Infections Are Associated with Higher Risk of Venous Thromboembolism in Hospitalized Children with Nephrotic Syndrome

Introduction: Although it is known that children with nephrotic syndrome (NS) are at greater risk for certain complications, the frequency of these complications and predisposing risk factors are poorly defined. In particular, nephrotic syndrome has long been considered a hypercoagulable state. Risk for development of venous thromboembolism (VTE) is known to be increased in the setting of an active infection. The objective of this study was to determine the prevalence of infection and VTE among a cohort of hospitalized children with NS, and the association of these complications on outcomes.

Methods: Records of hospitalized children with NS admitted to any of 17 participating pediatric hospitals across North America from 2010-2012 were included. Data including demographics, clinical pattern of NS, renal biopsy results, number of hospitalizations, nephrotoxic medication usage, infection and VTE history were recorded. Descriptive statistics were used to determine prevalence of infection and VTE. Wilcoxon rank sum was used to perform comparisons between groups. Logistic regression analysis was utilized to determine predictors of VTE development.

Results: Seven-hundred thirty hospitalizations occurred among 370 children. One-hundred forty-eight children (40%) had at least 1 infection with a total of 211 infectious episodes; 11 (3%) had VTE. Those with infection were more likely to have VTE (p = 0.0457). Infections associated with VTE were C. difficile (1 subject), methicillin sensitive S. Aureus (2), Streptococcus pneumoniae (1), and unknown (3). There were no differences between those with and without infection regarding gender or ethnicity. Those with infection were younger at NS diagnosis (3.0 vs. 4.0 years; p = 0.008), and steroid resistant NS was more highly associated with infection than all other clinical diagnoses (steroid-sensitive NS, steroid-dependent NS, other) (p = 0.003). The most common types of infections encountered included peritonitis (23%), pneumonia (22%), and bacteremia (16%). Bacterial pathogens (Streptococcus pneumoniae 41%, Escherichia coli 16%, Clostridium difficile 10%) were most commonly identified. Children with VTE, infection, or both, also required significantly more days in hospital. The median hospital stay for those without infection was 5 days vs. 10 in those with infection (p< 0.0001). Similarly, median hospital days for those without VTE were 6 days as compared to 22 in those with VTE (p < 0.0001). Of those with infection, 13% had an ICU stay compared with 3.3% of those without. Those with VTE also had a median of 4 days in the intensive care unit as compared to 0 days in those without VTE (p < 0.0001). In a logistic regression analysis, only the number of ICU days was predictive of the presence of VTE (OR 1.074, 95% CI 1.013 - 1.138).

Conclusions: Children with NS who are hospitalized have high rates of infection. While the rate of VTE was not high in this cohort, presence of VTE was associated with infection. Both infection and VTE were associated with longer hospitalizations and intensive care unit stays. Streptococcus pneumoniae remains the most commonly identified bacterial pathogen in children with nephrotic syndrome, though methicillin sensitive S. Aureus was identified in 2 of 11 patients with VTE. Further studies are needed to identify potentially modifiable risk factors that could minimize these complications in this already high risk population.