EDUCATIONAL REVIEW

Acute pyelonephritis in children

William Morello1 & Claudio La Scola1 & Irene Alberici1 & Giovanni Montini2

Received: 12 November 2014 /Revised: 22 June 2015 /Accepted: 30 June 2015 /Published online: 4 August 2015# IPNA 2015

Abstract Acute pyelonephritis is one of the most seriousbacterial illnesses during childhood. Escherichia coli is re-sponsible in most cases, however other organisms includingKlebsiella, Enterococcus, Enterobacter, Proteus, andPseudomonas species are being more frequently isolated. Ininfants, who are at major risk of complications such as sepsisand meningitis, symptoms are ambiguous and fever is notalways useful in identifying those at high risk. A diagnosisof acute pyelonephritis is initially made on the basis of urinal-ysis; dipstick tests for nitrites and/or leukocyte esterase are themost accurate indicators of infection. Collecting a viable urine

sample for urine culture using clean voided methods is feasi-ble, even in young children. No gold standard antibiotic treat-ment exists. In children appearing well, oral therapy and out-patient care is possible. New guidelines suggest less aggres-sive imaging strategies after a first infection, reducing radia-tion exposure and costs. The efficacy of antibiotic prophylaxisin preventing recurrence is still a matter of debate and the riskof antibiotic resistance is a warning against its widespread use.Well-performed randomized controlled trials are required inorder to better define both the imaging strategies and medicaloptions aimed at preserving long-term renal function.

Keywords Urinary tract infections . Acute pyelonephritis .

Vesicoureteral reflux . Guidelines . Antibiotic prophylaxis .

Antibiotic resistance

AbbreviationsAAP American Academy of PediatricsAP Acute pyelonephritisCKD Chronic kidney diseaseDMSA Dimercaptosuccinic acidE. coli Escherichia colifUTI Febrile urinary tract infectionsISPN Italian Society of Pediatric NephrologyLUTI Lower urinary tract infectionsNICE National Institute for Clinical ExcellencePCT ProcalcitoninRCT Randomized controlled trialSPA Suprapubic bladder aspirationTDA Top-down approachU-CATH Urethral catheterizationUPEC Uropathogenic E. coliUS UltrasoundUTI Urinary tract infections

Key summary points (1) Very young children with acute pyelonephritishave ambiguous symptoms and are at major risk of complications. Thepresence of fever is not helpful in identifying high-risk infants.(2) Collecting a correct urine sample for urine culture using clean voidedmethods is reliable and effective, even in infants.(3) Oral antibiotic treatment is recommended in well-appearing children,while hospital admission and intravenous therapy are suggested for chil-dren in bad clinical condition and for newborns.(4) The usefulness of a full imaging work-up after a first fUTI isquestioned. The new guidelines suggest less aggressive imaging strate-gies, to reduce radiation exposure and costs.(5) The efficacy of antibiotic prophylaxis in preventing recurrence is stilla matter of debate, even in patients with VUR. It seems to reduce the rateof recurrence, but with no influence on the appearance of kidney scarring.The risk of antibiotic resistance is a warning against its routine use.

* Giovanni Montinigiovanni.montini@unimi.it

1 Nephrology and Dialysis Unit, Department of Pediatrics, AziendaOspedaliero Universitaria Sant’Orsola-Malpighi, Via Massarenti 11,40138 Bologna, Italy

2 Pediatric Nephrology and Dialysis Unit, Department of ClinicalSciences and Community Health, University of Milan FondazioneIRCCS Cà Granda -Ospedale Maggiore Policlinico Via dellaCommenda, 9 20122 Milano, Italy

Pediatr Nephrol (2016) 31:1253–1265DOI 10.1007/s00467-015-3168-5

http://crossmark.crossref.org/dialog/?doi=10.1007/s00467-015-3168-5&domain=pdf

VCUG Voiding cystourethrographyVUR Vesicoureteral reflux

Introduction

Acute pyelonephritis (AP) is an infection involving the renalparenchyma, which is generally associated with systemicsigns of inflammation. As the presence of fever is usually anindicator of renal involvement, the terms febrile urinary tractinfection (fUTI) and AP are often used interchangeably andwill be used synonymously in this paper.

AP is considered to be one of the most serious bacterialillnesses during childhood. These concerns are warranted bythe high risk of sepsis in young children in the acute phase [1]and the potential risk of renal scarring with possible long-termmorbidity. In the past, a great effort was made to try to mini-mize these consequences through the aggressive treatment ofthe acute infection, an intensive imaging work-up in order todiscover possible anatomical defects, and the use of antibioticprophylaxis to prevent recurrences. Over the last three de-cades, however, it has become apparent that congenital bilat-eral renal hypodysplasia is the main reason for renal damagein the children who progress towards the need for dialysis andkidney transplantation [2], even in the absence of a history ofAP and/or vesicoureteral reflux (VUR). Therefore, a less in-tensive approach in the management of children following aAP has been suggested by the most recent guidelines. How-ever, a number of major concerns still remain, especially re-garding diagnosis, the need to perform imaging in order todiagnose reflux and scarring, and the role of antibiotic pro-phylaxis. Here we summarize the state of the art, focusing onthe most controversial topics.

Etiology/physiopathology

The kidneys and urinary tract are usually germ-free. Mostcases of AP result from the ascension of fecally derived or-ganisms through the urethra and periurethral tissues into thebladder, with subsequent invasion of the kidney. Usually,urine flow prevents infection, washing out the bacteria pene-trating into the urinary tract [3]. When bacteria colonize theurinary tract, some children will develop asymptomatic bac-teriuria or lower urinary tract infections (LUTIs), while only aminority will experience AP, with systemic symptoms second-ary to immune system activation. A variety of host factors orgerm characteristics contribute to the risk of AP in earlychildhood.

Regarding the host, the most important condition associat-ed with AP is the presence of anatomical, renal, and urinarytract abnormalities, such as VUR, obstructive megaureter, orneurogenic bladder, in relation to urine stasis. Other host

factors could include dysfunctional bladder emptying [4],detrusor instability [5], constipation, and fecal soiling.

On the other hand, germ virulence also plays a central rolein the pathogenesis of AP. Escherichia coli (E. coli) is themost frequent bacteria, with a prevalence of about 80–90 %[6–8]. The primary reservoir ofE. coli is the human gut, wherethis germ is a normal commensal. The anatomical proximityto the urethral orifice increases the risk of colonization of theurinary tract. The isolate responsible for AP in a given indi-vidual often matches rectal isolates from that same person [9].

Among the different strains ofE. coli, uropathogenicE. coli(UPEC) are characterized both by additional virulence mech-anisms that facilitate their invasion of the urinary tract andkidneys and their resistance to innate immune responses.UPECs are equipped with fimbriae (or pili) that facilitateuroepithelial adherence, even in the presence of adequateurine flow. Their ability to bind to host tissues is essentialfor the colonization of the urinary tract, against the flow ofurine. Type 1 and type P pili are the two best-known types,type P being more frequently associated with AP than LUTI[10]. Other types of pili have also been described. The switchin the expression of different types of pili seems to be influ-enced by the environment (a process known as phase varia-tion) [11]. These processes increase the likelihood of adher-ence to host tissue [10]. Other UPEC characteristics that con-fer a survival advantage are virulent capsule antigens, ironacquisition systems, and toxin secretion [10, 12]. Moreover,the presence of plasmids can contribute to antibiotic resistance[13].

UPECs act as opportunistic intracellular pathogens. OnceUPECs invade the uroepithelium, the formation of an intra-cellular biofilm, containing thousands of rapidly multiplyingorganisms, can protect themselves from the host immune sys-tem. From the bladder, bacteria ascend to the kidney, especial-ly in the presence of anatomical factors such as VUR or majordilation with obstruction. The host’s inflammatory response tocolonization by UPECs is characterized by cytokine produc-tion, neutrophil influx, exfoliation of infected bladder epithe-lial cells, and the generation of reactive nitrogen and oxygenspecies [14]. A prolonged inflammatory state could result inscarring, although the exact underlying mechanisms are stillunknown (Fig. 1).

The remaining 10–20 % cases of AP are caused by a vari-ety of other organisms including Klebsiella, Enterococcus,Enterobacter, Proteus, and Pseudomonas species. A recentreport by pediatric nephrologists from 18 units in ten Europe-an countries focused on the causative organisms detected in4745 positive urine cultures between July 2010 and June 2012from both hospitalized and non-hospitalized infants under24 months of age. E. coli was the most frequent bacteriumisolated from the urine cultures. However, in 10/16 hospitalsand in 6/15 community settings, E. coli was isolated in lessthan 50 % of the total positive urine cultures. Other isolated

1254 Pediatr Nephrol (2016) 31:1253–1265

bacterial strains were Klebsiella, Enterococcus, Proteus, andPseudomonas, not only from hospital settings. This underlinesthe fact that E. coli is the most common organism causingUTIs in infants, however other bacterial strains are now beingisolated more frequently than in the past [15].

Clinical manifestations

Symptomatology of AP in pediatric patients is variable andinfluenced by the age of the child, the virulence of the organ-ism, and the inflammatory immune response. Fever (38.5 °Cand over) is commonly considered a marker of renal paren-chyma involvement, while localized symptoms such as dys-uria, frequency, malodorous urine, and urinary incontinenceare associated with urethra and bladder involvement. Howev-er, symptoms are often non-specific in very young children(

support. In the same study, the presence of bacteremia wasassociated with a higher frequency of complications [18].Similar data has also been reported in a smaller cohort of140 children [19].

The emission of malodorous urine can be reported by par-ents or caregivers, but as shown in a recent study by Gauthieret al. [20], its presence is neither specific nor sensitive enoughto rule in or rule out a diagnosis of AP. Macroscopic analysismay also reveal cloudy urine. In older children, recurrent APmay result from voiding disturbances, including hyperactivityand dysfunctional bladder emptying. A precise history ofvoiding modality including incontinence, enuresis, frequencyof micturition, urgency and bowel habits are useful in thissetting.

In conclusion, a diagnosis of AP has to be taken in consid-eration in all infants with fever and no signs of localization.

Diagnosis

The diagnosis of AP is initially made on the basis of urinalysisresults and the presence of clinical symptoms due to the factthat urine culture results take 24–48 h to obtain. If AP isstrongly suspected, particularly in the case of clinically illyoung children, empirical antibiotic treatment should bestarted, always in consideration of local drug-sensitivity pat-terns. While waiting for urine culture results, the diagnosis ofAP can be supported by the presence of white blood cells orbacteria on microscopic examination of an uncentrifugedurine sample. Manual microscopy is accurate, but can be timeconsuming, while automated urine microscopy is faster andless costly. In a recent prospective study, both techniques gavecomparable results in terms of the detection of pyuria, whileautomated analysis is less sensitive and specific for bacteriuriathan Gram-stained smears [21]. A urine dipstick, a chemicallysensitive strip of paper that can identify one or more constit-uents of urine by immersion, provides a rapid, easy and cost-effective way of guiding initial diagnosis and management.When more abnormalities are found together, this increasesthe likelihood of AP. A positive leukocyte esterase test resultsfrom the presence of white blood cells, but it may be related toinfections other than AP or to non-steroidal anti-inflammatory

agents as well. Leukocyte esterase is also present when lysedleucocytes are not visible onmicroscopy. A positive nitrite testindicates bacteriuria; most uropathogens can indeed convertnitrate to nitrite. Generating sufficient nitrite for a positive testcan take up to 4 h, so in the case of urine frequency (infants),the possibility of false negatives should be considered. There-fore, leukocyte esterase has a good sensitivity but a lowerspecificity than nitrite; a combination of both tests can behelpful in guiding interpretation [22, 23].

A systematic review published by Whiting et al. in 2006[24] showed that the combination of results of leukocyte ester-ase and nitrite on a urine dipstick is a reliable test both forruling in or out UTI. A subsequent meta-analysis carried outin 2010 evaluated the effect of age on the performance ofdipstick and compared this test to microscopy [25]. Of thesix studies included in the analysis, only two compared theperformance of dipstick in younger and older children. Whenboth nitrites and leukocyte esterase are considered, the abilityof dipstick to rule bacteriuria both in and out was good inchildren over 2 years, but the performance was significantlyless reliable in younger children. However, in a recent retro-spective study [26] comparing the performance of urine dip-stick and urine microscopy as screening tests for AP in 6394febrile infants aged 1 to 90 days, the dipstick had a greaterpositive predictive value (PPV) than combined urinalysis(66.8 vs. 51.2 %; p

identification of children at major risk for complications, renalscarring, and long-term sequelae. Technetium-99 m–dimercaptosuccinic acid (DMSA) scanning is considered thereference standard for the confirmation of AP [28, 29], but itsroutine use is not generally recommended due to the radiationdose and several practical issues related to the availability ofthe test. Therefore, clinical signs, laboratory tests, and otherimaging techniques have been considered as surrogates for thediagnosis of AP. Ultrasound (US) has been found to be a poortest for the localization of UTI [24]. Fever higher than 38.5 °Cis commonly considered as a marker of renal parenchymalinvolvement even if specificity and sensitivity are low [24,30, 31] . Moreover, as mentioned previously, fever can beabsent in infants under 90 days. Regarding laboratorymarkers, the elevation of C-reactive protein levels and whiteblood cell count can suggest the presence of renal involve-ment, but sensitivity and specificity are low [32]. PCT, a pre-cursor of calcitonin, produced by the thyroid gland and re-leased during bacterial infections, is a new promising markerof renal parenchymal involvement [33], and also in veryyoung children [34].

A meta-analysis of 18 studies involving 1011 patients eval-uated the role of PCTas a predictor of both AP and scarring inchildren with UTI [32]. PCT was associated with AP andscarring and demonstrated a significantly higher area underthe curve than either C-reactive protein or white blood cellcount. A value ≥0.5 ng/ml predicted early and late (scar) renalparenchymal involvement [32]. This cut-off provided an oddsratio of 7.9 for the identification of AP with a sensitivity of71 % and specificity of 72 %. Sensitivity was 79 % for latescarring with a lower specificity of 50 %. Even if PCT cannotreplace the DMSA scan as the gold standard for parenchymalinvolvement, it can be used as an available biomarker to dis-criminate between LUTIs and AP and identify children whowould benefit from a late DMSA scan [32, 34]. This has beenconfirmed by a recent Cochrane review [35].

We believe that in well-appearing children with AP bloodtests and DMSA scans are not necessary in the majority ofcases; in selective cases or in hospitalized children, PCT rep-resents a useful marker of renal parenchymal involvement.

Collection of urine samples for microbiologicaldiagnosis

The diagnosis of AP is confirmed by the culture of a singlestrain of bacteria in significant numbers from an appropriatelycollected urine specimen. Particular efforts have been made tobetter understand how to avoid false-positive tests due to con-tamination during collection. Whether the child can controlhis/her bladder must be taken into account when selectingthe appropriate method of collection, and the best methodfor urine sample collection is still a matter of debate in non-

toilet trained children. Methods can be either invasive or non-invasive. The cut-off point necessary for the positivity of aurine culture test differs according to the collection technique;the decreased risk of contamination associated with invasivemethods allows for a lower cut-off of positivity. Invasive tech-niques are suprapubic bladder aspiration (SPA) and urethralcatheterization (U-CATH), while non-invasive methods in-clude mainly the clean-voided method (mid-stream andclean catch) and the sterile bag.

There is some concern regarding the low specificity of non-invasive techniques due to the contamination rate. Sensitivitycan be lower in very young infants (

A recent survey [44] on current practice in primary care ofchildren aged 1–36 months, performed in 26 European coun-tries, identified bag as the most frequently used method inEurope, with a significant difference being seen in children2 months of age,unless the child is seriously ill and/or unable to tolerate oralantibiotics. To date, no data from RCTs are available to deter-mine the optimal total duration of antibiotic therapy for AP.

Oral antibiotic administration is therefore recommended inthe outpatient setting. Hospital admission for intravenous ther-apy is suggested for children in bad clinical condition, if theyare vomiting, or if poor compliance is suspected [23, 30].

There is no gold standard empirical antibiotic treatment;resistance patterns can be very different between countries,as demonstrated by the above-mentioned recent European sur-vey [15], which evaluated the resistance patterns of E. coli. Ahigh rate of resistance to amoxicillin was reported by almostall the centers. Data on co-amoxiclavulanate and oral cepha-losporin showed a large geographic variability, while a highprevalence of trimethoprim-resistant E. coli was found, prob-ably due to its widespread use as a prophylactic antibiotic.Nitrofurantoin showed a good rate of efficacy, with some iso-lated but important exceptions. Therefore, pediatriciansshould be aware of the local resistance patterns in order tobetter define the initial therapy; the antibiotic can be subse-quently modified according to antibiogram results.

Regarding the prompt initiation of therapy after the onset ofsymptoms, a retrospective analysis involving 287 childrenwith AP did not show an increased risk of scarring related tothe delay in antibiotic treatment [54]. Further evidence isneeded to confirm this initial observation. However, as men-tioned above, empirical antibiotic treatment should be startedsoon after AP is suspected (urinalysis and symptoms), partic-ularly in young children. The association of steroid therapy,during the acute phase, has been proposed for the prevention

Table 2 Urine collection methods in non-toilet-trained children according to the most recent guidelines

Guidelines Suprapubic bladder aspiration (SPA) Urethral catheterization (U-CATH) Clean catch Sterile bag

National Institute for ClinicalExcellence (NICE) [30]

Second option* First choice Not recommended**

American Academy ofPediatrics (AAP) [31]

First choice Not considered No

Italian Society of PediatricNephrology (ISPN) [23]

Not considered In case of bad clinical conditions First choice Second choice***

*If other non-invasive methods are not possible

**If clean catch is not possible, other non-invasive methods (pads) are recommended

***In case of good clinical condition

1258 Pediatr Nephrol (2016) 31:1253–1265

of subsequent scarring. A randomized trial of oral methylpred-nisolone compared with placebo in 84 children with a firstepisode of AP on DMSA scan, demonstrated a significantreduction in scarring at 6 months (33 vs. 60 %; p < 0.05) inthose given steroids [55].

As mentioned above, a subgroup of children that requirespecial attention and rapid hospitalization are newborns whopresent unwell with unstable temperature. These children needintravenous antibiotics after appropriate cultures, includingblood and urine cultures.

Imaging

In the past, children were subjected to extensive diagnosticimaging procedures after a first AP, which involved US,voiding cystourethrography (VCUG), and DMSA scanning[56]. This approach was aimed at detecting scarring and iden-tifying VUR of any grade, with the intention of preventing“reflux nephropathy” and its long-term sequelae (hyperten-sion and renal failure) [57]. It was believed that early detectionof VUR and scars would permit the prompt initiation of anti-biotic prophylaxis and/or surgical correction of the reflux,with the intent of reducing AP recurrence and the appearanceof renal scarring. The true benefit of this approach has beenreconsidered over time [23, 31, 58]. Data from pediatric reg-istries for chronic kidney disease (CKD) together with theimprovement and diffusion of antenatal US has shown thatrenal damage, which was previously associated with acquiredpyelonephritic scarring, is very often congenital in nature,caused by alterations in kidney development, particularlyhypodysplasia [59, 60], and can be associated with urinarytract anomalies, such as obstruction or high-grade VUR. In

effect, distinguishing between congenital damage and AP-related renal scarring is quite impossible with the availablediagnostic tools (renal US and DMSA scan).

Furthermore, recent publications have highlighted a lowcorrelation between AP and its long-term sequelae. In a sys-tematic review by Toffolo et al. it was observed that of the1029 children evaluated in prospective studies with normalrenal function at the time of the fUTI, only 0.4 % showed adeterioration in renal function during the follow-up period[61]. Salo et al. reported that the etiologic fraction of recurrentchildhood fUTIs as a main cause of CKD was, at most, 0.3 %in the absence of structural kidney abnormalities evident inimaging studies after the first childhood fUTI [62]. The use-fulness of a complete imaging work-up in children with con-firmed AP has never been proved, while a systematic reviewshowed no evidence of a reduction in the recurrence of infec-tion or renal scarring [63]. The role of surgery [58, 64, 65] andantibiotic prophylaxis [65–70] in children with VUR has alsobeen recently reevaluated.

In light of these new emerging data, the current guidelinesfor the management of a first fUTI in children have beenmodified, favoring less aggressive imaging strategies(Table 3). However, there is no agreement regarding the bestscreening test, the nature of malformations or the degree ofreflux or damage that merits detection [2].

The AAP guidelines suggest performing a routine renal andbladder US after a first fUTI, while VCUG is recommendedonly if hydronephrosis, scarring, or other anomalies are de-tected at US [31] or in the presence of “other atypical orcomplex clinical circumstances”, not specified in detail.DMSA scanning is not recommended. NICE [30] and ISPN[23] integrate the results of US with the presence of risk fac-tors for the identification of children in need of further

Table 3 Imaging strategies after a first febrile urinary tract infection (fUTI) according to the different guidelines

National Institute forClinical Excellence(NICE) [30]

American Academy ofPediatrics (AAP) [31]

Italian Society ofPediatric Nephrology(ISPN) [23]

Top-down approach(TDA) [28]

6 months

US Yes If atypical UTIa Yes Yes No

VCUG If abnormal USand/or atypical UTIa

If risk factorsb If abnormal US If abnormal US and/orrisk factorsc

If positive acuteDMSA

Acute DMSA No No No No Yes

Late DMSA If atypical UTIa If atypical UTIa No If abnormal USand/or VUR

If positive acuteDMSA

UTI urinary tract infection, US ultrasound, VCUG voiding cystourethrography, DMSA dimercaptosuccinic acida Seriously ill, poor urine flow, abdominal or bladder mass, raised creatinine, septicemia, failure to respond to correct antibiotic treatment within 48 h,infection with non-E. coli organismsbDilatation on US, poor urine flow, non-E. coli infection, family history of VURcAbnormal prenatal US of the urinary tract, family history of VUR, septicemia, renal failure, age

imaging (VCUG and/or DMSA scan). However, in clinicalpractice, it is common to perform an initial DMSA scan inchildren with a first fUTI, during the acute phase, onlyperforming VCUG in those with a renal involvement (top-down approach, TDA) [28].

Recently, Nelson et al. [71] analyzed data from 2259 patientsunder 60 months of age who underwent VCUG and US for ahistory of UTI in order to assess the sensitivity, specificity, andpredictive values of US for VCUG abnormalities. The authorsconcluded that in children with a history of UTI, US is a poorscreening test for genitourinary abnormalities, with low sensi-tivity and specificity and that sonography and cystographyshould be considered complimentary. However, in the samepaper, among the 1203 children aged 2 to 24 months whounderwent imaging after a first fUTI, the negative predictivevalue was 72–74 % for VUR grade II and 95–96 % for VURgrade>III, even though the likelihood ratio is not available forthe interpretation of the data. This interesting finding suggeststhat with a normal renal and bladder US we can confidentlyexclude those refluxes at higher risk of recurrent fUTIs andtherefore possible renal damage. Further diagnostic proceduresshould be limited to those children who have recurrent febrileinfections or documented renal developmental anomalies (e.g.,hypodysplasia) that represent an independent risk factor for thedevelopment of chronic kidney disease.

In a recent study [72], the authors retrospectively simulatedthe application of these different guidelines to a cohort of 304children aged 2 to 36 months enrolled in the Italian RenalInfection Study 1 [6], comparing the efficacy of exclusive oralwith initial parenteral antibiotic treatment, after a first fUTI.The results of US, VCUG, acute and late DMSA scans wereavailable for all the recruited children. The missed rate ofreflux grades III–V was 27 % for ISPN, 50 % for NICE,61% for AAP and 15 % for the TDA, while the rate of missedscars was 53 % for ISPN, 62 % for NICE and 100 % for AAP.Clearly, the TDA would have detected the presence of allscars. All the above-mentioned imaging approaches, apartfrom the TDA, showed low sensitivity and failed to identifya good proportion of patients with VUR and scars. Conse-quently, all three diagnostic algorithms are unable to rule chil-dren with high-grade VUR or scarring either in or out. On theother hand, a less aggressive imaging work-up allows for asubstantial reduction in economic costs and radiation expo-sure. A recent study associated the exposure to diagnosticradiography in early infancy with an increased risk of lympho-ma (odds ratio, 5.14; 95 % CI, 1.27–20.78) [73]. Although theresults referred to a small number and must be confirmed bymeans of further studies, the radiation risks connected to ra-diographic and scintigraphic imaging should not beunderestimated.

Moreover, the clinical significance of missing some chil-dren with VUR or scars is still unclear regarding the long-termconsequences.

Another interesting approach is reported in a recent meta-analysis in which Shaik et al. [8] evaluated data from publishedstudies of children (0–18 years old) with a first UTI whounderwent a DMSA scan at least 5 months after the index epi-sode and tested three prediction models to identify children atmajor risk of scarring. The authors identified nine studies thatmet the criteria and for which data was available, six were ob-servational and three were RCTs. Data on the primary outcomewas available for a total of 1280 children. Renal scarring waspresent in 199 children (15.5 %) and 100 of these (50.3 %) hadVUR. The presence of scars was associated, in decreasing order,with: grade IV–VVUR; abnormal US findings; grade III VUR;C-reactive protein level; temperature; organism other thanE. coli; polymorphonuclear cell count; grade I–II VUR. Age,sex, and duration of fever did not influence the presence of scarsat late DMSA scan. They also developed a predictionmodel thatcombines US finding + clinical information (temperature + or-ganism other thanE. coli) that can identify children at higher riskof scarring. The other two models studied, which included in-flammatory markers (model 2) and presence and grade of VUR(model 3), appeared less robust in terms of sensitivity, specific-ity, PPV, NPV, positive and negative likelihood ratios.

Screening all children after a first fUTI would reveal a lowprevalence of VUR (20–30 %), above all for grades IV–V (1–4 %) [6, 8, 31]. Furthermore, only 15 % of children presentscarring at late DMSA scan after a first fUTI [8]. As childrenwith recurrent infections have an increased risk of VUR andscars [8], a complete imaging work-up is usually required forrecurrent infections, therefore VUR or scars would be correct-ly identified at this point.

In conclusion, we believe that, in light of current knowl-edge, a less aggressive diagnostic approach should be adoptedafter a first fUTI. Therefore, we suggest performing an US,conversely we discourage the routine execution of VCUG andDMSA scans, considering the high rate of spontaneous reso-lution of VUR with age and the good renal outcome for pa-tients with scarring but without major congenital renal abnor-malities. Identifying the high risk population for which a fullimaging work-up is necessary allows for a reduction in thenumber of unnecessary imaging tests, psychological stressand economic and radiation costs.

Outcome

With the improvement of antibiotic therapies, acute infectionsusually resolve without sequelae. The long-term outcome offUTIs is mostly related to the appearance of renal scarring.However, the frequency and severity of scarring as a conse-quence of AP, the time point at which it occurs and the long-term sequelae, such as the risk of consequent CKD, hyperten-sion and pre-eclampsia, have been recently questioned. Thediffusion of routine prenatal US over the past 20–30 years has

1260 Pediatr Nephrol (2016) 31:1253–1265

demonstrated that much of the renal damage previously attrib-uted to AP is related to the congenital mal-development of thekidneys and is often associated with urinary tract abnormali-ties (high-grade VUR or obstruction). As a consequence, therole AP plays in renal scarring and its subsequent adverseoutcome has been reconsidered [74]. Just a small minority ofchildren (0.4 %) enrolled in prospective studies showed adeterioration of renal function to CKD after a fUTI onfollow-up [61]. Conversely, virtually all the children with de-creased renal function at the conclusion of studies had scarringor renal dysplasia at enrolment. The risk of hypertension islow [61]. The rate of hypertension only increased from 2.4 to4.6 % in 713 children enrolled in five studies where bloodpressure was measured at the beginning and end of follow-up (from 5 to 20 years). In the studies reporting a higherincidence of hypertension, up to 35 %, scarring and renaldamage were almost always present at enrolment [61]. In con-trast, one study [75] that followed two groups of children aftera first UTI for 16 to 26 years found no significant differencesin ambulatory blood pressure monitoring between the 53 in-dividuals with scars when compared with 51 controls withoutscars. Childhood UTI has not been seen to influence growth orcause complications during pregnancy [61]. We believe thatthe long-term outcome of children following a single AP, inthe absence of pre-existent renal damage, has to be consideredgood.

Risk of recurrence and prevention

While the prognosis of a single episode of AP is good, thereare many concerns regarding the effect of recurrent fUTIs onscarring [76], renal function, and quality of life for childrenand caregivers. Identifying children at major risk could there-fore allow for the implementation of preventive measures toreduce the risk of recurrences and preserve the final renaloutcome in these children.

There is a lack of solid evidence and some controversyregarding the risk factors predisposing recurrence. A majorrole for AP recurrence is played by dilating reflux, whilegrades I and II are not associatedwith frequent relapses, unlessbladder dysfunction is also present.

Panaretto et al., in a cohort of 290 children (aged up to5 years) after a first fUTI, who developed 46 relapses, identi-fied an age of less than 6 months at the time of the first UTI(OR 2.9) and grade III–V VUR (OR: 3.5) as independent riskfactors for recurrence [76].

Conway et al. evaluated a cohort of 611 children under6 years of age, recruited from a network of 27 pediatric pri-mary care centers, 83 of whom developed recurrent UTI [77].Factors associated with recurrences in multivariate analysiswere white race, age between 3 and 4 years, age between 4

and 5 years, and grade IVand V VUR. Sex, grade I–III VUR,and no circumcision did not influence the risk of recurrence.

The role of circumcision in preventing AP in male infantsis still a matter of debate. Two systematic reviews analyzed therole it plays with different conclusions; the first one performedby Sing-Grewal et al. [78] demonstrated that circumcisionreduces the risk of UTI, but 111 circumcisions are requiredto prevent one infection in boys with no other risk factors. Alower number-needed-to-treat is necessary in case of recurrentUTI or high-grade VUR (11 and 4, respectively). Instead, amore recent meta-analysis by Morris et al. [79] reported lackof circumcision as an important risk factor for UTI duringlifetime, irrespective of other risk factors. Moreover, aCochrane review [80] failed to identify any randomized con-trolled study on the use of routine neonatal circumcision forthe prevention of UTI in male infants. We believe that circum-cision could be helpful in children with high-grade VUR andrecurrent UTIs while on antibiotic prophylaxis.

Other described risk factors relating to AP recurrence werefamily history of UTI, dysfunctional voiding syndrome, poorfluid intake, and functional stool retention.

While some of the identified risk factors are not modifiable(age, white race, familiarity), others (presence of reflux,voiding habits, phimosis, bladder function, constipation, andfluid intake) can be modified through behavioral changes and/or medical interventions.

Historically, antibiotic prophylaxis has been used to pre-vent recurrence in children after fUTI, especially when VURwas detected. Antibiotic prophylaxis is the only preventivemeasure considered by the most recent guidelines, but noneof these recommend its routine use [23, 31].

In a recent meta-analysis on the efficacy of antibiotic pro-phylaxis in children with VUR carried out byWang et al. [81],the results of the eight RCTs that met the criteria were ana-lyzed, and while the pooled results showed a reduced risk ofrecurrence in children undergoing antibiotic prophylaxis(pooled OR=0.63, 95 % CI=0.42–0.96), no differences werefound in the appearance of new renal scars between the twogroups. Furthermore, the number of renal scars was low in allthe RCTs included. Antibiotic prophylaxis was associatedwith an increased risk of resistant bacteria (pooled OR 8.75,95 % CI=3.52–21.73, p

in the risk of renal scarring, with about an 8 % incidence ofnew scars occurring in both groups. Furthermore, 16 patient-years of antibiotics were required to prevent one UTI and 22patient-years of antibiotics were needed to prevent one fUTI.The treatment group received 600 years of prophylaxis inexcess. Moreover, an increased risk of antibiotic resistancewas found in the antibiotic group; among the 87 children witha first recurrence caused by E. coli, the proportion of isolatesthat were resistant to trimethoprim-sulfamethoxazole was63 % in the prophylaxis group and 19 % in the placebo group.Furthermore, some biases have to be considered in the inter-pretation of the results. Around 92 % of children enrolled inthe trial were female. This distribution is different from othersimilar published studies and from real-life settings. The chil-dren enrolled were aged up to 71 months, 126 patients werealready toilet-trained and about 30 % of recurrences wereafebrile. In addition, 92 % of patients had grade I–III VUR.

In conclusion, the lack of difference in scarring and theincreased risk of resistance at present do not justify, in ouropinion, the routine use of prophylaxis. As stated by the edi-torial accompanying the RIVUR trial in the New EnglandJournal ofMedicine [83]: “Sadly, the decision to use antibioticprophylaxis in children with reflux remains a clinical dilem-ma, despite this well-done study. In the face of the emergenceof antibiotic resistance, the lack of a significant between-group difference in renal parenchymal scarring, and questionsabout generalizability, the RIVUR study results would implythat the general recommendation of prophylactic antibioticsfor vesicoureteral reflux in young children awaits more evi-dence before universal adoption.”

Multiple-choice questions (answers are providedfollowing the reference list)

1) Which children are at major risk of UTIs andpyelonephritis?

a) Children undergoing immunosuppressive therapyb) No risk factors can be associated with fUTI in

childrenc) Children with urinary tract abnormalitiesd) Neonates

2) Which are the best predictors of complications in infants(20 %

5) What is the best treatment of a well-appearing infant>2 months of age with AP, according to the most recentguidelines?

a) Parental antibiotic treatment and hospitalizationb) Oral antibiotic treatment for 10–14 daysc) Initial oral antibiotic followed by parenteral treatmentd) Initial parenteral antibiotic followed by oral treatment

Conflict of interest The authors declare that they have no conflict ofinterest.

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Answers

1. C2. D3. B4. A5. B

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Acute pyelonephritis in childrenAbstractIntroductionEtiology/physiopathologyClinical manifestationsDiagnosisDiagnosis of renal parenchymal involvementCollection of urine samples for microbiological diagnosisTreatment and hospitalizationImagingOutcomeRisk of recurrence and preventionMultiple-choice questions (answers are provided following the reference list)References