Giovanni Montini Milano,...

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Nefrologia pediatrica tra aggiornamento e linee guida Sabato 14 novembre 2015 Università degli Studi di Milano-Bicocca, Monza Le infezioni delle vie urinarie…:…novita’ e linee guida Giovanni Montini Milano, Italy [email protected] CLINICA PEDIATRICA Direttore : Prof Andrea Biondi

Transcript of Giovanni Montini Milano,...

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Nefrologia pediatrica tra aggiornamento e linee guida

Sabato 14 novembre 2015

Università degli Studi di Milano-Bicocca, Monza

Le infezioni delle vie urinarie…:…novita’ e linee guida

Giovanni Montini

Milano, [email protected]

CLINICA PEDIATRICA

Direttore : Prof Andrea Biondi

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UTI - VUR

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UTIs• Epidemiology

• Pathophysiology

• Long term consequences

• DiagnosisUrinalysis and urine culture

• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)

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UTI - EPIDEMIOLOGYUTI - EPIDEMIOLOGY

INCIDENCE: 1.7/1000 boys/year3.1/1000 girls/year

PREVALENCE: girls 8 %

(0-6 y) boys 2,5 %

INCIDENCE: 1.7/1000 boys/year3.1/1000 girls/year

PREVALENCE: girls 8 %

(0-6 y) boys 2,5 %

(Jodal ESPN 2002)(Jodal ESPN 2002)

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UTIs• Epidemiology

• Pathophysiology

• Long term consequences

• DiagnosisUrinalysis and urine culture

• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)

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UTIs: Pathophysiology

• Kidneys and urinary tract are germ free

• When bacteria enter a number of conditions maydevelop:

– Bacteriuria

– Cystitis

– Febrile UTIs with activation of the inflammatory process

• Adequate urine flow and intact uroepithelium are key in the prevention of UTI.

• E. coli have P fimbriae that facilitate uroepithelialattachment

UTIs: Pathophysiology

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Modified from Montini G, Tullus K and Hewitt I, 2011

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UTIs• Epidemiology

• Pathophysiology

• Long term consequences

• DiagnosisUrinalysis and urine culture

• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)

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The old conceptThe old concept

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0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

months

Cu

mu

lati

ve

%

2 3 3, 5 4 5 6 6, 5 7 8 8, 5 9, 5 10 11 12

years

males

f emales

Age at diagnosis of VUR

Age at diagnosis of vesicoureteral reflux (as cumulative percent) by sex in children with CRF (n:187)

ItalKid 2002

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Outcome renal function

• Recruited children 3479

• Prevalence of patients with impaired renal function: 0-56%

• 1029 children included in 8 prospective studies; of the 55

children with CKD at the end of follow-up, only in 4 (0.4%)

renal function was normal at start.

• Almost all children with a decreased renal function at the

end of follow-up showed scars or hypodysplastic kidneys

at start.

Toffolo A, Acta Paediatrica 2012

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Febrile Urinary Tract Infections

Vesico- ureteric reflux

Renal hypo-dysplasia

Post infectious scarring

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UTIs• Epidemiology

• Pathophysiology

• Long term consequences

• DiagnosisUrinalysis and urine culture

• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)

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UTIs• Epidemiology

• Pathophysiology

• Long term consequences

• DiagnosisUrinalysis and urine culture

• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)

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Primary and Secondary outcomes in the Primary and Secondary outcomes in the Primary and Secondary outcomes in the Primary and Secondary outcomes in the 502 502 502 502 randomisedrandomisedrandomisedrandomised childrenchildrenchildrenchildren

Montini, G. et al. BMJ 2007;335:386

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Italian Society of Pediatric Nephrology

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Hewitt 2008

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UTIs• Epidemiology

• Pathophysiology

• Long term consequences

• DiagnosisUrinalysis and urine cultureBlood inflammatory markers

• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)

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IMAGING AFTER A FIRST FEBRILE UTI

• Ultrasonography

• Voiding cystourethrography with a

radiopaque, radioactive, or echocontrast

medium

• Renal scintigraphy with DMSAAcute

Late

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Elizabeth

Elizabeth is a 30 months old girl, whose family and past medical history is uneventful. Normal prenatal US, good general health, good statural and ponderal growth. She comes to the clinic because of fever (38.7° C). She is in good general conditions, normal physical examination.

Urine dipstick and subsequent culture (E. coli) confirmed a febrile UTI

• Would you recommend an acute DMSA?

• Would you recommend US?

• US shows normal kidneys and urinary tract

• Would you proceed to cystography?

• Grade II reflux

• Would you recommend late DMSA scan?

• Normal kidneys

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Philip

Philip is an 8 months old uncircumcised boy, whose prenatal US demonstrated mild dilatation of both renal pelves. Otherwise he is in good general health, satisfactory growth percentiles. He comes to the clinic because of fever (38.7° C). He appears otherwise well, with normal physical examination.

Urine dipstick and subsequent culture (Pseudomonas) confirmed a febrile UTI

• Would you recommend an acute DMSA?

• Would you recommend US?

• US shows hyperechogenic kidneys, with the right kidney at the 10th %ile

• Would you proceed to cystography?

• Right grade IV reflux; left grade II

• Would you recommend late DMSA scan?

• Mild hypodysplastic kidneys

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Demographic and clinical characteristics

of 502 children with febrile UTI

Number of children 502

median Age in months (range) 8 (1-99)

No girls (%) 322/502 (64%)

Confirmed AP (%) 278/438 (63.4%)

With VUR (%) 102/473 (21.5%)

VUR grade

I 24

II 37

III 34

IV 6

V 1

G. Montini et al. BMJ 2007

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The reason for imaging is to detect:

• obstructive malformations,

• vesicoureteral reflux,

• and kidney damage.

yet consensus on the malformations, grade of reflux,

and degree of damage that are important to detect is

lacking

IMAGING AFTER A FIRST FEBRILE UTI

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Guidelines Ultrasound VCUG DMSA

NICE (2007) YES

Atypical UTI;

< 6 months

NO

unless > 6 months of

age with positive US or atypical UTI

YES

> 6/12 m from UTI

AAP (2011) YES NO

Unless abnormal US

NO

Italian (2012) YES NO

Unless abnormal US

or risk factors

YES

>6/12 m from UTI ifabnormal US or VUR

Australian (2014) YES if no 2°or 3°trimester US ;

< 3 months;

Atypical UTI

NO

Unless abnormal US

NO

Canadian (2014) YES NO

Unless abnormal US

NO

IMAGING RECOMMENDATION AFTER a FIRST fUTI ACCORDING TO GUIDELINES

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First febrile UTI

US

� Abnormal

and/or

�Risk factors including:

• Abnormal prenatal US

• Chronic kidney disease• Abnormal bladder emptying• Bacteria other than E.coli

Further imaging ( cystography, renal radionuclide scan)

� Normal� No risk factors

2nd febrile UTI

No necessary

further imaging

ISPN

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Elizabeth & Philip

•An healthy infant (Elizabeth) with an uncomplicated first febrile UTI is not in need of aggressive investigation and management.

•An apparently healthy infant (Philip) with an abnormal US and atypical UTI warrants investigation

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1129 paediatricians

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UTIs• Epidemiology

• Pathophysiology

• Long term consequences

• DiagnosisUrinalysis and urine cultureBlood inflammatory markers

• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)

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VESCICO URETERAL REFLUX

• Idiopathic

• Secondary to

– Posterior uretral valves

– Neurogenic Bladder

– Bladder functional abnormalities

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International Classification of Vesicoureteral Reflux.

Montini G et al. N Engl J Med 2011

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6.7%

5.7%

8%

27.5%

42.8%

n = 516

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The old conceptThe old concept

G. Montini, I. Hewitt and K Tullus

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• The International Reflux Study in Children (1981)

• The Birmingham study (1983)

• The London study (2001)

Overall favorable outcome.

No difference in progression of existing scarring (9%) or new scarring (2%).

RANDOMIZED STUDIES

Surgery vs Prophylaxis

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Medical Surgical

t0 GFR 72.4 (24.1) 71.7 (22.6)

n 27 25

t4 years GFR 70.2 (26.3) 73.7 (24.9)

n 26 24

t10 years GFR 68.3 (29.8) 74.1 (35.6)

n 26 22

JM Smellie The Lancet, 2001

Outcome for GFR from the plasma clearance of

51Cr-EDTA at 4 and 10 years follow-up

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JM Smellie The Lancet, 2001

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The old conceptThe old concept

G. Montini, I. Hewitt and K Tullus

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Bacteria and Humans: diverse behaviours!!

Bacteria

• Extremely numerous

• Memorise generational experiences within a few hours

• Capacity to transfer vast quantities of information in seconds

• Extraordinary ability to adapt under the selective pressure of antibiotics

• Outstanding collaboration

Humans

• Often few and isolated

• Endless discussions!!

• Difficulty in confronting and resolving issues

• Tendency to maintain the same diagnostic and therapeutic approaches

• Scarce collaboration for the most part

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J De Bessa, J Urol 2015

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May 4, 2014

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Hoberman, NEJM 2014

71/126

toilet-

trained

children

VUR GRADE II-III = 80%

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RESULTS: primary endpoint

The treatment proved statistically significant, but of doubtful clinical value:

requiring 16 or 22 patient years of antibiotics to prevent 1 UTI or 1 febrile UTI,

respectively

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RESULTS

p. NS

p < 0,001

The treatment group had in excess of 600 years of prophylaxis without a

demonstrable effect on scar formation but a much higher propensity to induce bacterial resistance

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Guidelines Antibiotic prophylaxis Others interventions

NICE

Not for routine use

Treat dysfunctional elimination syndromes and constipation

Drink an adequate amount of fluid Do not delay voiding

AAP

Not for routine use Not considered

ISPN

For reflux III-V Recurrent febrile UTI*

Not considered

* ≥3 febrile UTIs within 12 months

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THE PREDICT TRIAL

Antibiotic Prophylaxis and REnal Damage In Congenital

abnormalities of the kidney and urinary Tract

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PREDICT Trial: DESIGN

Prospectic, Controlled, Randomized, Open-label, Multicentric Trial

PURPOSE: To study the role of antibiotic prophylaxis in children with VUR grade III-V

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PREDICT Trial: INCLUSION/EXCLUSION

CRITERIA

INCLUSION CRITERIA

•Age 1 - 4 months (until the 20th week of post-natal age!)

•Gestational age > 35 weeks

•GFR (according to Schwartz) > 15 ml/min/1.73 m2

•Grade III to V vesico-ureteral reflux

•No previous symptomatic UTI

EXCLUSION CRITERIA

-Neurogenic bladder - Myelomeningocele- Uretero-pelvic junction and/or uretero-vescico junction obstruction- Malformations leading to potential voiding disturbances

--Urethral valves

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436 PATIENTS with VUR III-V

36 months FOLLOW-UP

STRATIFICATION

Renal damage

CAKUT (prenatal or postnatal US screening)

PRE-RANDOMIZATION

renal function, US, VCUG and DMSA

GROUP B

Antibiotic

prophylaxis

GROUP A

Follow-up

RANDOMIZATION

24 months (renal function, US + DMSA +/- VCUG+ BMI)

60 months (renal function, US + DMSA + VCUG+ BMI)

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Aims:

- explore the modification in gut microbiota induced by antibiotic exposure

in early infancy

- Modifications in the pattern of resistance genes coded by gut microbiota

(gut resistome profile).

collect and freeze a

STOOL SAMPLE

from every patient

8 time points:

(0, 4, 8, 12, 24, 36, 48, 60 m)

New Partner: Dr MARCO CANDELA (Bologna, ITALY)

GUT MICROBIOTA

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STATE OF THE ART:

COUNTRIES

+ AUSTRALIA14

EUROPEAN

COUNTRIES

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SCREENED PATIENTS

RANDOMIZED 87

NOT ELEGIBLE 95

ENROLLABLE PATIENTS 70

TOTAL SCREENED 252

252 PATIENTS 38 CENTERS 7 COUNTRIES

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RANDOMIZED PATIENTS:

BASELINE CHARACTERISTICS

87 PATIENTS 27 CENTERS 4 COUNTRIES

SEX N°°°° %

FEMALE 23 26.4

MALE 64 73.6

GROUP N°°°°PROPHYLAXIS 44

NO PROPHYLAXIS 43 AGE at registration Media Median

(months) 2.5 2

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TRIAL MALE (%) FEMALE (%)

Garin, 2006 40/178 (18%) 178/218 (82%)

Pennesi, 2008 48/100 (48%) 52/100 (52%)

Montini, 2008 104/338 (31%) 234/338 (69%)

Roussey-Kesler, 2008 69/225 (31%) 156/225 (69%)

Craig, 2009 207/576 (36%) 369/576 (64%)

Brandstrom, 2010 75/203 (37%) 128/203 (63%)

Hoberman, 2014 49/607 (8%) 558/607 (92%)

SEX DISTRIBUTION IN UTIs TRIALS

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Hydronephrosis in most cases

2 Hypodisplasia

3 renal agenesia

BASELINE CHARACTERISTICS:

IMAGING

87 PATIENTS 27 CENTERS 4 COUNTRIES

PRENATAL US

ABNORMALITIES

N°°°° %

YES 64 73.6

NO 23 26.4

VUR GRADE N°°°° %

III 23 26.4

IV 35 40.2

V 29 33.3

73% grade IV-V

RIVUR study

VUR GRADE II-III = 80%

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31 patients with DMSA split

function <40%

in one kidney

(range 0-38%)

BASELINE CHARACTERISTICS:

IMAGING

87 PATIENTS 27 CENTERS 4 COUNTRIES

RENAL DAMAGE N°°°° %

NO 38 44

ONE KIDNEY 41 47

BOTH KIDNEYS 8 9

56% with RENAL DAMAGE

DMSA

ABNORMALITIES

N°°°° %

NO 53 61

1 or more 34 39

DMSA defects N°°°°

1 16

2 5

3 1

diffuse 10

1 scar + diffuse 2

Total 34

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RANDOMIZED PATIENTS: UTIs

14 TOTAL UTIs 9 PTs WITH UTIs 87 RANDOMIZED PTs

*2 patient with UTIs from different pathogens

PATHOGEN N°°°°OF UTIs * N°°°°PATIENTS*

E.coli 4 4

Pseudomonas Aeruginosa 3 2

Enterobacter cloacae 2 2

Klebsiella 2 2

Citrobacter koseri 1 1

Enterococcus faecium 1 1

Enterococcus faecalis 1 1

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14

EUROPEAN

COUNTRIES

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Additional therapies• Probiotics

• Circumcision

– no randomized trials

– 2 systematic reviews reached opposite conclusions

– routine circumcision not indicated in normal boys with the NNT to prevent one UTI at 111

– considered in those with recurrent urinary tract infections or high grade reflux

• Cranberry Juice

• a recent Cochrane review of 24 trials failed to demonstrate any significant benefit

• Treatment of constipation and soiling – no randomized controlled trials

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Current Understanding of Febrile Urinary Tract Infections and Renal Scarring.

Montini G et al. N Engl J Med 2011;365:239-250