신 실질 질환에서 정량적 자기공명영상의 유용성: 쥐 만성 신 질환 모델을 이용한 실험연구

학위논문 (박사) -- 서울대학교 대학원 : 의과대학 의학과, 2021. 2. 조정연.연구 목적 아데닌을 이용한 만성 신질환 실험동물 모델을 이용하여 만성 신질환의 실질섬유화를 평가함에 있어 정량적 자기공명영상의 유용성을 검증하고 적절한 이미지 바이오 마커를 제안하고자 한다. 연구 방법 총 16마리의 수컷 위스타 (Wistar) 쥐를 세 개의 그룹으로 나누어 – 대조군 (n=7), 만성신질환 실험군 1 (n=5), 만성신질환 실험군2 (n=4)- 실험군의 경우, 각각 0.25% 아데닌을 3주 또는 6주 기간 동안 노출시켜 만성 신질환을 유발한 뒤, 9.4T 소동물 MRI 기기를 이용하여 확산강조영상 (DWI), T1ρ (T1 rho), T2*맵 (mapping), 생체 내 MR 분광분석(in vivo 1H-MRS) 검사를 시행하였다. 영상 검사 후, 적출한 신장의 반정량적 조직병리학적 분석을 시행하여 만성 신질환 병리 분석 결과와 영상 분석을 통해 얻은 정량적 파라 미터 값 사이의 통계적 유의성은 검증하였다. 연구 결과 정상신을 가진 대조군과 비교하였을 때, 아데닌 노출 기간에 따라 만성 신질환의 유의한 조직병리학적 변화가 관찰되었다. 확산계수(ADC), T1ρ (T1 rho) 값은 만성신질환 실험군에서 유의한 증가를 보였다. 신장 피질(CO)과 바깥 수질(OM)에서 측정한 확산계수, T1ρ값의 유의한 증가를 보였다. 확산계수 값은 노출 기간에 따라 증가하는 경향이 있었고, T1ρ (T1 rho) 값은 3주 동안 노출시킨 만성신질환 실험군 1에서 증가하다가 6주 실험군에서는 감소하는 경향을 보였다. MR 분광분석 대사 물 가운데, 신 수질에서 얻은 myo-inositol (Ins)-glycine (Gly) 대비 콜린 (choline) 화합물 (glycerophosphorylcholine (GPC)-choline (Cho)-phosphatidylcholine (PC)의 비율이 만성신질환 실험군에서 유의하게 낮은 소견을 보였다. 결론 우리는 이 실험을 통해 정량적 MR 영상은 비 침습적인 방법으로 만성 신질환을 진단하고 평가하는 도구로서 잠재적 가능성을 확인하였다. 특히 T1ρ은 신실질의 섬유화를 정량적으로 평가하는데 적합한 정량적 MR 시퀀스 파라 미터임을 확인하였다. 생체 내 MR 분광분석을 이용한 대사물의 변화 추적이 만성 신의 osmolality변화를 반영하는 비침습적 방법이 될 수 있음을 확인하였다.Objective This study aimed to validate the usefulness of quantitative multiparametric magnetic resonance imaging (MRI) sequence parameters and suggest the suitable spectroscopic metabolites in the evaluation of parenchymal fibrosis using an experimental animal model of chronic kidney disease (CKD) by long-term adenine intake. Materials and Methods Experimental adenine intake in rats induces renal dysfunction due to the deposition of 2,8-dihydroxyadenine crystals in the renal parenchyma. This pathophysiologic progression resembles that of human CKD. A total of 16 male Wistar rats were analyzed. They were divided into three groups: control (n = 7), CKD1 (n = 5), and CKD2 (n = 4). The CKD groups were kept under the 3- or 6-week term intake of 0.25% adenine. According to group assignment, quantitative MRI sequences, including diffusion-weighted image, T1ρ (T1 rho), T2* mapping, and in vivo MR spectroscopy (1H-MRS), were performed using a 9.4T animal MR scanner. A semiquantitative histopathologic analysis for renal fibrosis was conducted. Comparative analyses of quantitative MR values measured from anatomic regions of kidneys between groups were performed. Results Compared to the control group, significant histopathologic changes were observed in CKD groups according to periods. The apparent diffusion coefficient (ADC) and T1 (T1 rho) values were significantly increased in all CKD groups compared with those in the control group. The differences in values measured from the cortex and outer medulla were significant between all CKD groups and control group. The total ADC values tended to increase according to periods. The T1ρ (T1 rho) values were increased in the CKD1 group and decreased in the CKD2 group. Among MRS metabolites acquired from each region, the ratio of glycerophosphorylcholine–choline–phosphatidylcholine signals to myo-inositol–glycine signals collected from voxels located at medulla region was significantly lower in the CKD groups than in the control group (0.17 vs. 0.456, P = 0.0448). Conclusion Quantitative MRI sequences could be a noninvasive assessment modality in the diagnosis and evaluation of CKD. In particular, T1ρ may be a suitable MR sequence parameter to assess renal parenchymal fibrosis in a quantitative manner. Moreover, monitoring the change in common metabolites using MRS may reflect the alteration of osmolality in the renal medulla in CKD.Abstract in English ----------------------------------------------- 1 Contents ------------------------------------------------------------ 4 List of tables and figures ---------------------------------------- 5 Introduction ------------------------------------------------------- 8 Material & Methods -------------------------------------------- 10 Results ------------------------------------------------------------- 16 Discussion --------------------------------------------------------- 25 References --------------------------------------------------------- 35 Abstract in Korean ---------------------------------------------- 42Docto

Muscle mass assessment in renal disease: The role of imaging techniques

Muscle wasting is a frequent finding in patients with chronic kidney disease (CKD), especially in those with end-stage kidney disease (ESKD) on chronic dialysis. Muscle wasting in CKD is a main feature of malnutrition, and results principally from a vast array of metabolic derangements typical of the syndrome, that converge in determining reduced protein synthesis and accelerated protein catabolism. In this clinical setting, muscle wasting is also frequently associated with disability, frailty, infections, depression, worsened quality of life and increased mortality. On these grounds, the evaluation of nutritional status is crucial for an adequate management of renal patients, and consists of a comprehensive assessment allowing for the identification of malnourished patients and patients at nutritional risk. It is based essentially on the assessment of the extent and trend of body weight loss, as well as of spontaneous dietary intake. Another key component of this evaluation is the determination of body composition, which, depending on the selected method among several ones available, can identify accurately patients with decreased muscle mass. The choice will depend on the availability and ease of application of a specific technique in clinical practice based on local experience, staff resources and good repeatability over time. Surrogate methods, such as anthropometry and bioimpedance analysis (BIA), represent the most readily available techniques. Other methods based on imaging modalities [dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging (MRI), and whole body computed tomography (CT)] are considered to be the “gold standard” reference methods for muscle mass evaluation, but their use is mainly confined to research purposes. New imaging modalities, such as segmental CT scan and muscle ultrasound have been proposed in recent years. Particularly, ultrasound is a promising technique in this field, as it is commonly available for bedside evaluation of renal patients in nephrology wards. However, more data are needed before a routine use of ultrasound for muscle mass evaluation can be recommended in clinical practice

Manganese-Enhanced Magnetic Resonance Imaging: Overview and Central Nervous System Applications With a Focus on Neurodegeneration

Manganese-enhanced magnetic resonance imaging (MEMRI) rose to prominence in the 1990s as a sensitive approach to high contrast imaging. Following the discovery of manganese conductance through calcium-permeable channels, MEMRI applications expanded to include functional imaging in the central nervous system (CNS) and other body systems. MEMRI has since been employed in the investigation of physiology in many animal models and in humans. Here, we review historical perspectives that follow the evolution of applied MRI research into MEMRI with particular focus on its potential toxicity. Furthermore, we discuss the more current in vivo investigative uses of MEMRI in CNS investigations and the brief but decorated clinical usage of chelated manganese compound mangafodipir in humans

Current and future perspectives on functional molecular imaging in nephro-urology: theranostics on the horizon

In recent years, a paradigm shift from single-photon-emitting radionuclide radiotracers toward positron-emission tomography (PET) radiotracers has occurred in nuclear oncology. Although PET-based molecular imaging of the kidneys is still in its infancy, such a trend has emerged in the field of functional renal radionuclide imaging. Potentially allowing for precise and thorough evaluation of renal radiotracer urodynamics, PET radionuclide imaging has numerous advantages including precise anatomical co-registration with CT images and dynamic three-dimensional imaging capability. In addition, relative to scintigraphic approaches, PET can allow for significantly reduced scan time enabling high-throughput in a busy PET practice and further reduces radiation exposure, which may have a clinical impact in pediatric populations. In recent years, multiple renal PET radiotracers labeled with C-11, Ga-68, and F-18 have been utilized in clinical studies. Beyond providing a precise non-invasive read-out of renal function, such radiotracers may also be used to assess renal inflammation. This manuscript will provide an overview of renal molecular PET imaging and will highlight the transformation of conventional scintigraphy of the kidneys toward novel, high-resolution PET imaging for assessing renal function. In addition, future applications will be introduced, e.g. by transferring the concept of molecular image-guided diagnostics and therapy (theranostics) to the field of nephrology

Blood Oxygenation Level-Dependent MRI to Assess Renal Oxygenation in Renal Diseases: Progresses and Challenges.

BOLD-MRI (blood oxygenation-level dependent magnetic resonance imaging) allows non-invasive measurement of renal tissue oxygenation in humans, without the need for contrast products. BOLD-MRI uses the fact that magnetic properties of hemoglobin depend of its oxygenated state:: the higher local deoxyhemoglobin, the higher the so called apparent relaxation rate R2(*) (sec(-1)), and the lower local tissue oxygen content. Several factors other than deoxyhemoglobin (such as hydration status, dietary sodium intake, and susceptibility effects) influence the BOLD signal, and need to be taken into account when interpreting results. The last 5 years have witnessed important improvements in the standardization of these factors, and the appearance of new, highly reproducible analysis techniques of BOLD-images, that are reviewed in this article. Using these new BOLD-MRI analysis techniques, it has recently been shown that persons suffering from chronic kidney diseases (CKD) have lower cortical oxygenation than normotensive controls, thus confirming the chronic hypoxia hypothesis. The acute alterations in R2(*) after the administration of furosemide are smaller in CKD, and represent an estimate of the oxygen-dependent tubular transport of sodium. BOLD-MRI-alone or in combination with other functional MRI methods- can be used to monitor the renal effects of drugs, and is increasingly used in the preclinical setting. The near future will tell whether or not BOLD-MRI represents a new tool to predict renal function decline an adverse renal outcome