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目的:分析2型糖尿病肾病(DN)患者肾小球足细胞损伤特点、影响因素及其与肾功能远期预后的关系。方法:回顾性分析经肾活检明确诊断并随访3年以上的24例2型DN患者的临床、病理资料。采用间接免疫荧光双标方法对肾活检组织分别进行足细胞标志物GLEPP1和Ⅳ型胶原α3链的双重染色,激光共聚焦显微镜采集图像,计算足细胞密度,并与临床、病理指标进行相关分析。详细记载随访过程中患者的实验室指标,根据Cockroft-Gault公式计算肌酐清除率(Ccr),对其进行线性回归分析,并据此分为肾功能稳定组(随访中Ccr保持稳定)和肾功能恶化组(随访中Ccr进行性减低)。结果:(1)DN患者足细胞密度较正常对照明显减少[(7.5±3.8%)vs(21.3±1.64%),P<0.01]。(2)肾活检时临床及病理资料相关分析显示,足细胞密度的减少与BMI、总胆固醇水平的增加有相关关系(r=-0.486,P<0.05;r=-0.438,P<0.05),长期血糖控制不佳者(糖化血红蛋白>7%)足细胞密度减少的更为明显(P<0.05)。(3)足细胞密度与蛋白尿水平呈显著负相关,进一步多重回归分析显示,足细胞密度是蛋白尿增加的独立危险因素。此外,足细胞密度的减低还与肾小管功能损伤指标、肾小球硬化比例、间质纤维化的程度呈负相关(P<0.05)。(4)肾功能稳定组和肾功能恶化组比较分析显示,尽管长期随访中两组间血压、血糖、血脂水平均无明显差别(P>0.05),但入组时两组间蛋白尿[(0.74±0.43)vs(3.51±1.17)g/24h,P<0.01]和足细胞密度[(9.8±3.0)vs(6.5±3.8)%,P<0.05]具有统计学差异。(5)长期随访,DN患者Ccr的斜率与足细胞密度有相关关系(r=0.424,P<0.05)。此外,糖尿病病程、蛋白尿、尿中大分子物质C3、α2-M均与Ccr的斜率相关(P<0.05)。结论:糖尿病状态下,血流动力学异常,糖、脂代谢紊乱是足细胞损伤的重要相关因素。足细胞密度的减低与蛋白尿、小管功能损伤、肾组织慢性化病变等提示肾脏预后不良的因素相关。长期随访观察,足细胞损伤程度与DN肾功能预后密切相关;足细胞密度测定有助于DN患者病情轻重和预后的判断。
Objective: To analyze the characteristics of glomerular podocyte injury in type 2 diabetic nephropathy (DN), its influencing factors and its relationship with long-term prognosis of renal function. Methods: The clinical and pathological data of 24 type 2 DN patients diagnosed by renal biopsy and followed up for more than 3 years were retrospectively analyzed. Indirect immunofluorescence double labeling method was used to double staining renal parenchyma cells with GLEPP1 and α3 chain of type Ⅳ collagen. Laser confocal microscopy was used to collect the images of podocytes. The correlation between clinical and pathological parameters was analyzed. Detailed records of patients during the follow-up of laboratory indicators, calculated according to Cockroft-Gault formula creatinine clearance (Ccr), and its linear regression analysis, and accordingly divided into stable renal function group (follow-up Ccr remained stable) and renal function Worsening group (Ccr progressively decreased at follow-up). Results: (1) The density of podocytes in DN patients was significantly lower than that in controls ([7.5 ± 3.8%] vs (21.3 ± 1.64%), P <0.01]. (2) The correlation analysis of clinical and pathological data on renal biopsy showed that the decrease of podocyte density correlated with the increase of BMI and total cholesterol (r = -0.486, P <0.05; r = -0.438, P < Patients with poor long-term glycemic control (HbA1c> 7%) had more podocyte densities (P <0.05). (3) There was a significant negative correlation between podocyte density and proteinuria. Further multiple regression analysis showed that podocyte density was an independent risk factor for increased proteinuria. In addition, the reduction of podocyte density was also negatively correlated with the indicators of renal tubular injury, the proportion of glomerulosclerosis, and the degree of interstitial fibrosis (P <0.05). (4) Compared with the stable renal function group and the deteriorated renal function group, although the blood pressure, blood glucose, blood lipid level had no significant difference between the two groups in long-term follow-up (P> 0.05), the albuminuria [ 0.74 ± 0.43 vs 3.51 ± 1.17 g / 24h, P <0.01] and podocyte density [(9.8 ± 3.0) vs (6.5 ± 3.8)%, P <0.05]. (5) Long-term follow-up, there was a correlation between the slope of Ccr in DN patients and podocyte density (r = 0.424, P <0.05). In addition, diabetes duration, proteinuria, urinary macromolecules C3, α2-M were associated with the slope of Ccr (P <0.05). Conclusion: Under the condition of diabetes, abnormal hemodynamics, disorders of glucose and lipid metabolism are important related factors of podocyte injury. Decreased podocyte density is associated with factors such as proteinuria, tubular dysfunction, and chronic renal lesions suggesting poor prognosis in the kidney. Long-term follow-up observation, the degree of podocyte injury is closely related to the prognosis of DN; podocyte densitometry is helpful for judging severity and prognosis of patients with DN.