Acta Pñdiatr 90: 628±631. 2001
Association between urinary tract infection, renal damage and birth
size
M Hellström1 , H Hessel1 , B Jacobsson2 , U Jodal3 , A Niklasson4 , M Wennerström3 and A Hellström4,5
Department of Radiology 1 , Sahlgrensk a University Hospital, Department of Radiology 2 , Department of Paediatrics3 , Internationa l
Paediatric Growth Research Centre4 , Department of Paediatrics , The Queen Silvia Children’s Hospital, and Department of Clinical
Neurosciences 5 , Section of Ophthalmology, Göteborg University, Göteborg, Sweden
Hellström M, Hessel H, Jacobsson B, Jodal U, Niklasson A, Wennerström M, Hellström A.
Association between urinary tract infection, renal damage and birth size. Acta Pædiatr 2001; 90:
628–631. Stockholm. ISSN 0803-5253
The aim of this study was to investigate whether birth size is associated with permanent renal
damage in children with urinary tract infection (UTI). A cohort of 1221 children under 16 y of age
was diagnosed with their rst symptomatic UTI between 1970 and 1979. Of these, 74 had
urographic renal scarring in childhood and 57 were re-examined as adults. The birth les of 48 of
these patients (35F, 13M) were available, and birthweight and birthlength in relation to gestational
age were analysed and compared with a Swedish reference population. Children who had renal
damage without vesicoureteric reux were signicantly smaller at birth (median weight, ¡0.76
SDS) compared with both children who had renal damage and reux (median weight, ¡0.01 SDS)
and the reference population.
Conclusion: The demonstration of low birthweight among children with UTI and renal damage but
no reux suggests that low birthweight may be a risk factor for the development of renal damage.
Key words: Birth size, renal damage, urinary tract infection, vesicoureteric reux
M Hellström, Department of Radiology, Sahlgrenska University Hospital, SE-413 45 Göteborg,
Sweden (Tel. ‡46 31 3421000, fax. ‡46 31 412897, e-mail. mikael.hellstrom@xray.gu.se)
The cumulative incidence of urinary tract infection
(UTI) in Sweden during the rst 6 y of life is
approximately 7% for girls and 2% for boys (1). About
half of the children have febrile infections, i.e. acute
pyelonephritis, which can potentially result in permanent renal damage. Such damage was demonstrated by
urography in 18 (11%) of 157 children at follow-up
after their rst recognized UTI and by the more
sensitive method of dimercaptosuccinic acid (DMSA)
scintigraphy in 59 (38%) of these 157 children (2).
Vesicoureteric reux (reux) has been shown to be an
important risk factor for kidney damage. Reux has
been estimated to occur in 1% of healthy children (3)
and in 30–40% of children with UTI (4, 5). The grade of
reux correlates with the extent of kidney damage as
seen by urography (6) or by DMSA scintigraphy (2, 5).
This type of kidney damage has consequently been
termed “reux nephropathy” (7). However, reux can
be demonstrated in only 50–80% of children with renal
scarring (2, 5, 6, 8). Factors other than reux must
therefore be of importance in the development of such
renal damage (9).
It has been suggested that the normal prenatal and
perinatal development of the kidney can be disturbed in
subjects with a low birthweight, and children with a low
birthweight may therefore be more susceptible for renal
Ó 2001 Taylor & Francis. ISSN 0803-525 3
disease in later life (10). It has also been shown that
children with low birthweight have an unfavourable
clinical course of immunoglobulin A (IgA) glomerulonephritis and minimal change nephrotic syndrome
(11, 12). Thus, the purpose of this investigation was to
analyse birthweight and birthlength in a well-dened
group of children with UTI and renal damage, in order
to study possible relationships.
Subjects and methods
Subjects
The patients were selected from a population-based
cohort of 1221 children under 16 y of age who were rst
diagnosed at The Queen Silvia Children’s Hospital,
Göteborg, with symptomatic UTI between 1970 and
1979 (13). The children were followed prospectively in
a single UTI clinic according to a standardized protocol.
Non-obstructive urographic renal damage was found
during childhood in 74 patients (54F, 20M). Three
children were excluded because of nephrectomy and 3
because of heminephrectomy. Between 1995 and 1997,
the 68 non-operated patients were invited for a clinical
and radiological reinvestigation a median of 22 y after
the rst UTI. Eleven patients did not participate: 5 had
Birth size and urinary tract infection
ACTA PÆDIATR 90 (2001)
moved abroad and could not be traced and 6 declined to
participate. Thus, 57 patients with renal damage were
reinvestigated as adults (14).
These 57 patients were requested to participate in the
present study. Informed written consent was obtained
from 54 patients. Birth les from 3 patients could not be
traced, and gestational age could not be estimated in 3
patients owing to irregular menstrual periods. Thus, the
original birth les of 48 patients, 10 without reux (all
females) and 38 (25F, 13M) with reux in childhood,
were available for analysis. Of the 10 patients without
reux, 7 had a normal rst urography and thus had an
acquired renal damage, while 21 of the 38 patients with
reux had an acquired renal damage.
The 26 patients with renal damage who were not
included were comparable with the 48 included patients
regarding gender (73% and 73% females, respectively),
reux occurrence (84% and 79%, respectively) and
frequency of acquired renal damage (50% and 58%,
respectively).
The study was approved by the Ethics Committee of
the Medical Faculty, Göteborg University.
Methods
Renal damage. Permanent renal damage (scarring) at
urography was dened as a reduction in parenchymal
thickness with corresponding calyceal deformation
(15). Standardized voiding cystourethrography (VCU)
was performed, and reux was classied according to
the International Reux Study (16). The maximum
grade of reux was used to represent the patient if
several VCUs were performed.
Birth size. Maternity health les and delivery reports
were reviewed for birthweight and birthlength, gestational age and rst day of the last menstrual period.
None of the children was born preterm; all had a
gestational age at birth ¶37 wk. Birthweight and birthlength were expressed as standard deviation scores (SDS)
for gestational age according to Swedish reference
values (17).
Urinary tract infection. UTI was dened as signicant
bacteriuria in 1 midstream or 2 bag urine samples with
Fig. 1. Birthweight standard deviation scores (SDS) for 10 children
without reux and 38 children with reux. The horizontal lines in the
box charts denote the 25th, 50th and 75th percentiles . The error bars
denote the 5th and 95th percentil e values. The individua l values are
denoted as solid circles. Non-reux children had signicantly lower
birthweigh t compared with children with reux (p = 0.01).
at least 105 colony-forming units ml¡1 of a single
bacterial species or any growth of bacteria in urine
obtained by suprapubic bladder aspiration.
Statistical methods
The median and range were calculated for birthweight,
birthlength and gestational age at birth, as well as for the
SDS of birthweight and birthlength. SDS expresses the
percentile value of each child adjusted for gestational
age in relation to the reference material. The Wilcoxon
2-sample test was used to evaluate differences in
distribution of birth size, expressed as SDS. A p-value
<0.05 was considered statistically signicant.
Results
Birthweight
Median and range for birth size and gestational age in
relation to childhood reux status are given in Table 1.
Table 1. Gestational age and size at birth in patients with renal damage following urinary tract infection accordin g to reux status
Birthweight
n
No reux
10 (F)
Reux
38 (F ‡ M)
629
Birthlength
Gestational age (wk)
(g)
SDS
(cm)
SDS
40
(39–41)
40
(37–43)
3210
(2540–3550)
3475
(2640–4550)
¡0.76
(¡2.14 to 0.86)
¡0.01
(¡1.77 to 2.38)
p = 0.01*
49
(47–52)
50
(47–54)
¡0.53
(¡1.82 to 0.86)
0.10
(¡1.53 to 1.69)
p = 0.04*
Data are medians (range).
SDS, standard deviation scores; F, females; M, males.
* Comparison with females without reux using the Wilcoxon 2-sample test.
630
M Hellström et al.
Among the children without reux (n = 10), the median
birthweight was ¡0.76 SDS, which was signicantly
lower than in the reference material (p = 0.02). In the
group with reux (n = 38) the corresponding gure was
¡0.01 SDS. The median birthweight was signicantly
lower in the non-reuxing group than in the reuxing
group (p = 0.01) (Table 1, Fig. 1). When the boys were
excluded from the analyses, as there were only girls in
the group without reux, there was still a signicant
difference (p = 0.02) in birthweight SDS between the
group without reux (¡0.76 SDS) and the group with
reux (n = 25) (¡0.08 SDS).
Birthlength
The median birthlength SDS was lower among children
in the non-reuxing group than in the reuxing group
(p = 0.04) (Table 1). A similar trend was noted when the
boys were excluded from the analyses (p = 0.05).
Among the children without reux (n = 10) the median
birthlength was ¡0.53 SDS, which was numerically, but
not signicantly lower than in the reference material
(p = 0.08).
Discussion
In the present study, girls with UTI-related renal
damage but no reux had a lower than expected
birthweight for gestational age. Reux, age and gender
have long been considered to be the main risk factors for
renal damage in children with UTI. Renal damage is
mostly found in infants and young children, and less
commonly in older children and adults (18). In boys, the
renal damage is present at birth more often than in girls,
in whom the damage mostly appears to be acquired and
related to the number of pyelonephritic attacks (14).
There is a clear gender difference in that boys with renal
damage mostly have reux (85%) and higher grades of
reux than girls (14). In children with malformations of
the urinary tract, there are often dysplastic elements in
kidneys investigated by microscopy (19). However,
dysplasia can rarely be differentiated from UTI-related
renal damage by the methods in clinical use, i.e.
urography, ultrasonography and DMSA scintigraphy.
Thus, the frequency and clinical impact of dysplasia are
difcult to assess. In this study, however, 7 of the 10
patients without reux had a normal rst urography and
developed the renal damage later. This indicates that the
renal changes in these patients were a secondary and not
a primary event.
An unfavourable intrauterine environment may affect
renal development well into the last trimester, as
nephrogenesis in humans proceeds up to week 35 of
gestation (20).
Experimental studies have shown that the prenatal
development of the kidney may be affected by impaired
intrauterine blood supply or by impaired maternal
nutrition, resulting in fewer nephrons (21, 22). In
ACTA PÆDIATR 90 (2001)
addition, pathological studies have demonstrated that
children with intrauterine growth retardation have lower
kidney weights and a lower number of nephrons at birth,
and that this abnormal renal morphology appears to
persist during infancy (10). It has also been shown that
patients with diabetes mellitus born small for gestational age are at increased risk for developing diabetic
nephropathy (23), and that children with low birthweight and IgA glomerulonephritis had a higher
incidence of glomerulosclerosis and arterial hypertension (11). In addition, an association has been found
between birthweight and the rate of deterioration of
glomerular function in patients with idiopathic membranous nephropathy (24). These studies suggest that
being born small for gestational age might be one of the
non-immune mechanisms affecting the clinical course
and prognosis of renal disease and that the mechanism
might partly be explained by a reduced number of
nephrons making the kidney more vulnerable. Zidar and
co-workers have also shown that in children with
minimal change nephrotic syndrome low birthweight
predicts an unfavourable clinical course (more relapses,
steroid dependency) (12). This nding was suggested to
indicate a higher morbidity due to other morphological
changes than lower number of nephrons, and/or changes
in physiology of the developing kidney in children with
low birthweight.
The nding of a low birthweight in girls without
reux, as demonstrated in the present study, is
consistent with the experimental and pathological
studies mentioned above. Thus, impaired foetal growth
may also make the kidneys more prone to develop renal
damage following infection (UTI). Interestingly, the
group with renal damage and reux had a normal
birthweight, suggesting that different mechanisms are
involved in reuxing and non-reuxing individuals.
It has recently been suggested that low birthweight is
associated with hypertension in later life (25) and with
an increased risk of death from cardiovascular disease
(26). The subnormal numbers of nephrons observed in
subjects with a low birthweight was proposed by
Brenner and Chertow as the cause of the hypertension
noted in later life (27). This hypothesis was recently
supported by an experimental study in rats deprived of
protein prenatally, which demonstrated an association
between impaired nephrogenesis and later hypertension
(28).
In conclusion, the demonstration of a low birthweight
among children with UTI and renal damage but no
reux in this limited series of patients suggests that a
low birthweight may be a risk factor for the development of renal damage. Further studies in a larger patient
population are needed to conrm these ndings.
Acknowledgements.—This work was supported by grants from The
Swedish Medical Research Council (7509, 9516, 10863), The Inga-Britt
and Arne Lundberg Foundation, The Knut and Alice Wallenberg
ACTA PÆDIATR 90 (2001)
Foundation, The Frimurare-Barnhusdirektione n and The Göteborg
Medical Society. We are grateful for the statistical support by Elisabeth
Svensson, PhD, Professor in Biostatistics.
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Received Nov. 1, 2000; revision received Jan. 26, 2001; accepted
Jan. 30, 2001
Ulf Jodal