Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN, USA.
Nephrol Dial Transplant. 2022 Sep 22;37(10):1844-1856. doi: 10.1093/ndt/gfac156.
Renal artery stenosis (RAS) is an important cause of chronic kidney disease and secondary hypertension. In animal models, renal ischemia leads to downregulation of growth factor expression and loss of intrarenal microcirculation. However, little is known about the sequelae of large-vessel occlusive disease on the microcirculation within human kidneys.
This study included five patients who underwent nephrectomy due to renovascular occlusion and seven nonstenotic discarded donor kidneys (four deceased donors). Micro-computed tomography was performed to assess microvascular spatial densities and tortuosity, an index of microvascular immaturity. Renal protein expression, gene expression and histology were studied in vitro using immunoblotting, polymerase chain reaction and staining.
RAS demonstrated a loss of medium-sized vessels (0.2-0.3 mm) compared with donor kidneys (P = 0.037) and increased microvascular tortuosity. RAS kidneys had greater protein expression of angiopoietin-1, hypoxia-inducible factor-1α and thrombospondin-1 but lower protein expression of vascular endothelial growth factor (VEGF) than donor kidneys. Renal fibrosis, loss of peritubular capillaries (PTCs) and pericyte detachment were greater in RAS, yet they had more newly formed PTCs than donor kidneys. Therefore, our study quantified significant microvascular remodeling in the poststenotic human kidney. RAS induced renal microvascular loss, vascular remodeling and fibrosis. Despite downregulated VEGF, stenotic kidneys upregulated compensatory angiogenic pathways related to angiopoietin-1.
These observations underscore the nature of human RAS as a microvascular disease distal to main vessel stenosis and support therapeutic strategies directly targeting the poststenotic kidney microcirculation in patients with RAS.
肾动脉狭窄（RAS）是慢性肾脏病和继发性高血压的重要原因。在动物模型中，肾缺血导致生长因子表达下调和肾内微循环丧失。然而，对于大血管闭塞性疾病对人类肾脏内微循环的后遗症知之甚少。
本研究纳入了 5 例因血管性肾闭塞而行肾切除术的患者和 7 例非狭窄废弃供肾（4 例为已故供者）。采用微计算机断层扫描评估微血管空间密度和迂曲度，这是微血管不成熟的指标。通过免疫印迹、聚合酶链反应和染色在体外研究肾蛋白表达、基因表达和组织学。
与供肾相比，RAS 显示中等大小血管（0.2-0.3mm）丢失（P=0.037），并且微血管迂曲度增加。RAS 肾脏中血管生成素-1、缺氧诱导因子-1α和血栓素-1 的蛋白表达增加，而血管内皮生长因子（VEGF）的蛋白表达降低。与供肾相比，RAS 的肾纤维化、肾小管周围毛细血管（PTCs）丢失和周细胞分离更为严重，但新生 PTCs比供肾多。因此，本研究定量评估了后狭窄人肾中的显著微血管重塑。RAS 导致肾微血管丢失、血管重塑和纤维化。尽管 VEGF 下调，但狭窄肾脏上调了与血管生成素-1相关的代偿性血管生成途径。
这些观察结果强调了 RAS 作为主要血管狭窄后微血管疾病的性质，并支持在 RAS 患者中直接针对狭窄后肾微循环的治疗策略。
