表 1 UTI 7 8 10 UTI UTI Escherichia coli (70 80%) Escherichia coli (50%) Enterococcus spp. Enterococcus spp. Klebsiella spp. Pseudomonas aeruginosa Pro



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総 説 26 10 6 26 10 7 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 1 6 3 2 UTI UTI 1. 疫 学 5 UTI 7 UTI 30 l 3 UTI 20 3 5 8 UTI 8 7 8 2 1 6 2 1 5 1 10 1 8 UTI 80 50 1 8 2. 分 類 UTI UTI UTI UTI 3 5 6 9 acute pyelonephritis acute focal bacterial nephritis; AFBN UTI 1 10 UTI CRP 1 10 53 84 44 92 3 573-1191 2-5-1 Key words / / / / 35 105

表 1 UTI 7 8 10 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 90 100% 50 70% UTI 1 10 UTI UTI 1 10 3 6 1 6 1 10 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 10 12 UTI 10 11 UTI Host- Parasite relationship 10 13 UTI 1. 病 原 体 因 子 ( 細 菌 の 付 着 性 と 病 原 性 ) UTI 表 1 1 10 UTI Escherichia coli E.coli 1 10 E.coli P 10 13 E.coli lipopolysaccharide toll-like receptor TLR 4 TLR4 CD14 nuclear factor κb NF-κB IL-6 IL-8 transforming growth factor β TGFβ 10 19 IL-6 IgA B C C-reactive protein; CRP 20 21 IL-8 CXCR1 CXCR2 20 21 2. 宿 主 因 子 ( 内 因 性 感 染 防 御 機 構 ) 36 106

microbiome Uromodulin Tamm-Horsfall protein 11 15 11 11 22 23 11 22 23 7 11 22 24 α β 11 α 22 26 β 22 26 25 26 11 27 11 28 29 7 11 30 33 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 9 8 1 10 UTI 9 8 図 1 34 UTI 2. 検 査 所 見 UTI 10 5 /m 5 10 4 /m 7 8 10 7 10 7 8 7.5 29 7 10 American Academy of Pediatrics: AAP 37 107

CFU 10 3 /m 95 99 35 10 400 5 7 8 10 2011 AAP UTI 5 10 4 /m 8 UTI 36 36 UTI 37 UTI 129 88 4.1 UTI 18 14.0 40 VUR 38 UTI UTI VUR 2007 National Institute for Health and Clinical Excellence: NICE UTI 37 UTI 80 85 7 10 83 78 53 98 7 1 UTI UTI Kova slide KOVA slide 10 1 91 98 10 39 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 1 8 1 DMSA dimercaptosuccininc acid 41 45 UTI 41 42 UTI 9 CT MRI 9 UTI の 治 療 UTI 7 8 UTI UTI 38 108

図 2 UTI ESBL 2006 2012 UTI 243 ESBL 45 18.5 15.0 22.7 UTI 24 UTI UTI 7 1. 下 部 UTI の 治 療 E.coli 3 5 7 8 10 ST + 10 2. 上 部 UTI の 治 療 UTI E.coli 2 3 7 UTI KOVA slide E. feacalis 7 10 E.coli E. feacalis 7 8 48 72 E.coli UTI Extended-spectrum beta-lactamases ESBL 9 2006 2012 UTI 243 ESBL 45 18.5 図 2 46 E.coli 19 Klebsiella 47 ESBL 46 ESBL 9 3 7 14 7 8 AFBN 3 7 10 7 10 RCT 47 39 109

表 2 UTI 7 8 37 AAP NICE 2007 1999 2011 48 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 1 10 1.VUR の 検 索 と 管 理 1 VUR VUR 48 52 VUR 100 9 VUR 9 10 VUR 48 52 VUR VUR VUR VUR 0.5 1.0 8 70 7 8 VUR low grade 7 53 VUR VUR overactive bladder; OAB 48 52 2 VUR VUR voiding cystourethrography; VCUG VUR UTI 8 50 1999 AAP 7 2 2 UTI VCUG 2007 NICE 37 2011 AAP 8 UTI VCUG 表 2 8 37 VCUG 8 DMSA VCUG top-down approach VCUG 41 44 DMSA 40 110

54 UTI VUR VUR VUR 41 45 UTI UTI VUR 55 4 200 306 35 VUR VUR 46 85 66 71 55 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 5 30 7 52 5 RN 7 8 VUR RN UTI 56 UTI RN UTI UTI 24 48 57 UTI 58 UTI UTI UTI 112 0.5 76 UTI 4 DMSA 59 74 38 60 36 77 22 19 26 p<0.001 59 ROC 31 84.2 92.0 59 UTI 31 VUR DMSA 2. 下 部 尿 路 異 常 の 検 索 UTI VUR 3 4 lazy bladder syndrome 60 60 41 111

1 VCUG VCUG VUR 60 VUR 60 2 VUR lower urinary tract dysfunction; LUTD 60 63 LUTD dysfunctional elimination syndrome DES 60 63 DES OAB 60 LUTD VUR LUTD VUR 1 5 3 18 LUTD 1 52 3 77 60 63 LUTD VUR UTI 60 63 LUTD α 60 63 LUTD VUR 1 50 60 60 63 UTI LUTD 64 5 UTI 24 6.8 17 表 3 LUTD 64 21 88 LUTD 12 50 VUR 4 17 III 64 14 58.3 5 mm 13 54 64 LUTD VUR UTI I II III IV V VI VII VIII IX X 表 3 1 3 1 8 72 3.UTI と VUR の 管 理 UTI 7 8 VUR UTI 9 1 VUR VUR 8 70 7 8 UTI UTI 7 8 2006 表 4 52 61 62 65 67 68 The RIVUR randomized intervention for children with vesicoureteral reflux trial UTI VUR ST 37.5 mg/kg/day 50 69 UTI 7 8 LUTD 42 112

表 4 VUR n VUR Grade UTI Garin, EH 65), 2006 218 3m-18y I-III 1y NS NS Conway, PH 61), 2007 611 <6y I-V (5 y) NS NA Pennesi, M 62), 2008 100 <30m II-IV 4 y NS NS Montini, G 66), 2008 338 2m- 7y I-III 1 y NS NS Rossey-Kesler, G 52), 2008 225 1m- 3y I-III 18 m grade III NA Craig JC 67), 2009 564 <18y 42 VUR 12 m 6% NA VUR, vesicoureteral reflux α 60 2 VUR 95 98 70 break-through UTI UTI VUR 70 grade III V VUR break-through UTI 60 6 7 8 70 VUR DMSA Deflux 1 I II VUR 78.5 V 51 VUR 2 3 85 71 おわりに 2 UTI UTI 80 85 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: 1967 1976. 2 Bachur RG, Harper MB: Predictive model for serious bacterial infections among infants younger than 3 months of age. Pediatrics 2001; 108: 311 316. 3 Beetz R: May we go on with antibacterial prophylaxis for urinary tract infections? Pediatr Nephrol 2006; 21: 5 13. 4 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: S233 239. 5 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: 232 234. 6 Mårild S, Jodal U: Incidence rate of first-time symptomatic urinary tract infection in children under 6 years of age. Acta Paediatr 1998; 87: 549 552. 7 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: 843 852. 8 Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB: Urinary tract 献 43 113

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: 595 610. 9 2012. 10 2003. 11 Spencer JD, Schwaderer AL, Becknell B, Watson J, Hains DS: The innate immune response during urinary tract infection and pyelonephritis. Pediatr Nephrol 2014; 29: 1139 1149. 12 Sobel JD: Pathogenesis of urinary tract infection. Role of host defenses. Infect Dis Clin North Am 1997; 11: 531 549. 13 Brading AF, Turner WH: The unstable bladder: towards a common mechanism. Br J Urol 1994; 73: 3 8. 14 Asscher AW, Sussman M, Waters WE, Davis RH, Chick S: Urine as a medium for bacterial growth. Lancet 1996; 2: 1037 1041. 15 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. 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Genomics 1997; 43: 316 320. 26 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: 423 430. 27 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: 636 641. 28 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: 3776 3781. 29 Park CH, Valore EV, Waring AJ, Ganz T: Hepcidin, a urinary antimicrobial peptide synthesized in the liver. 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a normal DMSA obviate the performance of voiding cystourethrography in evaluation of young children after their first urinary tract infection? J Pediatr 2007; 150: 96 99. 46 β ESBL Fosfomycin 2013; 22: 217. 47 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: 195 202. 48 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: 386. 49 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: 1019 1022. 50 Sjöström S, Sillén U, Bachelard M, Hansson S, Stokland E: Spontaneous resolution of high grade infantile vesicoureteral reflux. J Urol 2004; 172: 694 698; discussion 699. 51 Willemsen J, Nijman RJ: Vesicoureteral reflux and videourodynamic studies: results of a prospective study. Urology 2000; 55: 939 943. 52 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: 1699 1702; discussion 1702 1703. 53 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: 674 679; discussion 679. 54 DMSA VCUG 2011; 24: 8 12. 55 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: 251 255. 56 Jakobsson B, Svensson L: Transient pyelonephritic changes on 99mTechnetium-dimercaptosuccinic acid scan for at least five months after infection. Acta Paediatr 1997; 86: 803 807. 57 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: 115 118. 58 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: 565 570. 59 2014; 118: 283. 60 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: 1134 1144. 61 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: 179 186. 62 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: e1489 1494. 63 Hodson EM: Interventions for primary vesicoureteric reflux. 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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 46 116