Young B A, Burdmann E A, Johnson R J, Alpers C E, Giachelli C M, Eng E, Andoh T, Bennett W M, Couser W G
Department of Medicine, University of Washington, Seattle, USA.
Kidney Int. 1995 Aug;48(2):439-48. doi: 10.1038/ki.1995.312.
Chronic cyclosporine (CsA) nephrotoxicity is a major complication of solid organ transplantation, and is characterized histologically by striped tubulointerstitial fibrosis, tubular atrophy, and hyalinization of the afferent arteriole, a highly specific finding in cyclosporine injury. The salt-depleted rat model of chronic cyclosporine nephropathy mimics these lesions in humans. We conducted sequential studies of this model in groups of pair fed rats (N = 6) treated with CsA (15 mg/kg, s.q.) or an equivalent dose of olive oil. Proliferation of tubular and interstitial cells was documented early in the medulla by day 5 (3.2 +/- 2.1 vs. 0.81 +/- 0.4 cells/HPF in CsA vs. control, P < 0.02), and was maximal in areas of interstitial fibrosis by day 35 (7.9 +/- 3.7 vs. 0.52 +/- 0.2 cells/HPF in CsA vs. control, P < 0.005). The interstitial fibrosis was associated with a significant macrophage influx by day 35 (13.9 +/- 3.5 vs. 1.5 +/- 0.32 cells/HPF, CsA vs. control, P < 0.005), which correlated with increased cortical tubular staining for the macrophage adhesion protein, osteopontin. Elevated serum creatinine correlated with interstitial fibrosis at day 35 (0.85 +/- 0.11 vs. 0.40 +/- 0.03 mg/dl Cr, CsA vs. control, P < 0.005) by linear regression (r = 0.9, P < 0.05). Medullary proliferation and interstitial fibrosis correlated with decreased tubular concentrating ability, and higher urinary volume. Cortical interstitial fibrosis was maximal at day 35 and was associated with an increase in type I and type IV collagen deposition, while tubular injury was associated with increased vimentin expression. Tubular interstitial cells also expressed increased vimentin early in the medulla (day 10) and later in the cortex. Both groups remained normotensive despite significantly elevated juxtaglomerular (JG) apparatus renin expression in CsA treated animals, implicating the intrarenal-renal renin-angiotensin system in this disease. We conclude that cyclosporine nephrotoxicity is associated with early tubular and interstitial cell proliferation, and a significant macrophage influx that precedes the development of cortical interstitial fibrosis and afferent arteriolar hyalinosis. These early cellular changes correlate with functional abnormalities including decreased creatinine clearance (CCr) and decreased medullary concentrating ability, which stabilized despite progressive fibrosis. These cellular events may be important in the pathogenesis of chronic CsA nephrotoxicity.
慢性环孢素（CsA）肾毒性是实体器官移植的主要并发症，其组织学特征为条纹状肾小管间质纤维化、肾小管萎缩以及入球小动脉玻璃样变，这是环孢素损伤的高度特异性表现。慢性环孢素肾病的低盐大鼠模型可模拟人类的这些病变。我们对成对喂养的大鼠组（N = 6）进行了该模型的系列研究，这些大鼠接受环孢素（15 mg/kg，皮下注射）或等量橄榄油治疗。到第5天，髓质中肾小管和间质细胞的增殖就已得到证实（环孢素组为3.2±2.1个细胞/高倍视野，对照组为0.81±0.4个细胞/高倍视野，P < 0.02），到第35天，在间质纤维化区域增殖达到最大值（环孢素组为7.9±3.7个细胞/高倍视野，对照组为0.52±0.2个细胞/高倍视野，P < 0.005）。到第35天，间质纤维化与巨噬细胞大量涌入相关（环孢素组为13.9±3.5个细胞/高倍视野，对照组为1.5±0.32个细胞/高倍视野，P < 0.005），这与巨噬细胞黏附蛋白骨桥蛋白的皮质肾小管染色增加相关。通过线性回归分析，第35天时血清肌酐升高与间质纤维化相关（环孢素组为0.85±0.11 mg/dl Cr，对照组为0.40±0.03 mg/dl Cr，P < 0.005）（r = 0.9，P < 0.05）。髓质增殖和间质纤维化与肾小管浓缩能力下降及尿量增加相关。皮质间质纤维化在第35天达到最大值，并与I型和IV型胶原沉积增加相关，而肾小管损伤与波形蛋白表达增加相关。肾小管间质细胞在髓质早期（第 10天）和后期皮质中波形蛋白表达也增加。尽管环孢素治疗的动物肾小球旁器肾素表达显著升高，但两组血压均保持正常，提示肾内肾素 - 血管紧张素系统参与了该疾病。我们得出结论，环孢素肾毒性与早期肾小管和间质细胞增殖以及在皮质间质纤维化和入球小动脉玻璃样变发展之前的显著巨噬细胞涌入相关。这些早期细胞变化与包括肌酐清除率（CCr）降低和髓质浓缩能力下降在内的功能异常相关，尽管纤维化进展，但这些功能异常仍保持稳定。这些细胞事件可能在慢性环孢素肾毒性的发病机制中起重要作用。
