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October 23, 2010 2

目次

• 膀胱尿管逆流症どは

• 膀胱尿管逆流症の症状

• 治療法の選択枝

− 抗生物質− 膀胱鏡下の注入療法− 手術

• 参考文献

October 23, 2010 3

膀胱尿管逆流症とは？

Vesicoureteral Reflux (VUR)?

• 膀胱尿管逆流症は、膀胱内にある弁の異常で、尿か膀胱から片側または両側の尿管から腎臓へ逆流する病気です。

• １％の小児にみられ、乳幼児期に尿路感染症をきっかけに発見されます。

1Hensle 2007a

腎臓

尿の逆流が腎に及ぶ

弁の異常

正常な弁

膀胱

尿の正常な流れ

尿管

October 23, 2010 4

膀胱尿管逆流症とは?

• 程度がひどくなるほど、腎の瘢痕や他の合併症の頻度が増します。（文献2,3より）

• 逆流の程度は以下のように逆流の及ぶ範囲と尿管の形の変化によって分類されています。（文献１より）

1Jacobson 1999; 2Gonzalez 2005; 3Caione 2004

腎臓 腎臓腎臓腎臓腎臓

尿管 尿管 尿管 尿管 尿管

膀胱 膀胱 膀胱 膀胱 膀胱

グレードⅠ グレードⅡ グレードⅢ グレードⅣ グレードⅤ

October 23, 2010 5

膀胱尿管逆流症の症状

• 尿が腎臓へ逆流すると尿路感染症を発症する危険性を増す。1

• 尿路感染症が原因で発熱のあった子供の70%以上で腎盂腎炎を発症する。2

− これらの子供の半分以上（57%）が増悪する腎瘢痕を伴っている。

• 尿路感染症は腎瘢痕をきたし、その影響は若年性高血圧症や腎機能の破綻につながります。 3

1Panaretto 1999; 2Lin 2003; 3American Academy of Pediatrics 1999

October 23, 2010 6

膀胱尿管逆流症の症状• 尿路感染の発症回数ごとに腎瘢痕が増悪する1

• 腎障害は３~5歳頃におきる2

1American Academy of Pediatrics 1999; 2Sherbotie 1991

尿路感染回数

腎瘢痕のリスク

October 23, 2010 7

膀胱尿管逆流症の症状

• 腎瘢痕・障害の症状

1Smellie 1998; 2McNiece 2007; 3Kiberd 2002; 42007 USRDS Annual Data Report; 5 US Census Bureau.

These data are a graphical representation of the data within these studies.

逆流あり 逆流なし 逆流なし逆流あり

12歳までの高血圧

October 23, 2010 8

治療効果判定

治療の目的

•腎瘢痕を防ぐこと

治療効果の評価

• 米国では、逆流がなくなった状態を治癒の判断基準としている

October 23, 2010 9

膀胱尿管逆流症の治療

抗生物質の予防内服 従来の手術

逆流は治らない自然治癒率は5 – 13% 1

治癒治癒率 95%2

治癒一回での治癒率 69%3

膀胱鏡下注入療法

治療成功率は69%以上である。4,5

1Schwab 2002; 2Capozza 2004; 3Deflux Package Insert (link); 4Kirsch 2004;5Yu 2006

October 23, 2010 10

膀胱尿管逆流症の治療

5年間での消失率は13%

(グレードⅠ~Ⅲ)1

5年間での消失率は5%

(グレード IV~V)1

逆流の自然消失率

Spontaneous Resolution Calculator2,3

1Schwab 2002; 2www.deflux.com; 3AUA 1997 Guidelines

Deflux はグレードII-IVの逆流症に適した治療法である

腎臓 腎臓腎臓腎臓腎臓

尿管 尿管 尿管 尿管 尿管

膀胱 膀胱 膀胱 膀胱 膀胱

グレードⅠ グレードⅡ グレードⅢ グレードⅣ グレードⅤ

October 23, 2010 11

治療法の選択

抗生物質の予防内服 従来の手術

治癒一回での治癒率 69%

治療期間は 1 – 5 年*

治療費用 $2,2001(3年)

膀胱鏡下注入療法

治癒治癒率 95%

治療日数は3日以上の(入院)1

治療費用 $15,4101 治療費用 $6,5301

逆流は治らない自然治癒率は5 – 13%

* Optimal duration of antibiotic prophylaxis is undetermined but clinical studies have used 1-5 years

** Majority of patients are cured after a single treatment

治療日数は1日(通院)1

1Kobelt 2003

October 23, 2010 12

治療法の選択

抗生物質の効果

抗生物質を予防内服している膀胱尿管逆流症患児の尿路感染の再発率は5年間で29~42%であり、発熱を伴う尿路感染の発症率は平均22%である。2

1Garin 2006; 2Wheeler 2003

抗生物質の予防内服

治療期間は 1 – 5 年*

治療費用 $2,2001(3年)

逆流は治らない自然治癒率は5 – 13%

尿路感染のおこる確率

抗生物質予防内服あり 抗生物質予防内服なし

患者の割合（％）

October 23, 2010 13

治療法の選択

抗生物質耐性菌の発症の危険性

• Pathogens: Escherichia coli (78%), other gram-negative rods, Enterococcus, and other

organisms

• Prophylactic antimicrobials prescribed: cotrimoxazole (61%), amoxicillin, nitrofurantoin, and

other antimicrobials including first- through third-generation cephalosporins

1Conway 2007 These data are a graphical representation of the data within this study.

抗生物質の予防内服

治療期間は 1 – 5 年

治療費用 $2,2001(3年)

逆流は治らない自然治癒率は5 – 13%

抗生物質予防内服は耐性菌の発現を増加させる１

抗生物質予防内服あり 抗生物質予防内服なし

患者の割合（％）

October 23, 2010 14

治療法の選択

ABX includes: TMP-SMX, amoxicillin-clavulanate, ampicillin, cefazolin, ciprofloxacin,

and nitrofurantoin

抗生物質耐性

1Gaspari 2006 These data are a graphical representation of the data within this study.

抗生物質の予防内服

治療期間は 1 – 5 年

治療費用 $2,2001(3年)

逆流は治らない自然治癒率は5 – 13%

多剤耐性大腸菌

患者の割合（％）

年齢

週 月 年

3剤以上に耐性

2剤以上に耐性

October 23, 2010 15

治療法の選択

N=10,975

1Hensle 2007b; 2Who Antibiotic Fact Sheet

Antibiotic Resistance抗生物質の予防内服

治療期間は 1 – 5 年

治療費用 $2,2001(3年)

逆流は治らない自然治癒率は5 – 13%

抗生物質耐性菌の増加

抗生物質有効例

抗生物質無効例

October 23, 2010 16

治療法の選択

従来の手術

治癒治癒率 95%

治療日数は3日以上の(入院)

治療費用 $15,410

1Handbook of Pediatric Urology

尿管

膀胱壁 膀胱三角

膀胱内で尿管をくりぬき、別の部位に移して縫着する

October 23, 2010 17

治療法の選択

膀胱鏡下注入療法

治癒一回での治癒率 69%

治療日数は1日(通院)

治療費用 $6,530

尿路感染症の頻度

1Elder 2007

尿路感染症の平均発症回数

尿路感染症の年間平均発症回数

抗生物質投与Deflux 注入

October 23, 2010 18

治療法の選択

膀胱鏡下注入療法

治癒一回での治癒率 69%

治療日数は1日(通院)

治療費用 $6,530

1Wadie 2007 These data are a graphical representation of the data within this study.

尿路感染症への効果

尿路感染症の年間平均発症回数

抗生物質投与Deflux 注入

尿路感染症の平均発症回数

October 23, 2010 19

治療法の選択

膀胱鏡下注入療法

治癒一回での治癒率 69%

治療日数は1日(通院)

治療費用 $6,530

発熱を伴う尿路感染症への影響1

1Stenberg 2006

方法:

-長期予後-21項目にわたる聞き取り調査

結果:

179名はDefluxの初回投与で治癒し、注入後７~

１２年で発熱を伴う尿路感染症は3.4%に見られた。

目的:

Deflux注入療法の予後について

*In Europe Grades I-II are considered positive outcomes.

October 23, 2010 20

治療法の選択

膀胱鏡下注入療法

治癒一回での治癒率 69%

治療日数は1日(通院)

治療費用 $6,530

HIT 法は STING 法より、改善率が高い2

STING

Subureteric transurethreal

injection1

Ureter

Bladder

Wall

Deflux

injection

1Handbook of Pediatric Urology; 2Kirsch 2004

注 入注 入

尿管

膀胱壁

October 23, 2010 21

• 米国ＦＤＡではDeflux注入はグレードII – IV の膀胱尿管逆流症に適応があるとしている。

グレードII – IV の膀胱尿管逆流症へのDeflux注入療法

• グレードII – IV の逆流症に対してDeflux注入は有効性が高い。1

* A response was defined as reflux grade 0 or 1

1Capozza 2002

逆流の程度

Defluxの有効率

Ｄｅｆｌｕｘの有効率

グレード グレードグレード

October 23, 2010 22

各治療法のリスクと限界

抗生物質の予防内服1,2,3 膀胱鏡下注入療法3従来の手術4

1. アレルギー反応

2. 下痢

3. 耐性菌

4. 治らない

5. 繰り返し侵襲的な検査が必要

6. Non-compliance

1. 膀胱鏡挿入による感染や出血のリスクがある

2. 麻酔のリスク3. 術後に閉塞をきたすこと

がまれにある4. まれだが、拡張のリスクが

ある

1. 術後に閉塞をきたすことがまれにある

2. 術後感染症

3. 麻酔のリスク

4. 術後下腹部不快感

(膀胱痙攣)

1Hensle 2007a; 2Gupta 1999; 3Deflux Package Insert 2007 (link); 4Fanos 2004

October 23, 2010 23

治療法選択の動向

家族の意向1

1Capozza 2003

膀胱鏡下注入療法80%

抗生物質5%

手術2%

未治療13%

October 23, 2010 24

Deflux は以下の理由から、

家族に好まれる選択法です。

1. 侵襲が少ない

2. 一回の治療で多くが治癒する

3. 尿路感染の発症頻度が減少する

4. 抗生物質に耐性の菌の発現を減らすことができる

October 23, 2010 25

製品概要Intended Use/Indications

Deflux® is indicated for treatment of children with vesicoureteral reflux (VUR) grades II-IV.

Contraindications

Deflux is contraindicated in patients with any of the following conditions:

• Non-functional kidney(s)

• Hutch diverticuli

• Ureterocele

• Active voiding dysfunction

• Ongoing urinary tract infection

Warnings

• Do not inject Deflux intravascularly. Injection of Deflux into blood vessels may cause vascular

occlusion.

Precautions

• Deflux should only be administered by qualified physicians experienced in the use of a cystoscope and

trained in subureteral injection procedures.

• Treatment of duplex systems has not been prospectively studied.

• Ureters with grossly dilated orifices may render the patient unsuitable for treatment.

• The risks of infection and bleeding are associated with the cystoscopic procedure used to inject Deflux.

The usual precautions associated with cystoscopy (e.g. sterile technique, proper dilation, etc.) should be

followed.

• The safety and effectiveness of the use of more than 6 ml of Deflux (3 ml at each ureteral orifice) at the

same treatment session have not been established.

• The safety and effectiveness of Deflux in the treatment of children under 1 year of age have not been

established.

October 23, 2010 26

Product Information

Adverse Events

List of treatment-related adverse events for 39 patients from a randomized study and 170 patients from

nonrandomized studies. (Follow-up for studies was 12 months).

Adverse Event Randomized (n=39 Deflux) Nonrandomized (n=170)

Urinary tract infection (UTI) (i) 6 (15.4%) (ii, iii) 13 (7.6%) (ii, iii)

Ureteral dilatation (iv) 1 (2.6%) 6 (3.5%)

Nausea/Vomiting/Abdominal pain (v) 0 (0%) 2 (1.2%)

(i) Cases of UTI typically occurred in patients with persistent reflux.

(ii) Patients in the nonrandomized studies received antibiotic prophylaxis until the 3-month VCUG.

After that only those patients whose treatment had failed received further antibiotic prophylaxis.

The patients in the randomized study received antibiotic prophylaxis 1 month post-treatment.

(iii) All UTI cases were successfully treated with antibiotics.

(iv) No case of ureteral dilation required intervention and most cases resolved spontaneously.

(v) Both cases of nausea/vomiting/abdominal pain were resolved.

October 23, 2010 27

Product Information

Adverse Events

Continued

Although vascular occlusion, ureteral obstruction, dysuria, hematuria/bleeding, urgency and urinary frequency have not been observed in any of the clinical studies, they are potential adverse events associated with subureteral injection procedures. Following approval, rare cases of postoperative dilation of the upper urinary tract with or without hydronephrosis leading to temporary placement of a ureteric stent have been reported.

October 23, 2010 28

参考資料• American Academy of Pediatrics. 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 Apr;103(4 Pt 1):843-52. 1999

May;103(5 Pt 1):1052, 1999 Jul;104(1 Pt 1):118. Erratum in: Pediatrics. 2000 Jan;105(1 Pt 1):141.

• American Urological Association 1997 Guidelines.

• Caione P, Villa M, Capozza N, De Gennaro M, Rizzoni G. Predictive risk factors for chronic renal failure in

primary high-grade vesico-ureteric reflux. BJU Int. 2004 Jun;93(9):1309-1312.

• Capozza N, Caione P. Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral reflux: a

randomized comparison with antibiotic prophylaxis. J Pediatr. 2002 Feb;140(2):230-234.

• Capozza N, Lais A, Matarazzo E, Nappo S, Patricolo M, Caione P. Treatment of vesico-ureteric reflux: a new

algorithm based on parental preference. BJU Int. 2003 Aug;92(3):285-288.

• Capozza N, Lais A, Nappo S, Caione P. The role of endoscopic treatment of vesicoureteral reflux: a 17-year

experience. J Urol. 2004 Oct;172(4 Pt 2):1626-1628; discussion 1629.

• 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 Jul; 11;298(2):179-186.

• Deflux [Product Information] Uppsala, Sweden: Q-Med AG; 2007 May. Available at:

http://deflux.qmed.episerverhotell.net/263dc0b5-c1f8-4cda-b0ba-4e10578d5cf9.fodoc

• Elder JS, Shah MB, Batiste LR, Eaddy M. Endoscopic injection versus antibiotic prophylaxis in the reduction of

urinary tract infection in patients with vesicoureteral reflux. Curr Res Med Opin. 2007 Sep;23(Suppl 4):S15-S20.

• Fanos V, Cataldi L. Antibiotics or surgery for vesicoureteric reflux in children. Lancet. 2004 Nov 6-

2;364(9446):1720-1722.

October 23, 2010 29

参考資料• 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 Mar;117(3):626-632.

• Gaspari RJ, Dickson E, Karlowsky J, Doern G. Multidrug resistance in pediatric urinary tract infections. Microb Drug

Resist. 2006 Summer;12(2):126-129.

• Gonzalez E, Papazyan JP, Girardin E. Impact of vesicoureteral reflux on the size of renal lesions after an episode

of acute pyelonephritis. J Urol. 2005 Feb; 173:571–575.

• Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing

acute uncomplicated cystitis in women. JAMA. 1999 Feb 24;281(8):736-738.

• Handbook of Pediatric Urology, Second Edition, Laurence S. Basken, Barry A. Kogan.

• Hensle TW, Grogg AL. Vesicoureteral reflux treatment: the past, present and future. Curr Res Med Opin. 2007

Sep;23(Suppl 4):S1-S6. (Hensle 2007a)

• Hensle TW, Hyun G, Grogg AL, Eaddy M. Examining pediatric vesicoureteral reflux: a real-world evaluation of

treatment patterns and outcomes. Curr Res Med Opin. 2007 Sep;23(Suppl 4):S1-S6. (Hensle 2007b)

• Jacobson SH, Hansson S, Jakobsson B. Vesico-ureteric reflux: occurrence and long-term risks. Acta Paediatrica.

1999;431:22-30.

• Kiberd BA, Clase CM. Cumulative risk for developing end-stage renal disease in the US population. J Am Soc

Nephrol. 2002 Jun;13(6):1635-1644. Erratum in: J Am Soc Nephrol. 2002 Oct;13(10):2617.

• Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux:

improved results with submucosal implantation within the intramural ureter. J Urol. 2004 Jun;171(6 Pt 1):2413-2416.

• Kobelt G, Canning DA, Hensle TW, Lackgren G. The cost-effectiveness of endoscopic injection of

dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol. 2003 Apr;169(4):1480-1480; discussion

1484-1485.

October 23, 2010 30

参考資料• Lin KY, Chiu NT, Chen MJ, et al. Acute pyelonephritis and sequelae of renal scar in pediatric first febrile urinary tract

infection. Pediatr Nephrol. 2003 Apr;18(4):362-365.

• McNiece KL, Poffenbarger TS, Turner JL, Franco KD, Sorof JM, Portman RJ. Prevalence of hypertension and pre-

hypertension among adolescents. J Pediatr. 2007 Jun;150(6):640-644.

• Panaretto K, Craig J, Knight J, Howman-Giles R, Sureshkumar P, Roy L. Risk factors for recurrent urinary tract

infection in preschool children. J Paediatr Child Health. 1999 Oct;35(5):454-459.

• Q-Med Scandinavia Inc. [homepage on the Internet]. Princeton, NJ. Spontaneous Resolution Calculator; [1 screen].

Accessed: 2007 Sep 20. Available at: http://deflux.qmed.episerverhotell.net/Templates/Page.aspx?id=1046

• Q-Med Scandinavia Inc. [homepage on the Internet]. Princeton, NJ. Injection Techniques; [4 screens]. Accessed:

2007 Sep 20. Available at: http://deflux.qmed.episerverhotell.net/Templates/Page.aspx?id=361

• Schwab CW, Wu HY, Selman H, Smith GH, Snyder HM, Canning DA. Spontaneous resolution of vesicoureteral

reflux: a 15-year perspective. J Urol. 2002 Dec;168(6):2594-2599.

• Sherbotie JR, Cornfeld D. Management of urinary tract infections in children. Med Clin North Am. 1991

Mar;75(2):327-338.

• Smellie JM, Prescod NP, Shaw PJ, Risdon RA, Bryant TN. Childhood reflux and urinary infection: a follow-up of 10-

41 years in 226 adults. Pediatr Nephrol. 1998 Nov;12(9):727-736.

• Stenberg A, Läckgren G. Treatment of vesicoureteral reflux in children using stabilized non-animal hyaluronic

acid/dextranomer gel: A long-term observational study. J Ped Urol. 2006 Nov;3:80-85.

• United States Renal Data System Annual Data Report 2007. http://www.usrds.org

• U.S.Census Bureau, Population Division, Interim State Population Projections, 2005.

• Wadie GM, Tirabassi MV, Courtney RA, Moriarty KP. The deflux procedure reduces the incidence of urinary tract

infections in patients with vesicoureteral reflux. J Laparoendosc Adv Surg Tech A. 2007 Jun;17(3):353-359.

October 23, 2010 31

参考資料• Wheeler D, Vimalachandra D, Hodson EM, Roy LP, Smith G, Craig JC. Antibiotics and surgery for vesicoureteral

reflux: a meta-analysis of randomised controlled trials. Arch Dis. Child. 2003;88:688-694.

• World Health Organization Antibiotic Fact Sheet. http://www.who.int/mediacentre/factsheets/fs194/en/

• Yu R, Roth D. Treatment of VUR using endoscopic injection of nonanimal stabilized hyaluronic acid/dextranomer

gel: Initial experience in pediatric patients by a single surgeon. Pediatrics 2006; 118; 698-703.