羟苯磺酸钙改善糖尿病肾病的微炎症状态和内皮细胞功能
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摘要
目的探讨羟苯磺酸钙(calcium dobesilate,CaD)对糖尿病肾病(diabetic kidney disease, DKD)导致的肾脏内皮功能紊乱和炎症的保护作用,及其对DKD的疗效和安全性。方法采用病例对照研究,观察DKD组患者与糖尿病无蛋白尿患者以及健康人群间,内皮相关标志物和炎症相关标志物的区别。采用前瞻性平行对照研究,选取DKD组患者,随机分为用药组(口服CaD,每次500mg,每天3次)、观察组,治疗3个月。检测治疗前后血管内皮生长因子(vascular endothelial growth factor,VEGF)、内皮素-1(endothelin-1,ET-1)、内皮型一氧化氮合酶(endothelial nitric oxide synthase,e NOS)、一氧化氮(nitric oxide,NO)和单核细胞趋化蛋白-1(monocyte chemotactic protein 1,MCP-1)、细胞间细胞粘附分子-1(intercellular cell adhesion molecule-1,ICAM)、五聚素3(pentraxin3,PTX3)。观察各项指标变化。结果 DKD组患者PTX3、MCP-1、ICAM、VEGF、ET-1显著高于糖尿病无蛋白尿患者,与24h尿微量白蛋白呈正相关(r值分别为0.356,0.254,0.247,0.267,0.216;P值分别为0.001,0.003,0.004,0.002,0.012),NO低于糖尿病无蛋白尿患者(P<0.001),与24h尿微量白蛋白呈负相关(r=-0.229,P=0.027)。Logistic回归分析显示PTX3、NO、HbAlc是DKD的影响因素(OR值分别为2.761,0.941,3.304;95%CI分别为1.358～5.615,0.905～0.979,1.228～8.884;P值分别为0.017,0.003,0.019)。ROC曲线显示,糖尿病患者PTX3、NO、糖化血红蛋白(blood hematoglobin Alc,HbAlc)水平对DKD有预测作用。前瞻性研究中,DKD组患者服用CaD 3个月后,24h尿微量白蛋白、24h尿总蛋白显著下降(P值分别为0.010,0.014)。此外,用药后,患者微炎症指标PTX3、MCP-1、hsCRP、ICAM,以及内皮损伤标志物VEGF、NO、ET-1较前皆有显著改善(P值分别为0.008,0.009,0.040,0.013,0.003,0.001,0.004)。结论 CaD可能通过改善DKD组患者的微炎症状态和内皮功能来减少尿蛋白、保护肾脏。
Objective The aim of the present study was to elucidate the protective effects of calcium dobesilate(CaD) against diabetes-induced endothelial dysfunction and inflammation as well as the safety and efficacy of CaD in the treatment of diabetic kidney disease(DKD). Methods This was a prospective and casecontrol study to observe the differences in endothelial and inflammation related markers among DKD patients,diabetic patients without proteinuria and healthy individuals. DKD patients were then randomly divided into the treatment group(CaD 500 mg, 3 times daily) and the observation group. They were treated for 3 months.Endothelial function markers including vascular endothelial growth factor(VEGF), endothelin-1(ET-1), endothelial nitric oxide synthase(eNOS) and nitric oxide(NO) and inflammation markers including monocyte chemotactic protein 1(MCP-1), intercellular cell adhesion molecule-1(ICAM) and pentraxin 3(PTX3) were assayed. Results In the 100 DKD patients, PTX3, MCP-1, ICAM, VEGF and ET-1 were significantly higher than those in diabetic patients without proteinuria(P<0.001) and were positively correlated with the microamount of albuminuria(r=0.356, 0.254, 0.247, 0.267, 0.216 respectively; P=0.001, 0.003, 0.004, 0.002 and0.012 respectively). NO was significantly lower in DKD patients than in diabetic patients without proteinuria(P<0.001) and was negatively correlated with the micro-amount of albuminuria(r=-0.229, P=0.027). Logistic regression analysis showed that PTX3(OR=2.761, 95% CI: 1.358～5.615, P=0.017), NO(OR=0.941, 95%CI: 0.905～0.979, P=0.003) and HbAlc(OR=3.304, 95% CI: 1.228～8.884, P=0.019) were the influence factors for DKD. ROC curve showed that PTX3, NO and HbAlc levels were the predictive markers for the presence of DKD in diabetic patients. In the prospectively study of DKD patients treated with CaD for 3 months,their 24 hours urinary albumin and 24 hours urinary protein decreased significantly(P=0.010 and 0.014 respectively) but their cystatin C based GFR did not change. In DKD patients after CaD treatment, inflammation markers of PTX3, MCP-1, hsCRP and ICAM and endothelial markers of VEGF, NO and ET-1 ameliorated significantly as compared with those before CaD treatment(P=0.008, 0.009, 0.040, 0.013, 0.003, 0.001 and 0.004 respectively). Conclusion CaD can improve renal function in DKD patients through the improvement of their micro-inflammation status and endothelial function to reduce proteinuria.
Objective The aim of the present study was to elucidate the protective effects of calcium dobesilate(CaD) against diabetes-induced endothelial dysfunction and inflammation as well as the safety and efficacy of CaD in the treatment of diabetic kidney disease(DKD). Methods This was a prospective and casecontrol study to observe the differences in endothelial and inflammation related markers among DKD patients,diabetic patients without proteinuria and healthy individuals. DKD patients were then randomly divided into the treatment group(CaD 500 mg, 3 times daily) and the observation group. They were treated for 3 months.Endothelial function markers including vascular endothelial growth factor(VEGF), endothelin-1(ET-1), endothelial nitric oxide synthase(eNOS) and nitric oxide(NO) and inflammation markers including monocyte chemotactic protein 1(MCP-1), intercellular cell adhesion molecule-1(ICAM) and pentraxin 3(PTX3) were assayed. Results In the 100 DKD patients, PTX3, MCP-1, ICAM, VEGF and ET-1 were significantly higher than those in diabetic patients without proteinuria(P<0.001) and were positively correlated with the microamount of albuminuria(r=0.356, 0.254, 0.247, 0.267, 0.216 respectively; P=0.001, 0.003, 0.004, 0.002 and0.012 respectively). NO was significantly lower in DKD patients than in diabetic patients without proteinuria(P<0.001) and was negatively correlated with the micro-amount of albuminuria(r=-0.229, P=0.027). Logistic regression analysis showed that PTX3(OR=2.761, 95% CI: 1.358～5.615, P=0.017), NO(OR=0.941, 95%CI: 0.905～0.979, P=0.003) and HbAlc(OR=3.304, 95% CI: 1.228～8.884, P=0.019) were the influence factors for DKD. ROC curve showed that PTX3, NO and HbAlc levels were the predictive markers for the presence of DKD in diabetic patients. In the prospectively study of DKD patients treated with CaD for 3 months,their 24 hours urinary albumin and 24 hours urinary protein decreased significantly(P=0.010 and 0.014 respectively) but their cystatin C based GFR did not change. In DKD patients after CaD treatment, inflammation markers of PTX3, MCP-1, hsCRP and ICAM and endothelial markers of VEGF, NO and ET-1 ameliorated significantly as compared with those before CaD treatment(P=0.008, 0.009, 0.040, 0.013, 0.003, 0.001 and 0.004 respectively). Conclusion CaD can improve renal function in DKD patients through the improvement of their micro-inflammation status and endothelial function to reduce proteinuria.
引文
[1]Mohamed Q,Gillies MC,Wong TY.Management of diabetic retinopathy:a systematic review[J].JAMA,2007,298(8):902-916.
[2]Mathers CD,Loncar D.Projections of global mortality and burden of disease from 2002 to 2030[J].PLoS Med,2006,3(11):e442.
[3]Bragg F,Holmes MV,Iona A,et al.Association Between Diabetes and Cause-Specific Mortality in Rural and Urban Areas of China[J].JAMA,2017,317(3):280-289.
[4]Mathiesen ER,Hommel E,Hansen HP,et al.Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria[J].BMJ,1999,Jul 3,319(7201):24-25.
[5]Gurley SB,Coffman TM.The renin-angiotensin system and diabetic nephropathy[J].Semin Nephrol,2007,27(2):144-152.
[6]Stehouwer CD,Gall MA,Twisk JW,et al.Increased urinary albumin excretion,endothelial dysfunction,and chronic low grade inflammation in type 2 diabetes:Progressive,interrelated,and independently associated with risk of death[J].Diabetes,2002,51(4):1157-1165.
[7]Persson F,Rossing P,Hovind P,et al.Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria(IRMA 2)study[J].Scand J Clin Lab Invest,2008,68(8):731-738.
[8]Stine E Nielsen,Katrine J Schjoedt,Kasper Rossing,et al.Levels of NT-proBNP,markers of low-grade inflammation,and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease[J].J Renin Angiotensin Aldosterone Syst,2013,14(2):161-166.
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[10]Akbulut B.Calcium dobesilate and oxerutin:effectiveness of combination therapy.Phlebology[J],2010,25(2):66-71.
[11]Zhang XY,Liu W,Wu SS,et al.Calcium dobesilate for diabetic retinopathy:a systematic review and metaanalysis[J].Sci China Life Sci,2015,58(1):101-107.
[12]Szabo ME,Haines D,Garay E,et al.Antioxidant properties of calcium dobesilate in ischemic/reperfused diabetic rat retina[J].Eur J Pharmacol,2001,428(2):277-286.
[13]Rabe E,Jaeger KA,Bulitta M,et al.Calcium dobesilate in patients suffering from chronic venous insufficiency:A double-blind,placebo-controlled,clinical trial[J].Phlebology,2011,26(4):162-168.
[14]Hall JF.Modern management of hemorrhoidal disease[J].Gastroenterol Clin North Am,2013,42(4):759-772.
[15]Jafarey M,Changizi Ashtiyani S,Najafi H.Calcium dobesilate for prevention of gentamicin-induced nephrotoxicity in rats[J].Iran J Kidney Dis,2014,8(1):46-52.
[16]Zhang X.Therapeutic effects of calcium dobesilate on diabetic nephropathy mediated through reduction of expression of PAI-1[J].Exp Ther Med,2013,5(1):295-299.
[17]Inker LA,Schmid CH,Tighiouart H,et al.Estimating glomerular filtration rate from serum creatinine and cystatin c[J].N Engl J Med,2012,367(1):20-29.
[18]Gerstein HC,Mann JF,Yi Q,et al.Albuminuria and risk of cardiovascular events,death,and heart failure in diabetic and nondiabetic individuals[J].JAMA,2001,286(4):421-426.
[19]Nakagawa T,Kosugi T,Haneda M,et al.Abnormal angiogenesis in diabetic nephropathy[J].Diabetes,2009,58(7):1471-1478.
[20]Tremolada G,Del Turco C,Lattanzio R,et al.The role of angiogenesis in the development of proliferative diabetic retinopathy:impact of intravitreal anti-VEGFtreatment[J].Exp Diabetes Res,2012,2012:728325.
[21]Theodoros Eleftheriadis,Georgia Antoniadi,Georgios Pissas,et al.The Renal Endothelium in Diabetic Nephropathy[J].Ren Fail,2013,35(4):592-599.
[22]Nakagawa T,Sato W,Kosugi T,et al.Uncoupling of VEGFwith Endothelial NO as a Potential Mechanism for Abnormal Angiogenesis in the Diabetic Nephropathy[J].J Diabetes Res,2013,2013:184539.
[23]Li Q,Verma A,Han PY,et al.Diabetic eNOS-knockout mice develop accelerated retinopathy[J].Invest Ophthalmol Vis Sci,2010,51(10):5240-5246.
[24]Lacava V,PellicanòV,Ferrajolo C,et al.Novel avenues for treating diabetic nephropathy:new investigational drugs[J].Expert Opin Investig Drugs,2017,26(4):445-462.
[25]Turkmen K.Inflammation,oxidative stress,apoptosis,and autophagy in diabetes mellitus and diabetic kidney disease:the Four Horsemen of the Apocalypse[J].Int Urol Nephrol,2017,49(5):837-844.
[26]Bertinat R,Westermeier F,Silva P.Anti-Diabetic Agent Sodium Tungstate Induces the Secretion of Proand Anti-Inflammatory Cytokines by Human Kidney Cells[J].J Cell Physiol,2017,232(2):355-362.
[27]Sugimoto H,Shikata K,Hirata K,et al.Increased expression of intercellular adhesion molecule-1(ICAM-1)in diabetic rat glomeruli:Glomerular hyperfiltration is a potential mechanism of ICAM-1 upregulation[J].Diabetes,1997,46(12):2075-2081.
[28]Guo X,Hou L,Cheng X,et al.Strong Negative Interference by Calcium Dobesilate in Sarcosine Oxidase Assays for Serum Creatinine Involving the Trinder Reaction[J].Medicine,2015,94(23):e905.
[2]Mathers CD,Loncar D.Projections of global mortality and burden of disease from 2002 to 2030[J].PLoS Med,2006,3(11):e442.
[3]Bragg F,Holmes MV,Iona A,et al.Association Between Diabetes and Cause-Specific Mortality in Rural and Urban Areas of China[J].JAMA,2017,317(3):280-289.
[4]Mathiesen ER,Hommel E,Hansen HP,et al.Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria[J].BMJ,1999,Jul 3,319(7201):24-25.
[5]Gurley SB,Coffman TM.The renin-angiotensin system and diabetic nephropathy[J].Semin Nephrol,2007,27(2):144-152.
[6]Stehouwer CD,Gall MA,Twisk JW,et al.Increased urinary albumin excretion,endothelial dysfunction,and chronic low grade inflammation in type 2 diabetes:Progressive,interrelated,and independently associated with risk of death[J].Diabetes,2002,51(4):1157-1165.
[7]Persson F,Rossing P,Hovind P,et al.Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria(IRMA 2)study[J].Scand J Clin Lab Invest,2008,68(8):731-738.
[8]Stine E Nielsen,Katrine J Schjoedt,Kasper Rossing,et al.Levels of NT-proBNP,markers of low-grade inflammation,and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease[J].J Renin Angiotensin Aldosterone Syst,2013,14(2):161-166.
[9]Akbulut B.Calcium dobesilate and oxerutin:effectiveness of combination therapy[J].Phlebology,2010,25(2):66-71.
[10]Akbulut B.Calcium dobesilate and oxerutin:effectiveness of combination therapy.Phlebology[J],2010,25(2):66-71.
[11]Zhang XY,Liu W,Wu SS,et al.Calcium dobesilate for diabetic retinopathy:a systematic review and metaanalysis[J].Sci China Life Sci,2015,58(1):101-107.
[12]Szabo ME,Haines D,Garay E,et al.Antioxidant properties of calcium dobesilate in ischemic/reperfused diabetic rat retina[J].Eur J Pharmacol,2001,428(2):277-286.
[13]Rabe E,Jaeger KA,Bulitta M,et al.Calcium dobesilate in patients suffering from chronic venous insufficiency:A double-blind,placebo-controlled,clinical trial[J].Phlebology,2011,26(4):162-168.
[14]Hall JF.Modern management of hemorrhoidal disease[J].Gastroenterol Clin North Am,2013,42(4):759-772.
[15]Jafarey M,Changizi Ashtiyani S,Najafi H.Calcium dobesilate for prevention of gentamicin-induced nephrotoxicity in rats[J].Iran J Kidney Dis,2014,8(1):46-52.
[16]Zhang X.Therapeutic effects of calcium dobesilate on diabetic nephropathy mediated through reduction of expression of PAI-1[J].Exp Ther Med,2013,5(1):295-299.
[17]Inker LA,Schmid CH,Tighiouart H,et al.Estimating glomerular filtration rate from serum creatinine and cystatin c[J].N Engl J Med,2012,367(1):20-29.
[18]Gerstein HC,Mann JF,Yi Q,et al.Albuminuria and risk of cardiovascular events,death,and heart failure in diabetic and nondiabetic individuals[J].JAMA,2001,286(4):421-426.
[19]Nakagawa T,Kosugi T,Haneda M,et al.Abnormal angiogenesis in diabetic nephropathy[J].Diabetes,2009,58(7):1471-1478.
[20]Tremolada G,Del Turco C,Lattanzio R,et al.The role of angiogenesis in the development of proliferative diabetic retinopathy:impact of intravitreal anti-VEGFtreatment[J].Exp Diabetes Res,2012,2012:728325.
[21]Theodoros Eleftheriadis,Georgia Antoniadi,Georgios Pissas,et al.The Renal Endothelium in Diabetic Nephropathy[J].Ren Fail,2013,35(4):592-599.
[22]Nakagawa T,Sato W,Kosugi T,et al.Uncoupling of VEGFwith Endothelial NO as a Potential Mechanism for Abnormal Angiogenesis in the Diabetic Nephropathy[J].J Diabetes Res,2013,2013:184539.
[23]Li Q,Verma A,Han PY,et al.Diabetic eNOS-knockout mice develop accelerated retinopathy[J].Invest Ophthalmol Vis Sci,2010,51(10):5240-5246.
[24]Lacava V,PellicanòV,Ferrajolo C,et al.Novel avenues for treating diabetic nephropathy:new investigational drugs[J].Expert Opin Investig Drugs,2017,26(4):445-462.
[25]Turkmen K.Inflammation,oxidative stress,apoptosis,and autophagy in diabetes mellitus and diabetic kidney disease:the Four Horsemen of the Apocalypse[J].Int Urol Nephrol,2017,49(5):837-844.
[26]Bertinat R,Westermeier F,Silva P.Anti-Diabetic Agent Sodium Tungstate Induces the Secretion of Proand Anti-Inflammatory Cytokines by Human Kidney Cells[J].J Cell Physiol,2017,232(2):355-362.
[27]Sugimoto H,Shikata K,Hirata K,et al.Increased expression of intercellular adhesion molecule-1(ICAM-1)in diabetic rat glomeruli:Glomerular hyperfiltration is a potential mechanism of ICAM-1 upregulation[J].Diabetes,1997,46(12):2075-2081.
[28]Guo X,Hou L,Cheng X,et al.Strong Negative Interference by Calcium Dobesilate in Sarcosine Oxidase Assays for Serum Creatinine Involving the Trinder Reaction[J].Medicine,2015,94(23):e905.