Sánchez-Lozada Laura G, Tapia Edilia, Johnson Richard J, Rodríguez-Iturbe Bernardo, Herrera-Acosta Jaime
Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, México City, México.
Kidney Int Suppl. 2003 Oct(86):S9-14. doi: 10.1046/j.1523-1755.64.s86.3.x.
Glomerular hemodynamic adaptations to loss of renal mass are thought to be the initiating factor of progression to renal failure; however, tubulointerstitial (TI) injury correlates better with progression than with glomerular damage. Thus, it is conceivable that tubulointerstitial alterations participate in the pathophysiology of renal disease progression by modifying the adaptive responses of glomerular hemodynamics. In experimental models of progressive renal disease, suppressing tubulointerstitial inflammatory cell infiltration with anti-inflammatory drugs reduces renal damage despite persistence of systemic hypertension. In recent studies in rats with subtotal renal ablation, we found that treatment with polysulphate pentosan (PPS) and with mycophenolate mofetil (MMF) prevented proteinuria, glomerular hypertension, and hyperfiltration, despite persisting arterial hypertension due to higher afferent resistance. In addition, arteriolopathy was significantly attenuated by MMF, suggesting preservation of vascular structure and function. Association of vascular injury of afferent arterioles, glomerular hemodynamic changes, and renal lesions has been described in other conditions such as hyperuricemia, protein overload, fawn-hooded rats, and aging spontaneously hypertensive rats (SHR). Arteriolopathy results in a maladaptive function that permits the transmission of systemic hypertension to glomerular capillaries. Glomerular hypertension results in mechanical damage to the capillary wall and increased filtration of proteins to tubular lumen. Enhanced tubular reabsorption induces synthesis of proinflammatory and profibrotic factors, resulting in tubulointerstitial inflammation and fibrosis. In conditions in which there is overactivity of the renin-angiotensin system (RAS), such as mild hyperuricemia and protein overload, arteriolopathy is associated with increased glomerular pressure and reduced glomerular plasma flow that results in post-glomerular ischemia and tubulointerstitial injury.
肾小球血流动力学对肾实质减少的适应性变化被认为是进展至肾衰竭的起始因素；然而，肾小管间质（TI）损伤与疾病进展的相关性比肾小球损伤更好。因此，可以想象肾小管间质改变通过改变肾小球血流动力学的适应性反应参与了肾脏疾病进展的病理生理学过程。在进行性肾脏疾病的实验模型中，使用抗炎药物抑制肾小管间质炎症细胞浸润可减少肾脏损伤，尽管系统性高血压持续存在。在最近对肾次全切除大鼠的研究中，我们发现，尽管由于入球小动脉阻力增加导致动脉高血压持续存在，但使用聚硫酸戊聚糖（PPS）和霉酚酸酯（MMF）进行治疗可预防蛋白尿、肾小球高血压和超滤。此外，MMF可显著减轻小动脉病变，提示血管结构和功能得以保留。在其他情况下，如高尿酸血症、蛋白超载、淡黄褐毛大鼠和衰老自发性高血压大鼠（SHR）中，也描述了入球小动脉的血管损伤、肾小球血流动力学变化与肾脏病变之间的关联。小动脉病变导致一种适应不良的功能，使系统性高血压传递至肾小球毛细血管。肾小球高血压导致毛细血管壁的机械性损伤，并增加蛋白质向肾小管管腔的滤过。增强的肾小管重吸收诱导促炎和促纤维化因子的合成，导致肾小管间质炎症和纤维化。在肾素-血管紧张素系统（RAS）过度活跃的情况下，如轻度高尿酸血症和蛋白超载，小动脉病变与肾小球压力升高和肾小球血浆流量减少相关，进而导致肾小球后缺血和肾小管间质损伤。
