Academic Nephrology Unit, Medical School, Sheffield, UK.
Invest Radiol. 2010 Sep;45(9):507-12. doi: 10.1097/RLI.0b013e3181eb51f2.
The development of nephrogenic systemic fibrosis (NSF) following MRI contrast examination has been associated with gadolinium (Gd) toxicity. Animal models should show the key features of NSF in man where, the only immutable epidemiological feature is renal impairment. A rat model of chronic renal insufficiency has been employed to establish whether tissue gadolinium retention and increased skin cellularity following a gadolinium based contrast agent (GBCA) can be correlated with a reduction in renal function. The GBCA chosen for investigation was Omniscan, the least stable of the commercially available agents.
Wistar rats were subjected to 5/6 subtotal nephrectomy (SNx) under isoflurane anesthesia. The glomerular filtration rate (GFR) was assessed from serum creatinine and creatinine clearance. Two SNx rats groups were established, following either 75% or 80% resection of the kidney, which reduced the GFR down to 40% and down to 20%, respectively, of sham-operated controls. Three months after surgery, rats received a single intravenous injection of either saline or Omniscan (gadodiamide 2.5 mmol/kg). Four weeks later, the Gd content of serum, skin, liver, and bone was measured by inductively coupled plasma mass spectrometry and skin cellularity determined.
In sham-operated rats, Gd was detected in skin < liver < bone. SNx rats with the GFR reduced down to 20% normal, had an increased tissue Gd concentration in bone (2.5-fold), skin (3-fold), and liver (10-fold) compared with sham-operated controls. The Gd concentration in all 3 tissues showed a positive linear correlation with serum creatinine (P < 0.01). No external skin lesions were observed. The skin cellularity of rats with the GFR reduced down to 20% of normal was increased following Omniscan, together with positive immunostain for CD34 and prolyl-4-hydroxylase.
The SNx rat is a sensitive model for investigating the pathophysiology of NSF. A positive linear correlation was obtained between tissue Gd and serum creatinine, the major clinical marker of renal function. An increase in skin cellularity, a feature of human NSF, was demonstrated in rats with a level of renal impairment equivalent of stage 4 chronic kidney disease following just a single intravenous dose of Omniscan. This response was obtained in the absence of ulcerogenic skin lesions, at skin Gd concentrations as low as 50 nmol/g.
磁共振对比检查后肾源性系统性纤维化（NSF）的发展与钆（Gd）毒性有关。动物模型应显示出与 NSF 相关的人类的关键特征，其中唯一不变的流行病学特征是肾功能损害。本研究采用慢性肾功能不全大鼠模型，以确定基于钆的造影剂（GBCA）后组织内的 Gd 蓄积和皮肤细胞增多是否与肾功能下降有关。选择用于研究的 GBCA 是 Omniscan，这是市售试剂中最不稳定的试剂。
Wistar 大鼠在异氟烷麻醉下接受 5/6 肾部分切除术（SNx）。通过血清肌酐和肌酐清除率评估肾小球滤过率（GFR）。建立了 2 个 SNx 大鼠组，分别进行 75%或 80%的肾脏切除，将 GFR 分别降低至 sham 操作对照组的 40%和 20%。手术后 3 个月，大鼠单次静脉注射生理盐水或 Omniscan（gadodiamide 2.5 mmol/kg）。4 周后，通过电感耦合等离子体质谱法测量血清、皮肤、肝脏和骨骼中的 Gd 含量，并测定皮肤细胞数。
在 sham 手术大鼠中，Gd 在皮肤<肝<骨中被检测到。GFR 降低至正常的 20%的 SNx 大鼠的骨（2.5 倍）、皮肤（3 倍）和肝脏（10 倍）中的组织 Gd 浓度增加，与 sham 操作对照组相比。所有 3 种组织中的 Gd 浓度均与血清肌酐呈正线性相关（P<0.01）。未观察到外部皮肤损伤。GFR 降低至正常的 20%的大鼠的皮肤细胞数增加，同时对 CD34 和脯氨酸-4-羟化酶的免疫染色呈阳性。
SNx 大鼠是研究 NSF 病理生理学的敏感模型。组织 Gd 与血清肌酐之间呈正线性相关，血清肌酐是肾功能的主要临床标志物。单次静脉注射 Omniscan 后，肾功能损害相当于慢性肾脏病 4 期的大鼠皮肤细胞增多，这是人类 NSF 的一个特征。在皮肤 Gd 浓度低至 50 nmol/g 时，在没有致溃疡皮肤损伤的情况下，获得了这种反应。
