利用彩色都卜勒超音波及阻力指數評估急性輸尿管結石尿路阻塞患者之腎臟血流動力學的變化與尿液中MCP-1及 IL-6之關聯性研究

The Association of Renal Vascular Resistive Index with Urinary MCP-1 & IL-6 in Patients with acute Ureteral Calculi Obstruction

蔡秀男(Hsiu-Nan Tsai)

指導教授 ： 黃俊雄

高雄醫學大學/醫學院/醫學研究所/碩士(2004年)

摘要

研究目的：
本研究對於輸尿管結石合併急性腎水腫的病人，探討其彩色都卜勒超音波及阻力指數，在診斷尿路結石阻塞性尿路病變的敏感度及特異性；並以彩色都卜勒超音波來追蹤輸尿管結石治療前後阻力指數的改變；我們也試圖研究輸尿管結石造成腎水腫的病人中有多少比例會引發白血球過多症，以及阻力指數與白血球上升之間的相關性；我們也收集尿路結石的患者尿液MCP-1以及IL-6的濃度做分析，研究與彩色都卜勒超音波阻力指數之間的相關性。

研究材料與方法：
自2000年8月起，我們收集輸尿管結石急性腎絞痛及急性腎水腫的病人，研究分組包括輸尿管結石合併腎水腫患者，腎結石患者，泌尿道感染患者，並以正常成人為對照組。傳統的診斷方法：有X光、超音波、靜脈注射腎盂攝影、逆行性腎盂攝影、電腦斷層。傳統的治療方式：依靠病人的症狀、結石的位置、結石的大小，以及腎水腫。我們為每一個病人在治療前、治療後都進行彩色都卜勒超音波阻力指數的檢查，檢查的時間是在腎絞痛發作之後6到24小時，治療後是在治療的1至3天來研究它短期的效果，彩色都卜勒超音波測量阻力指數，是在腎臟不同的三個地方計算RI值，三者平均是平均mean RI。我們收集各種尿路結石患者的尿液，分析其尿中MCP-1及 IL-6的變化。同時，利用彩色都卜勒超音波，計算阻力指數(RI)來評估治療前後，腎臟血流動力學的變化。尿液收集及處理後，尿中MCP-1及IL-6之濃度分析採MCP-1&IL-6 ELISA (Enzyme-Linked ImmunoSorbant Assay)，資料收集後進行統計分析。排除其他有泌尿道感染、雙側輸尿管結石、本身有腎臟衰竭的疾病、血液方面的疾病或者是全身性感染以及慢性的腎臟病的病人。

研究結果:
我們收集60位正常成人共120個腎臟，平均年齡是44.4歲(22 ~ 75歲)，統計平均RI正常值為0.60 ±0.03 (RI range 0.53-0.69)。此外，我們收集60位輸尿管結石合併急性腎水腫病人，進行彩色都卜勒超音波阻力指數的檢查，以RI cutoff point 0.7，診斷功能上是否阻塞的敏感度(RI sensitivity)有90﹪。
自2000年8月起我們收集302例輸尿管鏡手術，有單側的輸尿管結石合併腎水腫急性腎絞痛，輸尿管結石造成急性腎水腫患者，其中收集60位輸尿管結石病人，進行彩色都卜勒超音波阻力指數的檢查，經URSL& ESWL等治療，前後RI有明顯改善(p<0.01)，這些輸尿管結石造成腎水腫的病人中有16.7%比例會引發白血球過多症。此外分四組實驗組與對照組中，總共收集有154個個案進行尿中MCP-1及 IL-6之濃度分析，及阻力指數之測量，統計結果發現：(1)腎結石患者接受ESWL治療前後，腎臟血流動力學上RI 及 MCP-1及 IL-6 並無明顯的變化。(p=0.529, 0.073, 0.425) 。(2) 輸尿管結石造成急性腎水腫患者，經ESWL治療前後，RI有明顯改善(p<0.01)。MCP-1及 IL-6 則無明顯的變化。( p=0.052, 0.185)。(3) 輸尿管結石造成急性腎水腫患者，經URSL治療前後，RI有明顯改善(p<0.01)。MCP-1及 IL-6 則無明顯的變化。( p=0.759, 0.822)。(4) 輸尿管結石造成急性腎水腫患者，尿中MCP-1 及 RI 有明顯偏高現象，與對照組比較，在統計上有明顯的差異性(p=0.002, 0.05)，IL-6則無明顯的差異性 ( IL-6 , p=0.130)。(5) 急性膀胱炎患者,阻力指數RI及尿中MCP-1 & IL-6,與對照組RI及尿中MCP-1 & IL-6比較, 在統計上並無明顯差異性。(6) 急性腎盂腎炎患者，阻力指數RI及尿中MCP-1 & IL-6,與對照組RI及尿中MCP-1 & IL-6比較，在統計上 RI及尿中MCP-1有明顯差異性 (p=0.001, p=0.025)，而IL-6 在兩組間並無明顯的差異(p=0.701)。(7) 尿路結石患者中有16.7%有白血球增多現象(urolithiasis-induced leukocytosis)。(8) 阻力指數與急性輸尿管阻塞引發之白血球增多現象，在統計上有明顯的正相關性，白血球過高這一組的平均阻力指數是有明顯的高於對照組，(0.7112±0.0519 vs. 0.6793±0.0569; p<0.05)，整體而言，阻力指數與白血球的數量有正相關(Pearson coefficient=0.541, p<0.01)。

研究結論:
阻力指數RI對於輸尿管結石阻塞治療前後，可用來當做追蹤腎臟功能的指標，可以提供很敏感可靠的資訊，以及決定治療策略的參考，幫助評估治療的效果。RI值跟白血球的上升有明顯的統計上的意義，尿路結石會引發白血球過高與一般感染無關。文獻上MCP-1 & IL-6證實可當作尿路結石阻塞性尿路病變的預後指標，我們的結果亦顯示，輸尿管結石腎水腫患者，尿中MCP-1，IL-6，及RI有明顯偏高現象，在統計上RI 與尿中MCP-1及 IL-6之間也有明顯相關性， 治療前後RI亦有明顯改善。在更大規模的研究之後，我們似乎更能以RI來當作理想的預後指標，用來追蹤腎功能的變化，以及決定治療策略的參考。

關鍵字

腎水腫 ； MCP-1 ； IL-6 ； 阻力指數 ； 彩色都卜勒超音波 ； 輸尿管結石 ； 白血球過多症 ； 阻塞性尿路病變 ； 尿路結石

並列摘要

Purpose:
To investigate the sensitivity and specificity of resistive index (RI, obtained from color Doppler sonography) in patients with acute ureteral obstruction due to ureteral calculi. To study the resistive index and the hemodynamic change after various treatment modality. To clarify the difference of leukocytosis induced by infection or by acute ureteral obstruction due to ureteral calculi. To investigate the correlation of the resistive index with leukocytosis induced by acute ureteral obstruction. Urinary cytokines and urinary levels of mediators of inflammation are becoming increasingly important as markers for urologic diseases in the literature review. The urinary concentration of monocyte chemoattractant protein-1(MCP-1) correlates with the degree of obstruction and subsequent renal damage in hydronephrosis. MCP-1 is an important mediator of renal tubular injury. The elevation in interleukin-6 (IL-6) may be useful in the understanding of the pathogenesis of urolithiasis or as a potential marker for stone disease. Resistive index (RI) shows significant improvement after treatment for acute ureteral obstruction due to ureteral stone. The purpose of this study is to investigate the association of RI with MCP-1 & IL-6 in patients with acute ureteral obstruction due to ureteral calculi.

Materials and Methods:
From Aug. 2000, a total of 302 consecutive patients with ureteral stone were collected under thorough clinical diagnosis and image diagnosis including color Doppler sonography.The study is divided into four groups of patients with various urologic diseases. Group A: Ureteral stone group. Patients suffered from acute renal colic, diagnosed with unilateral ureteral stone and hydronephrosis. Group B: Renal stone group. Group C: Acute pyelonephritis (APN) group. Group D: Control healthy group. Exclusion criteria: hematological disease, chronic renal parenchymal disease, preexisting renal failure and bilateral ureteral stone. We perform color Doppler sonography and measure the RI for each patient. Color Doppler sonography (TOSHIBA model SSA-340A) and RI will be done. 154 Urine samples were obtained from renal pelvis urine and voided urine. The urine samples were kept at 4℃, centrifuged at 1000 g for 15 minutes and divided into smaller amounts which were then stored at -70℃. The divided samples were thawed for cytokine evaluation. (MCP-1 enzyme-linked immunosorbant assay and IL-6 Cytokine assays).

Results:
We performed color Doppler sonography and measure the RI for 60 normal healthy persons and total 120 kidneys. The normal mean RI value is 0.60 ±0.03 (RI range 0.53-0.69)。Besides, the RI sensitivity using the RI cutoff point 0.7 is 90﹪to detect the functional obstruction among those patients with acute ureteral obstruction stone due to ureteral calculi. Resistive index (RI) shows significant improvement after treatment for acute ureteral obstruction due to ureteral stone (p<0.01). A total of 154 cases were collected for urine cytokine evaluation and color Doppler sonography measuring RI. The resistive index (RI) and concentrations of MCP-1 and IL6 obtained from voided urine did not show significant change after ESWL for patients with renal stone (p=0.529, 0.073, 0.425). The RI showed significant improvement after treatment for acute ureteral obstruction due to ureteral stone (p<0.01), however the concentrations of MCP-1 and IL6 obtained from renal pelvic and bladder urine did not show significant change (p=0.759, 0.822). The resistive index (RI) and concentrations of MCP-1 and IL6 also shows significant correlation (p<0.05) among patients with acute ureteral obstruction. The RI and MCP-1 in the APN group showed significantly higher than those in the UTI group (p=0.001, p=0.025), but IL-6 showed no significant difference (p=0.701).

Conclusions:
In our study, The RI can provide us useful and sensitive information for clinical diagnosis in addition to stone location, stone size, and hydronephrosis. We suggest the use of RI in determining the treatment strategy and monitoring the renal function after treatment of ureteral obstruction. The resistive index (RI) correlates significantly with the leukocytosis induced by acute ureteral obstruction. The mean RI of the unaffected kidney in the leukocytosis group is relatively higher. Immune mediators induced by acute unilateral ureteral obstruction are suggested to affect kidneys bilaterally. In addition, we also find the positive correlation of resistive index with age. The resistive Index correlates significantly with urinary MCP-1 & IL-6 in patients with urolithiasis. Further study is needed to test if RI as an image marker for obstructive uropathy correlates with the biological markers (MCP-1 and IL6) for obstructive uropathy.

並列關鍵字

ureteral calculi ； urolithiasis ； Interleukin-6 (IL-6) ； resistive Index (RI) ； color Doppler sonography ； monocyte chemoattractant protein-1 (MCP-1) ； leukocytosis ； obstructive uropathy ； hydronephrosis

參考文獻

1. Tanagho EA. McAninch JW. Smith’s General Urology. The McGraw-Hill Company, Inc, 15th ed., 2000.

2. Walsh PC et al. Campbell’s Urology. The Saunders Company. 8th ed., 2002.

3. Ellenbogen, P. H., Scheible, F.W., Talner, L.B. et al: Sensitivity of gray scale ultrasound in detecting urinary tract obstruction. Am J Roengenol 1978; 130: 731-735.

4. Shokeir, A. A., Provoost, A. P., Nijman R. J. M. et al: Resistive index in obstructive uropathy. Br J Urol 1997; 80: 195-200.

5. Shokeir, A. A., Provoost, A. P., el-Azab, M. et al: Renal Doppler ultrasound in children with normal upper urinary tracts: effect of fasting, hydration with normal saline, and furosemide administration. Urology 1998; 47: 740.