Burdmann E A, Rosen S, Lindsley J, Elzinga L, Andoh T, Bennett W M
Division of Nephrology, Oregon Health Sciences University, Portland 97201.
Transplantation. 1993 May;55(5):963-6. doi: 10.1097/00007890-199305000-00001.
Chronic tubulointerstitial nephropathy during long-term cyclosporine A (CsA) use has led to a search for equally effective but safer analogues. In this study we evaluated one of these analogues, cyclosporine G (CsG), in a rat model of chronic cyclosporine nephrotoxicity. CsG has immunosuppressive effects equivalent to CsA when dosed on a weight basis. Pair-fed Sprague-Dawley rats kept on a low-salt rice diet were given CsA 15 mg/kg, CsG 15 mg/kg, CsG 25 mg/kg, or vehicle subcutaneously. After 21 days, CsA animals had a lower glomerular filtration rate, measured by inulin clearance (0.16 +/- 0.04 ml/min/100 g) and higher serum creatinine (0.94 +/- 0.06 mg/dl) than CsG 15 mg/kg (GFR: 0.41 +/- 0.10 ml/min/100 g and serum creatinine: 0.68 +/- 0.09 mg/dl), CsG 25 mg/kg (GFR: 0.39 +/- 0.16 ml/min/100 g) or control rats (GFR: 0.62 +/- 0.06 ml/min/100 g; serum creatinine: 0.56 +/- 0.03 mg/dl), respectively (P < 0.05). The CsA group had considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), whereas both groups of CsG animals had more limited changes. Despite the same or larger doses of CsG on a weight basis, cyclosporine blood levels were significantly lower in CsG than CsA rats. We conclude that CsG, an analogue of cyclosporine with immunosuppressive activity equivalent to that of CsA, produced less nephrotoxicity in a model of chronic renal injury in rats, using both functional and structural parameters.
长期使用环孢素A（CsA）导致的慢性肾小管间质性肾病促使人们寻找同样有效但更安全的类似物。在本研究中，我们在慢性环孢素肾毒性大鼠模型中评估了其中一种类似物环孢素G（CsG）。按体重给药时，CsG具有与CsA相当的免疫抑制作用。将成对喂养的Sprague-Dawley大鼠置于低盐大米饮食中，皮下注射给予15mg/kg CsA、15mg/kg CsG、25mg/kg CsG或赋形剂。21天后，与15mg/kg CsG组（肾小球滤过率：0.41±0.10ml/min/100g，血清肌酐：0.68±0.09mg/dl）、25mg/kg CsG组（肾小球滤过率：0.39±0.16ml/min/100g）或对照组大鼠（肾小球滤过率：其0.62±0.06ml/min/100g；血清肌酐：0.56±0.03mg/dl）相比，CsA组大鼠的菊粉清除率测定的肾小球滤过率较低（0.16±0.04ml/min/100g），血清肌酐较高（0.94±0.06mg/dl）（P<0.05）。CsA组有明显的皮质和髓质损伤（间质纤维化和肾小管萎缩），而两组CsG动物的变化则较为有限。尽管按体重计算CsG的剂量相同或更大，但CsG组大鼠的环孢素血药浓度明显低于CsA组大鼠。我们得出结论，CsG作为一种免疫抑制活性与CsA相当的环孢素类似物，在大鼠慢性肾损伤模型中，无论是从功能还是结构参数来看，产生的肾毒性都较小。
