表 1 UTI UTI UTI Escherichia coli (70 80%) Escherichia coli (50%) Enterococcus spp. Enterococcus spp. Klebsiella spp. Pseudomonas aeruginosa Pro

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1 総 説 要 旨 小 児 の UTI の 疫 学 と 分 類 UTI UTI UTI UTI VUR UTI UTI UTI KOVA slide UTI UTI VUR VUR はじめに urinary tract infection; UTI UTI UTI 1. 疫 学 5 UTI 7 UTI 30 l 3 UTI UTI UTI 分 類 UTI UTI UTI UTI acute pyelonephritis acute focal bacterial nephritis; AFBN UTI 1 10 UTI CRP Key words / / / /

2 表 1 UTI UTI UTI Escherichia coli (70 80%) Escherichia coli (50%) Enterococcus spp. Enterococcus spp. Klebsiella spp. Pseudomonas aeruginosa Proteus mirabilis Klebsiella. spp Pseudomonas aeruginosa Proteus mirabilis Streptococcus aureus % 50 70% UTI 1 10 UTI UTI UTI UTI UTI vesicoureteral reflux; VUR 1 10 UTI UTI UTI reflux nephropathy; RN 1 6 UTI 小 児 の UTI の 病 因 と 病 態 UTI UTI UTI UTI Host- Parasite relationship UTI 1. 病 原 体 因 子 ( 細 菌 の 付 着 性 と 病 原 性 ) UTI 表 UTI Escherichia coli E.coli 1 10 E.coli P E.coli lipopolysaccharide toll-like receptor TLR 4 TLR4 CD14 nuclear factor κb NF-κB IL-6 IL-8 transforming growth factor β TGFβ IL-6 IgA B C C-reactive protein; CRP IL-8 CXCR1 CXCR 宿 主 因 子 ( 内 因 性 感 染 防 御 機 構 )

3 microbiome Uromodulin Tamm-Horsfall protein α β 11 α β 小 児 の UTI の 臨 床 所 見 と 検 査 所 見 1. 臨 床 所 見 UTI UTI 1 10 UTI 図 1 UTI n=84 UTI UTI 9 8 図 1 34 UTI 2. 検 査 所 見 UTI 10 5 /m /m American Academy of Pediatrics: AAP

4 CFU 10 3 /m AAP UTI /m 8 UTI UTI 37 UTI UTI VUR 38 UTI UTI VUR 2007 National Institute for Health and Clinical Excellence: NICE UTI 37 UTI UTI UTI Kova slide KOVA slide UTI 10 UTI KOVA slide UTI UTI 40 KOVA slide E.coli Klebsiella Enterococcus feacalis 10 2 UTI UTI UTI UTI RN UTI 2 UTI 7 CRP UTI DMSA dimercaptosuccininc acid UTI UTI 9 CT MRI 9 UTI の 治 療 UTI 7 8 UTI UTI

5 図 2 UTI ESBL UTI 243 ESBL UTI 24 UTI UTI 7 1. 下 部 UTI の 治 療 E.coli ST 上 部 UTI の 治 療 UTI E.coli UTI KOVA slide E. feacalis 7 10 E.coli E. feacalis E.coli UTI Extended-spectrum beta-lactamases ESBL UTI 243 ESBL 図 2 46 E.coli 19 Klebsiella 47 ESBL 46 ESBL AFBN RCT

6 表 2 UTI AAP NICE UTI UTI UTI 6 DMSA 4 6 AAP, American Academy of Pediatrics; NICE, National Institute for Health and Clinical Excellence; UTI, urinary tract infection; UTI, serious illness; poor urinary flow, abdominal or bladder mass, raised serum creatinine level, septicemia, non-e.coli organism from urine culture, and poor response to suitable antibiotics AAP 7 2 RCT 47 3 UTI を 起 こした 乳 幼 児 に 対 する 基 礎 疾 患 の 検 索 UTI UTI RN VUR congenital anomalies of the kidney and urinarytract; CAKUT CAKUT UTI 1 10 UTI UTI CAKUT VUR の 検 索 と 管 理 1 VUR VUR VUR VUR 9 10 VUR VUR VUR VUR VUR VUR low grade 7 53 VUR VUR overactive bladder; OAB VUR VUR voiding cystourethrography; VCUG VUR UTI AAP UTI VCUG 2007 NICE AAP 8 UTI VCUG 表 VCUG 8 DMSA VCUG top-down approach VCUG DMSA

7 54 UTI VUR VUR VUR UTI UTI VUR VUR VUR VUR 70 DMSA UTI VCUG UTI VUR UTI VCUG UTI VCUG bottom-up approach top-down approach VCUG VUR grade 7 10 UTI top-down approach bottom-up approach 8 37 VCUG 3 VUR RN RN VUR UTI VUR UTI VUR RN RN RN 7 8 VUR RN UTI 56 UTI RN UTI UTI UTI 58 UTI UTI UTI UTI 4 DMSA p< ROC UTI 31 VUR DMSA 2. 下 部 尿 路 異 常 の 検 索 UTI VUR 3 4 lazy bladder syndrome

8 1 VCUG VCUG VUR 60 VUR 60 2 VUR lower urinary tract dysfunction; LUTD LUTD dysfunctional elimination syndrome DES DES OAB 60 LUTD VUR LUTD VUR LUTD LUTD VUR UTI LUTD α LUTD VUR UTI LUTD 64 5 UTI 表 3 LUTD LUTD VUR 4 17 III mm LUTD VUR UTI I II III IV V VI VII VIII IX X 表 UTI と VUR の 管 理 UTI 7 8 VUR UTI 9 1 VUR VUR UTI UTI 表 The RIVUR randomized intervention for children with vesicoureteral reflux trial UTI VUR ST 37.5 mg/kg/day UTI 7 8 LUTD

9 表 4 VUR n VUR Grade UTI Garin, EH 65), m-18y I-III 1y NS NS Conway, PH 61), <6y I-V (5 y) NS NA Pennesi, M 62), <30m II-IV 4 y NS NS Montini, G 66), m- 7y I-III 1 y NS NS Rossey-Kesler, G 52), m- 3y I-III 18 m grade III NA Craig JC 67), <18y 42 VUR 12 m 6% NA VUR, vesicoureteral reflux α 60 2 VUR break-through UTI UTI VUR 70 grade III V VUR break-through UTI VUR DMSA Deflux 1 I II VUR 78.5 V 51 VUR おわりに 2 UTI UTI UTI KOVA slide UTI UTI VUR VUR VCUG UTI VUR UTI 文 1 Saadeh SA, Mattoo TK: Managing urinary tract infections. Pediatr Nephrol 2011; 26: Bachur RG, Harper MB: Predictive model for serious bacterial infections among infants younger than 3 months of age. Pediatrics 2001; 108: Beetz R: May we go on with antibacterial prophylaxis for urinary tract infections? Pediatr Nephrol 2006; 21: Chesney RW, Carpenter MA, Moxey-Mims M, Nyberg L, Greenfield SP, Hoberman A, Keren R, Matthews R, Matoo TK; members of the RIVUR Steering Committee: Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR): background commentary of RIVUR investigators. Pediatrics 2008; 122 Suppl 5: S Hellström A, Hanson E, Hansson S, Hjälmås K, Jodal U: Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 1991; 66: Mårild S, Jodal U: Incidence rate of first-time symptomatic urinary tract infection in children under 6 years of age. Acta Paediatr 1998; 87: Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Urinary Tract Infection. Pediatrics 1999; 103: Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB: Urinary tract 献

10 infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011; 128: Spencer JD, Schwaderer AL, Becknell B, Watson J, Hains DS: The innate immune response during urinary tract infection and pyelonephritis. Pediatr Nephrol 2014; 29: Sobel JD: Pathogenesis of urinary tract infection. Role of host defenses. Infect Dis Clin North Am 1997; 11: Brading AF, Turner WH: The unstable bladder: towards a common mechanism. Br J Urol 1994; 73: Asscher AW, Sussman M, Waters WE, Davis RH, Chick S: Urine as a medium for bacterial growth. Lancet 1996; 2: Wolfe AJ, Toh E, Shibata N, Rong R, Kenton K, Fitzgerald M, Mueller ER, Schreckenberger P, Dong Q, Nelson DE, Brubaker L: Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol 2012; 50: Song J, Abraham SN: Innate and adaptive immune responses in the urinary tract. Eur J Clin Invest 2008; 38 Suppl 2: Bäckhed F, Söderhäll M, Ekman P, Normark S, Richter-Dahlfors A: Induction of innate immune responses by Escherichia coli and purified lipopolysaccharide correlate with organ- and cell-specific expression of Toll-like receptors within the human urinary tract. Cell Microbiol 2001; 3: Gluba A, Banach M, Hannam S, Mikhailidis DP, Sakowicz A, Rysz J: The role of Toll-like receptors in renal diseases. Nat Rev Nephrol 2010; 6: Song J, Abraham SN: TLR-mediated immune responses in the urinary tract. Curr Opin Microbiol 2008; 11: Ragnarsdóttir B, Svanborg C: Susceptibility to acute pyelonephritis or asymptomatic bacteriuria: host-pathogen interaction in urinary tract infections. Pediatr Nephrol 2012; 27: Cheng CH, Lee YS, Tsau YK, Lin TY: Genetic polymorphisms and susceptibility to parenchymal renal infection among pediatric patients. Pediatr Infect Dis J 2011; 30: Ali AS, Townes CL, Hall J, Pickard RS: Maintaining a sterile urinary tract: the role of antimicrobial peptides. J Urol 2009; 182: Zasloff M: Antimicrobial peptides, innate immunity, and the normally sterile urinary tract. J Am Soc Nephrol 2007; 18: Ohlsson S, Ljungkrantz I, Ohlsson K, Segelmark M, Wieslander J: Novel distribution of the secretory leucocyte proteinase inhibitor in kidney. Mediators Inflamm 2001; 10: Liu L, Zhao C, Heng HH, Ganz T: The human beta-defensin-1 and alpha-defensins are encoded by adjacent genes: two peptide families with differing disulfide topology share a common ancestry. Genomics 1997; 43: Linzmeier RM, Ganz T: Human defensin gene copy number polymorphisms: comprehensive analysis of independent variation in alpha- and beta-defensin regions at 8p22-p23. Genomics 2005; 86: Chromek M, Slamová Z, Bergman P, Kovács L, Podracká L, Ehrén I, Hökfelt T, Gudmundsson GH, Gallo RL, Agerberth B, Brauner A: The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med 2006; 12: Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC: Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 2002; 100: Park CH, Valore EV, Waring AJ, Ganz T: Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276: Wang H, Schwaderer AL, Kline J, Spencer JD, Kline D, Hains DS: Contribution of structural domains to the activity of ribonuclease 7 against uropathogenic bacteria. Antimicrob Agents Chemother 2013; 57: Spencer JD, Schwaderer AL, Wang H, Bartz J, Kline J, Eichler T, DeSouza KR, Sims-Lucas S, Baker P, Hains DS: Ribonuclease 7, an antimicrobial peptide upregulated during infection, contributes to microbial defense of the human urinary tract. Kidney Int 2013; 83: Spencer JD, Schwaderer AL, Dirosario JD, McHugh KM, McGillivary G, Justice SS, Carpenter AR, Baker PB, Harder J, Hains DS: Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract. Kidney Int 2011; 80: Boix E, Nogués MV: Mammalian antimicrobial proteins and peptides: overview on the RNase A superfamily members involved in innate host defence. Mol Biosyst 2007; 3: ; 23: Downs SM: Technical report: urinary tract infections in febrile infants and young children. The Urinary Tract Subcommittee of the American Academy of Pediatrics Committee on Quality Improvement. Pediatrics 1999; 103: e ; 34: National lnstitute for Health and Clinical Excellence: Urinary tract infection in children. Diagnosis, treatment and long term management, ; 22: Hiraoka M, Hida Y, Mori Y, Tsukahara H, Ohshima Y, Yoshida H, Mayumi M: Quantitative unspun-urine microscopy as a quick, reliable examination for bacteriuria. Scand J Clin Lab Invest 2005; 65: ; 22: Rushton HG, Majd M, Chandra R, Yim D: Evaluation of 99mtechnetium-dimercapto-succinic acid renal scans in experimental acute pyelonephritis in piglets. J Urol 1988; 140: Tse NK, Yuen SL, Chiu MC, Lai WM, Tong PC: Imaging studies for first urinary tract infection in infants less than 6 months old: can they be more selective? Pediatr Nephrol 2009; 24: Hardy RD, Austin JC: DMSA renal scans and the top-down approach to urinary tract infection. 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11 a normal DMSA obviate the performance of voiding cystourethrography in evaluation of young children after their first urinary tract infection? J Pediatr 2007; 150: β ESBL Fosfomycin 2013; 22: Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER: Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003; 348: Montini G, Toffolo A, Zucchetta P, Dall Amico R, Gobber D, Calderan A, Maschio F, Pavanello L, Molinari PP, Scorrano D, Zanchetta S, Cassar W, Brisotto P, Corsini A, Sartori S, Da Dalt L, Murer L, Zacchello G: Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial. BMJ 2007; 335: Koff SA, Wagner TT, Jayanthi VR: The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol 1998; 160: Sjöström S, Sillén U, Bachelard M, Hansson S, Stokland E: Spontaneous resolution of high grade infantile vesicoureteral reflux. J Urol 2004; 172: ; discussion Willemsen J, Nijman RJ: Vesicoureteral reflux and videourodynamic studies: results of a prospective study. Urology 2000; 55: Palmer LS, Franco I, Rotario P, Reda EF, Friedman SC, Kolligian ME, Brock WA, Levitt SB: Biofeedback therapy expedites the resolution of reflux in older children. J Urol 2002; 168: ; discussion Roussey-Kesler G, Gadjos V, Idres N, Horen B, Ichay L, Leclair MD, Raymond F, Grellier A, Hazart I, de Parscau L, Salomon R, Champion G, Leroy V, Guigonis V, Siret D, Palcoux JB, Taque S, Lemoigne A, Nguyen JM, Guyot C: Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study. J Urol 2008; 179: ; discussion DMSA VCUG 2011; 24: Kimata T, Kitao T, Yamanouchi S, Tsuji S, Kino M, Kaneko K: Voiding cystourethrography is mandatory in infants with febrile urinary tract infection. Tohoku J Exp Med 2013; 231: Jakobsson B, Svensson L: Transient pyelonephritic changes on 99mTechnetium-dimercaptosuccinic acid scan for at least five months after infection. Acta Paediatr 1997; 86: Hiraoka M, Hashimoto G, Tsuchida S, Tsukahara H, Ohshima Y, Mayumi M: Early treatment of urinary infection prevents renal damage on cortical scintigraphy. Pediatr Nephrol 2003; 18: Oh MM, Kim JW, Park MG, Kim JJ, Yoo KH, Moon du G: The impact of therapeutic delay time on acute scintigraphic lesion and ultimate scar formation in children with first febrile UTI. Eur J Pediatr 2012; 171: ; 118: Peters CA, Skoog SJ, Arant BS, Copp HL, Elder JS, Hudson RG, Khoury AE, Lorenzo AJ, Pohl HG, Shapiro E, Snodgrass WT, Diaz M: Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children. J Urol 2010; 184: Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R: Recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. JAMA 2007; 298: Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, Ronfani L, Minisini S, Ventura A; North East Italy Prophylaxis in VUR study group: Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics 2008; 121: e Hodson EM: Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2007; 18: ; 117: Garin EH, Olavarria F, Garcia Nieto V, Valenciano B, Campos A, Young L: Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006; 117: Montini G, Rigon L, Zucchetta P, Fregonese F, Toffolo A, Gobber D, Cecchin D, Pavanello L, Molinari PP, Maschio F, Zanchetta S, Cassar W, Casadio L, Crivellaro C, Fortunati P, Corsini A, Calderan A, Comacchio S, Tommasi L, Hewitt IK, Da Dalt L, Zacchello G, Dall Amico R; IRIS Group: Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial. 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12 Current concept on urinary tract infections in children Takahisa Kimata, Shoji Tsuji, Kazunari Kaneko Department of Pediatrics, Kansai Medical University School of Medicine Urinary tract infection (UTI) is one of the most common infections encountered by pediatricians. UTI can occur either as bladder infections (lower UTI) or infections involving the kidneys (upper UTI). Upper UTI can be an important cause for end stage renal failure as it may lead to renal scarring without inappropriate management. Therefore, we should have high index of suspicion that all febrile infants without evident focal signs have upper UTI. To make a correct diagnosis of upper UTI, urine samples for culture should be obtained by bladder catheterization before administration of antimicrobial agents. Furthermore, bacteriuria should be screened using KOVA slide immediately for the prompt treatment which alleviate the risk of renal scarring. In order to prevent recurrent UTI, all infants with first upper UTI should be screened for underlying conditions predisposing to UTI, such as vesicoureteral reflux (VUR) or lower urinary tract dysfunctions by voiding cystourethrography (VCUG). If he/she has high grade VUR by VCUG, they should receive continuous antibiotic prophylaxis for recurrent UTI based on the recent findings from the RIVUR (Randomized Intervention for Children With Vesicoureteral Reflux) trial. Key words: renal ultrasound, urinary tract infection, 99m-technetium dimercaptosuccinic acid scintigraphy, vesicoureteral reflux, voiding cystourethrography

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