Tran, Cheryl L.

There is no evidence-based definition for diagnosing crescentic glomerulonephritis. The prognostic implications of crescentic lesions on kidney biopsy have not been quantified. Our objective was to determine risk factors for end-stage kidney disease (ESKD) in patients with glomerulonephritis and crescents on kidney biopsy. A query of the Pediatric Nephrology Research Consortium’s Pediatric Glomerulonephritis with Crescents registry identified 305 patients from 15 centers. A retrospective cohort study was performed with ESKD as the primary outcome. Median age at biopsy was 11 years (range 1–21). The percentage of crescents was 3–100% (median 20%). Etiologies included IgA nephropathy (23%), lupus (21%), IgA vasculitis (19%) and ANCA-associated GN (13%), post-infectious GN (5%), and anti-glomerular basement membrane disease (3%). The prevalence of ESKD was 12% at one year and 16% at last follow-up (median = 3 years, range 1–11). Median time to ESKD was 100 days. Risk factors for ESKD included %crescents, presence of fibrous crescents, estimated GFR, and hypertension at biopsy. For each 1% increase in %crescents, there was a 3% decrease in log odds of 1-year renal survival (p = 0.003) and a 2% decrease in log odds of renal survival at last follow-up (p < 0.001). These findings provide an evidence base for enrollment criteria for crescentic glomerulonephritis in future clinical trials.

Introduction . There is a paucity of information about risk behaviors in adolescents with chronic kidney disease (CKD). We designed this study to assess the prevalence of risk behaviors among teens with CKD in the United States and to investigate any associations between risk behavior and patient or disease characteristics. Methods . After informed consent, adolescents with CKD completed an anonymous, confidential, electronic web-based questionnaire to measure risk behaviors within five domains: sex, teen driving, alcohol and tobacco consumption, illicit drug use, and depression-related risk behavior. The reference group was composed of age-, gender-, and race-matched US high school students. Results . When compared with controls, teens with CKD showed significantly lower prevalence of risk behaviors, except for similar use of alcohol or illicit substances during sex (22.5% vs. 20.8%, p = 0.71 ), feeling depressed for ≥2 weeks (24.3% vs. 29.1%, p = 0.07 ), and suicide attempt resulting in injury needing medical attention (36.4% vs. 32.5%, p = 0.78 ). Furthermore, the CKD group had low risk perception of cigarettes (28%), alcohol (34%), marijuana (50%), and illicit prescription drug (28%). Use of two or more substances was significantly associated with depression and suicidal attempts ( p < 0.05 ) among teens with CKD. Conclusions . Teens with CKD showed significantly lower prevalence of risk behaviors than controls. Certain patient characteristics were associated with increased risk behaviors among the CKD group. These data are somewhat reassuring, but children with CKD still need routine assessment of and counselling about risk behaviors.

Abstract 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. Disclosures No relevant conflicts of interest to declare.

Abstract BACKGROUND: Complement-mediated thrombotic microangiopathies (TMAs) are a subset of TMAs in which the thrombocytopenia, microangiopathic hemolytic anemia, and end organ damage are caused by mutations in genes encoding the alternative complement pathway. Numerous complement genes have been implicated in complement-mediated TMAs including complement factor H (CFH), CD46 (MCP), complement factor I (CFI), complement component 3 (C3), complement factor B (CFB), factor H related 5 (CFHR5), and thrombomodulin (THBD) among others. Genetic analysis typically yields a mutation in 60% of patients whose TMA is presumed to be mediated by complement dysregulation. However, the description of novel disease-associated variants may increase this proportion. METHODS: A retrospective study of patients with TMAs diagnosed between 2000 and 2014 was performed. TMA diagnosis was made based on thrombocytopenia and evidence of microangiopathic hemolytic anemia. Analysis was performed with Alamut¨ software with additional in silico prediction tools (SIFT, MutationTaster, and Polyphen) for classification of gene variants. Variants of unknown significance (VUS) and likely pathogenic variants were further assessed using several mutation databases, including HGMD, ClinVar, and Factor H database RESULTS: Of patients diagnosed with a TMA, genetic analysis was performed in only a 10% of patients. Of the 29 patients with genetic studies performed, mutations were identified in 18 patients (62%). The majority of the mutations had been described previously in the literature, but four novel variants were identified: three missense and one splice-site. The table below summarizes these variants as well as laboratory findings on presentation. These were two variants of CFH, one variant of CFHR5, and one variant of CFI. In silico modeling of these variants revealed two polymorphisms likely to be pathogenic, one polymorphism likely benign given the lack of predicted splicing changes, and one VUS. Table 1. Protein Mutation Classification Age Sex Hemoglobin (g/dL) Platelets (thousands) Creatinine (mg/dL) CFH c.245-10_245-9dup Likely benign 61 F 11.6 51 6.7 CFH c.476G>A, p.Ser159Asn Likely pathogenic 43 F 9.1 101 9.1 CFHR5 c.1412G>A p.Gly471Glu Likely pathogenic 30 F 9.8 129 4.9 CFI c.1190T>A p.Val397Glu Unknown significance 51 M 9.4 125 6.1 DISCUSSION: With therapy available to target the alternative complement pathway, genetic analysis to identify genetic variants capable of causing complement mediated TMAs is an essential part of the evaluation. This genetic data must be interpreted and correlated with functional analysis and clinical phenotype. The reporting of novel variants in clinical databases, with inclusion of relevant clinical findings, is necessary to accurately classify and verify variants as pathologic mutations or benign polymorphisms. The full understanding of this diverse disease requires a more complete understanding of its genetics. While complement pathway-directed therapies are available, their rational use requires thorough interpretation of laboratory data, including genetic analysis. Disclosures Murray: Mayo Clinic: Patents & Royalties: Patent Application Filed.