卡格列净对早期糖尿病肾病尿白蛋白/肌酐比值和尿足细胞相关蛋白裂隙素的影响

doi:10.16138/j.1673-6087.2021.06.004

摘要/Abstract

摘要：

目的：探讨卡格列净（钠-葡萄糖耦联转运体2抑制药）对早期糖尿病肾病尿白蛋白/肌酐比值（urinary albumin-to-creatinine ratio,UACR）和尿液足细胞相关蛋白裂隙素的影响。方法：选取2018 年1月至 2019年7月期间在南方科技大学医院内分泌科住院的116例早期糖尿病肾病患者,随机数字表法1∶1分为卡格列净组和对照组,各58例。最终105例（90.5%）患者完成全部研究,卡格列净组51例,对照组54例。卡格列净组常规予以卡格列净100~300 mg/d,对照组接受基础胰岛素加氯沙坦钾片100 mg/d,均治疗24周。分别在治疗前、治疗12周及24周对患者生化指标进行检测,在此期间检测UACR、尿液足细胞相关蛋白裂隙素进行组间及组内自身对照比较。结果：卡格列净组和对照组在12周及24周后UACR及裂隙素2组指标较治疗前均有改善（P<0.05）。治疗前与治疗12周后,UACR及裂隙素2组指标差异无统计学意义（P>0.05）;治疗24周,卡格列净组的UACR及裂隙素显著优于对照组（P<0.05）。结论：卡格列净可以持续降低早期糖尿病肾病患者尿液中足细胞相关蛋白裂隙素含量,推测钠-葡萄糖耦联转运体2抑制药肾脏保护作用独立于降糖之外。

关键词: 卡格列净, 钠-葡萄糖耦联转运体2抑制剂, 糖尿病肾病, 尿白蛋白/肌酐比值, 足细胞相关蛋白

Abstract:

Objective To investigate the effect of canagliflozin (sodium-glucose cotransporter 2 inhibitor, SGLT-2i) on the ratio of urine albumin-to-creatinine ratio(UACR) and urine podocyte-related protein nephrin in early diabetic nephropathy. Methods From January 2018 to July 2019, 116 patients with early diabetic nephropathy who were hospitalized in the Department of Endocrinology, Southern University of Science and Technology Hospital were enrolled. They were divided into canagliflozin group and control group with 1∶1 random number method. One hundred and five(90.5%) patients completed all studies, 51 were in the canagliflozin group and 54 were in the control group. The canagliflozin group was routinely given canagliflozin 100-300 mg/d, the control group received basal insulin and losartan potassium tablets 100 mg/d, and the patients in both groups were treated 24 weeks. The biochemical indicators of the patients were tested before treatment, 12-weeks and 24-weeks treatment. The UACR and the urine podocyte-associated protein nephrin before and after treatment were compared between groups and within groups. Results Compared with before treatment, both UACR and nephrin in the canagliflozin and the control groups improved after 12 weeks and 24 weeks treatment (P<0.05). Before treatment and after 12-weeks treatment, the UACR and nephrin indexes in canagliflozin and control groups didn’t show significant difference (P>0.05); while after 24-weeks treatment, these indexes in the canagliflozin group were significantly better than the control group(P<0.05). Conclusions Canagliflozin can continuously reduce the content of podocyte-associated protein nephrin in urine of early diabetic nephropathy. It is speculated that the renal protection of SGLT-2i drugs is independent of the effect of lowering the blood sugar.

Key words: Canagliflozin, Sodium-glucose cotransporter 2 inhibitor, Diabetic kidney disease, Urinary albumin-to-creatinine ratio, Podocyte associated protein

中图分类号:

R587.1

孙艳, 代丹娇, 陈智伟, 张华清. 卡格列净对早期糖尿病肾病尿白蛋白/肌酐比值和尿足细胞相关蛋白裂隙素的影响[J]. 内科理论与实践, 2021, 16(06): 387-391.

SUN Yan, DAI Danjiao, CHEN Zhiwei, ZHANG Huaqing. Effect of canagliflozin on urinary albumin / creatinine ratio and urinary podocyte-associated protein nephrin in patients with early diabetic kidney disease[J]. Journal of Internal Medicine Concepts & Practice, 2021, 16(06): 387-391.

图/表 3

表1

表2

表3

参考文献 19

[1]	Audzeyenka I, Rogacka D, Piwkowska A, et al. Viability of primary cultured podocytes is associated with extracellular high glucose-dependent autophagy downregulation[J]. Mol Cell Biochem, 2017, 430(1-2): 11-19. doi: 10.1007/s11010-017-2949-5 pmid: 28236091
[2]	中华医学会内分泌学分会. 中国成人糖尿病肾脏病临床诊断的专家共识[J]. 中国内分泌代谢杂志, 2015, 31(5): 379-385.
[3]	Kumar Pasupulati A, Chitra PS, Reddy GB. Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy[J]. Biomol Concepts, 2016, 7(5-6): 293-309. doi: 10.1515/bmc-2016-0021 pmid: 27816946
[4]	Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy[J]. N Engl J Med, 2019, 380(24): 2295-2306. doi: 10.1056/NEJMoa1811744 URL
[5]	Li W, Du M, Wang Q, et al. FoxO1 promotes mitophagy in the podocytes of diabetic male mice via the PINK1/Parkin pathway[J]. Endocrinology, 2017, 158(7): 2155-2167. doi: 10.1210/en.2016-1970 URL
[6]	Lioudaki E, Stylianou KG, Petrakis I, et al. Increased urinary excretion of podocyte markers in normoalbuminuric patients with diabetes[J]. Nephron, 2015, 131(1): 34-42. doi: 10.1159/000438493 URL
[7]	中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2017年版)[J]. 中华糖尿病杂志, 2018, 10(4): 4-67.
[8]	Koye DN, Magliano DJ, Reid CM, et al. Risk of progression of nonalbuminuric CKD to end-stage kidney disease in people with diabetes[J]. Am J Kidney Dis, 2018, 72(5): 653-661. doi: 10.1053/j.ajkd.2018.02.364 URL
[9]	Cho NH, Shaw JE, Karuranga S, et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045[J]. Diabetes Res Clin Pract, 2018, 138: 271-281. doi: 10.1016/j.diabres.2018.02.023 URL
[10]	Ito Y, Hsu MF, Bettaieb A, et al. Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury[J]. Metabolism, 2017, 76: 56-69. doi: 10.1016/j.metabol.2017.07.009 URL
[11]	Jiang XS, Chen XM, Wan JM, et al. Autophagy protects against palmitic acid-induced apoptosis in podocytes in vitro[J]. Sci Rep, 2017, 7: 42-64. doi: 10.1038/s41598-017-00093-z URL
[12]	Garofalo C, Borrelli S, Liberti ME, et al. SGLT2 inhibitors: nephroprotective efficacy and side effects[J]. Medicina (Kaunas), 2019, 55(6): E268.
[13]	Lee YL, Chen BK, Lin KD, et al. The impact of severe hypoglycemia on renal impairment in type 2 diabetes[J]. Diabetes Res Clin Pract, 2015, 108(3): 448-455. doi: 10.1016/j.diabres.2015.02.028 URL
[14]	Sakai S, Kaku K, Seino Y, et al. Efficacy and safety of the SGLT2 inhibitor luseogliflozin in Japanese patients with type 2 diabetes mellitus stratified according to baseline body mass index[J]. Clin Ther, 2016, 38(4): 843-862. doi: 10.1016/j.clinthera.2016.01.017 URL
[15]	李宁, 高政南, 李欣宇, 等. 卡格列净联合胰岛素治疗肥胖或超重2型糖尿病患者的临床观察[J]. 中国慢性病预防与控制, 2019, 191(9): 66-68.
[16]	Inagaki N, Harashima S, Maruyama N, et al. Efficacy and safety of canagliflozin in combination with insulin: a double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus[J]. Cardiovasc Diabetol, 2016, 15: 89. doi: 10.1186/s12933-016-0407-4 pmid: 27316668
[17]	Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease[J]. Diabetes Obes Metab, 2013, 15(5): 463-473. doi: 10.1111/dom.12090 pmid: 23464594
[18]	Zuo H, Wang S, Feng J, et al. BRD4 contributes to high-glucose-induced podocyte injury by modulating Keap1/Nrf2/ARE signaling[J]. Biochimie, 2019, 165: 100-107. doi: 10.1016/j.biochi.2019.07.012 URL
[19]	王荣珍, 姚灿, 刘沨. nephrin表达与糖尿病肾病预后相关性研究[J]. 临床荟萃, 2019, 34(5): 431-435.

项目	对照组（n=54）	卡格列净组（n=51）	t/χ²	P
年龄（岁）	44.61±7.89	46.54±6.18	0.653	0.69
男性 [n（%）]	30（55.5）	29（56.8）	0.385	0.87
病程（月）	13.24±2.67	12.52±2.54	0.410	0.81
其他药物使用 [n（%）]
调脂药	26（48.2）	25（49.1）	0.721	0.61
降压药	20（37.0）	18（35.2）	0.952	0.58
BMI（kg/m²）	24.44±3.06	23.58±3.77	0.994	0.55
WHR（m）	0.91±0.06	0.89±0.08	0.520	0.76
SBP（mmHg）	137.08±20.66	135.89±18.94	0.531	0.78
DBP（mmHg）	77.23±9.14	75.34±8.91	0.895	0.56
FPG（mmol/L）	9.02±0.89	8.94±0.77	0.356	0.84
PPG（mmol/L）	13.81±3.31	12.71±2.98	0.221	0.92
HbA_1c（%）	7.72±1.78	7.30±1.82	0.512	0.79
TG(mmol/L）	3.08±0.29	2.87±0.31	1.058	0.40
TC（mmol/L）	5.98±1.85	6.00±1.79	0.021	0.96
LDL-C（mmol/L）	3.14±0.17	3.05±0.16	0.934	0.58
UA（mmol/L）	311.09±31.82	305.16±38.43	1.128	0.34

项目	对照组（n=54）	卡格列净组（n=51）	t	P
FPG（mmol/L）
治疗12周	7.11±0.95	6.62±0.67	-0.129	0.178
治疗24周	6.58±0.43	6.43±0.56	-1.090	0.059
PPG（mmHg）
治疗12周	8.77±1.99	8.98±2.12	0.086	0.897
治疗24周	8.18±1.87	8.07±1.98	-1.828	0.071
HbA_1c（%）
治疗12周	6.12±0.67	6.17±0.78	1.281	0.302
治疗24周	5.97±0.73	6.02±0.64	-0.118	0.928
LDL-C（mmol/L）
治疗12周	2.69±0.95	2.76±0.91	-0.172	0.864
治疗24周	2.22±0.43	2.31±0.66	-1.080	0.057
SBP（mmHg）
治疗12周	127.5±44.0	130.4±42.8	0.289	0.776
治疗24周	123.2±30.6	127.1±28.7	-1.273	0.054
UA（mmol/L）
治疗12周	300.3±88.7	296.6±85.1	-1.828	0.071
治疗24周	278.3±73.5	224.5±64.4	-2.107	0.038
WHR（m）
治疗12周	0.87±0.07	0.85±0.06	0.009	0.496
治疗24周	0.86±0.08	0.82±0.05	5.181	0.000
BMI(kg/m²)
治疗12周	23.44±3.10	22.45±3.12	0.016	0.494
治疗24周	22.89±3.02	21.01±3.05	4.057	0.000

项目	对照组（n=54）	卡格列净组（n=51）	t	P
治疗前
UACR(mg/g)	45.9±9.5	46.8±8.2	0.069	0.793
裂隙素(μg/L)	5.85±1.3	6.12±1.2	1.026	0.41
治疗12周
UACR(mg/g)	42.7±9.2^1）	41.5±9.1^1）	0.521	0.687
裂隙素(μg/L)	5.1±0.79^1）	5.0±0.98^1）	0.687	0.572
治疗24周
UACR(mg/g)	39.5±4.33^1）	34±4.58^1）2）3）	4.029	<0.05
裂隙素(μg/L)	4.55±0.23^1）	3.05±0.17^{1）2）3）4）}	6.328	<0.001