Validation of a composite scoring scheme in the diagnosis of folate deficiency in a pediatric and adolescent dialysis cohort.

BACKGROUND: Laboratory indices are often poorly diagnostic of folate deficiency (FD). Compared with iron depletion in hemodialysis (HD) populations, the impact of FD is less appreciated. The composite scoring of hematologic indices of FD may facilitate a prompt and accurate diagnosis, and enhance operational research on folic acid therapy. OBJECTIVE: Our objectives were to (1) validate composite scores of folate diagnostic indices, and (2) determine the reliability index of the diagnostic tool. METHODS: A cohort of 30 subjects, with a mean age of 16 (SD +/- 3.2 years), on HD and erythropoietin (EPO) for a minimum of 3 months was studied. After a baseline hematologic assessment, routine folates were administered for 6 months. Composite FD scores (FDS) of baseline mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), random distribution width (RDW), and hemoglobin were determined. Validation and reliability statistics were then analyzed, using the quantitative change in red blood cell folate/plasma homocysteine, or EPO requirement after 6 months of folate use, as diagnostic criteria. RESULTS: The mean FDS for FD and non-FD subsets were 3.0 +/- 1.3 and 1.4 +/- 0.9, respectively (analysis of variance; P = .0001). The correlation coefficient, r(2), between FD total and FDS was 0.61 (P = .001), and the coefficient between 2 (weekly) values of RDW, MCV, MCH, and MCHC was >0.84 (P = .0001). Scoring tools derived from the first (P = .002) and second (P = .01) halves of the laboratory indices remained discriminatory for the FD and non-FD groups. Baseline serum folate is poorly specific for FD, whereas FD score >or=3 had sensitivity, specificity, and positive and negative predictive values close to 90%. CONCLUSIONS: Composite scoring of erythrocyte indices was predictive of the FD diagnosis, as defined by the quantitative response of red blood cell folate, homocysteine, and EPO dose to folate therapeutic intervention. The diagnostic items yielded a high reliability coefficient. The FDS scheme is a potential tool for the diagnosis and surveillance of FD, particularly in at-risk populations (e.g., dialysis subjects).

The role of obesity and its bioclinical correlates in the progression of chronic kidney disease.

In spite of a progressive fall in the incidence of traditional risk factors of cardiovascular morbidity (cigarette smoking, high blood pressure, and hyperlipidemia), there is an upward trend in the prevalence of obesity and chronic kidney disease (CKD). Furthermore, there is a strong correlation between body mass indices and the relative risk of progression of CKD. The close biophysiological interaction between obesity and CKD is evident by a similar occurrence of comorbidities including insulin resistance, hyperlipidermia, endothelial dysfunction, and sleep disorders. Truncal obesity is a primary component of metabolic syndrome; unlike peripheral fat, the visceral adipocytes are more resistant to insulin. In addition, lipolysis results in a release of free fatty acid and TG, whereas hypertriglycedemia is potentiated by uremic activation of fatty acid synthase. Hypertriglycedemia and low HDL cholesterol increase the relative risk of progression of CKD. Furthermore, endothelial inflammation and premature atherosclerosis are promoted by hyperhomocysteinemia and oxidation of LDL, both of which are commonly observed in CKD and obesity. Predominance of oxidative stress in both obesity and azotemia stimulate synthesis of angiotensin II, which in turn increases TGF-B and plasminogen activator inhibitor-1, thereby propagating glomerular fibrosis. Furthermore, local synthesis of angiotensinogen by adipocytes, leptin activation of sympathetic nervous system, and hyperinsulinemia contribute to the development of hypertension in obesity and CKD. In addition, increased renal tubular expression of Na-K-ATPase and a blunted response to natiuretic hormones in obesity promote salt and water retention. Glomerular hyperfiltration from systemic volume load and hypertension results in mesangial cellular proliferation and progressive renal fibrosis. In addition, maternal nutritional deprivation increases the incidence of obesity, hypertension, and diabetes in adulthood. Reduced fetal protein synthesis contributes to oxidative glomerular injury and impairment of renal morphogenesis. Thus, kidneys are poorly equipped to handle physiologic stress that may result from the rapid body growth and programmed metabolic dysfunction later in life. Finally, in order to minimize morbidity of obesity-related kidney disease, preventive strategy must include optimal maternal health care, promotion of healthy nutrition and routine physical exercise, and early detection of CKD.

Symmetric ambulatory arterial stiffness index in the young.

The ambulatory arterial stiffness index (AASI) and the symmetric ambulatory arterial stiffness index (s-AASI) have been shown to correlate to arterial stiffness in adults. This study assesses these indices with anthropometric and blood pressure (BP) measures in children. A total of 102 children at a pediatric hypertension clinic who had ambulatory blood pressure monitoring (ABPM) done from 2009 to 2013 were included (75% males, 7-22yo, 47% hypertensive, 24% prehypertensive, and 34% white-coat hypertensives). AASI is 1 minus the regression slope of diastolic BP values on systolic BP values from a 24-hour ambulatory blood pressure monitoring. s-AASI is the symmetric regression of AASI. Obese patients had a significantly higher AASI. s-AASI correlated with systolic BP variability. In multivariable regression, BP variability independently correlated with AASI and s-AASI. s-AASI is related to systolic dipping.AASI and s-AASI are highly dependent on BP variability in children. Further studies are necessary to assess their utility.

Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates: Design of a Retrospective Cohort Study.

INTRODUCTION: Acute kidney injury (AKI) affects ~30% of hospitalized neonates. Critical to advancing our understanding of neonatal AKI is collaborative research among neonatologists and nephrologists. The Neonatal Kidney Collaborative (NKC) is an international, multidisciplinary group dedicated to investigating neonatal AKI. The AWAKEN study (Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates) was designed to describe the epidemiology of neonatal AKI, validate the definition of neonatal AKI, identify primary risk factors for neonatal AKI, and investigate the contribution of fluid management to AKI events and short-term outcomes. METHODS AND ANALYSIS: The NKC was established with at least one pediatric nephrologist and neonatologist from 24 institutions in 4 countries (USA, Canada, Australia, and India). A Steering Committee and four subcommittees were created. The database subcommittee oversaw the development of the web-based database (MediData Rave™) that captured all NICU admissions from 1/1/14 to 3/31/14. Inclusion and exclusion criteria were applied to eliminate neonates with a low likelihood of AKI. Data collection included: (1) baseline demographic information; (2) daily physiologic parameters and care received during the first week of life; (3) weekly "snapshots"; (4) discharge information including growth parameters, final diagnoses, discharge medications, and need for renal replacement therapy; and (5) all serum creatinine values. ETHICS AND DISSEMINATION: AWAKEN was proposed as human subjects research. The study design allowed for a waiver of informed consent/parental permission. NKC investigators will disseminate data through peer-reviewed publications and educational conferences. DISCUSSION: The purpose of this publication is to describe the formation of the NKC, the establishment of the AWAKEN cohort and database, future directions, and a few "lessons learned." The AWAKEN database includes ~325 unique variables and >4 million discrete data points. AWAKEN will be the largest, most inclusive neonatal AKI study to date. In addition to validating the neonatal AKI definition and identifying risk factors for AKI, this study will uncover variations in practice patterns related to fluid provision, renal function monitoring, and involvement of pediatric nephrologists during hospitalization. The AWAKEN study will position the NKC to achieve the long-term goal of improving the lives, health, and well-being of newborns at risk for kidney disease.

The CTSA mentored career development program: supporting the careers of child health investigators.

UNLABELLED: Training translational scientists is a priority of the Clinical and Translational Science Award (CTSA) consortium. OBJECTIVES: 1) Describe the landscape of CTSA Mentored Research Career Development Awards (CDA) and 2) evaluate participation and outcomes of child health investigators in these programs. DESIGN: Survey of the CTSA Child Health Oversight Committee (CC-CHOC) and review of nonresponders' CTSA Websites. RESULTS: Thirty-two of 53 CC-CHOC members (60%) responded and all nonresponder Websites were reviewed. Institutions supported 1,166 CDA positions from 2006 to 2011, with 134 awarded to child health investigators (11.5%). Respondents reported a mean of 29.8 KL2 positions (95% CI 17.5-42.2) during their award period, with a mean of 2.8 (95% CI 1.8-3.8) awarded to child health investigators. The proportion of child health awardees varied from 0% to 50% across institutions. We identified 45 subsequent National Institutes of Health (NIH) awards to the 134 child health investigators (34%). CONCLUSIONS: The CTSA program contributes substantially to training the next generation of translational investigators. One-third of child health investigators obtained subsequent NIH awards in the short follow-up period demonstrating success of the CTSA CDA programs. Child health investigators are represented variably across the consortium. Pediatric institutions can partner with the CTSA program to further support training child health investigators.

Analyses of age, gender and other risk factors of erythropoietin resistance in pediatric and adult dialysis cohorts.

Previous studies often report lower responses to erythropoietin (EPO) therapy in pediatric patients on chronic dialysis than those of adults. Because of the greater capacity for hematopoiesis in the younger population, these studies may be confounded by poorly identified variables. Thus, we made parallel studies of pediatric and adult cohorts to explore the relationship between age, gender and other risk factors with EPO resistance. Thirty pediatric subjects (aged 8-20 years) and 66 adult subjects (aged 22-85 years) on chronic hemodialysis and EPO were enrolled. After stratification by 50th percentile of EPO response, the best predictive model was identified by backward elimination of the risk factors with the least contribution to the regression. Relationship between age, gender and EPO resistance was examined by analysis of covariance (ANCOVA). The most predictive model of EPO response for the pediatric cohort had, as the major variables, urea clearance x dialysis duration/total body water (Kt/V), urea reduction ratio (URR), intact parathyroid hormone (iPTH), blood loss, normalized protein catabolic rates (nPCR) and indices of malnutrition and inflammation, whereas adults had iron and folate deficiencies as the dominant variables. Although EPO resistance was more common in female subjects than in male subjects, relationship with neither age nor gender was significant. Furthermore, the prescription of a larger (initiating) EPO dose by pediatric physicians compared with adult nephrologists confounded the interaction between age and EPO resistance. In summary EPO resistance in the pediatric dialysis cohort was predicted by nutritional deficits, inflammation, poor dialysis, and hyperparathyroidism, while iron and folate deficits were the major determinants in adults. Although confounded by the pattern of EPO prescription, neither age nor gender was predictive of EPO resistance in the two study groups.

Association of proteinuria with race, cause of chronic kidney disease, and glomerular filtration rate in the chronic kidney disease in children study.

BACKGROUND AND OBJECTIVES: Proteinuria is associated with chronic kidney disease (CKD), and heavy proteinuria predicts a rapid decline in kidney function. However, the epidemiologic distribution of this important biomarker study is not well described in the pediatric CKD population. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: This cross-sectional study of North American children with CKD examined the association of proteinuria among the baseline clinical variables in the cohort. Urinary protein-to-creatinine ratios (Up/c) were used to measure level of proteinuria. RESULTS: Of the 419 subjects studied, the median GFR as measured by iohexol disappearance (iGFR) was 42 ml/min per 1.73 m(2), median duration of CKD was six yr, and glomerular diseases accounted for 22% of the CKD diagnoses. Twenty-four percent of children had normal range (Up/c <0.2), 62% had significant, and 14% had nephrotic-range proteinuria (Up/c >2.0). A decrease in iGFR was associated with an increase in Up/c. At any level of GFR, a higher Up/c was associated with a glomerular cause of CKD and non-Caucasian race. Among subjects with a glomerular cause of CKD, Up/c was lower in subjects reporting utilization of renin-angiotensin system (RAS) antagonists (median Up/c = 0.93) compared with those who did not (median Up/c = 3.78). CONCLUSIONS: Proteinuria is associated with level of iGFR, cause of CKD, and race. The longitudinal study design of Chronic Kidney Disease in Children (CKiD) cohort study and the large number of subjects being studied has created an opportunity to better define the association between proteinuria and CKD progression.

Non-cardiogenic pulmonary edema during basiliximab induction in three adolescent renal transplant patients.

BACKGROUND: Introduction of the anti-CD-25 mAb basiliximab into renal transplant protocols has reduced the incidence of acute rejection. However, its side-effect profile is still unfolding. We report three adolescents who developed severe non-cardiogenic PE within 2 days of renal transplantation. METHODS: Pretransplant cardiorespiratory evaluation was normal in all cases. Transplant immunosuppression consisted of basiliximab induction, corticosteroids, and tacrolimus. Patients received standard fluid management during and after the transplant surgery. CASE REPORTS: Patients 1 and 2 were 17- and 21-yr-old females. Pretransplant Hct values were 35 and 25% respectively. Each received 5-L normal saline during surgery. EBL was 200 and 500 mL in patients 1 and 2, respectively. There was immediate post-operative diuresis. Both developed non-cardiogenic PE by POD no. 2. BIPAP and PRVC were administered respectively. In both cases PE resolved within 1 wk. Patient 3 was a 19-yr-old male with pretransplant Hct of 43% who received a cadaveric renal transplant after 23.5-h cold-ischemia; 3.5 L normal saline was given during surgery. EBL was 100 mL. Non-cardiogenic PE ensued on POD no. 2 warranting assisted ventilation. The patient died following a sudden cardiopulmonary arrest on POD no. 3. CONCLUSIONS: Potential mechanisms for the development of PE include cytokine release from basiliximab with increased capillary permeability, volume overload and ischemic-reperfusion injury. Improved awareness of this potential complication, prudent fluid management, and efforts to minimize graft-ischemia are recommended to prevent further cases.