Bangstad Hans-Jacob, Seljeflot Ingebjørg, Berg Tore J, Hanssen Kristian F
Department of Paediatrics, Ullevål University Hospital, Oslo, Norway.
Scand J Clin Lab Invest. 2009;69(1):138-44. doi: 10.1080/00365510802444080.
Diabetic nephropathy has been considered to be primarily of glomerular origin, but there is now compelling evidence that disruption of the tubulointerstitial architecture determines the outcome of diabetic nephropathy in interplay with the glomerular damage. We investigated whether reactive oxidative species, pro-inflammatory cytokines and endothelial dysfunction were implicated in the progression of tubulointerstitial damage in young subjects with type 1 diabetes.
In a prospective study, we investigated 18 young subjects (mean age 21 years) with type 1 diabetes and microalbuminuria. Quantitative morphometry concerning glomerular and tubulointerstitial changes was performed at baseline (i.e. mean duration of diabetes 10 years) and 2.5 and 8 years later. Markers of endothelial activation and inflammation, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumour necrosis factor-alpha, interleukin-6, interleukin-8 and highly sensitive C-reactive protein were measured at baseline and after 8 years. Tissue plasminogen activator antigen and plasminogen activator inhibitor (PAI-1 activity) and asymmetric dimethylargine (ADMA) were measured at baseline and after 2.5 years.
PAI-1 activity at baseline was a significant independent variable of the 8-year increment in interstitial volume fraction (Vv(Int/cortex)). ADMA/L-arginine ratio at baseline was associated with the increment in Vv(Int/cortex) during 2.5 years (p<0.01), still significant after adjustment for covariates (p = 0.02). No associations between Vv(Int/cortex) and glomerular parameters, HaemoglobinA1c and urinary albumin excretion were observed.
Biomarkers involved in interstitial volume expansion seem to be different from those of mesangial expansion in early diabetic nephropathy. PAI-1 activity may have a predictive role in the development of the tubulointerstitial expansion.
糖尿病肾病一直被认为主要起源于肾小球，但现在有确凿证据表明，肾小管间质结构的破坏在与肾小球损伤的相互作用中决定了糖尿病肾病的预后。我们研究了活性氧、促炎细胞因子和内皮功能障碍是否与1型糖尿病年轻患者肾小管间质损伤的进展有关。
在一项前瞻性研究中，我们调查了18名患有1型糖尿病和微量白蛋白尿的年轻患者（平均年龄21岁）。在基线时（即糖尿病平均病程10年）以及2.5年和8年后，对肾小球和肾小管间质变化进行了定量形态学分析。在基线时和8年后测量内皮激活和炎症标志物，细胞间黏附分子-1、血管细胞黏附分子-1、肿瘤坏死因子-α、白细胞介素-6、白细胞介素-8和高敏C反应蛋白。在基线时和2.5年后测量组织纤溶酶原激活物抗原和纤溶酶原激活物抑制剂（PAI-1活性）以及不对称二甲基精氨酸（ADMA）。
基线时的PAI-1活性是间质体积分数（Vv(Int/cortex)）8年增加的显著独立变量。基线时的ADMA/L-精氨酸比值与2.5年期间Vv(Int/cortex)的增加相关（p<0.01），在对协变量进行调整后仍具有显著性（p = 0.02）。未观察到Vv(Int/cortex)与肾小球参数、糖化血红蛋白和尿白蛋白排泄之间的关联。
早期糖尿病肾病中，参与间质体积扩大的生物标志物似乎与系膜扩大的生物标志物不同。PAI-1活性可能在肾小管间质扩张的发展中具有预测作用。
