【作者】 王伟；

【导师】 唐宽晓；

【作者基本信息】 山东大学 ， 全科医学（专业学位）， 2025， 硕士

【摘要】 研究背景2型糖尿病(type2diabetesmellitus,T2DM)患者约20%-40%有可能进展为糖尿病肾病(diabetickidney disease,DKD),成为终末期肾病的主要病因之一。传统血糖指标(如HbA1c)和肾功能评估指标(血清肌酐水平、估计的肾小球滤过率等)难以敏感反映血糖波动性、肾脏早期损伤以及动态变化。近几年研究表明,血糖波动(glucose variability,GV)通过氧化应激、慢性炎症等机制加剧微血管损伤,其参数如血糖标准差(standarddeviation ofblood glucose,SDBG)、变异系数(variablecoefficient,CV)、平均血糖波动幅度(mean amplitude of glycemic excursions,MAGE)、最大血糖波动幅度(largestamplitudeofglycemicexcursions,LAGE)、葡萄糖目标范围内时间百分比(time in range,TIR)与糖尿病并发症风险密切相关。然而,GV引发肾功能受损的机制尚不明确。99m锝-二乙三胺五乙酸肾动态显像(dynamic renal scintigraphy with 99mTc-diethylenetriamine-pentaacetic acid,99mTc-DTPA)可无创评估分肾肾小球滤过率(glomerular filtration rate,GFR),早期发现肾功能异常。99mTc-DTPA检测的标准化GFR(normalized glomerular filtration rate,nGFR)是公认的评估肾功能的金指标。目前缺乏GV参数与肾动态显像功能指标的相关研究,对DKD不同阶段的血糖特点研究较少。本研究旨在探讨GV与肾动态显像相关参数的相关性,为优化血糖管理策略、延缓DKD进展提供新依据。研究目的:1.分析DKD不同分期患者血糖波动的特征;2.探讨血糖波动参数与肾动态显像指标的相关性;3.探讨DKD患者血糖控制策略以减缓肾功能损伤发生与发展。研究方法:选取2023年12月至2024年12月于山东大学齐鲁医院就诊的DKD患者,按纳入及排除标准共纳入研究对象103例。病例分组:根据99mTc-DTPA肾动态显像检测的nGFR将研究对象分为三组:即nGFR正常组(nGFR≥90ml*min-1*1.73m-2)、nGFR 轻度受损组(nGFR:60-89ml*min-1*1.73m-2)、nGFR 中、重度受损组(nGFR<60ml*min-1*1.73m-2)。研究内容:1.收集临床资料:采集患者一般资料、病史、糖尿病并发症、生命体征和检验报告等数据。2.观察血糖变异性:采用指尖血糖监测评估患者血糖波动水平,评估GV相关指标选用 MBG、SDBG、CV、LAGE、TIR 等。3.动态评估肾功能:采用99mTc-DTPA肾动态显像技术检测的nGFR等。统计分析:采用方差分析、秩和检验等统计学方法分析DKD患者不同分期血糖波动特点。通过Spearman相关分析评估肾动态显像相关指标与血糖波动参数的相关性;采用Logistic回归分析DKD的危险因素和保护因素;选用ROC曲线确定TIR预测肾功能中、重度受损的截断值。研究结果:1.肾功能不同分期患者一般资料的比较:共纳入103例DKD患者,平均年龄62.7±11.8岁。nGFR正常组18例,nGFR轻度受损组38例,nGFR中、重度受损组47例。结果显示,三组间年龄存在显著性差异(F=6.449,P=0.002),nGFR中、重度受损组患者年龄相对较大。三组患者的性别、吸烟史、饮酒史、糖尿病病程、糖尿病并发症[糖尿病性视网膜病变(diabetic retinopathy,DR)、糖尿病性周围神经病(diabetic peripheral neuropathy,DPN)]、收缩压(systolic blood pressure,SBP)、舒张压(diastolic blood pressure,DBP)以及体重指数(body mass index,BMI)的差异均无统计学意义(P>0.05)。2.DKD不同分期患者检验指标的比较:nGFR正常组血清白蛋白(albumin,ALB)水平显著高于中、重度受损组(P=0.048)。随着nGFR受损程度的逐渐加重,血清尿素氮(blood urea nitrogen,BUN)、血清肌酐(serum creatinine,Scr)、血清胱抑素 C(cystatin C,CysC)、血清尿酸(uricacid,UA)水平及尿白蛋白肌酐比值(urinary albumin-creatinine ratio,UACR)逐渐升高(P<0.05),而外周血血红蛋白(hemoglobin,HGB)水平、估算的肾小球滤过率(estimatedglomerular filtration rate,eGFR)逐渐降低(P<0.05)。血清总胆固醇(total cholesterol,TC)、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-c)、低密度脂蛋白胆固醇(low-density lipoproteincholesterol,LDL-c)、甘油三酯(triglyceride,TG)、空腹血糖(fasting blood glucose,FBG)水平及HbA1c水平三组间无显著性差异(P>0.05)。3.DKD不同分期患者血糖变异性指标比较:平均血糖水平(meanblood glucose,MBG)三组间差异具有统计学意义(F=13.523,P<0.001),轻度和中、重度nGFR受损组的MBG值均高于nGFR正常组。TIR在三组间差异显著(Z=23.56,P<0.001),肾功能正常组的TIR显著高于轻度和中、重度肾功能受损组(P<0.05),中、重度受损组TIR最低。而SDBG、CV和LAGE在三组间无显著性差异(P>0.05)。4.nGFR与各研究指标之间的相关性分析:Spearman相关性分析:nGFR与多个指标存在显著性相关。nGFR与年龄(Age)、病程、BUN、Scr、CysC、UA、MBG 呈显著性负相关(P<0.05);与 TIR、ALB、eGFR、HGB 呈显著性正相关(P<0.05)。而 nGFR 与 SBP、DBP、BMI、TC、TG、HDL-c、LDL-c、HbA1c、糖化血浆白蛋白(glycated albumin,GA)等指标无显著性相关。线性相关分析:nGFR与TIR、ALB、eGFR、HGB呈显著性正相关(P<0.05),TIR每增加1%,nGFR平均升高0.51 ml*min-1*1.73m-2,而nGFR与Age、糖尿病病程、BUN、Scr、CysC、UA、MBG 呈显著性负相关(P<0.05)。5.糖尿病肾病多因素回归分析:单因素Logistic回归分析:Age(P=0.007)、糖尿病病程(P=0.029)、高血压分级(P=0.018)、UA(P=0.008),MBG(P=0.015)可能是nGFR中、重度受损的危险因素相关。TIR(P<0.001)升高可能与肾功能保护有关。BUN(P<0.001)、Scr(P<0.001)、CysC(P<0.001)随着nGFR受损加重而逐渐升高。HGB(P<0.001)随着nGFR受损加重而逐渐降低。性别、吸烟、饮酒、SBP、DBP、BMI、AST、ALT、TC、TG、HDL-c、LDL-c、FBG、LAGE、SDBG、CV、HbA1c 及 GA 与 nGFR 损伤无显著性相关(P>0.05)。多因素Logistic回归:Age(P=0.039)、UA(P=0.007)是肾功能中、重度受损的独立危险因素。TIR(P=0.013)是肾功能的独立保护因素,TIR每增加1%,肾功能中、重度受损的风险降低7%。MBG(P=0.358)及糖尿病病程(P=0.437)在多因素模型中未显示显著性意义。6.TIR预测肾损伤进展ROC曲线分析:TIR预测nGFR中、重度受损的ROC曲线下面积为0.746,95%置信区间为0.646-0.847,表明TIR对肾功能中、重度损伤有较高的预测能力。当TIR的截断值为64%时,最大约登指数为0.512,其预测肾功能中、重度损伤的特异性为0.851,敏感度为0.661(P<0.01)。7.高血压亚组分析:非 3 级高血压组(n=50):MBG(P=0.004)、SDBG(P=0.039)与 nGFR 呈显著性负相关。CV、LAGE、TIR与nGFR在非3级高血压中无显著性相关(P>0.05)。3级高血压组(n=53):MBG与nGFR显著性负相关(P=0.008)。TIR与nGFR呈正相关(P<0.0001)。CV、SDBG、LAGE与nGFR在3级高血压中无显著性相关(P>0.05)。研究结论:1.随着肾功能受损的加重,TIR逐渐降低,MBG逐步升高,提示TIR与nGFR可能互为因果关系。nGFR与TIR呈正相关,TIR每提高1%,DKD中重度进展风险降低0.072 倍。2.TIR是DKD的保护因素,TIR水平高于64%可能有助于延缓中、重度肾功能损伤进程。在合并3级高血压的DKD患者中,需同时重视血压水平及TIR的调控。3.首次提出DKD患者基于nGFR血糖分层管理目标值:(1)nGFR≥60ml*min-1*1.73m-2:建议 TIR≥70%;(2)nGFR 30-59ml*min-1*1.73m-2:建议 TIR 为 60%-70%;(3)透析患者:TIR≥50%。更多还原

【Abstract】 Research Background:Approximately 20%-40%of patients with type 2 diabetes mellitus may progress to diabetic kidney disease,a leading cause of end-stage renal disease.Traditional glycemic markers(HbA 1c)and renal function indicators(serum creatinine,estimated glomerular filtration rate)lack sensitivity in reflecting glucose variability and early renal injury.Recent studies suggest that GV exacerbates microvascular damage through oxidative stress and inflammation.GV parameters,including standard deviation of blood glucose(SDBG),coefficient of variation,mean amplitude of glycemic excursions,largest amplitude of glycemic excursions,and time in range,are closely associated with diabetic complications.However,the mechanisms linking GV to renal impairment remain unclear.99mTc-diethylenetriamine-pentaacetic acid renal dynamic scintigraphy noninvasively evaluates split renal glomerular filtration rate,enabling early detection of renal dysfunction.Normalized GFR(nGFR)measured by 99mTc-DTPA is the gold standard for renal function assessment.Currently,there is limited research on the correlation between GV parameters and renal dynamic imaging indices,as well as insufficient characterization of glycemic patterns across DKD stages.This study aims to explore the relationship between GV and renal scintigraphy parameters,providing new insights for optimizing glycemic management and delaying DKD progression.Research Objectives:1.Analyze glycemic variability characteristics in patients at different DKD stages.2.Investigate correlations between GV parameters and renal dynamic imaging indices.3.Propose glycemic control strategies to mitigate renal injury in DKD patients.Methods:A total of 103 subjects meeting the inclusion and exclusion criteria were enrolled from patients with DKD who received treatment at Qilu Hospital of Shandong University between December 2023 and December 2024.Case grouping:According to the nGFR measured by 99mTc-DTPA renal dynamic imaging,the patients were divided into three groups:the normal nGFR group(nGFR≥90ml*min-1*1.73m-2),the mildly impaired nGFR group(nGFR:60-89ml*min-1*1.73m-2),and the moderately to severely impaired nGFR group(nGFR<60ml*min-1*1.73m-2).Research Content:1.Clinical data collection:Demographic characteristics,medical history,history of diabetic complications,vital signs,and laboratory test results were systematically obtained from all enrolled patients.2.Assessment of glycemic variability:Capillary blood glucose monitoring was performed to evaluate glucose fluctuations.GV-related indices included MBG,SDBG,CV,LAGE,and TIR.3.Dynamic assessment of renal function:GFR and other parameters were measured via 99mTc-DTPA renal dynamic scintigraphy.Statistical Analysis:Statistical analysis was performed to evaluate glycemic variability characteristics across different stages of DKD using ANOVA for normally distributed data and nonparametric ranksum tests for non-normally distributed variables.Correlation assessment:Spearman’s rank correlation analysis was employed to evaluate the associations between renal dynamic imaging parameters.Multivariate logistic regression analysis was performed to identify both risk factors and protective factors associated with DKD.ROC curve analysis was utilized to determine the optimal cutoff value of TIR for predicting moderate-to-severe renal impairment.Results1.Comparison of General Information of Patients in Different Stages of Renal Function:A total of 103 patients with DKD were enrolled,with an average age of 62.7±11.8 years.There were 18 patients in the group with normal nGFR,38 patients in the group with mildly impaired nGFR,and 47 patients in the group with moderately and severely impaired nGFR.The results showed that there was a significant difference in age among the three groups(F=6.449,P=0.002),and the patients in the group with moderately and severely impaired nGFR were relatively older.There were no statistically significant differences in gender,smoking history,drinking history,duration of diabetes,diabetic complications(DR,DPN),SBP,DBP,and BMI among the three groups of patients(P>0.05).2.Comparison of laboratory indicators among patients with different stages of DKD:The level of ALB in the normal nGFR group was significantly higher than that in the moderate and severe impairment groups(P=0.048).As the degree of nGFR impairment gradually increased,the levels of BUN,Scr,CysC,UA in serum,and UACR gradually increased(P<0.05),while the level of HGB in peripheral blood and the eGFR gradually decreased(P<0.05).There were no significant differences in the levels of TC,HDL-c,LDL-c,TG,FBG,and HbA1c among the three groups(P>0.05).3.Comparison of Blood Glucose Variability Indexes among Patients with Different Stages of DKD:There were statistically significant differences in the MBG levels among the three groups(F=13.523,P<0.001).The MBG values in the groups with mild and moderate to severe nGFR impairment were both higher than those in the group with normal nGFR.There were significant differences in TIR among the three groups(Z=23.56,P<0.001).The TIR in the group with normal renal function was significantly higher than that in the groups with mild and moderate to severe renal function impairment(P<0.05),and the TIR in the group with moderate to severe impairment was the lowest.However,there were no significant differences in SDBG,CV,and LAGE among the three groups(P>0.05).4.Correlation analysis between nGFR and various research indicators:Spearman correlation analysis:nGFR was significantly correlated with multiple indicators.nGFR was significantly negatively correlated with Age,Disease duration,BUN,Scr,CysC,UA,and MBG(P<0.05);it was significantly positively correlated with TIR,ALB,eGFR,and HGB(P<0.05).However,nGFR had no significant correlation with indicators such as SBP,DBP,BMI,TC,TG,HDL-c,LDL-c,HbA1c,and GA.Linear correlation analysis:nGFR was significantly positively correlated with TIR,ALB,eGFR,and HGB(P<0.05).For every 1%increase in TIR,nGFR increased by an average of 0.51ml·min-1·1.73m-2.Meanwhile,nGFR was significantly negatively correlated with Age,Diabetes duration,BUN,Scr,CysC,UA,and MBG(P<0.05).5.Multivariate regression analysis of diabetic nephropathy:Univariate Logistic regression analysis showed that Age(P=0.007),Diabetes duration(P=0.029),HTN stage(P=0.018),UA(P=0.008),and MBG(P=0.015)might be risk factors associated with moderate to severe impairment of the nGFR.An increase in TIR(P<0.001)might be related to the protection of renal function.BUN(P<0.001),Scr(P<0.001),and CysC(P<0.001)gradually increased as the impairment of nGFR worsened.HGB(P<0.001)gradually decreased as the impairment of nGFR worsened.Gender,smoking,alcohol consumption,SBP,DBP,BMI,AST,ALT,TC,TG,HDL-c,LDL-c,FBG,LAGE,SDBG,CV,HbA1c,and GA had no significant correlation with nGFR impairment(P>0.05).6.Analysis of the ROC Curve for Predicting the Progression of Renal Injury by TIR:The area under the ROC curve of TIR for predicting moderate and severe impairment of nGFR is 0.746,with a 95%confidence interval of 0.646-0.847,indicating that TIR has a relatively high predictive ability for moderate and severe impairment of renal function.When the cutoff value of TIR is 64%,the maximum Youden index is 0.512.The specificity of predicting moderate and severe impairment of renal function is 0.851,and the sensitivity is 0.661(P<0.01).7.Subgroup analysis of hypertension:Group without grade 3 hypertension(n=50):MBG(P=0.004)and SDBG(P=0.039)showed a significant negative correlation with nGFR.There was no significant correlation between CV,LAGE,TIR and nGFR in the group without grade 3 hypertension(P>0.05).Group with grade 3 hypertension(n=53):MBG showed a significant negative correlation with nGFR(P=0.008).TIR was positively correlated with nGFR(P<0.0001).There was no significant correlation between CV,SDBG,LAGE and nGFR in the group with grade 3 hypertension(P>0.05).Conclusions:1.As the impairment of renal function worsens,the TIR gradually decreases,while the MBG gradually increases,suggesting a possible causal relationship between TIR and nGFR.There is a significant positive correlation between nGFR and TIR.For every 1%increase in TIR,the risk of moderate to severe progression of DKD is reduced by 0.072 times.2.TIR is a protective factor for DKD.A TIR level higher than 64%may help delay the progression of moderate and severe renal function impairment.In DKD patients with grade 3 hypertension,both the regulation of blood pressure levels and TIR should be emphasized simultaneously.3.For the first time,the target values of glycemic stratification management based on nGFR for DKD patients are proposed:(1)When nGFR≥60 ml·min-1·1.73m-2,TIR≥70%;(2)When nGFR is between 30 and 59 ml·min-1·1.73m-2,the target of TIR is 60-70%;(3)For dialysis patients,TIR≥50%.更多还原