Original Studies
Urinary Tract Infection in Children With Nephrotic Syndrome
Upma Narain, DPhil,* and Arvind Gupta, MD, DNB†
Background: The occurrence of urinary tract infection (UTI) in nephrotic
syndrome has been reported. However, the only causes for the infection
reported to date are bacteria and prior reported series did not identify yeast
or fungi as causative organisms.
Methods: A retrospective study of 2880 children with nephrotic syndrome
was made to determine the incidence of UTI, predisposing factor and bacte-
rial and fungal etiologies.
Results: Between January 2000 and November 2016, we identified that 15%
of the children developed UTI. Within this group, bacterial UTI and fungal
UTI were 84.0% and 16.0%, respectively. The genus Klebsiella (25.33%)
predominates among bacteria, while Candida cruzi (26.08%) predominates
among fungal etiologies. Statistical analysis was performed for biochemical
indices and UTI and was found significant for low serum albumin and high
serum cholesterol (P ≤ 0.05).
Conclusion: This study emphasizes the importance of UTI in children and
can be underdiagnosed in children with nephrotic syndrome because steroid
therapy is anti-inflammatory and can mask the symptoms of UTI.
Key Words: urinary tract infection, nephrotic syndrome, children, bacteria,
fungi
(Pediatr Infect Dis J 2018;37:144–146)
N ephrotic syndrome (NS) results in proteinuria of more than 3.5 g
protein per day and is characterized by edema, hyperlipidemia,
hypoproteinemia and other metabolic disorders.1 The course of NS is
often complicated by frequent relapses, steroid resistance, thrombosis
and infections.2 The common infections seen in NS are pneumonia,
urinary tract infection (UTI), bacteremia, peritonitis and cellulitis.3 Of
these, UTI is often underdiagnosed in NS and may also be responsible
for poor response to steroid therapy.4 Some studies have shown that
UTI is the most common infectious complication of NS.5,6 However,
some others suggest that the incidence of UTI is low in the first episode
and higher following the relapses in NS.7–10 The aim of this retrospec-
tive study is to analyze the incidence of UTI, its predisposing factors
along with its bacterial and fungal etiologies in patients with NS.
MATERIALS AND METHODS
Between January 2000 and November 2016, we retrospec-
tively analyzed the data of 2880 children, under 16 years of age,
fulfilling all the necessary criteria required for the International
Study of Kidney Disease in Children suffering from NS.11
These 2880 children were treated using standard Arbeitsge-
meinschaft für Pädiatrische Nephrologie protocol.12 The initial epi-
sode was treated with prednisolone in doses of 60 mg/m2 daily for
Accepted for publication August 12, 2017.
From the *Department of Microbiologist and Immunologist, Tejas Microdiag-
nostics, and †Division of Nephrology, Moti Lal Nehru Medical College,
Allahabad, Uttar Pradesh, India.
The authors have no funding or conflicts of interest to disclose.
Address for correspondence: Upma Narain, DPhil, Department of Microbiolo-
gist and Immunologist, Tejas Microdiagnostics, 62, Jawaharlal Nehru Road,
Tagore Town, Allahabad, Uttar Pradesh, India 211002. E-mail: upmanarain@
gmail.com.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0891-3668/18/3702-0144
DOI: 10.1097/INF.0000000000001747
144 | www.pidj.com The Pediatric Infectious Disease Journal  •  Volume 37, Number 2, February 2018
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
6 weeks followed by 40 mg/m2 on alternate days for 6 weeks. Any
form of relapse was treated with prednisolone in doses of 60 mg/
m2/d until remission for 3 days followed by 40 mg/m2 on alter-
nate days for 4 weeks. An adjunctive therapy (cyclophosphamide,
mycophenolate, tacrolimus or cyclosporine) was administered in
standard regimens to frequent relapsers, steroid dependents and
steroid resistants according to guidelines whenever indicated.
Examinations for microscopy and cultures of urine, sputum,
throat swab, blood and fluid were also carried out in the children,
along with routine examination, if found necessary.
Urine was cultured in the following circumstances: (1) for a
screening investigation before the initiation of steroid therapy; (2)
when the response to a standard 4-week course of steroids was null
and (3) when remission suggested symptoms of UTI such as fever,
dysuria or hematuria.5
Each specimen was divided into 2 parts, one was taken
for direct routine and microscopic examination and the other was
inoculated on Columbia sheep blood Agar (Biomerieux, Marcy-
l’Étoile, France) and Sabouraud Cycloheximide Chloramphenicol
agar (M664; Hi-Media, Mumbai, India) for 24 hours incubation at
37°C. The identification of individual bacteria and fungi was done
by Vitek-2 (Biomerieux, France).
A positive urine culture was defined as follows: (1) suprapu-
bic aspirate (a) isolation of ≥102 colony-forming units (CFUs)/mL
of a single Gram-negative bacillus or (b) isolation of ≥103 CFUs/
mL of a single Gram-positive cocci; (2) midstream clean-voided
specimens in symptomatic patients with isolation of ≥105 CFUs/
mL of a single organism and (3) midstream specimens in sympto-
matic patients with ≥103 CFUs/mL of a single organism.5
Data were expressed as mean ± standard deviation. Statisti-
cal significance was defined at a P value of 0.05 by using IBM
SPSS 24 version (IBM Corporation, Armonk, NY).
RESULTS
During the period between January 2000 and November 2016,
the aforesaid children with NS were registered in the Nephrology Out
door patient department, Allahabad. Out of these 2880 children, 844
(29.3%) developed various infections (UTI: 15.00%, Lower respira-
tory tract infection: 8.33%, Upper respiratory tract infection: 4.28%,
diarrhea: 0.59%, septicemia: 0.31%, Tuberculosis: 0.04, skin lesion:
0.21%, peritonitis: 0.55%) and the rest 2036 (70.7%) did not show
any signs of infections. Out of the 844 patients, 432 (51%) patients
developed UTI of which 363 (84.03%) developed bacterial UTI and
69 (15.97%) developed fungal UTI. A point to be noted, however,
was that there was no case of genitourinary tuberculosis.
Their demographic and baseline data were described as fol-
lows. Out of the 432 cases, the mean age of patients with UTI was
7.8 ± 2.1 years with males being about 77% and females about 23%.
The mean duration of the follow-up was 16.7 months. The age and
sex distribution in children who developed UTI were similar to the
control group comprising 2036 children with no infection. This is
depicted in Table 1 along with the laboratory values.
In our case series, the other clinical features that were noted
were dysuria, fever, abdominal pain and gross hematuria. None of
the children exhibited any signs of pyelonephritis. Out of the 432
episodes observed in all (432) children, 96 developed recurrent
episodes of UTI later on. An ultrasound was carried out for the
432 children, while a micturating cystourethrogram was performed
The Pediatric Infectious Disease Journal  •  Volume 37, Number 2, February 2018 Urinary Tract Infection in Children

respectively. However, Moorani and Mukesh17 and Ritonga18 were

TABLE 1.  Demographic Features and Biochemical
found only in 25%.
Parameters in Children With UTI and Control Group In the present study, we recorded UTI in 77% males and in
23% females. David W. C Jacobs studied case of UTI in NS and
No Infections
Variable UTI (n = 432) (n = 2036) found a male preponderance in 81% cases of his series.19 He was
of the opinion that the incidence of UTI is more in uncircumcised
Age 7.8 ± 2.1 8.2 ± 2.5 boys because of colonization of periurethral and prepucial area by
Sex Male = 77% Male = 74% organisms such as Escherichia coli. In the present series, the higher
Female = 23% Female = 26%
Blood urea nitrogen (µmol/L) 5.3 ± 0.81 5.4 ± 0.19
incidence of male UTI can be explained in the same light. Ibadin16
Serum creatinine (µmol/L) 82.2 ± 5.3 84.4 ± 8.0 and Adeleke and Asani7 also reported high prevalence of UTI in
Serum protein (g/L) 47.1 ± 1.8 48.8 ± 0.84 males.
Serum albumin (g/L) 20.1 ± 8.4 27.8 ± 6.8 Urine routine microscopy reveals the presence of proteinuria
Serum cholesterol (mmol/L) 11.9 ± 2.7 9.2 ± 4.1 (ranging from trace to ++++) in every patient while the presence
24-h urine protein (mg/m /h)
2
64.0 ± 2.34 64.0 ± 1.10
of white blood cell was reported in 92.1% cases and granular cast
was reported in 9.7% cases. Statistical analysis was done between
on the 96 children who developed recurrent UTI. Then results UTI and biochemical parameters, and it was found significant for
obtained were normal. The etiologic spectrum of UTI is illustrated serum albumin and serum cholesterol at 0.05 levels. Hypercholes-
in Figures 1 and 2, respectively. terolemia may have a direct pathophysiologic role as it has been
observed that hypercholesterolemic serum inhibits lymphocyte
proliferation in response to specific and nonspecific antigen stimu-
DISCUSSION lation.5
Infections, including UTI, are an important cause of mor- In our study, we found that the genus Klebsiella (25.33%), E.
bidity and mortality in children with NS especially in the develop- coli (16.82%) and Citrobacter freundii (13.49%) were the predomi-
ing countries.6 The factors that result in high frequency of UTI in nant ones among bacterial etiology, while Candida cruzi (26.08%),
children with NS may be both local as well as systemic. Locally, Candida tropicalis (21.74%) and Candida parapsilosis (18.85%)
the pressure on the collecting system by the edematous pyramids were predominant among yeast. Subandiyah20 reported that E. coli
causes narrowing and functional obstruction to the flow of urine was the etiologic agent in 48.9% of UTIs in both the outpatients and
predisposing them to UTI.5 Systemic cause occurs as a result of the hospitalized children in Saiful Anwar Hospital, Malang. Simi-
many factors, particularly hypoglobulinemia as a result of the uri- larly, another study revealed the most common causes of UTI were
nary losses of immunoglobulin G, protein deficiency, decreased E. coli and Citrobacter diversus (23% each, or 8/34 children).21
bactericidal activity of the leukocytes, immunosuppressive therapy However, Adeleke and Asani7 found Staphylococcus aureus to be
and decreased perfusion of the spleen caused by hypovolemia. the most common cause of UTI in NS patients (67.9%). This find-
Apart from this, defects in the complement cascade from urinary ing is similar to the study done by Ibadin16 who reported that 54.3%
loss of complement factors (predominantly C3 and C5) as well as of the isolates were that of S. aureus. However, Tsau et al22 reported
alternative pathway factors B and D lead to impaired opsonization Gram-negative bacilli as the predominant cause of infections that
of microorganisms.13 includes UTI in patients with NS. This difference observed may be
In our case series, we found that 15% of children with NS due to variations in location that may lead to variations in bacterial
had a UTI that is very similar with the findings of Gulati et al.5 trends.
However, Arcana,14 Adeleke and Asani,7 McVicar et al15 and Iba- Registering a total of 2880 patients, this study is the largest
din16 reported UTIs in 42%, 66.7%, 21% and 44.8% of NS patients, study till date. Also worth mentioning is the fact that never before

FIGURE 1.  Spectrum of bacteria isolated from the urine of children with NS.

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Narain and Gupta The Pediatric Infectious Disease Journal  •  Volume 37, Number 2, February 2018
FIGURE 2.  Spectrum of fungi isolated from the urine of children with NS.
has such a varied bacterial spectrum been isolated in the cases of
UTI. Fungal isolates have not been mentioned as of yet. This is the
largest series and widest etiologic review.
Out of the 432 patients that were tested, we did not find any
congenital anomaly as the causative factor for UTI and 56.2%
episodes were asymptomatic with UTI being detected as a part
of the screening investigation for relapse or steroid resistant.
Patients who had developed UTI while taking steroid therapy
and had previously been considered as resistant became steroid
responsive after the eradication of UTI. All children were treated
with antibiotics for 7 days on the basis of culture and sensitivity
report. They were subsequently treated using oral prednisolone
as per Arbeitsgemeinschaft für Pädiatrische Nephrologie proto-
col. Hence, asymptomatic UTI may be one of the underdiagnosed
causes of relapse in a child with NS.
This study identified a wide spectrum of etiologic organ-
isms of UTI, although important is often left undiagnosed in chil-
dren suffering from NS. Therefore, to avoid such incidents from
happening, children suffering from NS exhibiting relapse or
those exhibiting no response toward any form of steroid therapy
should be screened for the presence of UTI. Also worth keeping
in mind is the fact that during screening, apart from the bacte-
rial etiology, one must consider and test for yeast as a causative
organism.
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