研究背景與目的:泌尿道的感染在嬰幼兒期是一種常見的細菌性感染疾病。先前的研究報告顯示在十歲以前的兒童，其泌尿道感染的發生率約為2-8%/每人每年。在罹患泌尿道感染且伴有發燒的病中，若同時使用腎臟同位素核子掃描(99mTc-dimercaptosuccinic acid)來檢查所有的病童，則顯示有高達55-75%的兒童其腎臟實質組織會出現急性發炎的病灶。並且其中約有將近10-65%的病童最後會導致永久性的腎臟細胞的傷害與腎臟結疤(renal scarring)的產生。且一旦形成了廣泛的腎臟結疤其可能後續出現的併發症包括高血壓、蛋白尿與腎功能的異常甚或衰竭等的發生。其中約有10-24%的兒童最後可能因此慢慢進展到慢性腎衰竭或尿毒症等所謂末期腎臟疾病(end-stage renal disease)的病況。細胞激素如介白素interleukin-(IL)1β、IL-6 與IL-8 等在人體遭受細菌感染後所引起的一連串發炎反應過程中扮演了一個很重要的角色。然而有關到底是何種細胞激素參與了兒童泌尿道感染的急性期炎症反應與後續腎臟結疤的形成，目前有關這個領域研究探討的文獻報告並不多且結果互異仍有爭議。我們設計此研究計畫的目的是希望探討在罹患第一次發燒性泌尿道感染的病童中，以腎臟同位素核子掃瞄來確認所有屬於急性腎盂腎炎的兒童。並檢查急性腎盂腎炎的病童其急性期血液或尿液中細胞激素IL-1β、IL-6 與 IL-8 等的濃度反應；另外亦探討這些細胞激素和發炎反應標記、膀胱輸尿管迴流及後續形成腎臟結疤之間存在的關聯性。
研究方法:本研究計畫依照所探討細胞激素種類的不同分為兩大部分:1)IL-6 與IL-8 的研究: 收集了78 個嬰幼兒(年齡從一個月到十歲)符合診斷為罹患第一次發燒性泌尿道感染的住院病童。測量發炎反應標記包括發燒、C-反應性蛋白質(CRP)與周邊白血球數等以及血清與尿液中IL-6 與 IL-8 在這些泌尿道感染病童的變化。所有收案病童第一次的尿液與血液檢體的收集是在住院後抗生素使用前，第二次尿液與血液檢體的收集則是在接受治療10-14 天後再收集。所有收案病童在住院的第一星期內安排腎臟超音波與腎臟核子掃描檢查。排尿性膀胱尿道攝影檢查則是在治療完成後一至二個星期後再施行。依照腎臟核子掃瞄結果，將78 個病童分為兩組，一組符合急性腎盂腎炎的診斷(n = 42)；另一組則屬於下泌尿道感染(n = 36)，並另外收集20 個為其它各種發燒性疾病的住院病童與12 個健康兒童作為對照組。尿液與血液中的細胞激素濃度是以enzyme-linked immunosorbent assay (ELISA)的方法來測量。追蹤性腎臟核子掃瞄則是在第一次腎臟感染六至十二個月後再施行一次以偵測是否有腎臟結疤的存在。 2)IL-1β 的研究: 收集了75 個嬰幼兒
(年齡從1-121 個月) 且符合診斷為第一次發燒性泌尿道感染的住院病童。探討尿液IL-β 濃度和發炎反應標記包括發燒、CRP、
周邊白血 球數與嗜中性球數等在這些泌尿道感染病童的變化與相互關係。所有收案病童第一次的尿液或血液檢體的收集是在住院後使用抗生素治療前第二次尿液檢體的收集則是在接受治療10-14 天後再收集。並依照腎臟核子掃瞄確認的結果，75 個病童再分為兩組，一組為急性腎盂腎炎(n = 41)；另一組則屬於下泌尿道感染(n = 34)，另外收集20 個其它各種發燒性疾病的住院病童作為對照組。罹患腎臟感染的這組病童則於六至十二個月後再施行一次追蹤性腎臟核子掃瞄以偵測是否出現了腎臟結疤。
研究結果: 1)血清與尿液IL-6 與IL-8 的研究:急性腎盂腎炎病童的發燒程度、CRP 值、周邊白血球數均明顯的高於下泌尿道感染病童(P <0.001)。急性腎盂腎炎病童其急性期血清與尿液中IL-6 與IL-8 的濃度皆顯著的高於下泌尿道感染病童、非腎臟的發熱性疾病的病童與健康兒童(P <0.001)。治療前後IL-6 與IL-8 濃度變化的比較，急性腎盂腎炎病童與下泌尿道感染病童其治療前血清與尿液中
IL-6 與IL-8 的濃度也都顯著的高於治療後的濃度(P <0.001)。在接受追蹤性腎臟核子掃瞄檢查的39 個急性腎盂腎炎病童中，偵測到其中的12 個病童(30.8%)出現了腎臟結疤。而這些有腎臟結疤的病童，我們發現其急性期血清與尿液中IL-6的濃度顯著的高於其他沒有腎臟結疤的病童(P <0.05 與 P <0.01)。並且有腎臟結疤的病童其平均年齡亦顯著的小於其他沒有腎臟結疤的病童(P <0.05)。 2)尿液IL-1β 的研究:急性腎盂腎炎病童的發燒程度、CRP 值、周邊白血球數與嗜中性白血球數均顯著的比下泌尿道感染病童(P <0.001)。急性腎盂腎炎病童其急性期尿液中IL-1β 的濃度顯著的高於下泌尿道感染病童與其他發燒性疾病的病童(P <0.001)。急性腎盂腎炎病童與下泌尿道感染病童兩者治療前尿液中IL-1β 的濃度也都顯著的高於治療後的濃度(P <0.001)。尿液中IL-1β 的濃度與發燒、CRP周
邊白血球數、嗜中性白血球數與尿液中白血球數(leucocyturia)均呈現顯著的正相關。在接受追蹤性腎臟核子掃瞄檢查的41 個急性腎盂腎炎病童中，偵測到其中12 個病童(29.3%)最後出現了腎臟結疤。而在這些有腎臟結疤的病童中，其急性期尿液中IL-1β 的濃度顯著的低於其他沒有腎臟結疤的病童(P <0.01)。
研究結論:本研究結果顯示在急性腎盂腎炎病童其發燒程度、CRP 值、周邊白血球數與嗜中性白血球數均顯著的高於下泌尿道感染病童。急性期血清或尿液中的IL-1β、IL-6 或IL-8 的濃度顯著的上升可作為診斷兒童罹患第一次發熱性急性腎盂腎炎的一個有用且可信賴的診斷標記。年齡較小的嬰幼兒罹患急性腎盂腎炎後其發生腎臟結疤的危險性增加。在急性腎盂腎炎病童，其急性期尿液中的IL-1β
和血清與尿液中的IL-6 的濃度變化可作為預測後續發生臟結疤的危險指標。

Backgrounds and Objectives: Urinary tract infection (UTI) is a common clinical disorder in younger infants and children. The cumulative incidence of UTIs has been reported to be 2-8% by 10 years of age. Isotope uptake studies with 99mTc-dimercaptosuccinic acid (DMSA) scan have shown that the renal parenchyma is affected in about 55-75% of children with febrile UTI. Approximately 10-65% of these children may result in permanent renal damage and renal scarring after the infection. Further, renal scarring later in life may lead to the development of subsequent hypertension, proteinuria and renal insufficiency that is one of the major causes of end-stage renal disease in many countries. The inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-8 play an important role in response to bacterial infection and the progression of renal inflammation. However, there have been relatively few studies of the role of these cytokines in children with acute pyelonephritis and subsequent renal scarring. The aims of this prospective study were to investigate the IL-1β, IL-6 and IL-8 responses in children with first-time acute pyelonephritis confirmed by DMSA scan, and also to evaluate the relationships of cytokines with other inflammatory markers, vesicoureteral reflux as well as renal
scarring.
Methods: The protocol was designed into two parts according to the variety of cytokines: 1) A total of 78 children aged 1 month to 10 years with a diagnosis of first-time febrile UTI were included. The following inflammatory markers were
assessed: fever; white blood cells (WBC) count; C-reactive protein (CRP); as well as serum and urine IL-6 and IL-8. Serum and urine samples were collected for IL-6 and IL-8 measurements by enzyme-linked immunosorbent assay (ELISA) before and after antibiotic treatment of the infection. All children underwent renal ultrasound examination and DMSA scan for detection of anomalies of the urinary tract and the
presence of pyelonephritic lesions within the first 1 week of hospitalization. The patients were divided into the acute pyelonephritis group (n = 42) and the lower UTI group (n = 36) according to the results of DMSA scans. We also collected 20 children with other febrile illnesses and 12 healthy children with age- and sex-matched served as conntrols. Follow-up DMSA scans were performed again at 6-12 months after the initial infection to detect renal scarring. 2)A total of 75 children aged 1-121 months with
a diagnosis of first-time febrile UTI were studied. The following inflammatory markers were assessed: fever; CRP; WBC count; neutrophil count; and urine IL-1β. Urine samples were collected for IL-1β measurement by ELISA before and after antibiotic treatment of the infection. The 75 children were divided into acute pyelonephritis (n = 41) and lower UTI (n = 34) groups according to the findings of
DMSA scans. Follow-up DMSA scan was performed at 6-12 months after the acute pyelonephritis to detect renal scarring. Twenty children with other febrile illnesses served as non-renal febrile controls.
Results: 1) Serum and urine IL-6 and IL-8 studies: Fever, WBC count and CRP levels were significantly higher in children with acute pyelonephritis than in those with lower UTI (all P &lt;0.001). There were significant differences in the initial serum and urine levels of IL-6 and IL-8 among the children with acute pyelonephritis and lower UTI and non-renal febrile controls and healthy controls (all P &lt;0.001). Compared to post treatment, the initial serum and urine IL-6 and IL-8 levels were significantly higher for both the acute pyelonephritis (P &lt;0.001) and lower UTI groups (P &lt;0.001). Renal scarring was detected at the follow-up DMSA scans in 12 (30.8%) of the 39 children with follow-up DMSA scans. Both serum and urine IL-6 levels during the acute phase of pyelonephritis were significantly higher in the children with renal scarring than in those without (P &lt;0.05 and P &lt;0.01, respectively). The mean age of children with renal scarring was significantly lower compared to those without (P &lt;0.05). 2) Urine IL-1β study: Fever, WBC count, neutrophil count and CRP were significantly higher in the children with acute pyelonephritis than in those with lower UTI (all P &lt;0.001). The initial urine IL-1β levels of children with acute pyelonephritis were significantly higher when compared with lower UTI and non-renal febrile controls (P &lt;0.001). The children with acute pyelonephritis had significantly higher initial urine IL-1β levels than after appropriate antibiotic treatment (P &lt;0.001). Urine IL-1β in children with acute pyelonephritis was positively correlated with fever, CRP, WBC, neutrophil and leucocyturia. Renal scarring wasfound in 12 (29.3%) of the 41 children with acute pyelonephritis. Initial urine IL-1β levels were significantly lower in children with renal scarring than in those without renal scarring (P &lt;0.01).
Conclusions: These results demonstrate that systemic inflammatory markers (fever, CRP, WBC count and neutrophil count) were significantly higher in children with acute pyelonephritis than in those with lower UTI. Serum or urine IL-1β, IL-6 and IL-8 levels are useful diagnostic markers for early recognition of acute pyelonephritis in febrile children. Furthermore, our findings demonstrate that in young children with first-time acute pyelonephritis, elevations of the acute-phase serum and urine IL-6 levels were correlated with the development of subsequent renal scarring. Our results also indicate that acute urine IL-1β level might be used as a predictor of later renal scarring.

Contents
Abstract in Chinese------------------------------------------------------------------------1
Abstract in English-------------------------------------------------------------------------5
Chapter 1. Introduction 9
1.1. Backgrounds-----------------------------------------------------------------------------9
1.2. DMSA Scintigraphy-------------------------------------------------------------------10
1.3. Proinflammatory Cytokines in UTI--------------------------------------------------12
1.3.1. IL-1β--------------------------------------------------------------------------------12
1.3.2. IL-6---------------------------------------------------------------------------------14
1.3.3. IL-8---------------------------------------------------------------------------------15
1.4. The Objectives of This Study--------------------------------------------------------16
Chapter 2. Methods and Materials 17
2.1. Subjects and Study Design for IL-6 and IL-8--------------------------------------17
2.2. Subjects Selection and Study Design for IL-1β------------------------------------18
2.3. Laboratory Analysis--------------------------------------------------------------------18
2.4. Renal Scintigraphy Study-------------------------------------------------------------19
2.4.1. DMSA protocol--------------------------------------------------------------------19
2.4.2. Definition of DMSA scans findings---------------------------------------------20
2.5. Radiological Studies--------------------------------------------------------------------21
2.5.1. Renal ultrasound examination----------------------------------------------------21
2.5.2. Voiding cystourethrography (VCUG) examination----------------------------21
2.6. Measurement of Cytokines------------------------------------------------------------ 22
2.7. Statistical Analysis----------------------------------------------------------------------23
Chapter 3. Results 25
3.I. Results of IL-6 and IL-8 Studies----------------------------------------------------25
3.I.1. Patient characteristics---------------------------------------------------------------25
3.I.2. Laboratory tests---------------------------------------------------------------------25
3.I.3. Radiological findings---------------------------------------------------------------26
3.I.4. Serum IL-6 and IL-8 levels--------------------------------------------------------26
3.I.5. Urine IL-6 and IL-8 levels---------------------------------------------------------28
3.I.6. Serum and urine IL-6 and IL-8 levels in relation to VUR--- -----------------29
3.I.7. Correlations of IL-6 and IL-8 levels with inflammatory markers------------29
3.I.8. Optimal cutoff values of inflammatory markers, IL-6 and IL-8 for the
diagnosis of acute pyelonephritis-------------------------------------------------29
3.I.9. IL-6 and IL-8 levels in relation to renal scarring-------------------------------30
3.II. Results of IL-1β Study---------------------------------------------------------------31
3.II.1. Patient characteristics--------------------------------------------------------------31
3.II.2. Laboratory findings----------------------------------------------------------------32
3.II.3. Radiological findings--- ----------------------------------------------------------32
3.II.4. Urine IL-1β levels and urine IL-1β/creatinine ratio in children with
acute pyelonephritis and lower UTI----------------------------------------------33
3.II.5. Urine IL-1β levels and urine IL-1β/creatinine ratio in VUR-----------------34
3.II.6. Correlations of urine IL-1β level with inflammatory markers, sex and age
in children with acute pyelonephritis--------------------------------------------34
3.II.7. Optimal cutoff values of inflammatory markers and urine IL-1β level
for the diagnosis of acute pyelonephritis-----------------------------------------35
3.II.8. Urine IL-1β levels in children with renal scarring-----------------------------35
Chapter 4. Discussion 37
4.1. The diagnosis of acute pyelonephritis in children----------------------------------37
4.2. The detective rate of cytokines in children with febrile UTI---------------------38
4.3. Inflammatory markers in children with acute pyelonephritis--------------------38
4.4. Relationship of cytokines to laboratory findings-----------------------------------39
4.5. IL-6 and IL-8 responses in children with acute pyelonephritis------------------40
4.6. IL-1β response in children with acute pyelonephritis-----------------------------42
4.7. Cytokines levels in acute pyelonephritis documented by DMSA scan----------43
4.8. Cytokines in children with VUR-----------------------------------------------------45
4.9. Cytokines in children with renal scarring------------------------------------------ 47
4.9.1. IL-1β and renal scarring--------------------------------------------------------47
4.9.2. IL-6 and renal scarring----------------------------------------------------------49
4.9.3. IL-8 and renal scarring----------------------------------------------------------51
Chapter 5. Conclusions and Suggestions 54
Chapter 6. Tables 56
Table I.1. Clinical characteristics of children with acute pyelonephritis and
lower UTI ------------------------------------------------------------------------56
Table I.2. Detective rates of the initial serum and urine IL-6 and IL-8 in children
with acute pyelonephritis, lower UTI, non-renal febrile controls and
healthy controls------------------------------------------------------------------57
Table I.3. Serum and urine levels of IL-6 and IL-8 in children with acute pyelonephritis,
lower UTI, non-renal febrile controls and healthy controls---------------------58
Table I.4. The initial serum and urine levels of IL-6 and IL-8 in children with
and without VUR----------------------------------------------------------------59
Table I.5. Correlations between serum and urine IL-6 and IL-8 levels and
inflammatory markers in children with acute pyelonephritis-------------60
Table.I.6. Sensitivity, specificity, PPV and NPV of inflammatory markers,
IL-6 and IL-8 for the diagnosis of acute pyelonephritis--------------------61
Table I.7. The initial serum and urine levels of IL-6 and IL-8 in relation to the
children with renal scarring---------------------------------------------------62
Table II.1. Clinical characteristics of children with acute pyelonephritis and
lower UTI in IL-1β study-----------------------------------------------------63
Table II.2. Detective rates of the initial urine IL-β in children with acute
pyelonephritis, lower UTI, non-renal febrile controls---------------------64
Table II.3. Urine IL-1β levels in children with acute pyelonephritis and lower
UTI and non-renal febrile controls ------------------------------------------65
Table II.4. Initial urine IL-1β levels in children with VUR----------------------------66
Table II.5. Correlation and multiple linear regression of urine IL-1β with
inflammatory markers, sex and age in children with acute
pyelonephritis ------------------------------------------------------------------67
Table II.6. Sensitivity and specificity of inflammatory markers and urine IL-1β
for the diagnosis of acute pyelonephritis------------------------------------68
Table II.7. Initial urine IL-1β levels in children with renal scarring-----------------69
Chapter 7. Figures 70
Fig. 1. A case of normal DMSA scan --------------------------------------------------70
Fig. 2. A case of acute pyelonephritis --------------------------------------------------70
Fig. 3. A case of renal scarring-----------------------------------------------------------71
Fig. 4. A case of moderate hydronephrosis---------------------------------------------71
Fig. 5. A case of duplex kidney----------------------------------------------------------72
Fig. 6. A case of ureterocele--------------------------------------------------------------72
Fig. 7. A case of normal VCUG examination------------------------------------------73
Fig. 8. A case of VUR, grade II----------------------------------------------------------73
Fig. 9. A case of VUR, grade III---------------------------------------------------------74
Fig. 10. A case of VUR, grade IV--------------------------------------------------------74
Fig. 11. A case of VUR, grade V---------------------------------------------------------75
Fig. 12 A and B. A case of acute pyelonephritis with subsequent renal scarring
at 8 months later-------------------------------------------------------------------76
Fig. 13. Urine IL-1β levels in children with acute pyelonephritis and lower
UTI and non-renal febrile controls--------------------------------------------77
References 78
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