Renal Magnetic Resonance Imaging Based On Chemical Exchange Saturation Transfer And Novel T₁ Contrast Agent

Kidney is one of the important organs for maintaining homeostasis and orderly metabolism,with the ability to discharge metabolic waste,maintain electrolyte and acid-base balance.Acute kidney injury（AKI）refers to a sudden decline in kidney function that may progress to chronic kidney injury or failure without early intervention.AKI was diagnosed mainly by urea nitrogen,serum creatinine and pathological examination.However,these tests are invasive and have a lag relative to the course of the disease.Magnetic resonance imaging（MRI）,as a non-invasive imaging method without irradiation,has been proven to obtain the anatomy of the kidneys,and reflect changes of water content,blood perfusion and water molecule movement in kidney,it is often used to evaluate the changes in the internal environment and renal function.Chemical Exchange Saturation Transfer（CEST）is a novel quantitative MRI technology.Through the chemical exchange between saturated protons and water protons,the MR signal will be changed,which reflects the body’s internal environment（such as temperature,acidity and alkalinity）and the concentration of macromolecules（such as proteins,amino acids and saccharides）.The exogenous CEST using iodine contrast agent is widely used to measure the potential of hydrogen（pH）change in kidneys.However,the existing studies on the amide-proton combination of various iodine agents are not sufficient,and the detectable pH range and accuracy are limited.In order to improve the accuracy and detection range of pH measurement,more optimal amide proton combinations need to be studied.In addition,when acute kidney injury caused by ischemia reperfusion injury（IRI）occurs,exogenous CEST-pH imaging based on iodide in existing studies bring burden for the kidneys.Therefore,the imaging of IRI-AKI using endogenous CEST showed good clinical potential.A major pathogenesis of acute kidney injury is oxidative stress,which is manifested by excessive reactive oxygen species（ROS）produced by mitochondria,and its strong oxidation will lead to oxidative damage to cellular components in the body.Therefore,targeting mitochondria and interfering oxidative stress is one of the ways to alleviate renal injury.At the same time,if the process of oxidative stress can be monitored by MRI,it will be more beneficial to assess the development of AKI.This article focused on the above-mentioned problems,and carried out following three studies:（1）Optimal design of amide protons for renal CEST-pH imaging.We firstly evaluated the pH response of single types of amide groups in three clinically used iodine contrast agents,and chosed the two agents whose CEST ratio reach the largest linearity（iodixanol and iobitridol）.Based on ratiometric modified by Lorentz fitting,we compared the pH responses of the iodixanol and iobitridol combinations at different proton concentration ratios and saturation power,and compared with the agents with two kinds of amide proton.The results showed that with the 1:1 combination of amide proton in iodixanol and iobitridol,and under a single saturation power of 1μT,the pH detection accuracy was improved and the range was extended to 5.6～7.6 by CEST ratio method.The pH values of cortex,medulla and renal pelvis were measured to be 7.23 ±0.09,6.55±0.15 and 6.29±0.23,respectively,which were consistent with the traditional gadolinium based renal pH detection.（2）Endogenous CEST imaging of acute kidney injury（AKI）induced by ischemia-reperfusion（IR）.In this study,a rat AKI model was established at different time points after ischemia-reperfusion,and multiparameter MR imaging including T₁,T2,blood oxygenation level dependent（BOLD）,arterial spin labeling（ASL）,quantitative magnetization transfer（qMT）and CEST was performed.Each parameter model was iteratively fitted by the least square method,and the correlation and sensitivity between each MR parameter and renal injury score were analyzed.The results showed that the endogenous amine CEST signal decreased significantly with the development of IRI-AKI,and was more sensitive and specific to renal tubular injury.This proves that amineCEST is a novel technique that can noninvasively diagnose and monitor the development of IRI-AKI.（3）A mitochondria-targeted MRI-T₁ contrast agent for diagnosing and alleviating renal injury.In this study,TPP-PROXYL,a MRI-T₁ contrast agent was synthesized to specifically capture reactive oxygen species（ROS）by targeting mitochondria,and used to reduce renal damage caused by rhabdomyolysis.In vitro study,we approved the MRI-T₁ enhancement effect and ROS consumption of this agent.Subsequently,the oxidative stress model of HK2 cells was established by induction of H2O2,we used TPP-PROXYL successfully inhibit the intracellular oxidative stress effect and protect mitochondria.Finally,TPP-PROXYL was used to treat the mouse AKI model caused by rhabdomyolysis,meanwhile,MRI-T₁ imaging of the kidney was performed,there was significant differences between the enhanced T₁ values of the AKI and AKI treated groups.The renal histopathology in treated group showed more normal and the mouse survival was improved.The 14-day toxicity test showed that the kidney tissue of the control group treated with TPP-PROXYL was normal.These results indicate that TPP-PROXYL proposed in this study is a safe MRI-T₁ contrast agent for AKI diagnosis and treatment.