Association between hyponatremia and disease severity in pediatric urinary tract infections (2024)

Background

Acute urinary tract infection (UTI) is a common disease in pediatrics, with around 8% of girls and 2% of boys experiencing a UTI by age 7y/o. UTIs can range from asymptomatic bacteriuria to acute pyelonephritis (APN) in severe cases involving renal parenchymal infection. UTI patients admitted to the pediatric ward usually have more severe clinical presentation, compared to those treated in the outpatient settings. Therefore, it will be helpful to have markers that predict the severity of the disease and the likelihood of having APN.

Methods

We performed a retrospective review on all pediatric UTI/APN patients treated in the inpatient setting at a Medical Center from October 2012 to September 2022. Patients were assigned to the “hyponatremia” or “eunatremia” group according to their serum sodium concentrations. Detailed information, including renal echo, blood, and urine test results, were collected for the analysis of multivariable logistic regression model.

Results

The study included 344 patients, of which 99 (28.8%) had hyponatremia, and 245 (71.2%) had normal serum sodium levels. The hyponatremia group had higher APN frequency, renal echo abnormality, and higher CRP level. In multivariable analysis, hyponatremia was independently associated with increased serum glucose (OR: 1.01, 95% CI: 1.00-1.03, p = 0.0365) and CRP levels (OR: 1.00, 95% CI: 1.00-1.01, p = 0.0417), without a significant increase in APN frequency as the final diagnosis.

Conclusions

Our findings suggest that hyponatremia in pediatric UTI patients may indicate a more severe disease, such as APNs, higher CRP levels, or renal echo abnormalities. The complex mechanisms underlying hyponatremia and its predictive value for disease severity warrant further investigation.

Acute urinary tract infection (UTI) is a common disease in pediatrics. It has been found that around 8% of girls and 2% of boys will have experienced UTI by the age of 7y/o [1]. UTI can be further classified into upper UTI (pyelonephritis and ureteritis) and lower UTI (cystitis and urethritis) [2]. When the urinary tract is infected by bacteria, the patient may present with asymptomatic bacteriuria, lower urinary tract infection symptom/signs, or acute pyelonephritis (APN) in a minority of patients due to renal parenchymal involvement [3]. UTI patients admitted to the pediatric ward usually have more severe clinical presentation, compared to those treated in the outpatient settings. Therefore, among these patients, identifying additional markers that can predict disease severity and the likelihood of developing APN could be beneficial. Factors proposed by previous studies include, fever peak > 39°C, Procalcitonin (PCT) level, C-reactive protein (CRP) level, and abnormal renal and urinary bladder sonography findings [4].

A more interesting, but rarely discussed marker, is hyponatremia (plasma sodium < 135 mmol/l). Hyponatremia is a very common electrolyte disorder [5]. Hyponatremia had been reported to occur frequently in children with pneumonia, Central nervous system (CNS) infections, and Kawasaki disease [6,7,8]. Hyponatremia had been noted to be associated with longer hospitalization and more severe outcomes in various infections [9]. A few studies in the past, had suggested hyponatremia to be associated with APN or reflect more severe inflammation in children with febrile UTI [10,11,12]. Hyponatremia has also been suggested to be associated with ultrasound abnormalities, such as pelviectasis [13]. Hyponatremia can occur as a result of free water excess (intravenous fluid or syndrome of inappropriate antidiuretic hormone secretion(SIADH)) or sodium wasting [14]. It had been proposed that infections involving the renal parenchyma may reduce the capacity to concentrate urine and pseudohypoaldosteronism secondary to renal tubular unresponsiveness can occur, which can cause a combination of hyponatremia, hyperkalemia, and acidosis [15]. Considering these findings, hyponatremia could potentially be a key indicator of more severe disease manifestations in pediatric infections. Therefore, the aim of in this study was to investigate the role of hyponatremia as a predictor of disease severity in pediatric patients hospitalized with UTI/APN.

Study design

We performed a retrospective review on all pediatric UTI/APN patients, treated in the inpatient setting at Chi Mei Medical Center, Tainan, Taiwan, between Oct, 2012 and Sep, 2022. We assigned enrolled patients into the “hyponatremia group” and “eunatremia group” according to their serum sodium level. Hyponatremia was defined as serum sodium  <135 mEq/L [16].

Inclusion and exclusion criteria of study population

All pediatric patients admitted to the pediatric ward (excluding NICU or PICU) at Chi Mei Medical Center for UTI during the study period were enrolled in this study. UTI was defined as the presence of pyuria in urinalysis and > 100, 000 CFU/mL in urine cultures [17]. The American Academy of Pediatrics recommends that renal and bladder ultrasound (RBUS) was performed in all infants (2–24 months) with febrile UTI [18]. In our study, RBUS is routinely performed during admission, typically within the first 24–72h, except in cases where a pediatric nephrologist was unavailable or the patient’s clinical condition did not require it. Blood tests, including CBC, CRP, and B/C, were also routinely conducted upon admission, with some variability in ordering blood electrolytes based on physician preference. Blood taking and intravenous catheter insertion is routinely performed at emergency room for children planned for admission to ward. For patients admitted from the outpatient department or young infants (more difficult to perform blood sampling), blood taking and intravenous catheter insertion is done upon arrival at ward. We excluded patients without blood sodium level or RBUS records, since these are important variables for this study.

Out of 1,748 patients initially diagnosed with UTI, 344 met the study criteria after excluding those whose urinalysis or urine culture results did not follow the study’s UTI definition, as well as those without renal ultrasound or blood sodium results. Among the 344 patients enrolled, 99 (28.8%) had hyponatremia, while 245 (71.2%) had normal serum sodium levels (Fig.1).

Measurements

The following data were collected during a chart review: age, sex, history of previous urinary tract infections (UTIs), presence of renal anatomical anomalies, and abnormal findings on renal and urinary bladder sonography. For the RBUS finding of pelviectasis, we used a cutoff value 10mm for the anterior–posterior renal pelvic diameter combined with the evidence of central calyceal dilation [13, 19, 20]. Although DMSA scan is the gold standard for assessing renal parenchymal injury, it is generally not necessary for most children with their first febrile UTI [17]. Due to the retrospective nature of this study, we could not validate the diagnosis of APN with DMSA scan. Therefore, the outcome of APN or lower UTI was determined according to the final diagnosis at discharge for all the patients admitted to the hospital for UTI, regardless of whether it was classified as upper or lower UTI. Laboratory data included complete blood count (CBC) parameters such as white blood cell count (WBC), hemoglobin (Hb), platelet count (PLT), band percentage, and absolute neutrophil count (ANC), as well as C-reactive protein (CRP), and glucose (Glu). Electrolyte measurements included sodium (Na) and potassium (K). Blood culture results, specifically the organism isolated, were also recorded. Urinalysis data comprised specific gravity, pH, protein, glucose, ketone bodies, WBC, RBC, and nitrite. The frequency of bacteremia was also considered.

Statistical analysis

All categorical variables were presented as frequencies with percentage, and Pearson’s chi-square test or Fisher’s exact test was used to compare the difference between two groups. Median with interquartile range was used to perform continuous variables. Since the normality test indicated that the data had no normal distribution, the Mann-Whitney U test was used to assess differences between the two groups. To identify potential risk factors associated with hyponatremia, we estimated the odds ratio (OR) with a 95% confidence interval (95% CI) using logistic regression analysis. We then used a multivariable logistic regression model with Firth’s approach to consider any potential small-sample bias. Variables with a p-value of < 0.1 from the univariate analysis were selected in this multivariable model. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). The level of significance was set as p < 0.05.

Ethics statement

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board (IRB) and Research Ethics Committee of Chi Mei Medical Center (IRB no.: 11109006). The IRB of Chi Mei Medical Center waived the requirement for written informed consent from all study participants according to the Taiwan’s Human Subjects Research Act, which allows for such waivers when the research involves minimal risk and uses anonymized clinical data. Informed consent was deemed unnecessary due to the retrospective and observational nature of the study, and this waiver did not affect patient welfare.

The baseline characteristics of the hyponatremia group and the eunatremia group are shown in Table1. There was no significant difference over the distribution of age or sex. The hyponatremia group had a significantly higher proportion of patient who had a final diagnosis of acute pyelonephritis compared to the eunatremia group (54.55% vs. 40.82% respectively, p = 0.0204). The hyponatremia group had a significantly higher frequency of abnormal RBUS findings (76.77% vs. 65.71%, p = 0.0450). Nephromegaly was also observed in 32.32% of the hyponatremia group compared to 18.37% of the eunatremia group (p = 0.0049). Most of the patients did not receive VCUG exam and there was no significant difference over the VCUG results among patient who had received the exam. For congenital anomalies of the kidney and urinary tract (CAKUT), there were only 2 cases, both in the eunatremia group. One case had right kidney atrophy and the other had left collecting system duplication. These two groups also have no difference in the duration (days) of hospital stay.

Table2 show the blood test results between these two groups. The hyponatremia group had significantly lower median hemoglobin level (10.80g/dl, IQR: 10.00-11.60) compared to the eunatremia group (11.10g/dL, IQR 10.30–11.80), with a p-value of 0.0384. Blood biochemistry tests showed significantly higher C-reactive protein level in the hyponatremia group (median: 64.50mg/L, IQR: 27.70-106.20 vs. 36.90mg/L, IQR: 16.00-71.10), p = 0.0002). Additionally, the hyponatremia group also had significantly higher frequency of glucose level abnormality, including both hypoglycemia and hyperglycemia, than the eunatremia group. The potassium concentration was similar in the two groups, and there was no difference in the frequency of bacteremia.

The differences in urinalysis results between the two study groups are presented in Table3. No significant differences were observed in specific gravity, whether analyzed as a continuous variable or categorized into normal, low, or high specific gravity groups. The WBC and RBC counts per microliter were also similar between the two groups. Additionally, there were no differences in the frequency of proteinuria, glucosuria, or positive urine nitrite tests. The average of urine pH presented a little higher in the eunatremia group (6.24 ± 0.61) compared to the hyponatremia group (6.06 ± 0.61), with a statistically significant difference (p = 0.0115). The urine culture results for the two study groups are shown in Table4. The pathogens isolated from the urine cultures were very similar between the two groups. Escherichia coli was the most common pathogen, accounting for over 90% of cases in both groups, followed by Klebsiella pneumoniae and Proteus mirabilis as the second and third most common pathogens, respectively.

Table5 show the estimated ORs of identifying potential risk factors associated with hyponatremia from the multivariable logistic regression analysis. Initially, the univariate analysis showed a significant association between APN and hyponatremia (OR: 1.73, 95% CI: 1.08–2.77, p = 0.0217), indicating that patients diagnosed with APN might be at higher risk for hyponatremia than those diagnosed with lower UTI. However, in the multivariable analysis, the association between lower UTI/APN final diagnosis or abnormal image finding on renal ultrasound became insignificant. Hyponatremia was also not associated with serum potassium level or urine specific gravity. However, hyponatremia was independently associated with increased serum glucose (OR: 1.01, 95% CI: 1.00-1.03, p = 0.0365) and CRP (OR: 1.00, 95% CI: 1.00-1.01, p = 0.0417). Despite the statistical significance, the estimated ORs suggest that these associations may have limited clinical significance.

In this study, 28.8% of the 344 UTI patients we enrolled had hyponatremia. Previous study showed hyponatremia prevalence of 37% in children hospitalized for different causes [21]. However, other studies focusing on UTI patients showed a rate of 45–50% when defining hyponatremia as Na + ≤ 135 mEq/L [11, 12]. In addition, another study defined hyponatremia as Na + ≤ 130 mEq/L, 2.8% of the enrolled patients with febrile UTI had hyponatremia [13]. Therefore, the prevalence of hyponatremia during febrile UTIs may not be consistent under different clinical situations and definitions. Most patients with hyponatremia are asymptomatic, while severe symptoms typically occur at levels below 120 mEq/L [22]. In our study, the range of all blood sodium levels was between 128.5 and 141.5 mEq/L. There was no case of hypernatremia or symptomatic hyponatremia. Therefore, we did not further stratify the hyponatremia group into symptomatic (severe) or asymptomatic cases.

Furthermore, about 60% of the patients were males in both the hyponatremia and eunatremia group. The study participants were mostly infants of several months old. Following a similar study design, the age distribution of participants in our study is consistent with findings from previous research [12]. In our study, we would like to investigate hyponatremia in childhood UTI. Although most study participants were mainly infants, we believe this is due to the reason that febrile infants are admitted to the hospital more often, while older children may be treated with take-home antibiotics. On the bright side, since our study population mainly consisted of infants, we can be less worried about possible confoundings such as medication use or underlying disease, since these are rare in infants.

In the univariate analysis, we noted significant association between hyponatremia and APN diagnosis, renal echo abnormality, and CRP level. Aside from APN, which is doubtlessly more severe than lower UTI, renal echo abnormality and CRP level have been proposed to be independent variables for predicting APN in children [4, 23]. Fang et al. reported significantly higher percentage of abnormal RUBS finding in their APN group than in the lower UTI group [4]. As for CRP, a recent Cochrane database systemic review suggested that a CRP value of < 20mg/L may be useful in ruling out pyelonephritis [24].

Sonographic features of APN can include loss of corticomedullary differentiation, increased renal size, loss of renal sinus fat due to edema, dilated renal pelvis, or urothelial thickening [25]. González-Bertolín et al. reported association between mild pelviectasis and hyponatremia, while no association was found between hyponatremia and urinary tract malformation [13]. In our study, we also noted significant association between hyponatremia and renal echo abnormality, as well as nephromegaly. However, we did not observe the previously suggested association with dilated renal pelvis.

We also noted an association between hyponatremia and lower Hb. This finding could not be explained by iatrogenic intravenous fluid infusion, since the serum sodium level were obtained before any intravenous catheter insertion per our hospital’s protocol. Another proposed mechanism for hyponatremia in children are excess ADH due to inflammatory cytokines [11]. However, considering the small difference in Hb value between these two groups, this difference may only have limited clinical relevance.

For the blood glucose level, we found that the hyponatremia group had significantly higher frequency of glucose level abnormality, including both hypoglycemia and hyperglycemia, than the eunatremia group. The association between hyponatremia and hypoglycemia may represent patients with poor feeding status, which may result in electrolyte imbalance, as well as lower blood glucose level. As for hyperglycemia, hyperglycemia has long been known to be associated with decreased serum sodium concentration. It has been suggested that corrected sodium level may be preferred over measured sodium levels among patients with severe hyperglycemia [26]. We had taken blood glucose into account during our study design to monitor for cases with extreme hyperglycemia. The highest blood glucose level in the patients enrolled was only 210mg/dL. Therefore, we did not perform extra correction for the measured serum sodium level.

Previous studies have suggested that the association between hyponatremia and more severe UTIs may be caused by transient resistance of the distal tubule to aldosterone, which could also explain the observed of hyperkalemia incidence [10, 27]. To explore this further, we measured serum potassium levels in our study. However, we did not find the association between hyponatremia and hyperkalemia in our study. Additionally, we aimed to investigate the possibility of hyponatremia being linked to SIADH. If SIADH were responsible for the hyponatremia observed during UTI, we would expect to see higher urine specific gravity in the hyponatremia group. However, our findings showed no significant difference in urine specific gravity between the hyponatremia and eunatremia groups.

In our multivariable analysis, hyponatremia was found to be independently associated with increased serum glucose and CRP levels, but it was not independently associated with APN diagnosis. A recent study by Pappo et al. employed a similar design, enrolling 246 patients to investigate the association between hyponatremia and severe diseases that defined as nephronia, abscess, abnormal renal parenchymal findings on ultrasound, or hospitalization for seven or more days [12]. The study reported that hyponatremia patients had longer hospital stay, higher prevalence of abnormal findings on renal ultrasound, and higher CRP levels [12]. In contrast, our study, despite enrolling more patients (344 vs. 246), did not find a significant difference in hospital stay between the hyponatremia and eunatremia groups. This could explain why, although we observed associations between hyponatremia, higher prevalence of APN, abnormal renal ultrasound findings, and elevated CRP, the association with APN did not remain significant after multivariable analysis. The persistent association between hyponatremia and higher CRP after adjustment also supports this interpretation.

There are several limitations in our study. First of all, as a retrospective study, we could not account for some potential unmeasured confounding factors. We also did not have data over volume status, serum osmolarity, or urine sodium concentration, which would be valuable for further differentiating the mechanisms of hyponatremia. Second, we only included patients with disease severity that required hospitalization. We could not be sure whether the association between hyponatremia and UTI severity can be observed in patients with lower UTI, who do not need to be hospitalized or receive blood testing. A prospective study would be necessary to address this question in our future study. Third, the potential bias introduced by excluding a significant number of patients due to incomplete investigations. In this study, 304 patients were excluded due to missing RBUS or blood electrolyte data. However, we think this reflects real-world clinical practice, where diagnostic decisions are influenced by factors such as parental consent, patient stability, and clinician judgment. Since most of our study participants were infants for whom RBUS is recommended, we believe the exclusion of patients without RBUS data introduces limited bias. Additionally, due to the retrospective design of this study, the timing of RBUS may vary depending on the availability of resources or clinical judgment, which could affect the detection of renal abnormalities. This limitation should be considered when interpreting our findings. Lastly, our data were collected from a single center in Southern Taiwan, which may limit the generalizability of our findings to other populations. However, our results still indicate an association between hyponatremia and the severity of UTI.

In conclusion, our study indicated that hyponatremia UTI patients may have a more severe disease presentation, such as a higher chance of having APNs, higher CRP levels, or renal echo abnormalities. After multivariable analysis, only a higher CRP level remained significantly associated with hyponatremia, though the odds ratio does not seem to be clinically significant. Indeed, several different mechanisms can lead to hyponatremia in a hospitalized pediatric patient with UTI. Moreover, more than one of these mechanisms may occur at the same time. Therefore, the role of hyponatremia and its value as a predictor of disease severity may be more complicated than it seems and future studies would be required for a better understanding of the underlying mechanisms.

UTI:

Acute urinary tract infection

APN:

Acute pyelonephritis

PCT:

Procalcitonin

CRP:

C-reactive protein

CNS:

Central nervous system

SIADH:

Syndrome of inappropriate antidiuretic hormone secretion

RBUS:

renal and bladder ultrasound

CBC:

Complete blood count

WBC:

White blood cell count

Hb:

Hemoglobin

PLT:

Platelet count

ANC:

Absolute neutrophil count

CRP:

C-reactive protein

Glu:

Glucose

Na:

Electrolyte measurements included sodium

K:

Potassium

RBC:

Red blood cell

IRB:

Institutional Review Board

OR:

Odds ratio

95% CI:

95% confidence interval

VCUG:

Voiding cystourethrogram

Authors and Affiliations

1. Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan

   Fu-Wen Liang

2. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

   Fu-Wen Liang

3. Center for Big Data Research, Kaohsiung Medical University, Kaohsiung, Taiwan

   Fu-Wen Liang

4. Department of Medical Research, Chi Mei Medicine Center, Tainan City, Taiwan

   Ying-Jia Lin&Chung-Han Ho

5. Department of Information Management, Southern Taiwan University of Science and Technology, Tainan City, Taiwan

   Chung-Han Ho

6. Department of Pediatrics, Chi Mei Medicine Center, No. 901, Zhonghua Road., Yongkang Dist, Tainan City, 710402, Taiwan

   Yu-Shao Chen

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ying-Jia Lin, Chung-Han Ho, and Yu-Shao Chen. The first draft of the manuscript was written by Fu-Wen Liang and Yu-Shao Chen. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yu-Shao Chen.

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board (IRB) and Research Ethics Committee of Chi Mei Medical Center (IRB no.: 11109006). The IRB of Chi Mei Medical Center waived the requirement for written informed consent from all study participants according to the Taiwan’s Human Subjects Research Act, which allows for such waivers when the research involves minimal risk and uses anonymized clinical data. Informed consent was deemed unnecessary due to the retrospective and observational nature of the study, and this waiver did not affect patient welfare.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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