Pediatr Nephrol (2004) 19:1122–1126DOI 10.1007/s00467-004-1501-5

O R I G I N A L A R T I C L E

Pilar Orellana · Paulina Baquedano ·Venkatesh Rangarajan · Jin Hua Zhao ·Ng David Chee Eng · Jurij Fettich ·Tawatchi Chaiwatanarat · Kerim Sonmezoglu ·Dilip Kumar · Yung Ha Park · Aban Meyer Samuel ·Rune Sixt · Veereshwar Bhatnagar · Ajit K. Padhy

Relationship between acute pyelonephritis, renal scarring,and vesicoureteral refluxResults of a coordinated research projectReceived: 19 August 2003 / Revised: 2 November 2003 / Accepted: 24 March 2004 / Published online: 16 July 2004� IPNA 2004

Abstract Acute pyelonephritis (APN) may produce per-manent renal damage (PRD), which can subsequentlylead to diverse complications. We prospectively evaluated147 females and 122 males (mean age 3.5 years) withAPN in order to analyze the relationship between thepresence of PRD, at the time of cortical renal scintigra-phy, and age, gender, episodes of urinary tract infection(UTI), and presence of vesicoureteral reflux (VUR).There were 152 children studied after the first provenUTI. VUR was present in 150 children. PRD was ob-served in 170 children. There were no significant differ-ences between boys and girls. PRD was found in 36.4% ofchildren younger than 1 year and in 70.1% of those olderthan 1 year (P<0.0001). Of children with VUR, 72% hadPRD compared with 52% of children without VUR(P<0.0001). Of children with a first episode of UTI,55.9% developed PRD as did 72.6% of those with re-current UTI (P=0.004). Our results showed that PRD inchildren with APN is important, especially in the presenceof VUR, recurrent UTI, and older age.

P. Orellana ())Nuclear Medicine Section, School of Medicine,Catholic University of Chile,Marcoleta 347, Santiago, Chilee-mail: pilar@med.puc.clTel.: +56-2-3546488Fax: +56-2-6333266

P. BaquedanoDepartment of Pediatric Urology, School of Medicine,Catholic University of Chile,Santiago, Chile

V. Rangarajan · A. M. SamuelRadiation Medicine Center (BARC),Mumbai, India

J. H. ZhaoNuclear Medicine Section, Shanghai Medical University,Hua Shan Hospital,China

N. D. C. EngNuclear Medicine Section,Singapore General Hospital,Singapore

J. FettichNuclear Medicine Section,University Medical Centre,Slovenia

T. ChaiwatanaratDepartment of Radiology, Faculty of Medicine,Chulalongkorn University,Thailand

K. SonmezogluDepartment of Nuclear Medicine, Cerrahpasa Medical Faculty,Istanbul University,Turkey

D. KumarAll India Institute of Medical Sciences,New Delhi, India

Y. H. ParkDepartment of Radiologyand Nuclear Medicine, St. Vincent’s Hospital,Catholic University of Korea,Korea

R. SixtDepartment of Pediatric Clinical Physiology,The Queen Silvia Children’s Hospital,Sweden

V. BhatnagarDepartment of Pediatric Surgery,All India Institute of Medical Sciences,New Delhi, India

A. K. PadhyInternational Atomic Energy Agency,Austria

Keywords Acute pyelonephritis · Renal scarring ·Vesicoureteral reflux · Renal scintigraphy

Introduction

Urinary tract infection (UTI) is common in childhood,with a prevalence of 8% in girls and 2% in boys up to7 years of age [1]. Acute pyelonephritis (APN) is a majorcause of morbidity in children with UTI, particularlyduring infancy [2], because of its association with irre-versible renal parenchymal damage, which carries a riskof subsequent hypertension, toxemia of pregnancy, andend-stage renal failure. The ultimate goal for the care ofchildren with UTI is to prevent progressive renal damage.

The main role of diagnostic imaging in UTI is toidentify children with a high risk for developing renalscarring, i.e., patients who need surgical correction ofanatomical anomalies or long-term prophylaxis with an-tibiotics and follow-up.

In the past decade investigations using renal corticalscintigraphy (RCS) with technetium 99m-dimercapto-succinic acid (99mTc-DMSA) have led to significantchanges in our understanding of the epidemiology andpathogenesis of pyelonephritis and subsequent permanentrenal damage (PRD) [3, 4, 5, 6, 7].

The actual etiology of PRD remains controversial.According to many authors, children with APN are at riskof PRD. This risk is apparently increased in the presenceof gross reflux, a delay of adequate treatment, and in thepresence of recurrent pyelonephritis [8]. Other factors,such as bacterial characteristics and the condition of theurinary bladder, are important in the development ofPRD, but the practical implications of available data areunclear [1, 4].

RCS with 99mTc-DMSA is currently the most sensitivetool for diagnosing renal cortical lesions [7, 9] and hasalso improved the accuracy of the diagnosis, allowingclinicians to provide appropriate treatment and follow-up.

The aim of this prospective multi-center clinical studywas to determine the incidence of PRD in children afterAPN and its relationship with vesicoureteral reflux(VUR) and demographic and clinical data such as age,gender, episodes of UTI, and growth of bacteria.

Patients and methods

In total, 269 children were prospectively entered into the study,which was initiated as a coordinated research project under theauspices of the International Atomic Energy Agency, between 1998and 2001. All children had a febrile UTI and an acute abnormalRCS with 99mTc-DMSA (<30 days of onset of the symptoms) and afollow-up scan, performed at least 6 months after the acute episodeof UTI. Children with urinary tract anomalies other than VUR wereexcluded.

UTI was confirmed by a positive urine culture with >100,000organisms/ml of urine of a single urinary tract pathogen (midstreamclean void) or more than 10,000 organisms/ml (catheterization) of asingle urinary tract pathogen. For every child a questionnaire wasfilled out to obtain name, date of birth, age, first or recurrent UTI,

urine culture growth (bacterial strain and number of colonies), andgrade of VUR. Parental consent was obtained.

Escherichia coli was the microorganism in 79.5% of the chil-dren. RCS with 99mTc-DMSA was performed within 1 month of theonset of symptoms. Planar images were acquired (300 K) with alow-energy high-resolution parallel-hole collimator and appropriatezoom according to the child’s size, in a matrix of 128�128 or256�256 4–6 h after the IV administration of 2 MBq/kg of 99mTc-DMSA (minimum 15 MBq). When possible, pinhole images wereobtained in posterior projection and left and right posterior obliqueprojection (150,000 counts).

The evaluation of the RCS considered position, shape, size ofthe kidneys, and characteristics of renal cortical uptake. Diffuse orfocal reduction of uptake and/or relative renal function below 45%was considered abnormal. Follow-up scan was performed at least6 months after the acute episode of UTI (mean 7.9 months, range6–36 months).

We defined the follow-up scintigram as normalized if the acuteabnormality had disappeared, improved if the abnormality was lesspronounced, or as unchanged. Absence of PRD after APN wasconsidered when there was a complete normalization of the acuterenal abnormalities. We considered PRD to be present when weobserved no change or improvement.

Micturating cystourethrography (MCU) was performed usingstandard procedures between 2 and 6 weeks after the diagnosis ofacute UTI or once bacteriuria was cleared. Presence of VUR andother anomalies (bladder and urethra) was considered. VUR wasclassified according to the International Reflux Study. Grades I–IIwere considered low-grade reflux and grades III–V high grade.

As an alternative to MCU, direct radionuclide cystogram wasused. With a negative urine culture, a tracer (generally 99mTc-col-loid) was instilled in the bladder through an indwelling catheter,filling the bladder with warm (37ºC) saline in order to avoid intenseearly contractions of the bladder. The complete filling and voidingphases were recorded with a frame rate of 10 s. When the childwanted, he/she voided around the catheter and a second filling wasdone. VUR was classified as low grade when only the ureter or anon-dilated pelvis was visualized and high grade when there was avisualization of a dilated pelvis. We classified the children intothree age groups: group I <1 year old, group II 1–5 years old, andgroup III older than 5 years.

Statistics

We used Student’s t-test to identify statistically significant groupdifferences. A P value of less than 0.05 was considered statisticallysignificant. To investigate possible correlation between variousobservations we used Spearman’s correlation coefficient and ap-plied logistic regression analysis.

Results

In total, 269 children were included in the study with amean age of 3.5€3.3 years (range 1 month to 14 years).There were 147 girls (4€ 2.8 years old) and 122 boys(2.8€3.2 years old). There were 85 children in group I,113 in group II, and 71 in group III. There were 152children with the first proven UTI and 117 with recurrentUTI, i.e., two or more episodes of UTI. VUR was con-firmed in 150 of 269 children, involving 234 renal units.High-grade (grade III–V) VUR was present in 101 renalunits. Among the 538 renal units, there were 360 (66.9%)with acute parenchymal changes during pyelonephritis;90 children had bilateral APN. During follow-up, therewas a normalization of the acute renal parenchymal

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changes in 99 (36.8%) of the 269 children and PRD in170 (63.2%).

There were 92 of 147 girls (62.6%) and 78 of 122 boys(63.9%) with PRD (NS). PRD was found in a signifi-cantly smaller proportion of children younger than 1 yearthan in older children (group I vs. group II P=0.0007 andgroup I vs. group III P=0.0007) (Fig. 1). The presence ofPRD did not differ significantly between groups II and III.

There were 55.9% of children with a first episode ofUTI that developed PRD and 72.6% with recurrent UTI(P=0.004) (Table 1). PRD was more frequent in childrenwith non-E. coli growth (85.7%) than those infected withE. coli (57.3%) (P<0.0001).

There were 72% of children with VUR that developedPRD compared with 52% of children without VUR(P=0.0007) (Fig. 2). There were 61.2% of children withmild reflux with PRD and 77.2% of those with severe

VUR (P=0.04). In the presence of VUR, PRD was morefrequent in boys and in children older than 1 year(P=0.001). In the absence of reflux only the recurrence ofUTI was an important factor in the development of PRD(P=0.022). The association of recurrent UTI and VURwas an important factor in the development of PRD(P=0.02) in all age groups, increasing the frequency ofPRD in older children with recurrent UTI.

PRD was present in 82.6% of boys in group III and in47.2% of boys in group I (P=0.0017) (Table 1). Therewere 76% of boys with VUR that developed PRD and44.7% of those without reflux that developed PRD(P=0.0004); PRD predominated in those with severe re-flux (83.3% vs. 57.1%) (P=0.0004). There were 81.8% ofboys infected with non-E. coli organisms and 57.3% ofthose infected with E. coli with PRD (P=0.01). Therewere no significant differences between boys with a firstepisode of UTI and those with recurrent UTI (59% vs.75%).

Fig. 1 Permanent renal damage and age in children with acutepyelonephritis

Table 1 Relationship between permanent renal damage (PRD) and demographic and clinical data in children with acute pyelonephritis(UTI urinary tract infection, VUR vesicoureteral reflux)

Total Girls Boys

(n) PRD (%) P (n) PRD (%) P (n) PRD (%) P

Episode of UTIFirst UTI 152 85 (56%) 0.004 66 34 (52%) 86 51 (59%) NSRecurrent UTI 117 85 (73%) 81 58 (72%) 0.01 36 21 (75%)Age groupGroup I 85 31 (36%) <0.0001 30 15 (50%) 55 26 (47%) 0.0017Group II 113 76 (67%) 75 48 (64%) NS 38 28 (74%)Group III 71 53 (75%) 42 29 (69%) 29 24 (83%)GrowthE. coli 213 122 (57%) <0.0001 124 71 (57%) 89 51 (57%) 0.01Non-E. coli 56 48 (86%) 23 21 (91%) 0.001 33 27 (81%)VURPresent 150 108 (72%) 0.0007 75 51 (68%) 75 57 (76%) 0.0004Absent 119 62 (52%) 72 41 (57%) NS 47 21 (45%)Grade of VURLow 49 30 (61%) 0.04 28 18 (64%) 21 12 (57%) 0.017High 101 78 (77%) 47 33 (70%) NS 54 45(83%)

Fig. 2 Permanent renal damage and vesicoureteral reflux in chil-dren with acute pyelonephritis

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PRD was present in 50% of girls in group I and 69% ofgirls in group III (NS) (Table 1). PRD was present in asignificantly higher number of girls with recurrent UTI(72%) than those with first UTI (52%). Girls with non-E.coli organisms had significantly more PRD than thosewith E. coli (91% vs. 57%) (P=0.001).

Discussion

To cause renal damage, the UTI must involve the kidneys.Pyelonephritis is a common problem in pediatric practice,particularly during infancy [2]. Several studies haveshown that PRD always develops at the same site as theprevious infection [4, 5]. The visualization of parenchy-mal involvement during APN allows the clinician toidentify children at risk of developing PRD. Currently themost reliable method for identifying and localizing aninfection in the kidney is RCS with 99mTc-DMSA [5, 7, 9,10, 11, 12, 13, 14].

Prospective studies using 99mTc-DMSA scintigraphyshow that 30%–40% of children will have persistent de-fects after acute febrile UTI [4, 5, 11, 15]. The higherpercentage of PRD in our group may be explained by themean age of the group (3.5 years) and also by the fact thatover 50% of the children presented with recurrent UTI.The higher mean age may imply that not all children withfirst-time UTI are truly first timers. Many of these chil-dren may have had preexisting renal abnormalities re-sulting from prior episodes of infection or antenatal renalabnormalities [7].

The young growing kidney is thought to be vulnerableto insults and it has been generally accepted that infantsrun the greatest risk of developing PRD after UTI [16].The initial infection when occurring during infancy maybe associated with more pronounced renal damage due tothe unique kidney papillary morphology at this age [17,18]. However, some authors could not confirm thatyounger children are at a greater risk for developing renalsequelae following pyelonephritis [4, 5, 6]. Severalstudies using RCS with 99mTc-DMSA have shown nodifference in age at the time of infection between childrenwho developed PRD and those who did not [4, 6, 11].Studies have shown that children over 1 year of age had ahigher frequency of PRD than infants [19]. Our results arein agreement with this, since in our study older childrenhad more PRD after APN than younger ones (P<0.0001).As in our experience, there are no data showing differ-ences in PRD between boys and girls [8].

There is ample evidence that recurrent pyelonephritisis dangerous for the kidney [16]. In studies where freshrenal lesions have been observed, these have always beenpreceded by a new episode of UTI [3, 20, 21, 22, 23]. Thisis in agreement with our results, where recurrence of UTIwas a significant risk factor for the development of PRD,especially in girls, in children older than 13 months, andin children without VUR.

The role of VUR in PRD has been debated for manydecades [24]. Several studies demonstrated that VUR is

an important risk factor for PRD after UTI and that highgrades of reflux carry a higher risk than low grades ofreflux [5, 23], as was found in our group. However, therelationship between VUR and PRD may not be simple.More evidence is accumulating that PRD may develop inthe absence of VUR. It has been demonstrated that not allchildren with gross VUR and UTI develop renal damageand there is overwhelming evidence that renal damagemay occur after UTI in the absence of VUR [5, 16, 25]. Inour experience, over 50% of children without VUR de-veloped PRD. However, VUR as a risk factor for acquiredPRD is directly related to its role as a risk factor for APN.

Bacterial characteristics are important in the develop-ment of PRD, but the practical implications of availabledata are unclear. In our experience, children infected withnon-E. coli organisms had significantly more PRD thanthose infected with E. coli, as seen by other authors [4].

PRD is an important cause of hypertension and end-stage renal disease in children and young adults and is tosome extent preventable. Although renal damage associ-ated with severe reflux may represent primary fetal ab-normalities, there is abundant clinical and experimentalevidence that PRD can be acquired at any stage inchildhood and that urinary infections as well as VUR areimportant in its pathogenesis.

The data from this multicenter-coordinated researchproject suggest that in children with febrile UTI a DMSAscan should be performed if it is going to change thepatient management; this applies particularly to thosechildren with a higher risk of future morbidity, i.e., thosewith recurrent UTI, VUR, and older age.

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