Guerbet, Research Division, Aulnay-sous-Bois, France.
Br J Pharmacol. 2012 Feb;165(4b):1151-62. doi: 10.1111/j.1476-5381.2011.01585.x.
Hyperphosphataemia is common in patients with nephrogenic systemic fibrosis (NSF). NSF has been linked to administration of gadolinium (Gd) chelates (GCs) and elevated serum phosphate levels accelerate the release of Gd from linear, non-ionic GCs but not macrocyclic GCs. Hence, we determined whether hyperphosphataemia is a cofactor or risk factor for NSF by investigating the role of hyperphosphataemia in renally impaired rats.
Firstly, the clinical, pathological and bioanalytical consequences of hyperphosphataemia were investigated in subtotal nephrectomized (SNx) Wistar rats following i.v. administration of the non-ionic, linear GC gadodiamide (5 × 2.5 mmol·kg(-1) ·day(-1) ). Secondly, the effects of several GCs were compared in these high-phosphate diet fed rats. Total Gd concentration in skin, femur and plasma was measured by inductively coupled plasma mass spectrometry (ICP-MS) and free Gd(3+) in plasma by liquid chromatography coupled to ICP-MS. Relaxometry was used to measure dissociated Gd in skin and bone.
Four out of seven SNx rats fed a high-phosphate diet administered gadodiamide developed macroscopic and microscopic (fibrotic and inflammatory) skin lesions, whereas no skin lesions were observed in SNx rats treated with saline, the other GCs and free ligands or in the normal diet, gadodiamide-treated group. Unlike the other molecules, gadodiamide gradually increased the r(1) relaxivity value, consistent with its in vivo dissociation and release of soluble Gd.
Hyperphosphataemia sensitizes renally impaired rats to the profibrotic effects of gadodiamide. Unlike the other GCs investigated, gadodiamide gradually dissociates in vivo. Our data confirm that hyperphosphataemia is a risk factor for NSF.
肾源性系统性纤维化（NSF）患者常伴有高磷血症。已有研究表明，NSF 与钆螯合物（GCs）的应用相关，且血清磷酸盐水平升高可加速线性、非离子型 GCs 中 Gd 的释放，但对大环型 GCs 无此作用。因此，我们通过研究高磷血症对肾功能不全大鼠的作用，来确定高磷血症是否为 NSF 的协同因子或危险因素。
首先，我们在接受非离子线性 GC 钆喷酸葡胺（5×2.5mmol·kg(-1)·day(-1)）静脉注射的部分肾切除（SNx）Wistar 大鼠中，研究了高磷血症的临床、病理和生物分析后果。其次，我们在这些高磷饮食喂养的大鼠中比较了几种 GCs 的作用。采用电感耦合等离子体质谱法（ICP-MS）测量皮肤、股骨和血浆中的总 Gd 浓度，采用液相色谱-ICP-MS 测量血浆中的游离 Gd(3+)。弛豫率法用于测量皮肤和骨骼中的游离 Gd。
在接受高磷饮食和钆喷酸葡胺治疗的 7 只 SNx 大鼠中，有 4 只出现了肉眼可见和显微镜下（纤维化和炎症）的皮肤损伤，而接受生理盐水、其他 GCs、游离配体或正常饮食及钆喷酸葡胺治疗的 SNx 大鼠均未出现皮肤损伤。与其他分子不同，钆喷酸葡胺的 r(1)弛豫率值逐渐升高，与体内的逐渐解离和可溶性 Gd 的释放一致。
高磷血症使肾功能不全的大鼠对钆喷酸葡胺的致纤维化作用更为敏感。与我们研究的其他 GCs 不同，钆喷酸葡胺在体内逐渐解离。我们的数据证实高磷血症是 NSF 的一个危险因素。
