Reduced kidney function and hypertension in adolescents with low birth weight, NHANES 1999-2016.

BACKGROUND: Chronic kidney disease (CKD) is a major health problem, and the risk of CKD and hypertension in children born low birth weight (LBW) is under-recognized. We hypothesized that children born with LBW would have a higher prevalence of reduced kidney function and hypertension. METHODS: Using the National Health and Nutrition Examination Survey (NHANES), we conducted a cross-sectional study to evaluate whether LBW (< 2500 g), very low birth weight (VLBW < 1500 g), and large birth weight (BW) (> 4000 g) were associated with kidney disease using 4 different estimating equations. We used the Counahan-Barratt, updated Schwartz, CKiD-U25, and full age spectrum creatinine-based GFR estimating equations to evaluate associations between a history of LBW/VLBW/large BW and reduced kidney function (eGFR < 90 mL/min/1.73 m2) in children. We also assessed blood pressure (BP) using the old and new pediatric hypertension guidelines. RESULTS: Our analysis included 6336 children (age 12-15 years) in NHANES representing over 13 million US individuals. Using the updated Schwartz, the prevalence of reduced kidney function was 30.1% (25.2-35.6) for children born with LBW compared to 22.4% (20.5-24.3) in children with normal BW. Equations yielded different estimates of prevalence of reduced kidney function in LBW from 21.5% for Counahan-Barratt to 35.4% for CKiD-U25. Compared to those with normal BW, participants with LBW and VLBW had a 7.2 and 10.3% higher prevalence of elevated BP and a 2.4 and 14.6% higher prevalence of hypertension, respectively. CONCLUSIONS: Children born with LBW are at higher risk of reduced kidney function and hypertension than previously described. A higher resolution version of the Graphical abstract is available as Supplementary information.

Pediatric Nurse and Pharmacist Knowledge of Acute Kidney Injury.

OBJECTIVES: In this study, we assessed the knowledge and experience of pediatric pharmacists and nurses at a US tertiary-care pediatric center regarding the risk factors for, recognition of, and best practices for managing an acute kidney injury (AKI) in children. METHODS: The authors developed a survey to assess the attitudes and knowledge of nurses and pharmacists regarding AKI in hospitalized children, which was reviewed by a small multidisciplinary group for content and length. The final 16-item survey consisted of demographic, self-assessment and attitude, and knowledge questions. All pediatric pharmacists and nurses at the study site received a voluntary online survey via e-mail. Data were analyzed by using descriptive statistics. RESULTS: A survey was sent to 620 nurses and 50 pharmacists; 148 (25%) and 22 (44%), respectively, completed it. Most respondents were <35 years old and had ≤10 years of experience in both their professions and pediatrics. A total of 72% of pediatric nurses felt identification of AKI was within their scope of practice, and ∼60% felt confident in their ability to do so. More than 80% of pediatric pharmacists felt confident in their abilities to adjust medication doses in pediatric patients with AKI, but <60% felt confident in their ability to estimate the glomerular filtration rate in these patients. Nurses and pharmacists were able to correctly identify specific AKI criteria 60% to 70% and 70% to 90% of the time, respectively. CONCLUSIONS: Although pediatric nurses and pharmacists have knowledge of AKI prevention and mitigation, gaps exist, and there is a desire for education in recognition of their key roles in the clinical team.

Prenatal blood lead levels and reduced preadolescent glomerular filtration rate: Modification by body mass index.

BACKGROUND: For the developing kidney, the prenatal period may represent a critical window of vulnerability to environmental insults resulting in permanent nephron loss. Given that the majority of nephron formation is complete in the 3rd trimester, we set out to test whether 1) prenatal lead exposure is associated with decreased preadolescent kidney function and 2) whether preadolescent obesity acts synergistically with early life lead exposure to reduce kidney function. METHODS: Our study included 453 mother-child pairs participating in the PROGRESS birth cohort. We assessed prenatal blood lead levels (BLLs) in samples collected in the 2nd and 3rd trimesters and at delivery, as well as tibial and patellar bone lead measures assessed one-month postpartum. Preadolescent estimated glomerular filtration rate (eGFR) was derived from serum levels of creatinine and/or cystatin C measured at age 8-12 years. We applied linear regression to assess the relationship between prenatal bone and BLL with preadolescent eGFR, and adjusted for covariates including age, sex, BMI z-score, indoor tobacco smoke exposure, and socioeconomic status. We also examined sex-specific associations and tested for effect modification by BMI status. RESULTS: We observed null associations between prenatal lead exposure and eGFR. However, in interaction analyses we found that among overweight children, there was an inverse association between BLL (assessed at 2nd and 3rd trimester and at delivery) and preadolescent eGFR. For example, among overweight participants, a one ln-unit increase in 2nd trimester BLL was associated with a 10.5 unit decrease in cystatin C-based eGFR (95% CI: -18.1, -2.8; p = 0.008). Regardless of lead exposure, we also observed null relationships between BMI z-score and eGFR overall, as well as among overweight participants. However, among participants with preadolescent obesity, we observed a significant 5.9-unit decrease in eGFR. We observed no evidence of sex-specific effects. CONCLUSIONS: Our findings, if confirmed in other studies, suggest a complex interplay between the combined adverse effects of adiposity and perinatal lead exposure as they relate to adolescent kidney function. Future studies will assess kidney function and adiposity trajectories through adolescence to better understand environmental risk factors for kidney function decline.

AKI in Hospitalized Children: Poorly Documented (and Underrecognized).

Background: Acute kidney injury (AKI) is common in hospitalized children. We hypothesized that hospital-acquired AKI would be underrecognized and under-reported, with potential implications for prevention of future AKI and CKD risk stratification. Methods: Five hundred thirty-two cases of AKI occurring over a 1 year period in a tertiary children's hospital in the United States were studied. AKI documentation was defined as any mention of AKI in the admission history and physical note, progress notes, or discharge summary. Nephrology follow-up was defined as a completed outpatient clinic visit within 1 year of discharge. Logistic regression was used to assess factors associated with documentation, consultation, and follow-up. Results: AKI developed during 584/7,640 (7.6%) of hospitalizations: 532 cases met inclusion criteria. Documentation was present in 34% (185/532) of AKI cases and 90 (16.9%) had an inpatient nephrology consult. Among 501 survivors, 89 (17.8%) had AKI in their hospital discharge summary and 54 had outpatient nephrology follow up. Stage 3 AKI, peak creatinine >1 mg/dL and longer length of stay were associated with documentation. Stage 3 AKI and higher baseline creatinine were associated with inpatient nephrology consultation. Inpatient nephrology consultation was positively associated with outpatient nephrology follow up, but documentation in the discharge summary was not. Conclusion: Most cases of AKI were not documented and the proportion of children seen by a nephrologist was low, even among those with more severe injury. Increased severity of AKI was associated with documentation and inpatient consultation. Poor rates of documentation has implications for AKI recognition and appropriate management and follow up.

Acute Kidney Injury in Hospitalized Pediatric Patients: A Review of Research.

INTRODUCTION: Pediatric patients who develop acute kidney injury (AKI) while hospitalized have longer hospital stays, increased morbidity and mortality, and are at an increased risk for developing chronic kidney disease. Early recognition of AKI is becoming a major clinical focus. There is little research focusing on nursing interventions that may affect a pediatric patient's risk for developing AKI. The purpose of this review is to summarize reported predictors of AKI to improve its early recognition and treatment among hospitalized pediatric patients. METHODS: A review of research was conducted to further identify risk factors of AKI among noncritically ill hospitalized pediatric patients. RESULTS: The current literature demonstrated inconsistent findings in early recognition of AKI among hospitalized pediatric patients. DISCUSSION: Interventions for early recognition and treatment of AKI should consider other variables, such as previous history of AKI and fluid status as risk factors, warranting additional research.

Serum-Associated Antibiotic Tolerance in Pediatric Clinical Isolates of Pseudomonas aeruginosa.

BACKGROUND: When grown in human serum, laboratory isolates of Pseudomonas aeruginosa exhibit tolerance to antibiotics at inhibitory concentrations. This phenomenon, known as serum-associated antibiotic tolerance (SAT), could lead to clinical treatment failure of pseudomonal infections. Our purpose in this study was to determine the prevalence and clinical impact of SAT in Pseudomonas isolates in hospitalized children. METHODS: The SAT phenotype was assessed in patients aged <18 years admitted with respiratory or blood cultures positive for P. aeruginosa. The SAT phenotype was a priori defined as a ≥2-log increase in colony-forming units when grown in human serum compared with Luria-Bertani medium in the presence of minocycline or tobramycin. RESULTS: SAT was detected in 29 (64%) patients. Fourteen patients each (34%) had cystic fibrosis (CF) and tracheostomies. Patient demographics and comorbidities did not differ by SAT status. Among CF patients, SAT was associated with longer duration of intravenous antibiotics (10 days vs 5 days; P < .01). CONCLUSIONS: This study establishes that SAT exists in P. aeruginosa from human serum and may be a novel factor that contributes to differences in clinical outcomes. Future research should investigate the mechanisms that contribute to SAT in order to identify novel targets for adjunctive antimicrobial therapies.

Urinary Concentration Correction Methods for Arsenic, Cadmium, and Mercury: a Systematic Review of Practice-Based Evidence.

BACKGROUND: Urinary biomonitoring is widely used to assess environmental chemical exposure; however, a critical gap exists in whether and how to correct for the physiological variation in water content of spot urine samples. OBJECTIVE: The aim of this systematic review is to summarize the available evidence comparing the performance of urinary concentration correction methods used to determine urinary levels of arsenic, cadmium, and mercury. METHODS: We searched PubMed/MEDLINE, Embase, LILIAC, Web of Science, and TOXNET up to Sept. 5, 2017 for articles evaluating urinary concentration correction methods (e.g., urine creatinine [U-Cre], specific gravity [U-SG], osmolality [U-Osm]) compared to 24-h or timed urine specimens for levels of arsenic, cadmium, and mercury. Data on study design, methods of urine collection, and the performance of selected correction methods were extracted. RESULTS: A total of 10 papers met the inclusion criteria. Two papers evaluated the performance of urinary concentration correction methods for arsenic, four for cadmium, three for mercury, and one for multiple metals. The median sample size for arsenic was 105, for cadmium 107, and for mercury 35. The studies were highly heterogeneous in population selection, urine collection, urine quality control, statistical comparison among selected correction methods, and presentation of the results. The median (range) of correlation coefficients comparing each corrected values with corresponding levels of timed urine specimens are 0.74 (0.17-0.92) for un-correction (n = 13), 0.82 (0.52-0.98) for U-Cre (n = 13), and 0.75 (0.28-0.98) (n = 12) for U-SG. CONCLUSION: Findings from limited evidence support that urine creatinine and urine-specific gravity corrections remain practical approaches to correct metal concentrations for urine dilution as compared to 24-h or 12-h urine samples. Further studies with larger sample sizes are needed to clarify this fundamental issue of environmental biomonitoring using spot urine samples in both general and priority populations.

Environmental lead exposure is associated with neurocognitive dysfunction in children with chronic kidney disease.

BACKGROUND: Environmental lead exposure is associated with cognitive impairment in healthy children, with deficits seen in intelligence quotient (IQ), attention, and behavior. Neurocognitive dysfunction is also a well-described complication among children with chronic kidney disease (CKD). The objective was to evaluate the association between blood lead levels (BLL) and performance on neurocognitive assessments in a cohort of children with CKD. METHODS: Cross-sectional study of children with mild to moderate CKD from the Chronic Kidney Disease in Children (CKiD) multicenter prospective cohort study. The primary exposure was BLL. The primary outcome was performance on age-specific neurocognitive assessments evaluating IQ, executive functioning, attention, hyperactivity, and behavior. Multivariable linear regression was used to evaluate the association between BLL and neurocognitive performance, adjusted for key sociodemographic and clinical variables. RESULTS: A total of 412 subjects were included with median age 15.4 years, median estimated GFR 39 mL/min/1.732, median BLL 1.2 mcg/dL, and median IQ score 99. In multivariable linear regression, higher BLL was associated with significantly lower IQ score (- 2.1 IQ points for every 1-mcg/dL increase in BLL, p = 0.029). Higher BLL was associated with worse scores on the Conners' Continuous Performance Test II Variability T-Score, a measure of inattention (+ 1.8 T-Score points for every 1-mcg/dL increase in BLL, p = 0.033). CONCLUSIONS: Low-level lead exposure is associated with significantly lower IQ and more inattention in children with CKD, a population already at high risk for neurocognitive dysfunction. Universal screening for elevated BLL should be considered for all children with CKD at age 12-24 months.

Tubulointerstitial Nephritis.

Tubulointerstitial nephritis (TIN) is a cause of acute kidney injury in children characterized histologically by an inflammatory cell infiltrate in the kidney interstitium. The most common causes of TIN in children include medications, infections, inflammatory disorders, and genetic conditions. TIN typically presents with nonoliguric acute kidney injury and may be associated with systemic symptoms, including fever, rash, and eosinophilia. The long-term prognosis is generally favorable, with full kidney recovery; however, some patients may develop progressive chronic kidney disease. Immunosuppressive therapy may be indicated for severe or prolonged disease.

Vitamin D insufficiency, hemoglobin, and anemia in children with chronic kidney disease.

BACKGROUND: 25-Hydroxyvitamin D (25OHD) deficiency is common in children with chronic kidney disease (CKD). It has been associated with an increased risk for anemia in both healthy US children and in adults with CKD. This association has not been explored in children with CKD. METHODS: Children aged 1-16 enrolled in the Chronic Kidney Disease in Children (CKiD) study with mild to moderate kidney dysfunction, and with 25OHD measured at baseline (n = 580), were included in the analysis. The cross-sectional associations between 25OHD and hemoglobin (g/dL) and anemia were assessed. Anemia was defined as hemoglobin < 5th percentile for age and sex. RESULTS: Overall 334 (57.59%) children were vitamin D insufficient/deficient and 137 (23.62%) were anemic. Of those who were vitamin D insufficient/deficient, 95 (28.44%) were anemic. In the overall cohort, the odds of being anemic was 1.9 times higher (95% CI, 1.22-3.04, p < 0.01) in vitamin D insufficient/deficient vs sufficient children, when adjusting for covariates (age, sex, race [black, white, or other], body mass index (BMI), iohexol GFR (iGFR), erythropoietin stimulation agent (ESA) use, iron supplementation use, and underlying cause of CKD). Stratified by race, the odds of being anemic was 2.39 times higher (95% CI, 1.41-4.05, p = 0.001) in vitamin D insufficient/deficient vs vitamin D sufficient white children. The association between vitamin D status and anemia was not significant in black children. CONCLUSIONS: The data support our hypothesis that vitamin D insufficiency/deficiency increases the odds of anemia in children with CKD. The effect was strong and significant among white, but not black, children.

Association of mood disorders with cardiovascular disease risk factors in overweight and obese youth with elevated blood pressure.

The American Heart Association defines mood disorders (MDO) as a tier-II cardiovascular disease risk factor in children. Cross-sectional analysis of overweight/obese children referred to an obesity hypertension clinic revealed 37% had a MDO (defined by clinical diagnosis or Patient Health Questionnaire-9/-A score ≥10), 55% had confirmed hypertension, and 75% left ventricular hypertrophy (LVH). Children with MDOs were older, had greater measures of adiposity, and had a greater prevalence of hypertension (78%) than those without MDOs (42%; P = .04). Hypertensive children were 2.8 times more likely to have a MDO than those without (52% vs 18%; P = .02). Multivariable logistic regression revealed a statistically significant independent association of MDOs with hypertension (Odds Ratio [OR] 6.3, P = .048), but not LVH (LVMI ≥ 51 g/m2.7 ; OR 1.13, P = .88). Overall, the prevalence of MDOs in this group of overweight/obese children with elevated blood pressure was well above national averages, suggesting that at-risk youth, particularly those with confirmed hypertension, should be regularly screened for MDOs.

Immunogenicity of the meningococcal polysaccharide conjugate vaccine in pediatric kidney transplant patients.

BACKGROUND: Immunosuppressed kidney transplant patients may have suboptimal response to vaccinations. The aim of this study was to determine antibody response to a quadrivalent meningococcal conjugate vaccine (MenACWY-D) in adolescents with a kidney transplant. METHODS: This was a prospective, single-center, cohort study. Adolescent patients (11-22 years old) with a functioning kidney transplant for at least 3 months and no previous meningococcal vaccination were eligible for enrollment. Antibody levels to all serogroups were measured before vaccination (baseline) and at 4 weeks and 1, 2 and 3 years after vaccination. Seropositivity was defined as a titer ≥ 1:8 at baseline, and seroconversion as a fourfold or greater increase in antibody titer from baseline at 4 weeks post-vaccination. Geometric mean titers (GMTs) were calculated at each time point and compared to published GMTs from vaccinated healthy adolescents. RESULTS: Nineteen patients were enrolled. No patient had seroprotective titers against all four serogroups at baseline. At 4 weeks post-vaccination 41% of patients seroconverted to all four serogroups, with seroconversion rates of 88, 53, 71 and 94% for serogroups A, C, W and Y, respectively. GMTs were significantly lower in adolescents with a kidney transplant than in healthy adolescents at 1 month (p = 0.02) and 3 years (p = 0.04) post-vaccination. There were no significant adverse events, episodes of rejection or death in any patient. CONCLUSIONS: Adolescents with a kidney transplant may not respond adequately to MenACWY-D and may experience more rapid declines in antibody titers than healthy adolescents. Further study is needed to determine if alternative dosing schedules can improve antibody response in this population.

Correlation between Cosyntropin Stimulation Study and Disease Severity in Children with Fluid- and Catecholamine-Refractory Shock in the Pediatric and Cardiovascular Intensive Care Unit.

BACKGROUND: The cosyntropin stimulation study (CSS) measures the patient's ability to adequately mount a cortisol response. Clinically, CSS results may not be used to guide hydrocortisone use. The objective of this study was to examine how the CSS results are associated with clinical parameters, mortality/disease severity, and use of glucocorticoids in pediatric patients with catecholamine- and fluid-resistant shock. METHODS: This was a retrospective cohort study of patients who had a CSS during 2009-2014 in the intensive care unit at a children's hospital. Data collected included clinical variables, mortality, biochemical studies, and glucocorticoid use. PRISM III scores were used to determine the association between CSS results and disease severity. Adequate response to cosyntropin was defined as peak cortisol of 18 µg/dL or higher. RESULTS: Of the 76 patients that underwent CSS, 68 (89%) had an adequate response to cosyntropin. There was a positive correlation between peak cortisol and PRISM III score (r = 0.45, r2 = 0.2). Glucocorticoid was administered in 52/76 (68%) despite several patients with normal CSS results. CONCLUSIONS: Sicker patients were more likely to have an adequate response to CSS. Clinically, glucocorticoid supplementation was not based on CSS results. Further prospective studies are needed to elucidate if CSS is a valuable clinical tool.

Renin-angiotensin II-aldosterone system blockers and time to renal replacement therapy in children with CKD.

BACKGROUND: Clinical care decisions to treat chronic kidney disease (CKD) in a growing child must often be made without the benefit of evidence from clinical trials. We used observational data from the Chronic Kidney Disease in Children cohort to estimate the effectiveness of renin-angiotensin II-aldosterone system blockade (RAAS) to delay renal replacement therapy (RRT) in children with CKD. METHODS: A total of 851 participants (median age: 11 years, median glomerular filtration rate [GFR]: 52 ml/min/1.73 m2, median urine protein to creatinine ratio: 0.35 mg/mg) were included. RAAS use was reported at annual study visits. Both Cox proportional hazards models with time-varying RAAS exposure and Cox marginal structural models (MSM) were used to evaluate the effect of RAAS use on time to RRT. Analyses were adjusted or weighted to control for age, male sex, glomerular diagnosis, GFR, nephrotic range proteinuria, anemia, elevated blood pressure, acidosis, elevated phosphate and elevated potassium. RESULTS: There were 217 RRT events over a 4.1-year median follow-up. At baseline, 472 children (55 %) were prevalent RAAS users, who were more likely to be older, have a glomerular etiology, have higher urine protein, be anemic, have elevated serum phosphate and potassium, take more medications, but less likely to have elevated blood pressure, compared with non-users. RAAS use was found to reduce the risk of RRT by 21 % (hazard ratio: 0.79) to 37 % (hazard ratio: 0.63) from standard regression adjustment and MSM models, respectively. CONCLUSIONS: These results support inferences from adult studies of a substantial benefit of RAAS use in pediatric CKD patients.

Immunogenicity of Human Papillomavirus Recombinant Vaccine in Children with CKD.

BACKGROUND AND OBJECTIVES: There is a disproportionate burden of human papillomavirus (HPV) -related genital tract disease in patients with CKD and kidney transplantation; therefore, the potential effect of the quadrivalent HPV vaccine (Gardasil; Merck GmbH, Darmstadt, Germany) is profound. Immune abnormalities associated with CKD and immunosuppression may prevent optimal vaccine response. Our objective was to determine antibody response to the HPV vaccine in adolescent girls with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cohort study conducted from 2008 to 2012 included 57 girls aged 9-21 years old with CKD (n=25), on dialysis (n=9), or with status postkidney transplantation (n=23) who received the standard three-dose vaccine series of the HPV vaccine recruited from two pediatric nephrology clinics. Antibody levels to HPV genotypes 6, 11, 16, and 18 were measured before vaccine dose 1 (baseline), <12 months after vaccine dose 3 (blood draw 2), and ≥12 months after vaccine dose 3 (blood draw 3). Seropositivity was defined as antibody level above an established threshold for each HPV genotype. Not all participants completed three blood draws. RESULTS: Antibody response to all four HPV genotypes was 100% in the CKD and dialysis groups with samples drawn at <12 and ≥12 months after dose 3 of the HPV vaccine. Among patients with transplants, the percentages of patients achieving seropositivity were significantly lower at blood draw 2 for HPV genotypes 6 (63.6%; P=0.003), 11 (63.6%; P=0.003), and 18 (72.7%; P=0.02) and blood draw 3 for HPV genotypes 6 (62.5%; P=0.02), 11 (50%; P=0.001), 16 (75%; P=0.04), and 18 (50%; P=0.001). CONCLUSIONS: Antibody response to the quadrivalent recombinant HPV vaccine was robust and sustained in girls and young women with CKD and on dialysis. A less robust response to the vaccine was observed among those with a kidney transplant. Additional study is needed to determine if vaccination before kidney transplantation or an alternative vaccination regimen would benefit transplant recipients.

Toxic environmental exposures and kidney health in children.

High-level exposures to a number of agents are known to have direct nephrotoxic effects in children. A growing body of literature supports the hypothesis that chronic, relatively low-level exposure to various nephrotoxicants may also increase the risk for chronic kidney disease (CKD) or accelerate its progression. In this review we highlight several environmental nephrotoxicants and their association with CKD in children and adolescents. We also discuss unique epidemiological challenges in the use of kidney biomarkers in environmental nephrotoxicology.

Challenges for environmental epidemiology research: are biomarker concentrations altered by kidney function or urine concentration adjustment?

Biomonitoring has become a standard approach for exposure assessment in occupational and environmental epidemiology. The use of biological effect markers to identify early adverse changes in target organs has also become widely adopted. However, the potential for kidney function to affect biomarker levels in the body and the optimal approach to adjustment of biomarker concentrations in spot urine samples for hydration status are two important but underappreciated challenges associated with biomarker use. Several unexpected findings, such as positive associations between urine nephrotoxicant levels and estimated glomerular filtration rate (eGFR), have been reported recently in research using biomarkers. These and other findings, discussed herein, suggest an impact of kidney glomerular filtration or tubule processing on biomarker levels. This is more commonly raised in the context of decreased kidney filtration, traditionally referred to as reverse causality; however, recent data suggest that populations with normal kidney filtration may be affected as well. Misclassification bias would result if biomarkers reflect kidney function as well as either exposures or early biological effect outcomes. Furthermore, urine biomarker associations with eGFR that differ markedly by approach used to adjust for urine concentration have been reported. Associations between urine measures commonly used for this adjustment, such as urine creatinine, and specific research outcomes could alter observed biomarker associations with outcomes. Research recommendations to address the potential impact of kidney function and hydration status adjustment on biomarkers are provided, including a range of approaches to study design, exposure and outcome assessment, and adjustment for urine concentration.