平在CKD早期(1～2期)开始升高,并与肾小球滤过率呈负相关,促进血管钙化,最新的研究表明高水平脂联素对FGF-23在冠状动脉钙化的作用中起调节作用。本文综述了CKD患者血管钙化发展机制的研究进展,为进一步寻找潜在的新治疗目标指出方向。
In patients with chronic kidney disease(CKD), progressive deterioration of renal function leads to mineral metabolism disorders, acidosis, malnutrition, inflammation and accumulation of uremic toxins, which can cause secondary hyperparathyroidism and elevated serum calcium. Increased phosphate levels and elevated serum fibroblast growth factor-23(FGF-23), resulting in CKD-related mineral and bone metabolism disorders, excess calcium and phosphate in the circulation can also promote protein-mineral complex called calpain particles(CPPs). In CKD, these CPPs contain little calcification inhibitors,induce inflammation, and promote calcification of vascular smooth muscle cells, thereby promoting the occurrence of vascular calcification. Many cross-sectional observation studies have shown that blood FGF-23 levels begin to increase in the early stage of CKD(stage 1-2) and are negatively correlated with glomerular filtration rate, promoting vascular calcification. The latest research indicates high levels of adiponectin plays a role in the effect of FGF23 on coronary artery calcification. This article reviews the research progress in the mechanism of vascular calcification in patients with CKD, and points out the direction for further search for potential new therapeutic goals.
In patients with chronic kidney disease(CKD), progressive deterioration of renal function leads to mineral metabolism disorders, acidosis, malnutrition, inflammation and accumulation of uremic toxins, which can cause secondary hyperparathyroidism and elevated serum calcium. Increased phosphate levels and elevated serum fibroblast growth factor-23(FGF-23), resulting in CKD-related mineral and bone metabolism disorders, excess calcium and phosphate in the circulation can also promote protein-mineral complex called calpain particles(CPPs). In CKD, these CPPs contain little calcification inhibitors,induce inflammation, and promote calcification of vascular smooth muscle cells, thereby promoting the occurrence of vascular calcification. Many cross-sectional observation studies have shown that blood FGF-23 levels begin to increase in the early stage of CKD(stage 1-2) and are negatively correlated with glomerular filtration rate, promoting vascular calcification. The latest research indicates high levels of adiponectin plays a role in the effect of FGF23 on coronary artery calcification. This article reviews the research progress in the mechanism of vascular calcification in patients with CKD, and points out the direction for further search for potential new therapeutic goals.
引文
[1]HéNAUT L,MASSY Z A.Magnesium as a calcification inhibitor[J].Advances Chronic Kidney Dis,2018,25(3):281-290.
[2]RENNENBERG R,KESSELS A,SCHURGERS,et al.Vascular calcifications as a marker of increased cardiovascular risk:A meta-analysis[J].Vasc Health Risk Manag,2009,5(default):185-197.
[3]HENAUT L,MENTAVERRI R,LIABEUF S,et al.Pathophysiological mechanisms of vascular calcification[J].Ann Biol Clin(Paris),2015,73(3):271-287.
[4]HéNAUT L,CHILLON J M,KAMEL S,et al.Updates on the mechanisms and the care of cardiovascular calcification in chronic kidney disease[J].Seminars Nephrol,2018,38(3):233-250.
[5]MARTIN A,DAVID V,QUARLES L D.Regulation and function of the FGF23/Klotho endocrine pathways[J].Physiol Rev,2012,92(1):131-155.
[6]ISAKOVA T,WAHL P,VARGAS G S,et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease[J].Kidney International,2011,79(12):1370-1378.
[7]RAMON I,KLEYNEN P,BODY J J,et al.Fibroblast growth factor 23 and its role in phosphate homeostasis[J].European JEndocrinol,2010,162(1):1-10.
[8]IX J H,KATZ R,KESTENBAUM B R,et al.Fibroblast growth factor-23 and death,heart failure,and cardiovascular events in community-living individuals:CHS(Cardiovascular Health Study)[J].J Am Coll Cardiol,2012,60(3):200-207.
[9]SCIALLA J J,WOLF M.Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease[J].Nature Rev Nephrol,2014,10(5):268-278.
[10]DESJARDINS L,LIABEUF S,RENARD C,et al.FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages[J].Osteoporosis Int,2012,23(7):2017-2025.
[11]SCIALLA J J,LAU W L,REILLY M P,et al.Fibroblast growth factor 23 is not associated with and does not induce arterial calcification[J].Kidney Int,2013,83(6):1159-1168.
[12]SRIVATHS P R,GOLDSTEIN S L,SILVERSTEIN D M,et al.Elevated FGF 23 and phosphorus are associated with coronary calcification in hemodialysis patients[J].Pediatric Nephrol,2011,26(6):945-951.
[13]KHAN A M,CHIRINOS J A,LITT H,et al.FGF-23 and the progression of coronary arterial calcification in patients new to dialysis[J].Clin J Am Soc Nephrol,2012,7(12):2017-2022.
[14]OZKOK A,KEKIK C,KARAHAN G,et al.FGF-23associated with the progression of coronary artery calcification in hemodialysis patients[J].BMC Nephrol,2013,14(1):241.Doi:10.1186/1471-2369-14-241.
[15]LIM K,LU T S,MOLOSTVOV G,et al.Vascular klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23[J].Circulation,2012,125(18):2243-2255.
[16]HYUN Y Y,KIM H,OH Y K,et al.High fibroblast growth factor 23 is associated with coronary calcification in patients with high adiponectin:analysis from the korean cohort study for outcome in patients with chronic kidney disease study[J].Nephrol Dial Transplant,2019,734(1):123-129.
[17]SAKURA T,OKUNO S,NISHIO E,et al.The association of serum adiponectin with abdominal aortic calcification in Japanese male hemodialysis patients:a cross-sectional observational study[J].Sci Rep,2017,7(1):6434.Doi:10.1038/s41598-017-06850-4.
[18]SINGH S,GRABNER A,YANUCIL C et al.Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease[J].Kidney Int,2016(90):985-996
[19]CONTIGUGLIA S R,ALFREY A C,MILLER N L,et al.Nature of soft tissue calcification in uremia[J].Kidney International,1973,4(3):229-235.
[20]SCHLIEPER G,ARETZ A,VERBERCKMOES S C,et al.Ultrastructural analysis of vascular calcifications in uremia[J].J Am Soc Nephrol,2010,21(4):689-696.
[21]HERENCIA C,RODRíGUEZ-ORTIZ M E,MU?OZ-CASTA?EDA J R,et al.Angiotensin II prevents calcification in vascular smooth muscle cells by enhancing magnesium influx[J].Eur J Clin Invest,2015,45(11):1129-1144.
[22]ISAKOVA T,WAHL P,VARGAS G S,et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease[J].Kidney Int,2011,79(12):1370-1378.
[23]SINEE D.Phosphate and cardiovascular disease beyond chronic kidney disease and vascular calcification[J].Int JNephrol,2018(2018):1-7.
[24]ADENEY K L,SISCOVICK D S,IX J H,et al.Association of serum phosphate with vascular and valvular calcification in moderate CKD[J].J Am Soc Nephrol,2009,20(2):381-387.
[25]COSCAS R,BENSUSSAN M,JACOB M P,et al.Free DNAprecipitates calcium phosphate apatite crystals in the arterial wall,in vivo[J].Atherosclerosis,2017(259):60-67.
[26]EWENCE A E,BOOTMAN M,RODERICK H L,et al.Calcium phosphate crystals induce cell death in human vascular smooth muscle cells:a potential mechanism in atherosclerotic plaque destabilization[J].Circ Res,2008,103(5):e28-e34.
[27]HéNAUT L,SANCHEZ-NINO M D,ALDAMIZ-ECHEVARRíACASTILLO G,et al.Targeting local vascular and systemic consequences of inflammation on vascular and cardiac valve calcification[J].Expert Opin Ther Targets,2016,20(1):89-105.
[28]WEN C,YANG X,YAN Z,et al.Nalp3 inflammasome is activated and required for vascular smooth muscle cell calcification[J].Int J Cardiol,2013,168(3):2242-2247.
[29]STENVINKEL P,KETTELER M,JOHNSON R J,et al.IL-10,IL-6,and TNF-alpha:central factors in the altered cytokine network of uremia-the good,the bad,and the ugly[J].Kidney Int,2005,67(4):1216-1233.
[30]SMITH E R,FORD M L,TOMLINSON L A,et al.Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD[J].Nephrol Dial Transplant,2012,27(5):1957-1966.
[31]THAMRATNOPKOON S,SUSANTITAPHONG P,TUMKOSIT M,et al.Correlations of plasma desphosphorylated uncarboxylated matrix Gla protein with vascular calcification and vascular stiffness in chronic kidney disease[J].Nephron,2017,135(3):167-172.
[32]RUSSO D,MIRANDA I,RUOCCO C,et al.,The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer[J].Kidney Int,2007,72(10):1255-1261
[33]KOLEGANOVA N,PIECHA G,RITZ E,et al.Acalcimimetic(R-568),but not calcitriol,prevents vascular remodeling in uremia[J].Kidney Int,2009,75(1):60-71.
[34]RAGGI P,CHERTOW G M,TORRES P U,et al.The ADVANCE study:a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis[J].Nephrol Dial Transplant,2011,26(4):1327-1339.
[35]WESTENFELD R,KRUEGER T,SCHLIEPER G,et al.Effect of vitamin K2 supplementation on functional vitamin Kdeficiency in hemodialysis patients:a randomized trial[J].Am J Kidney Dis,2012,59(2):186-195.
[2]RENNENBERG R,KESSELS A,SCHURGERS,et al.Vascular calcifications as a marker of increased cardiovascular risk:A meta-analysis[J].Vasc Health Risk Manag,2009,5(default):185-197.
[3]HENAUT L,MENTAVERRI R,LIABEUF S,et al.Pathophysiological mechanisms of vascular calcification[J].Ann Biol Clin(Paris),2015,73(3):271-287.
[4]HéNAUT L,CHILLON J M,KAMEL S,et al.Updates on the mechanisms and the care of cardiovascular calcification in chronic kidney disease[J].Seminars Nephrol,2018,38(3):233-250.
[5]MARTIN A,DAVID V,QUARLES L D.Regulation and function of the FGF23/Klotho endocrine pathways[J].Physiol Rev,2012,92(1):131-155.
[6]ISAKOVA T,WAHL P,VARGAS G S,et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease[J].Kidney International,2011,79(12):1370-1378.
[7]RAMON I,KLEYNEN P,BODY J J,et al.Fibroblast growth factor 23 and its role in phosphate homeostasis[J].European JEndocrinol,2010,162(1):1-10.
[8]IX J H,KATZ R,KESTENBAUM B R,et al.Fibroblast growth factor-23 and death,heart failure,and cardiovascular events in community-living individuals:CHS(Cardiovascular Health Study)[J].J Am Coll Cardiol,2012,60(3):200-207.
[9]SCIALLA J J,WOLF M.Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease[J].Nature Rev Nephrol,2014,10(5):268-278.
[10]DESJARDINS L,LIABEUF S,RENARD C,et al.FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages[J].Osteoporosis Int,2012,23(7):2017-2025.
[11]SCIALLA J J,LAU W L,REILLY M P,et al.Fibroblast growth factor 23 is not associated with and does not induce arterial calcification[J].Kidney Int,2013,83(6):1159-1168.
[12]SRIVATHS P R,GOLDSTEIN S L,SILVERSTEIN D M,et al.Elevated FGF 23 and phosphorus are associated with coronary calcification in hemodialysis patients[J].Pediatric Nephrol,2011,26(6):945-951.
[13]KHAN A M,CHIRINOS J A,LITT H,et al.FGF-23 and the progression of coronary arterial calcification in patients new to dialysis[J].Clin J Am Soc Nephrol,2012,7(12):2017-2022.
[14]OZKOK A,KEKIK C,KARAHAN G,et al.FGF-23associated with the progression of coronary artery calcification in hemodialysis patients[J].BMC Nephrol,2013,14(1):241.Doi:10.1186/1471-2369-14-241.
[15]LIM K,LU T S,MOLOSTVOV G,et al.Vascular klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23[J].Circulation,2012,125(18):2243-2255.
[16]HYUN Y Y,KIM H,OH Y K,et al.High fibroblast growth factor 23 is associated with coronary calcification in patients with high adiponectin:analysis from the korean cohort study for outcome in patients with chronic kidney disease study[J].Nephrol Dial Transplant,2019,734(1):123-129.
[17]SAKURA T,OKUNO S,NISHIO E,et al.The association of serum adiponectin with abdominal aortic calcification in Japanese male hemodialysis patients:a cross-sectional observational study[J].Sci Rep,2017,7(1):6434.Doi:10.1038/s41598-017-06850-4.
[18]SINGH S,GRABNER A,YANUCIL C et al.Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease[J].Kidney Int,2016(90):985-996
[19]CONTIGUGLIA S R,ALFREY A C,MILLER N L,et al.Nature of soft tissue calcification in uremia[J].Kidney International,1973,4(3):229-235.
[20]SCHLIEPER G,ARETZ A,VERBERCKMOES S C,et al.Ultrastructural analysis of vascular calcifications in uremia[J].J Am Soc Nephrol,2010,21(4):689-696.
[21]HERENCIA C,RODRíGUEZ-ORTIZ M E,MU?OZ-CASTA?EDA J R,et al.Angiotensin II prevents calcification in vascular smooth muscle cells by enhancing magnesium influx[J].Eur J Clin Invest,2015,45(11):1129-1144.
[22]ISAKOVA T,WAHL P,VARGAS G S,et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease[J].Kidney Int,2011,79(12):1370-1378.
[23]SINEE D.Phosphate and cardiovascular disease beyond chronic kidney disease and vascular calcification[J].Int JNephrol,2018(2018):1-7.
[24]ADENEY K L,SISCOVICK D S,IX J H,et al.Association of serum phosphate with vascular and valvular calcification in moderate CKD[J].J Am Soc Nephrol,2009,20(2):381-387.
[25]COSCAS R,BENSUSSAN M,JACOB M P,et al.Free DNAprecipitates calcium phosphate apatite crystals in the arterial wall,in vivo[J].Atherosclerosis,2017(259):60-67.
[26]EWENCE A E,BOOTMAN M,RODERICK H L,et al.Calcium phosphate crystals induce cell death in human vascular smooth muscle cells:a potential mechanism in atherosclerotic plaque destabilization[J].Circ Res,2008,103(5):e28-e34.
[27]HéNAUT L,SANCHEZ-NINO M D,ALDAMIZ-ECHEVARRíACASTILLO G,et al.Targeting local vascular and systemic consequences of inflammation on vascular and cardiac valve calcification[J].Expert Opin Ther Targets,2016,20(1):89-105.
[28]WEN C,YANG X,YAN Z,et al.Nalp3 inflammasome is activated and required for vascular smooth muscle cell calcification[J].Int J Cardiol,2013,168(3):2242-2247.
[29]STENVINKEL P,KETTELER M,JOHNSON R J,et al.IL-10,IL-6,and TNF-alpha:central factors in the altered cytokine network of uremia-the good,the bad,and the ugly[J].Kidney Int,2005,67(4):1216-1233.
[30]SMITH E R,FORD M L,TOMLINSON L A,et al.Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD[J].Nephrol Dial Transplant,2012,27(5):1957-1966.
[31]THAMRATNOPKOON S,SUSANTITAPHONG P,TUMKOSIT M,et al.Correlations of plasma desphosphorylated uncarboxylated matrix Gla protein with vascular calcification and vascular stiffness in chronic kidney disease[J].Nephron,2017,135(3):167-172.
[32]RUSSO D,MIRANDA I,RUOCCO C,et al.,The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer[J].Kidney Int,2007,72(10):1255-1261
[33]KOLEGANOVA N,PIECHA G,RITZ E,et al.Acalcimimetic(R-568),but not calcitriol,prevents vascular remodeling in uremia[J].Kidney Int,2009,75(1):60-71.
[34]RAGGI P,CHERTOW G M,TORRES P U,et al.The ADVANCE study:a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis[J].Nephrol Dial Transplant,2011,26(4):1327-1339.
[35]WESTENFELD R,KRUEGER T,SCHLIEPER G,et al.Effect of vitamin K2 supplementation on functional vitamin Kdeficiency in hemodialysis patients:a randomized trial[J].Am J Kidney Dis,2012,59(2):186-195.