Research progress of sodium-dependent glucose transporter 2 inhibitor in renal benefit
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摘要: 钠-葡萄糖共转运蛋白2抑制剂（SGLT-2i）是一类新型的口服降糖药，其通过抑制钠-葡萄糖共转运蛋白2（SGLT-2）而降低肾糖阈，促进尿葡萄糖排泄，进而起到降低血液循环中葡萄糖水平的作用。目前，约40%糖尿病患者合并慢性肾脏病（CKD），其中很大一部分会进展至终末期肾病（ESRD）。SGLT-2i不仅具有良好的降糖作用，还能减少心血管不良事件，延缓肾病进展，在非糖尿病的CKD患者中也能观察到肾脏获益。本研究总结了SGLT-2i在肾脏方面的临床试验结果，探讨其可能的作用机制及不良反应。Abstract: Sodium-dependent glucose transporter 2 inhibitor (SGLT-2i) is a new type of oral hypoglycemic agent, which can reduce the renal glucose threshold and promote urinary glucose excretion by inhibiting sodium-dependent glucose transporter 2 (SGLT-2), and finally achieve the effect of reducing the level of glucose in blood circulation. At present, about 40% of diabetic patients have chronic kidney disease (CKD), and a large part of them will progress to end-stage renal disease (ESRD). SGLT-2i not only have a good hypoglycemic effect, but also can reduce incidence of adverse cardiovascular events and delay the progression of kidney disease, and the renal benefits can be observed even in non-diabetic patients with CKD. This study summarized the clinical trial results of SGLT-2i in kidney, and explored its possible mechanism of action and adverse reactions.
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上尿路结石(UUC)是泌尿外科常见疾病, 主要是因机体摄入纤维素减少而精制糖、动物蛋白等摄入增多导致[1]。UUC患者早期通常表现为呕吐、恶心、血尿、尿急、尿频和腰腹部疼痛等症状，随着病情的恶化，可合并肾周围脓肿、肾积脓、肾盂肾炎，甚至引发尿毒症，威胁患者生命安全[2]。目前, UUC的治疗方法以手术为主，其可在安全、微创的前提下清除结石，但大部分UUC患者术前即存在感染迹象，不仅影响手术效果，还影响预后情况[3]。相关研究[4]发现，术后即刻引流对感染的预防与控制有一定作用，但其整体应用效果尚存争议。本研究深入分析UUC感染的病原学特征和药敏试验结果，并观察术后即刻引流的效果，旨在为预防及控制感染提供依据。
1. 资料与方法
1.1 一般资料
回顾性分析2018年7月—2021年7月保山市人民医院收治的100例UUC感染患者的临床资料。纳入标准: ①经体征评估，患侧肾区叩击痛阳性，耳温>37.3 ℃, 处于发热状态者; ②经实验室检查，白细胞计数>9.2×109/L或 < 4.0×109/L者; ③临床资料齐全者。排除标准: ①合并重度高血压、糖尿病者; ②无法耐受手术治疗者; ③存在严重心脏疾病者; ④对抗菌药过敏者; ⑤存在全身性出血疾病者。100例患者中，男69例、女31例，平均病程(3.26±1.15)个月，平均年龄(51.13±4.46)岁，结石直径(5.29±1.11) cm, 结石位置左侧63例、右侧37例，手术类型为输尿管双J管植入术59例、经皮肾穿刺微造瘘术41例。
1.2 治疗方法
100例患者均接受手术治疗，并接受电子计算机断层平扫检查。无肾积水或轻度肾积水患者采用患侧输尿管双J管植入术治疗，中度及以上肾积水患者采用经皮肾穿刺微造瘘术治疗。①输尿管双J管植入术: 嘱患者保持截石位，将丁卡因胶浆涂抹于患者尿道内部，并在膀胱镜(F18)或输尿管镜(F9.5)直视下进入膀胱，确定尿管开口后，直视下将斑马导丝置入，沿着导丝再放置1根双J管，退镜，留置导尿管。②穿刺微造瘘术: 嘱患者取仰卧截石位，局部麻醉后，常规消毒、铺巾，在影像引导下定位患侧肾脏中盏，行微穿刺，经皮肾穿刺(使用F14扩张通道)，留置引流管并外接。2种术式患者术后均接受即刻引流，引流前需检测血常规指标、降钙素原(PCT)、白细胞介素-6(IL-6)水平和体温。
1.3 观察指标
分析患者病原菌分布情况，并针对大肠埃希菌、粪肠球菌进行药敏试验分析。于患者发热时选取其血标本、尿标本进行菌种鉴定、细菌培养和药敏试验，根据试验结果合理应用抗菌药物。观察即刻引流的治疗效果，分别于治疗前(术后引流前即刻)和治疗后1、2、3 d抽取肘静脉血3 mL, 分离血清(离心10 min, 1 500转/min, 离心半径10 cm), 使用贝克曼库尔特LH755型号全自动分析仪，以酶联免疫吸附法检测检测白细胞、中性粒细胞百分比(NEU%)、C反应蛋白(CRP)、PCT和IL-6水平，并检测患者体温。
1.4 统计学处理
采用SPSS 22.0统计学软件分析数据，白细胞、NEU%、CRP、体温、PCT、IL-6等符合正态分布的计量资料以(x±s)表示，不同时点比较采用t检验，病原菌分布、药敏结果用例数或百分比表示, P＜0.05为差异有统计学意义。
2. 结果
2.1 病原菌分布情况
100例UUC感染患者中, 58.00%为革兰阴性菌感染, 31.00%为革兰阳性菌感染, 11.00%为真菌感染，病原菌分布情况见表 1。
表 1 100例上尿路结石感染患者病原菌分布情况感染类型 病原菌 n 占比/% 革兰阳性菌感染(n=31) 粪肠球菌 21 21.00 屎肠球菌 5 5.00 金黄色葡萄球菌 3 3.00 表皮葡萄球菌 2 2.00 革兰阴性菌感染(n=58) 大肠埃希菌 29 29.00 铜绿假单胞菌 14 14.00 肺炎克雷伯菌 8 8.00 产气肠杆菌 3 3.00 阴沟肠杆菌 2 2.00 不动杆菌属 2 2.00 真菌感染(n=11) 白色假丝酵母菌 6 6.00 热带念珠菌 5 5.00 2.2 大肠埃希菌药敏试验结果分析
药敏试验结果显示，大肠埃希菌对氨苄西林、头孢唑啉、头孢曲松和诺氟沙星耐药性较高，对头孢哌酮舒巴坦、阿米卡星和哌拉西林他唑巴坦敏感性较高，见表 2。
表 2 大肠埃希菌药敏试验结果(n=29)[n(%)]抗菌药物 耐药 中敏 敏感 头孢哌酮舒巴坦 1(3.45) 2(6.90) 26(89.66) 阿米卡星 2(6.90) 3(10.34) 24(82.76) 环丙沙星 20(68.97) 7(24.14) 2(6.90) 诺氟沙星 21(72.41) 6(20.69) 2(6.90) 哌拉西林他唑巴坦 5(17.24) 5(17.24) 19(65.52) 氨苄西林 25(86.21) 2(6.90) 2(6.90) 头孢呋辛 15(51.72) 10(34.48) 4(13.79) 头孢他啶 20(68.97) 6(20.69) 3(10.34) 头孢曲松 22(75.86) 4(13.79) 3(10.34) 头孢唑啉 25(86.21) 2(6.90) 2(6.90) 2.3 粪肠球菌药敏试验结果分析
药敏试验结果显示，粪肠球菌对庆大霉素、青霉素G和红霉素耐药性较高，对万古霉素、替考拉宁和氨苄西林敏感性较高，见表 3。
表 3 粪肠球菌药敏试验结果(n=21)[n(%)]抗菌药物 耐药 中敏 敏感 氧氟沙星 3(14.29) 4(19.05) 14(66.67) 加替沙星 3(14.29) 5(23.81) 13(61.90) 利奈唑胺 9(42.86) 5(23.81) 7(33.33) 替考拉宁 0 3(14.29) 18(85.71) 氨苄西林 2(9.52) 3(14.29) 16(76.19) 万古霉素 0 2(9.52) 19(90.48) 链霉素 4(19.05) 10(47.62) 7(33.33) 红霉素 14(66.67) 5(23.81) 2(9.52) 庆大霉素 19(90.48) 1(4.76) 1(4.76) 青霉素G 16(76.19) 4(19.05) 1(4.76) 2.4 治疗效果
100例患者均顺利完成手术，手术时间为(39.58±3.36) min, 术中出血量为(175.23±33.11) mL。对于术后发热患者，给予物理降温、消炎等对症治疗，并根据药敏结果合理选用抗菌药物。100例患者均未发生感染性休克、败血症和大出血等严重并发症。
2.5 血常规指标变化情况
治疗后1、2、3 d, 患者白细胞、NEU%、CRP水平均低于治疗前，差异有统计学意义(P＜0.05); 治疗后3 d, 患者白细胞、NEU%、CRP水平均低于治疗后1、2 d, 差异有统计学意义(P＜0.05)。见表 4。
表 4 100例患者治疗前后血常规指标水平变化(x±s)指标 治疗前 治疗后1 d 治疗后2 d 治疗后3 d CRP/(mg/L) 95.13±6.65 84.45±4.13* 42.23±3.33*# 20.69±2.22*#△ NEU%/% 91.03±4.45 81.12±3.23* 73.77±2.45*# 62.84±3.11*#△ 白细胞/(×109/L) 18.65±2.31 15.79±1.22* 10.13±1.58*# 5.13±1.19*#△ NEU%: 中性粒细胞百分比; CRP: C反应蛋白。
与治疗前比较, * P＜0.05; 与治疗后1 d比较, #P＜0.05; 与治疗后2 d比较, △P＜0.05。2.6 体温、PCT和IL-6水平变化情况
治疗后1、2、3 d, 患者体温、PCT和IL-6水平均低于治疗前，差异有统计学意义(P＜0.05); 治疗后3 d, 患者体温、PCT和IL-6水平均低于治疗后1、2 d, 差异有统计学意义(P＜0.05)。见表 5。
表 5 100例患者治疗前后体温、PCT和IL-6水平变化(x±s)指标 治疗前 治疗后1 d 治疗后2 d 治疗后3 d 体温/℃ 38.56±0.54 38.10±0.11* 37.76±0.42*# 37.02±0.11*#△ PCT/(ng/mL) 20.39±2.45 12.75±1.17* 5.59±1.02*# 0.09±0.01*#△ IL-6/(pg/mL) 16.33±1.74 12.16±1.89* 7.39±1.15*# 4.58±0.22*#△ PCT: 降钙素原; IL-6: 白细胞介素-6。
与治疗前比较, * P＜0.05; 与治疗后1 d比较, #P＜0.05; 与治疗后2 d比较, △P＜0.05。3. 讨论
感染性UUC是一种尿道病变，患者有腰痛、尿急和尿频等症状，手术治疗可缓解病症，但病原菌感染会影响手术效果与预后，临床应积极分析UUC感染的病原学特点，从而为疾病的诊断与后期治疗方案的制订提供依据[5-6]。本研究100例UUC感染患者中，最常见的病原菌是革兰阴性菌(占58.00%), 其次是革兰阳性菌(31.00%); 革兰阴性菌中，大肠埃希菌最常见; 革兰阳性菌中，粪肠球菌最常见。大肠埃希菌是目前院内感染最常见的一类致病菌，分布广泛，常存在于动物和人的肠道内，作为条件致病菌，其可诱发呼吸道感染和泌尿道感染，尤其好发于接受侵袭性操作、长期应用广谱抗生素、患严重疾病、长期住院的人群，临床医生需综合分析条件致病菌的多重耐药情况，有针对性地制订相应预防措施，降低院内细菌性肺炎的发生率[7-8]。大肠埃希菌可产生超广谱β-内酰胺酶，该成分对青霉素、第1~3代头孢菌素、单环酰胺类抗生素均具有较高耐受性，临床应根据药敏试验结果合理选用抗生素。本研究发现，大肠埃希菌对头孢哌酮舒巴坦、阿米卡星敏感性较高，对氨苄西林、头孢唑啉、头孢曲松和诺氟沙星耐药性较高，表明大肠埃希菌对头孢菌素类、喹诺酮类药物耐药性较高，故提议将头孢哌酮舒巴坦、阿米卡星作为治疗用药(根据患者经济条件、过敏情况和病情合理选用)[9-11]。本研究药敏试验结果还显示，粪肠球菌对万古霉素、替考拉宁、氨苄西林敏感性较高，对青霉素G、庆大霉素、红霉素耐药性较高。由此提示，不同病原菌的耐药情况不同，为了减少耐药菌株的产生，临床需慎重使用超广谱抗生素，严格根据药敏试验结果合理用药，避免单一抗生素长疗程治疗，还应密切关注耐药菌株的流行趋势，做好感染防控措施[12-13]。
UUC感染患者多伴有高热、寒战、腰痛表现，可出现全身炎症反应，严重时还可诱发化脓、败血症，危及生命，故需尽早诊治[14]。目前, UUC感染的治疗原则为恢复肾功能，解除梗阻，引流脓液。本研究结果显示，患者治疗后1、2、3 d的体温、PCT、IL-6、白细胞、NEU%、CRP水平均低于治疗前，且以治疗后3 d时状态最佳，与庄剑秋等[15]研究结果相似，说明即刻引流对感染具有良好的控制作用。推测原因，借助通道充分引流脓液，可避免化脓、败血症的发生，还可促进机体免疫状态的稳定，从而尽快控制感染，降低体温[16-17]。但相关研究[18]发现，长时间留置管道会为细菌繁殖提供有利机会，造成反复感染，因此在条件允许的情况下应尽可能缩短引流管留置时间(气候炎热时尤其需加强管道护理)，并时刻秉持无菌操作理念，从而降低术后感染率。本研究尚存在不足之处，例如样本量较少，且未对不同时点的引流效果进行对比评估，未来可开展更深入的研究进一步探讨。
综上所述, UUC感染患者的病原菌以大肠埃希菌为主，但其他菌属的感染率也较高，因此不可依据经验给药，而应严格按照药敏试验结果用药。术后即刻引流可更好地控制感染，预防败血症等严重并发症的发生，建议在临床推广应用。
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