1. EVIDENCE-BASED INVESTIGATIONS AND
TREATMENT OF URINARY TRACT
INFECTIONS

2. ESRF CAUSES
FOREMAN JW,CHAN JCM. J PEDIATR 1988,113,793-800
ERA-EDTAANNUAL REPORT 2005, REGISTERED CHARITY №1060134
ПМР/ РН
Обструкция
ИМП
Другие
0 10 20 30 40
Гломерулопатии
Наследственные
нефропатии
Васкулиты
UTI, VUR,
RN
Cong. NP
Glomerulopath.

3. Russian State Statistic Survice –
last decade- incidence of renal
diseases- in children under
increased in 1,6 times, theenagers –
in 2 times
(http://www.gks.ru )

4. Stable increasing of UTI in
children
In children of 1-3 years of life UTI
is more frequent than acute respir.
infection
-Соматичекие болезни у детей, Руководство для врачей //
Под ред. М.С. Игнатовой / Москва-Оренбург.-2002.- 669 с,
-Bhat RG, Katy TA, Place FC. Pediatric urinary tract
infections. Emerg Med Clin North Am. 2011 Aug;29(3):637-53

5. UTI is possible in neonates.
In mature neonates with fever and
malaise –UTI in 1,1 - 7% cases
Beetz R.Evaluation and management of
urinary tract infections in the neonate.
Curr Opin Pediatr. 2012 Jan 5.

6.  1/3 of 1-st year babies (36,4%)-
renal scarring after first episode of
UTI.
Lin D.S., Huang S.H., Lin C.C. et al. Urinary tract
infection in febrile infants younger than eight weeks
of age. // Pediatrics. -2000. –v.105, №2. –P.E20,
Remington J.S, Klein J. Infectious diseases of the
fetus and newborn. 5th edition Philadelphia: WB
Saunders, 2001

7. UTI (inflammation)
-CD14 –macrofage marker
-Co-receptor of
CD14/TLR4/MD2 complex
-NF-κB –transcription factor
(I-kB- inhibitor)
- Controls gene expression of
immune response, apoptosis
and cellular cycle
-TLR4- binds LPS of bacter.
wall
-the most ancient in
antibacter. protect. system
-similar to IL-1

8. UTI (urodynamics)
 Abnormal
urodynamics
 High
intrapelvic
pressure
 Intrarenal
reflux

9. RENAL SCARRING IN UTI
 Abnormal urodynamics (IRR)
 UTI- p-fimbria E. сoli, number of PN relapses ang age
of debuite
 GeГенетическая предрасположенность (DD-генотип
АПФ - почечный фиброз, делеция 13q хромосомы –
тяж. ПМР, РН, ХПН, полиморфизм гена ТФР-β1 – у
82% больных с РН,
 Нарушение равновесия ФНО-а, ИЛ-6, ИЛ-8, ИЛ-10
 Гиперпродукция ТФР, ФРФ, ИФР-1
 Нарушение механизма апоптоза

10. Shaikh N et al. Pediatrics 2010;126:1084-1091
©2010 by American Academy of Pediatrics
Shaikh N, et al..
Risk of renal scarring in
children with a first urinary
tract infection: a systematic
review. Pediatrics 2010,
Dec;126(6):1084-91
Medline и Embase (english-,
french-, spanish)
Kea words: "Technetium
(99m)Tc dimercaptosuccinic
acid (DMSA)," "DMSA,"
"dimercaptosuccinic,"
"scintigra*," "pyelonephritis,"
and "urinary tract infection."
Children of 0-18 years with 1st
episode of UTI
МЕТА-ANALYSIS - RENAL SCARRING RISK IN UTI

11. Risk of acute pyelonephritis according to the presence or absence of VUR.
Shaikh N et al. Pediatrics 2010;126:1084-1091
©2010 by American Academy of Pediatrics

12. Risk of renal scarring according to the grade of VUR.
Shaikh N et al. Pediatrics 2010;126:1084-1091
©2010 by American Academy of Pediatrics

13.  Vesicoureteral reflux associated renal damage:
congenital reflux nephropathy and acquired
renal scarring. Peters C, Rushton HG. J Urol.
2010 Jul;184(1):265-73.
 Microflora virulence
 Local and general inflam. response
pecularities
 Tissue ability to restoration
 Sterile reflux dose not lead to RN

15. ЗАВИСИМОСТЬ РАСПРОСТРАНЕННОСТИ НЕФРОСКЛЕРОЗА ОТ
ГОДА ПУБЛИКАЦИЙ
(хорошая диагностическая база, качественное лечение и наблюдение)
Shaikh N et al. Pediatrics 2010;126:1084-1091
©2010 by American Academy of Pediatrics

16. DIAGNOSIS OF UTI
 Clinical manifestations
 Laboratory methods of urine examination:
-urinary sediment,
-bacteriuria,
-urine osmolality,
-daily excretion of β2-microglobulin, etc
 Blood count, ESR
 Visual methods of voiding system evaluation:
-Renal US with doppler imaging of intrarenal
hemodynamics,
-Nuclear examination

17. CLINICAL MANIFESTATIONS OF UTI
 In neonates-the only sign of the UTI-prolonged jaundice
 Patients under the age of 2 years-general toxic
symptoms: fever, anxiety, insomnia, decreased appetite,
vomiting, dyspepsia, etc.
 Children under 5 years-common abdominal pain
without a specific localization.
 Only after 5 years of age-specific symptoms of the
urinary system lesions appear

19. АНАЛИЗ МОЧИ
 До назначения лечения
 Сбор мочи «clean catch», а не в мочеприемник!!!
 Бактериурия истинная (рост боле 100 000
колониеобразующих единиц в свежевыделенной
моче)
У детей раннего возраста – 50 000 КОЕ (малая
экспозиция мочи в мочевом пузыре)
Вид микрофлоры (протей, клебсиела, с/г
палочка)
 Симптоматическая, асимптоматическая

20. DIAGNOSTIC ALGORITHM

21. US OF VOIDING SYSTEM
 Screening or an additional assessment method
of anatomofunctional status of VS
 Modern digital ultrasound devices with high
resolution and Doppler of renal
hemodynamics- early detection of scaring and
foci-infiltrative changes in renal parenchyma
 Contrast voiding urosonographia, where
instead of iodine used gas bubbles (Levovist
"drug")
 In 70% of cases, this method has a higher
degree of detected reflux than was revealed by
MCUG (Darge K. Pediatr Radiol. 2008 Jan;38(1):40-
53.)

22. Эхографическая картина
мочевого пузыря и
расширенного дистального
отдела левого мочеточника у
ребенка 5 лет с
левосторонним смешанным
ПМР 2-3 степени и
левосторонней РН.

23. RENAL US OF 3-mo CHILD

25. ТЯЖЕЛАЯ РЕФЛЮКС-НЕФРОПАТИЯ
Маленькая сморщенная почка
с толстостенной расширенной
собирательной системой и
почти полным отсутствием
функционирующей паренхимы
Резкое обеднение
интраренального
кровотока

26. Imaging Studies after a First Febrile Urinary Tract
Infection in Young Children
Alejandro Hoberman, M.D., Martin Charron, M.D.,
Robert W. Hickey, M.D., Marc Baskin, M.D., Diana H.
Kearney, R.N., and Ellen R. Wald, M.D.
N Engl J Med 2003; 348:195-202January 16, 2003
Visual diagnostic
methods

27. РЕНОГРАФИЯ С ПЕНТАТЕХОМ
К., 10 years, right VUR
3 grade, left VUR 2 grade,
rightside RN (X-Ray
MCUG, IVU)
Obstructive curve of
right kidney
Arrows - VUR
Right kidney
Left kidney

28. НЕПРЯМАЯ (MAG-3) ЦИСТОГРАФИЯ

29. НЕПРЯМАЯ (MAG-3) ЦИСТОГРАФИЯ

30. DMSA
Не ранее 6 мес.
после стихания
ИМС

31. MCUG
 Children younger than 6 months-whith atypical or
recurring UTI+
 The boys from 6 months to 3 years-high risk of
VUR+/-
 Дети 3-5-7 лет – visual changes of kidneys (US,
nuclear invest), familial history of VUR or RN
(CAKUT), relapses of UTI
 Children over 7 years – ИНДИВИДУАЛЬНО !!! -
выраженные изменения верхних отделов мочевой
системы, ранее выявленные нарушения
уродинамики

32. Treatment and prevention of UTI -
the most complicated and
controversial issue of pediatric
nephrology
(What, how, how long to treat?)

33. MODERN ANTIBACTERIAL DRUGS
 Protected 3-4 generation of Penicillins (Tikarcillin, Mecillinam),
aminoglycosides, cephalosporins, fluoroquinolones, karbopenems
 Cyclic lipopeptide (daptomycin-kubicin)-, Gram+
 Oxazolidinons (linezolid, Zyvox) – Gram+/- (~ 20.000 rub=620 – 10 tablets)
 Antagonists of Н-fimbria (J Med Chem. 2010 Dec 23;53(24):8627-41. FimH antagonists for the oral
treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation. Klein T, с соавт.,
Швейцария)
 Products based on plant extracts:
- Cress and horseradish (Curr Med Res Opin. 2007 Oct;23(10):2415-22. A randomised, double-blind,
placebo-controlled trial of a herbal medicinal product containing Tropaeoli majoris herba (Nasturtium) and
Armoraciae rusticanae radix (Horseradish) for the prophylactic treatment of patients with chronically recurrent
lower urinary tract infections. Albrecht U, Goos KH, Schneider B., Германия)
- Solidago- семейство Астровых, Ortosophones- почечный чай, Birch (Cai T, Caola I,
Tessarolo F, Piccoli F, et al. Solidago, orthosiphon, birch and cranberry extracts can decrease microbial
colonization and biofilm development in indwelling urinary catheter: a microbiologic and ultrastructural pilot
study. World J Urol. 2013 Oct 4. [Epub ahead of print]
- Canephron– lovage, wild rose, centaury, Rosemary

34. WHAT?
 Aminoglycosides in low dosage – strong
proapoptotic effect
(El Mouedden M., et al, Apoptosis in renal proximal tubules of
rats treated with low doses of aminoglycosides, Antimicrobial
Agents and Chemotherapy 2000, March 44 (3):665-675).
Penicillin acid inhibits Fas-
induced-apoptosis
(Bando M., Hasegawa M., Tsuboi Y. et al. The Mycotoxin
Penicillin Acid inhibits Fas Ligand-iduced apoptosis by blocking
self-processing of caspase-8 in death-inducing signaling
complex. J Biol Chem 2003, 278(8):5786-5793

35.  Ceftriaxone associated nephrolithiasis: a
prospective study in 284 children. Mohkam M, Karimi
A, Gharib A, Daneshmand H, Khatami A, Ghojevand N, Sharifian M. Pediatr
Nephrol. 2007 May;22(5):690-4.
 Ceftriaxone-associated biliary pseudolithiasis
in children. [J Clin Ultrasound. 2006]
 Nephrolithiasis associated with ceftriaxone
therapy: a prospective study in 51 children.
[Arch Dis Child. 2004] –8% of patients - stones
d=2 мм in 7 mo after treatment
 Ceftriaxone-associated nephrolithiasis and
biliary pseudolithiasis in a child. [Pediatr
Radiol. 2003]

36. PLANT DERIVATES
 Cranberry juice (Orange, pineapple) prevents the
adhesion of E. Coli strains to uroepitelial cells (P-
fimbriae and L-fimbriae)
 Damage of Р-fimbriae-polymer of E. сoli cover и
reduction of its length in 3 times (from 148 to 48 nm)
 Cranberry Proanthocyanidins selective action on the
urinary tract microflora (safety of oropharyngeal and
intestinal biocenosis)
Zafriri D., Ofek I., Adar R., Pocino M., Sharon N. Inhibitory activity of cranberry juice on adherence of type
1 and type P fimbriated Escherichia coli to eucaryotic cells // Antimicrob Agents Chemother. -1989.- v.33,№1.-
Р.92–98
Kontiokari Т., Salo J., Eerola E., Uhari U. Cranberry juice and bacterial colonization in children—A placebo-
controlled randomized trial // Clinical Nutrition.- 2005.- v.24,№6.- Р.1065-1072
Liu Y, Black M.A., Caron L., Camesano T.A. Role of cranberry juice on molecular-scale surface
characteristics and adhesion behavior of Escherichia coli // Biotechnol Bioeng.- 2006.- v.93,№2.- Р.297-305

37.  Does early treatment of urinary tract infection
prevent renal damage? Doganis D, et al. Pediatrics.
2007 Oct;120(4):e922-8. Greece.
 278 infants (153 males, 125 females) age-0.5 to
7.5 mo. with acute pyelonephritis
 Early in the first 24 hours adequate treatment
reduces the possibility of the kidneys
involvement in acute inflammation,
 but does not prevent the development of
nephrosclerosis

38. HOW AND FOR HOW LONG?
SCHEME OF ANTIMICROBIAL THERAPY
 Antibiotic treatment for pyelonephritis in
children: multicentre randomised controlled non-
inferiority trial (BMJ. 2007 August 25; 335(7616):
386 )
 28 pediatric clinics of North Italy
 502 child (age 1-7 years) with pyelonephritis
 Oral co-amoxyclav (50 mg/kg/day in 3
admission for 10 days) or parenteral
ceftriaxone (50 mg/kg/day once for 3 days)
switch on to oral co-amoxyclav (50
mg/kg/day in 3 admission for 7 days)

39.  Criteria of efficiency : signs of
nephrosclerosis on scintigramms through 12
months
 The result: no reliable differences between
groups (13.7 vs 17.7%)

40. PREVENTION OF RECURRING UTI (1)
 The main task-appropriate antibacterial
prevention of recurring UTI -
amoxicillin in infants and trimethoprim
in senior schildren
Update on Vesicoureteral Reflux:
Pathogenesis, Nephropathy, and Management
Ross M Decter, MD Rev Urol. 2001 Fall; 3(4):
172–178

41. PREVENTION OF RECURRING UTI (2)
 Long-term antibiotics for preventing recurrent urinary tract
infection in children Cochrane Database Syst Rev. 2006 Jul
19;3:CD001534
 Total - 8 researches (618 children)
 5 of them (406 children)-comparison of antibiotics and
placebo
 Duration of treatment-from 10 weeks to 12 months
 1 study-nitrofurantoin is more effective than
trimethoprim, but poor compliance of nitrofurantoina

42. AUTHORS' CONCLUSIONS:
Large, properly randomised, double blinded
studies are needed !!!!
to determine the efficacy of long-term antibiotics
for the prevention of UTI
Cochrane Database Syst Rev. 2006 Jul 19;3:CD001534

43. MODERN DATA ON THE A/B PREVENTION OF UTI
 Randomized controlled study (over 2 years) a/b
prevention of UTI relapses by TRIMETHOPRIM
 100 children under 30 mo with VUR 2-4 grade
 4 years follow-up
 The equal frequency of UTI relapses and RN the
formation Pennesi M et al, Is antibiotic profylaxis in children with VUR
effective in preventing pyelonephritis and renal scars ? A randomized controlled trial,
PEDIATRICS Vol. 121, № 6, 2008, pp.e1489-1494

44. MODERN DATA ON THE A/B PREVENTION OF UTI
 Specialists from UK [National Institute for
Health and Clinical Excellence (NICE), UK]
 10 randomized controlled trials – antibacterial
prevention of UTI relapses and NS development
in children with VUR, based on Medline,
EMBASE, CINAHL и Cochrane Library.
 No reliable data from the point of view of
evidence-based medicine Verier-Jones K et al.
Effectiveness of antibiotic prophylaxis for children at risk of
developing UTI and renal scarring: Results of systematic review
carried out on behalf of the National Institute for Health and
Clinical Excellence (NICE), UK, Pediatric Nephrol 2008, v23, n9,
p1595

45.  Since 1975, the 11 major comparative
studies (1550 children with UTI)-
effectiveness of prolonged antibacterial
therapy (an equatorial comparison with
placebo)
 There is no reliable differences in the
frequency of exacerbations after 12 months.
treatment-20% develop recurrence:
 3 studies (394 ch)- the efficiency of
cranberry derivatives
 2 researches (252 ch)- the efficiency of
vitamin A
 Conclusion: the largest evidence base-
small efficiency of prolonged antibiotic
therapy.
 Possible efficiency of cranberry derivatives.
Finnell SM, Carroll AE,
Downs SM; Subcommittee
on Urinary Tract Infection.
- Technical report—
Diagnosis and management
of an initial UTI in febrile
infants and young children.
Pediatrics. 2011
Sep;128(3):e749-70
Williams GJ, Craig JC,
Carapetis JR. Preventing
urinary tract infections in
early childhood. Adv Exp
Med Biol. 2013;764:211-8.
Review

46. HOME MESSAGE
 NEED FOR A WELL-DESIGNED STUDY !!!
Randomized Intervention for Children With Vesicoureteral
Reflux (RIVUR): Background Commentary of RIVUR Investigators
Russell W. Chesney, MDa, Myra A. Carpenter, PhDb, Marva Moxey-Mims, MDc, Leroy Nyberg, MDc, Saul P. Greenfield, MDd, Alejandro Hoberman, MD, MPHe,
Ron Keren, MD, MPHf, Ron Matthews, MDg, Tej K. Matoo, MDh, members of the RIVUR Steering Committee Pediatrics. 2008 Dec;122 Suppl 5:S233-9.
Adv Chronic Kidney Dis. 2011 Sep;18(5):348-54. Vesicoureteral reflux and reflux nephropathy. Mattoo TK. (USA)
 The need to establish of the national
programme?
NICE UTI Guidelines, 2008

47. INDICATIONS FOR CLINICAL URINE ANALYSIS !!!!!!!
 Т >380С or long subfebrilitet for no apparent
reason (all children, in particular, young
children)
 Unexplained vomiting and abdominal pain
 Frequent urination, dysuria, enuresis
 Decrease or loss of appetite
 Prolonged jaundice in neonates
 Vague signs of well-being
 Hematuria (visually) and hypertension