EVIDENCE-BASED INVESTIGATIONS ANDTREATMENT OF URINARY TRACT

INFECTIONS

ESRF CAUSESFOREMAN JW,CHAN JCM. J PEDIATR 1988,113,793-800

ERA-EDTA ANNUAL REPORT 2005, REGISTERED CHARITY №1060134

ПМР/ РН Обструкция

ИМП

Другие

0 10 20 30 40

Гломерулопатии

Наследственныенефропатии

Васкулиты

UTI, VUR, RN

Cong. NP

Glomerulopath.

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 )

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

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.

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

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

UTI (urodynamics)

Abnormal urodynamics

High intrapelvic pressure

Intrarenal reflux

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

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

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

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

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

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

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

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

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

DIAGNOSTIC ALGORITHM

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.)

Эхографическая картина

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

RENAL US OF 3-mo CHILD

ТЯЖЕЛАЯ РЕФЛЮКС-НЕФРОПАТИЯ

Маленькая сморщенная почка с толстостенной расширенной собирательной системой и почти полным отсутствием функционирующей паренхимы Резкое обеднение

интраренального кровотока

Imaging Studies after a First Febrile Urinary Tract Infection in Young ChildrenAlejandro 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

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

НЕПРЯМАЯ (MAG-3) ЦИСТОГРАФИЯ

НЕПРЯМАЯ (MAG-3) ЦИСТОГРАФИЯ

DMSA

Не ранее 6 мес. после стихания ИМС

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

Treatment and prevention of UTI -the most complicated and

controversial issue of pediatric nephrology

(What, how, how long to treat?)

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

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

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]

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

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

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)

Criteria of efficiency : signs of nephrosclerosis on scintigramms through 12 months

The result: no reliable differences between groups (13.7 vs 17.7%)

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

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

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

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

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

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

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

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