肥胖相关性肾病患者的足细胞损伤

Podocyte lesions in patients with obesity-related glomerulopathy

目的:探讨肥胖相关性肾病(ORG)患者,肾小球足细胞损伤的特点及其可能的影响因素。方法:借助足细胞特定标志物WT1荧光染色准确计数肾小球内足细胞的数目,通过Weibel-Gomez方法计算肾小球内足细胞的绝对数目和相对密度。采用病例对照研究的方法,观察足细胞绝对数目正常的ORG患者26例及足细胞数目减少的ORG患者20例。检测、记录两组患者的体重指数、血脂、血糖、胰岛素抵抗等相关指标。结果:ORG患者的肾小球体积明显增大,足细胞相对密度显著降低。与对照组相比,足细胞数目处于正常范围的ORG患者,肾小球体积明显增大[(4·69±0·99)vs(2·94±1·00)×106μm3,P<0·001],足细胞相对密度显著下降[(125±23)vs(203±39)/106μm3,P<0·001];同时,内生肌酐清除率显著增加[(134·66±24·57)vs(103·29±15·13)ml/min·1·73m2,P<0·05],左肾长径明显增大[(114·77±7·47)vs(102·8±7·14)mm,P<0·01];而与足细胞数目减少的ORG患者相比,局灶节段性肾小球硬化(FSGS)比例相对较低(57·7%vs75·0%,P=0·182),尿蛋白、血清肌酐水平也较低。此外,足细胞绝对数目明显减少的ORG患者,高血压的比例(P=0·026),空腹血糖(P=0·007)及胰岛素抵抗程度(P=0·044)均明显增加,体重指数、脂质代谢等指标间并无明显差异。多元逐步回归分析显示,空腹血糖升高是足细胞绝对数目减少的独立危险因素。在足细胞绝对数目的减少的ORG患者中,足细胞绝对数目的进一步减少与平均动脉压(r=-0·639,P=0·002)及胆固醇水平(r=-0·544,P=0·013)相关。结论:ORG患者存在足细胞损伤,并表现出足细胞相对密度下降和绝对数目减少两种类型。肾小球体积增加导致足细胞相对密度下降,细胞间机械牵张力增加,是ORG患者足细胞损伤的因素之一。这种改变经积极治疗有一定的可逆性。糖、脂代谢异常进一步加重足细胞损伤,导致足细胞绝对数目减少,ORG患者出现足细胞绝对数目减少者,其肾脏损伤明显,更趋向形成FSGS,提示损伤向不可逆方向发展。

Objective： Podocyte lesions lead to proteinuria and development of glomerulosclerosis in many renal diseases. However, podocyte lesions in patients with obesity-related glomerulopathy （ORG） and the underlying mechanisms remain unclear. In this study, we explored the relevance of podocyte lesions with renal damage and metabolic disturbance. Methodology： The absolute number of podocytes per glomerulus （Epi N/glom）, the numerical density of podocytes per glomerulus [Nv（epi/glom）], and the mean glomerular volume were evaluated in 46 patients with ORG using the method of Weibel and Gomez （N = Nv × V, Nv = K/β√N3A/Vv）. Renal tissue from the donors of kidney transplantation served as controls （n = 10）. The patients were further divided into two groups, according to with （Epi N/glom = 337±77） or without （Epi N/glom = 572±108） the decrease in the number of podocytes. Results： The glomerular volume increased and podoeyte numerical density decreased （P〈0.001） in all of these patients. The glomerular volume [（4.69±0.99） vs （2.94±1.00）×10^6μm^3, P〈0.001 ] was significantly higher, while the podocyte density [（125±23 ） vs （203±39）×10^61μm^3, P〈0.001 ] was lower than that in controls. The endogenous creatinine clearance rate （Ccr） level [（134.66±24.57 ） vs （103.29±15.13 ） ml/（min·1.73m^2 ）, P〈0.05] was markedly higher in patients without decrease of podocyte absolute number as compared to controls. However, proteinuria, the level of serum creatinine and the present of focal and segmental glomerularsclarosis （FSGS） （57.7% vs 75.0%, P=0.182） were relatively lower in ORG patients without podocyte reduction compared to those with reduction. In addition, a strong correlation was found between the absolute decrease in the number of pudocyte and the present of hypertertsion （P = 0.026）, the impaired glucose tolerance （P = 0.007 ）, and the insulin resistance （P = 0.044） in patients with ORG. The mean artery pressure （r = -0.639, P = 0.002） and the level of cholesterul （r = -0.544, P = 0.013 ） were inversely related to Epi N/glom only in the ORG patients with reduction of podocytes. Conclusion： A relative decrease of the density and an absolute decrease in the number of podocytes was observed in ORG patients, and varied at different stage of the disease. The descent in podocyte density was related to glomerular enlargement and capillary expanse, which might be reversible. However, the decrease of podocyte number was related to metabolism disorders and tended to FSGS, which suggested an irreversible lesion.