Urinary Tract Infection in Children With Nephrotic Syndrome

Abstract

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 bacterial 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.

Nephrotic 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 retrospective 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 retrospectively 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 Arbeitsgemeinschaft für Pädiatrische Nephrologie protocol.¹² The initial episode was treated with prednisolone in doses of 60 mg/m² daily for 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 alternate 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) suprapubic 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 symptomatic patients with ≥10³ CFUs/mL of a single organism.⁵

Data were expressed as mean ± standard deviation. Statistical 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 respiratory 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 follows. 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.

TABLE 1.: Demographic Features and Biochemical Parameters in Children With UTI and Control Group

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 on the 96 children who developed recurrent UTI. Then results obtained were normal. The etiologic spectrum of UTI is illustrated in Figures 1 and 2, respectively.

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

FIGURE 2.: Spectrum of fungi isolated from the urine of children with NS.

DISCUSSION

Infections, including UTI, are an important cause of morbidity and mortality in children with NS especially in the developing countries.⁶ The factors that result in high frequency of UTI in children with NS may be both local as well as systemic. Locally, the pressure on the collecting system by the edematous pyramids causes narrowing and functional obstruction to the flow of urine predisposing them to UTI.⁵ Systemic cause occurs as a result of many factors, particularly hypoglobulinemia as a result of the urinary losses of immunoglobulin G, protein deficiency, decreased bactericidal activity of the leukocytes, immunosuppressive therapy and decreased perfusion of the spleen caused by hypovolemia. Apart from this, defects in the complement cascade from urinary loss of complement factors (predominantly C3 and C5) as well as alternative pathway factors B and D lead to impaired opsonization of microorganisms.¹³

In our case series, we found that 15% of children with NS had a UTI that is very similar with the findings of Gulati et al.⁵ However, Arcana,¹⁴ Adeleke and Asani,⁷ McVicar et al¹⁵ and Ibadin¹⁶ reported UTIs in 42%, 66.7%, 21% and 44.8% of NS patients, respectively. However, Moorani and Mukesh¹⁷ and Ritonga¹⁸ were found only in 25%.

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 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 boys because of colonization of periurethral and prepucial area by organisms such as Escherichia coli. In the present series, the higher incidence of male UTI can be explained in the same light. Ibadin¹⁶ and Adeleke and Asani⁷ also reported high prevalence of UTI in males.

Urine routine microscopy reveals the presence of proteinuria (ranging from trace to ++++) in every patient while the presence of white blood cell was reported in 92.1% cases and granular cast was reported in 9.7% cases. Statistical analysis was done between UTI and biochemical parameters, and it was found significant for serum albumin and serum cholesterol at 0.05 levels. Hypercholesterolemia may have a direct pathophysiologic role as it has been observed that hypercholesterolemic serum inhibits lymphocyte proliferation in response to specific and nonspecific antigen stimulation.⁵

In our study, we found that the genus Klebsiella (25.33%), E. coli (16.82%) and Citrobacter freundii (13.49%) were the predominant ones among bacterial etiology, while Candida cruzi (26.08%), Candida tropicalis (21.74%) and Candida parapsilosis (18.85%) were predominant among yeast. Subandiyah²⁰ reported that E. coli was the etiologic agent in 48.9% of UTIs in both the outpatients and the hospitalized children in Saiful Anwar Hospital, Malang. Similarly, another study revealed the most common causes of UTI were E. coli and Citrobacter diversus (23% each, or 8/34 children).²¹ However, Adeleke and Asani⁷ found Staphylococcus aureus to be the most common cause of UTI in NS patients (67.9%). This finding is similar to the study done by Ibadin¹⁶ who reported that 54.3% of the isolates were that of S. aureus. However, Tsau et al²² reported Gram-negative bacilli as the predominant cause of infections that includes UTI in patients with NS. This difference observed may be due to variations in location that may lead to variations in bacterial trends.

Registering a total of 2880 patients, this study is the largest study till date. Also worth mentioning is the fact that never before 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 protocol. 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 organisms of UTI, although important is often left undiagnosed in children 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 bacterial etiology, one must consider and test for yeast as a causative organism.