探討慢性腎臟病於膝關節軟骨與軟骨下骨髓腔變化及其相關性：藉由磁振造影T2值、擴散權重影像、頻譜之研究

Abstract

近年來，在台灣各種原因造成的慢性腎臟病盛行率升高，慢性腎臟病容易造成骨骼關節系統病症如骨折、關節病變等，尤其是發生在脊椎與膝關節，所以了解慢性腎臟病對骨骼關節系統所造成病變的病生理機制非常重要。查詢相關文獻得知，目前僅少量文獻討論關於慢性腎臟病於膝關節軟骨以及軟骨下骨髓腔的變化，既無定量也無系統性地從膝關節結構、功能以及分子等各面向分析。 本研究將建立三個主要目標：第一是使用MR T2值（T2 value）、擴散權重影像（diffusion weighted images, DWI）評估慢性腎臟病患者膝關節軟骨與半月軟骨之損傷情形。第二個目標是使用磁振頻譜（MR spectroscopy, MRS）來分別量測慢性腎臟病患者膝關節軟骨下骨髓腔中水和脂肪成分的含量，並探討膝關節軟骨與骨質的相互關係。第三個目標是比較磁振造影所得之各項量化參數與腎絲球過濾率、骨質密度三者間的關聯性 論文中納入20位腎臟專科醫師評估為第三期到第五期的慢性腎臟病之病患、20位性別年齡配對之健康受試者，包含22位男性以及18位女性，根據美國腎臟基金會所提出的疾病分期標準，慢性腎臟病可以根據患者的腎絲球過濾率（estimated glomerular filtration rate, eGFR）高低區分為一至五期。我們採用MR T2值、ADC值針對組群間（慢性腎臟病與正常受試者兩個組群）所呈現之數值差異性作統計分析比較，在T2圖像（T2 mapping）、ADC圖像（ADC mapping），使用感興趣區（region of interest, ROI）方式針對膝關節軟骨以及半月軟骨的八個區域（內外側股骨髁、脛骨內外側、前角內外側半月板、後角內外側半月板）所得到之各區域性的量化指標來系統性比較兩個群組的差異性。另一方面，使用磁振頻譜在軟骨下骨髓腔採集訊號，透過LC model進行之水和脂肪定量分析。其群組之間的平均值統計差異則用獨立樣本t檢定的統計方法，並觀察對應之傳統血清生化指標、骨質密度的數值與本研究的結果間有無關連性，關連性的檢測以Pearson檢定的統計方法，當P值小於0.05則認為兩個群組之間的影像表現有顯著差異。 本研究結果發現在膝關節軟骨T2圖像的參數中，慢性腎臟病之男性外側股骨髁之T2值有顯著增加（P = 0.02），其中脛骨內側有些微增加但未達到顯著差異（P = 0.08），慢性腎臟病之女性也在外側股骨髁膝關節軟骨T2值有顯著增加（P = 0.03），其中脛骨外側有些微增加但未達到顯著差異（P = 0.09）。此外，不論性別，前後角內外側半月板T2值以及內側股骨髁膝關節軟骨之T2值並無顯著差異，不過與男性組T2值變化相比，女性的變化有些微增加的趨勢。然而在膝關節軟骨ADC的參數中，與對照組相比，慢性腎臟病之不論性別，前後角內外側半月板MR T2值以及內外側股骨髁、脛骨內外側膝關節軟骨之ADC值並無顯著差異（P > 0.05） 磁振頻譜結果發現與對照組相比，女性慢性腎臟病患者膝關節軟骨下骨髓腔中的水含量和不飽和脂肪指數顯著增加（分別為P = 0.04和P = 0.02），但男性則沒有顯著改變。關連性的結果發現不論是慢性腎臟病或對照組，膝關節軟骨、半月軟骨T2值與身體質量指數（body mass index, BMI）、腎絲球過濾率（eGFR）、關節炎疼痛指數（WOMAC）皆沒有相關性，但是慢性腎臟病的T2值與退化性關節炎分級（KL grade）、磁振造影膝關節炎評分（MOAKS）具正相關並達顯著差異（r=0.47、P = 0.04和r=0.59、P=0.01），但對照組的T2值與KL grade 、MOAKS則沒有相關性（P > 0.05）。另外發現對照組軟骨下骨髓腔中水含量與eGFR存在負相關並且有達顯著差異（r=-0.77、P < 0.001），但慢性腎臟病組軟骨下骨髓腔中水含量與eGFR則不存在相關性（P > 0.05）。 我們的結論是，慢性腎臟病相關的MR T2值變化，外側膝關節軟骨的表現可能在其他軟骨之前，膝關節軟骨下骨髓腔水含量、不飽和脂肪變化，在性別表現上有所差異，並觀察到之間是否具有關連性，未來在合理的影像訊雜比資料下，膝關節軟骨和半月軟骨MR T2以及磁振頻譜的測量可作為調查慢性腎臟病膝關節軟骨退化有效之工具。

Chronic kidney disease (CKD) is associated with a wide range of disorders of mineral and bone metabolism, including phosphate, calcium and parathyroid hormone dysregulation, renal osteodystrophy and vascular calcifications. Understanding this pathophysiology in mineral metabolism and bone diseases is very important, as recent evidence has suggested the concept of bone-vascular axis in CKD. However, the information for the articular cartilage and meniscus in CKD is limited. Specifically, the stage of this study are three-fold: 1) to assess composition variation of knee cartilage at the CKD using measurements of T2 relaxation time and the parameters of diffusion weighted imaging; 2) to quantify water and lipids changes of knee bone narrow at the CKD using MRS; and 3) to compare MR parameters (including MRI T2 values, DWI and MRS) with other traditional serum biomarkers and analyzing the correlation between its level and bone mineral densities of lumbar spine. We prospectively enrolled 20 patients with CKD and 20 age- and sex-matched controls for this study, including 22 men and 18 women. All subjects underwent 3.0T MR examinations (GE Healthcare, Discovery MR750, USA), blood tests, bone mineral density examinations, and standard standing anteroposterior radiographs. Quantitative MR T2 measurement provides a noninvasive method to evaluate the early changes of fiber architecture and water content in cartilage and meniscus. Apparent diffusion coefficient (ADC) generated by DWI also can be used to detect early stage cartilage damage. We adopted the water and lipid content from MR spectroscopy (MRS) to verify the pathological characteristics of subchondral bone of the knee joint. The statistical analyses were performed with SPSS software (version 20, SPSS, Inc, Chicago, IL, USA). To compare groups with CKD and the controls, the Independent Sample t test was applied. T2 values of the lateral femoral condyles cartilage were significantly increased (P = 0.02) in CKD patients as compared with the controls for men, and T2 values of the medial tibia cartilage increased slightly but did not reach a significant difference(P = 0.08). T2 values of the lateral femoral condyles were also significantly increased (P = 0.03) in CKD patients as compared with the controls for women, in which T2 values of the lateral tibia cartilage increased slightly but did not reach a significant difference (P = 0.09). The ADC of cartilage and meniscus were not significantly different in CKD patients compared with the controls for both genders. The water content and index of unsaturation lipid in the knee subchondral bone marrow was significantly increased (P = 0.04 and 0.02, respectively) in women CKD patients as compared with the women controls, but not significant in men. T2 values of cartilage and meniscus were positively correlated with the KL grade and MOAKS (r=0.47、P = 0.04 and r=0.59、P=0.01, respectively ) for CKD group, but not significant in control group ( P > 0.05). In conclusion, CKD-related T2 changes in the lateral femoral condyles cartilage may precede alterations in other cartilage regions. The changes of water and lipids changes of knee bone marrow at the CKD are different in gender and the correlation between them is observed. These techniques may serve as effective tools in the investigation of knee cartilage degradation in CKD.