Inter-individual differences in anti-proteinuric response to ACE in established adriamycin nephrotic rats are predicted by pretreatment renal damage
Inter-individual differences in anti-proteinuric response to ACE in established adriamycin nephrotic rats are predicted by pretreatment renal damage
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DOI：
10.1002/path.1405
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发表时间：
2003-09-01
影响因子：
7.3
通讯作者：
Navis, G
中科院分区：
文献类型：
--
作者：
Kramer, AB;Laverman, GD;Navis, G
ACE抑制（ACEi）可减少蛋白尿并提供肾保护，但并非所有受试者都受益于ACEi。治疗开始时蛋白尿减少和治疗期间剩余蛋白尿的个体差异预测了肾脏预后的差异。本研究探讨在阿霉素肾病大鼠中，ACEi抗蛋白尿疗效的个体差异是否可以通过预处理肾脏结构损害程度的差异来解释，以及治疗期间剩余蛋白尿水平的差异是否可以通过当时肾脏结构损害程度来解释。暴露于阿霉素（2mg /kg iv） 6周后，在活检中评估预处理肾结构损伤。然后给予ACEi（赖诺普利75 mg/l， n = 23）或对照药（n = 10）；抗蛋白尿反应稳定后再次进行肾活检（第8周）。对早期肾损害（间质a-平滑肌肌动蛋白表达和巨噬细胞积聚）和既定病变（局灶性肾小球硬化（FGS）和间质纤维化）进行评分。在ACEi期间，蛋白尿从预处理前的834 (487-851)mg/24 h下降到第8周时的153 (66-265)mg/24 h (p < 0.05)；第12周时，FGS从27（4-70）个任意单位（AU）预处理稳定到26(4-84)，而载药不影响蛋白尿，导致FGS进展：18（10-26）个任意单位预处理，而第12周时为88（46-130）个任意单位预处理（p < 0.05）。预处理损伤各参数均能显著预测抗蛋白尿反应。ACEi期间剩余蛋白尿与当时肾脏结构损伤参数显著相关。预处理肾损害也可预测延长治疗期间的肾脏预后。因此，在本实验环境中，在具有相同肾脏疾病和相同疾病持续时间的大鼠中，预处理肾损伤的个体差异尽管相对较小，但可以解释肾对ACEi的反应性的个体差异。这意味着ACEi的疗效限制取决于普遍的肾损害。需要进一步研究个体对ACEi抗蛋白尿作用的抵抗机制，以制定附加干预策略。版权所有：John Wiley Sons， Ltd。
ACE inhibition (ACEi) reduces proteinuria and provides reno-protection, but not all subjects benefit from ACEi. Individual differences in the reduction in proteinuria at the onset of treatment and in residual proteinuria during therapy predict differences in renal outcome. The present study investigated whether individual differences in the anti-proteinuric efficacy of ACEi are explained by differences in the severity of pretreatment renal structural damage and whether differences in the level of residual proteinuria during therapy are explained by the severity of renal structural damage at that time, in adriamycin nephrosis in the rat. Pretreatment renal structural damage was assessed in biopsies 6 weeks after exposure to adriamycin (2 mg/kg iv). Then ACEi (75 mg/l lisinopril, n = 23) or vehicle (n = 10) was administered; renal biopsies were repeated after stabilization of the anti-proteinuric response (week 8). Early renal damage (interstitial a-smooth muscle actin expression and macrophage accumulation) and established lesions [focal glomerulosclerosis (FGS) and interstitial fibrosis] were scored. During ACEi, proteinuria fell from 834 (487-851) mg/24 h pretreatment to 153 (66-265) mg/24 h at week 8 (p < 0.05); FGS stabilized from 27 (4-70) arbitrar units (AU) pretreatment to 26 (4-84) at week 12, whereas the vehicle did not affect proteinuria, resulting in progressive FGS: 18 (10-26) AU pretreatment versus 88 (46-130) at week 12 (p < 0.05). All parameters of pretreatment damage significantly predicted the antiproteinuric response. Residual proteinuria during ACEi correlated significantly with renal structural damage parameters at that time. Pretreatment renal damage also predicted renal outcome during extended treatment. Thus, in this experimental setting, in rats with the same renal disorder and the same duration of disease, individual differences in pretreatment renal damage, albeit relatively modest, explain individual differences in renal responsiveness to ACEi. This implies that the limits of the efficacy of ACEi are set by prevalent renal damage. Further studies into the mechanisms of individual resistance to the anti-proteinuric action of ACEi are needed to develop additive intervention strategies. Copyright (C) 2003 John Wiley Sons, Ltd.