Effects of iodinated contrast agents on renal oxygenation level determined by blood oxygenation level dependent magnetic resonance imaging in rabbit models of type 1 and type 2 diabetic nephropathy

Jia-huan Wang 0 1 Ke Ren 0 1 Wen-ge Sun 1 Li Zhao 1 Hong-shan Zhong 0 Ke Xu 0 1 0 Key Laboratory of Imaging Diagnosis and Interventional Radiology of Liaoning Province , Shenyang, Liaoning 110001 , People's Republic of China 1 Department of Radiology, The First Hospital of China Medical University , Shenyang, Liaoning 110001 , People's Republic of China Background: To evaluate the effects of contrast agents containing increasing concentrations of iodine on the renal oxygenation level determined by blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) in a rabbit model of diabetic nephropathy. Methods: BOLD-MRI was performed using saline or iodinated (I) contrast agents (200, 240, 300, 350 and 400 mg I/mL) at 1, 24, 48, and 72 h after experimentally inducing type 2 diabetic nephropathy in rabbits. Differences in renal oxygenation levels between type 1 and type 2 diabetic nephropathy were also assessed by BOLD-MRI after injecting 400 mg I/mL of contrast agent. Results: Contrast agents increased the R2* values of the renal cortex, outer medulla, and inner medulla to the maximum levels at 24 h. The R2* values then decreased to their lowest levels at 72 h. The R2* was highest following injection of 400 mg I/mL, especially in the outer medulla. The R2* values were not significantly different between types 1 and 2 diabetic nephropathy. Conclusions: Iodinated contrast agents had the greatest influence on renal outer medulla oxygenation level at 24 h in type 2 diabetic nephropathy, with the greatest effects observed at the 400 mg I/mL dose level. There were no differences in BOLD-MRI values between type 1 and type 2 diabetic nephropathy after administering the contrast agent at 400 mg I/mL. - Background The development of an international economy and improvements in living standards have led to progressive increases in the morbidity and prevalence of diabetes mellitus, such that diabetes mellitus is now a major public health concern. Worldwide, 284 million people were estimated to have diabetes in 2010, representing 6.4% of the total population. Furthermore, it was predicted that 439 million individuals worldwide, 7.7% of the total population, will have diabetes mellitus in 2030 [1]. Diabetic nephropathy affects 1525% of patients with type 1 diabetes and 3040% of patients with type 2 diabetes [2]. Iodinated contrast agents are mainly metabolized in the kidneys. Contrast agents sometimes cause hypoxia in the kidneya deficiency of oxygenation and the primary feature of progressive chronic kidney disease [3-5]. According to the studies by Pakfetrat et al. [6] and Toprak and Cirit [7], renal insufficiency and chronic kidney disease are major risk factors for contrast-induced nephrotoxicity (CIN), especially in patients with diabetes. CIN is defined as an increase in the serum creatinine level of 0.5 mg/dL or an increase of 25% above baseline [8]. Generally, CIN is usually transient because the serum creatinine starts to rise within 2448 h after exposure and reaches its peak value within 35 days after administration of the contrast agent, and subsequently declines [9]. Therefore, early detection of CIN is challenging. Functional magnetic resonance imaging (MRI), especially blood oxygenation level dependent (BOLD) MRI, can facilitate detailed noninvasive assessment of renal function. This technique has been used to study the effects of iodinated contrast agents on the kidney in initial feasibility studies in humans [10,11]. Tissue oxygenation bioavailability can be evaluated in terms of the R2* values. The increase of transverse relaxation rate R2* values reflect a poor oxygenation content in tissue [12]. Prasad [13] reported that the baseline R2* values in the renal medulla of spontaneously hypertensive rats were significantly greater than those of WistarKyoto rats, implying lower oxygenation in spontaneously hypertensive rats. In the present study, we used BOLD-MRI to examine the effects of iodine-containing contrast agents on renal oxygenation in a New Zealand white rabbit model of diabetic nephropathy. Methods Experimental subjects All animal procedures were approved by the ethics committee of China Medical University and complied with guidance for the Care and Use of Laboratory Animals (National Research Council, National Academy Press, Washington, DC, 1996). Ninety-six male New Zealand rabbits (68 months old; weighing 2.03.0 kg) were obtained from the Animal Department of China Medical University. All procedures were performed under general anesthesia. Food and water was withheld for 6 h during the experiments. The rabbits were allocated to three experimental groups (control, type 1 diabetic nephropathy, and type 2 diabetic nephropathy). Type 1 diabetic nephropathy This group included 12 rabbits, which were injected with 150 mg/kg alloxan monohydrate (Sigma Chemical Co., St, Louis, MO, USA) dissolved in physiological saline (5 g/100 mL) via a 22 G venous indwelling needle through the auricular vein. Because alloxan damages islet cells, severe hypoglycemia was expected to occur within 2448 h after injection. Therefore, the rabbits had free access to 10% glucose water for 48 h after injection. The development of type 1 diabetes mellitus was considered successful if the blood glucose was 16 mmol/L [14] at 23 weeks after injection. The rabbits were fed a conventional diet for 12 weeks. After 12 weeks, blood glucose levels and the extent of kidney damage were assessed using blood and urine biochemical examinations. Type 2 diabetic nephropathy Type 2 diabetic nephropathy was induced in 72 rabbits by providing them a high-glucose and high-fat diet (5 g saccharose and 1 g cholesterol per 100 g of food; cholesterol was obtained from Sigma Chemical Co.). Granulated sugar with a glycemic index of >100 was dissolved in drinking water to a dilution of 1 g/mL. After 8 weeks, blood samples were obtained from the auricular vein for biochemical examinations, including fasting blood glucose, serum lipids, and high-sensitivity C reactive protein. Insulin resistance was considered to be present if these indices had increased from baseline [15]. After 12 weeks, blood glucose levels and the extent of kidney damage were assessed using blood and urine biochemical examinations. Preparation of contrast agents Five iodinated (I) contrast agents were obtained from the GE Pharmaceutical Shanghai Co. Ltd. (Shanghai, China) and were used in the experiment: 200 mg I/mL (viscosity: 0.20 NS/M2 at 37C; osmolality: 413 mOsm/ kg H2O); 240 mg I/mL (viscosity: 0.33 NS/M2 at 37C; osmolality: 510 mOsm/kg H2O); 300 mg I/mL (viscosity: 0.61 NS/M2 at 37C; osmolality: 640 mOsm/kg H2O); 350 mg I/mL (viscosity: 1.06 NS/M2 at 37C; osmolality: 780 mOsm/kg H2O); and 400 mg I/mL (viscosity: 1.26 NS/M2 at 37C; osmolality: 920 mOsm/kg H2O). Experimental protocols Protocol 1 Control rabbits and rabbits with experimentally induced type 2 diabetic nephropathy were divided into seven groups of 12 rabb (...truncated)