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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
UTI - VUR
UTIs• Epidemiology
• Pathophysiology
• Long term consequences
• DiagnosisUrinalysis and urine culture
• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)
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)
UTIs• Epidemiology
• Pathophysiology
• Long term consequences
• DiagnosisUrinalysis and urine culture
• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)
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
Modified from Montini G, Tullus K and Hewitt I, 2011
UTIs• Epidemiology
• Pathophysiology
• Long term consequences
• DiagnosisUrinalysis and urine culture
• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)
The old conceptThe old concept
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
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
Febrile Urinary Tract Infections
Vesico- ureteric reflux
Renal hypo-dysplasia
Post infectious scarring
UTIs• Epidemiology
• Pathophysiology
• Long term consequences
• DiagnosisUrinalysis and urine culture
• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)
UTIs• Epidemiology
• Pathophysiology
• Long term consequences
• DiagnosisUrinalysis and urine culture
• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)
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
Italian Society of Pediatric Nephrology
Hewitt 2008
UTIs• Epidemiology
• Pathophysiology
• Long term consequences
• DiagnosisUrinalysis and urine cultureBlood inflammatory markers
• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)
IMAGING AFTER A FIRST FEBRILE UTI
• Ultrasonography
• Voiding cystourethrography with a
radiopaque, radioactive, or echocontrast
medium
• Renal scintigraphy with DMSAAcute
Late
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
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
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
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
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
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
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
1129 paediatricians
UTIs• Epidemiology
• Pathophysiology
• Long term consequences
• DiagnosisUrinalysis and urine cultureBlood inflammatory markers
• Management Treatment of the acute episodeImaging investigationsVUR (surgery, prophylaxis or nothing?)
VESCICO URETERAL REFLUX
• Idiopathic
• Secondary to
– Posterior uretral valves
– Neurogenic Bladder
– Bladder functional abnormalities
International Classification of Vesicoureteral Reflux.
Montini G et al. N Engl J Med 2011
6.7%
5.7%
8%
27.5%
42.8%
n = 516
The old conceptThe old concept
G. Montini, I. Hewitt and K Tullus
• 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
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
JM Smellie The Lancet, 2001
The old conceptThe old concept
G. Montini, I. Hewitt and K Tullus
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
J De Bessa, J Urol 2015
May 4, 2014
Hoberman, NEJM 2014
71/126
toilet-
trained
children
VUR GRADE II-III = 80%
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
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
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
THE PREDICT TRIAL
Antibiotic Prophylaxis and REnal Damage In Congenital
abnormalities of the kidney and urinary Tract
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
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
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)
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
STATE OF THE ART:
COUNTRIES
+ AUSTRALIA14
EUROPEAN
COUNTRIES
SCREENED PATIENTS
RANDOMIZED 87
NOT ELEGIBLE 95
ENROLLABLE PATIENTS 70
TOTAL SCREENED 252
252 PATIENTS 38 CENTERS 7 COUNTRIES
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
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
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%
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
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
14
EUROPEAN
COUNTRIES
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
Current Understanding of Febrile Urinary Tract Infections and Renal Scarring.
Montini G et al. N Engl J Med 2011;365:239-250