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Dysregulated lysophosphatidic acid receptor 1 (LPAR1) signaling is implicated in fibrotic diseases, including systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Fipaxalparant (HZN-825) is a small molecule acting as a negative allosteric modulator of LPAR1 and is in phase 2 clinical evaluations for treating diffuse cutaneous SSc and IPF. This open-label, phase 1 study examined the pharmacokinetics (PKs), food effect, and safety of fipaxalparant in healthy volunteers. Dose proportionality was evaluated for fipaxalparant single doses of 150, 300, and 450 mg under fasted conditions. Food effect was tested with a 450-mg single dose under fasted conditions or with a high-fat meal. Multiple-dose PKs for twice-daily dosing of either 300 or 450 mg with low- or high-fat meals was also assessed. Fipaxalparant was safe and well tolerated in healthy volunteers (n = 36) under all conditions. Fipaxalparant exposure increased in a less than dose-proportional manner from 150 to 450 mg. At 450 mg, a high-fat meal increased the maximum observed concentration and area under the curve by approximately 1.9- and 2.1-fold, respectively. These results, combined with prior preclinical and phase 2a data, informed dose selection of fipaxalparant 300 mg once and twice daily with a meal for phase 2b studies.

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CONTEXT: Elevated levels of the phosphate-regulating hormone, fibroblast growth factor-23 (FGF-23) are associated with skeletal and cardiovascular disease. Levels of FGF-23 are elevated in neonates, but the mechanisms are poorly understood. Iron deficiency is a recently described stimulus for FGF-23 production. OBJECTIVE: To test the hypothesis that lower fetal iron status, as measured by lower cord blood ferritin, is independently associated with elevated FGF-23 levels in neonates. DESIGN AND PARTICIPANTS: This is a cross-sectional study of 64 full-term, healthy neonates. SETTING: This study took place in a university-based, tertiary care center. MAIN OUTCOME MEASURES: Plasma levels of second generation C-terminal FGF-23 (cFGF-23) and intact FGF-23 (iFGF-23). RESULTS: Levels of cFGF-23 ranged from 108 to 7508 reference units (RU)/ml (median, 824 RU/ml), and iFGF-23 from undetectable (<8.5) to 135.4 pg/ml (median, <8.5 pg/mL). Ferritin ranged from 58 to 719 ng/ml (mean, 203 ng/ml). Lower cord blood ferritin levels were associated with higher cFGF-23 (r = −0.320; P = .014), but not iFGF-23 levels (r = −0.222; P = .082). In multivariate analyses adjusted for glycemic indices, maternal race, and parity, lower ferritin levels remained independently associated with higher cFGF-23 levels (B = −0.261, P = .01). In the full models, higher cord blood glucose and C-peptide levels were also independently associated with higher cFGF-23 levels. CONCLUSIONS: cFGF-23, but not iFGF-23 levels, are elevated in cord blood of healthy term neonates and independently associated with lower serum ferritin and higher glycemic indices.

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Stakeholder-developed interventions are needed to support pediatric intensive care unit (PICU) communication and decision-making. Few publications delineate methods and outcomes of stakeholder engagement in research. We describe the process and impact of stakeholder engagement on developing a PICU communication and decision-making support intervention. We also describe the resultant intervention. Stakeholders included parents of PICU patients, healthcare team members (HTMs), and research experts. Through a year-long iterative process, we involved 96 stakeholders in 25 meetings and 26 focus groups or interviews. Stakeholders adapted an adult navigator model by identifying core intervention elements and then determining how to operationalize those core elements in pediatrics. The stakeholder input led to PICU-specific refinements, such as supporting transitions after PICU discharge and including ancillary tools. The resultant intervention includes navigator involvement with parents and HTMs and navigator-guided use of ancillary tools. Subsequent research will test the feasibility and efficacy of our intervention.

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OBJECTIVES: Fibroblast growth factor-23 (FGF23) is a biomarker for cardiovascular disease. Obesity may promote FGF23 production in the absence of chronic kidney disease. We sought to determine among normotensive African American adolescents whether FGF23 levels are greater in obese compared with normal-weight adolescents and to determine the relationship of FGF23 with markers of cardiac structure and insulin resistance. STUDY DESIGN: Cross-sectional data were obtained from a cohort of 130 normotensive, African American adolescents ages 13-18 years without chronic kidney disease; 74 were obese; 56 were normal weight. Plasma C-terminal FGF23, fasting glucose and insulin, and high-sensitivity C-reactive protein were measured; participants underwent M-mode echocardiography. RESULTS: FGF23 was skewed and approximately normally distributed after natural log transformation (logFGF23). FGF23 levels were greater in obese vs normal-weight participants (geometric mean 43 vs 23 RU/mL, P < .01). FGF23 values were significantly greater in participants with eccentric or concentric cardiac hypertrophy compared with those without hypertrophy P < .01). LogFGF23 directly correlated with body mass index, body mass index z-score, waist circumference, fasting insulin levels, and homeostasis model assessment scores. Regression models adjusted for age, sex, and high-sensitivity C-reactive protein suggest that each 10% increase in FGF23 is associated with a 1.31 unit increase in left ventricular mass (P < .01), a 0.29-unit increase in left ventricular mass index (P < .01), and a 0.01-unit increase in left atrial dimension indexed to height (P = .02). CONCLUSIONS: In this sample of obese African American adolescents, FGF23 blood levels were associated with abnormal cardiac structure. We postulate that FGF23 may be an early marker of cardiac injury in obese but otherwise-healthy African American adolescents.

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AIM: Children with steroidresistant (SR) and steroid-dependent (SD) nephrotic syndrome (NS) pose a treatment challenge. Literature on the use of tacrolimus (TAC), a calcineurin inhibitor, for maintenance treatment of NS is sparse. We aimed to evaluate the efficacy and safety of low-dose, long-term TAC for inducing and sustaining remission in children with SD/SR NS. METHODS: Data from patients treated at our center from 1999 to 2009 were analyzed. RESULTS: 40 patients with NS were treated with TAC for 3 - 80-month periods (median 25.2 months). Diagnoses included focal segmental glomerulosclerosis (FSGS) (60%), IgM nephropathy (15%), minimal change disease (20%) and membrano-proliferative glomerulonephritis (MPGN) (5%). 58% of patients had been previously treated with alternate agents. After 1, 2, and 3 years on TAC, complete remission was achieved in 26%, 48%, and 29% of patients; complete or partial remission was achieved in 85%, 100%, and 86%, respectively (p < 0.05). Median time to remission was 41 days (range: 10 - 270 days). FSGS and SR diseases were associated with lower likelihood of remission (p < 0.05). Remission was equally likely in both treatment naïve patients and those who had received prior second-line agents. CONCLUSION: Our results demonstrate that TAC treatment for children with SR/SD NS is associated with high rates of sustained remission, even when prior second-line agents failed.

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BACKGROUND: Acute kidney injury (AKI) carries a large burden of morbidity and mortality. Early diagnosis may lead to better strategies of clinical care. Cardiac surgery involving cardiopulmonary bypass is associated with a significant incidence of AKI. The study objective was to determine whether or not preoperative fibroblast growth factor-23 (FGF23) levels differed among pediatric patients who did or did not develop AKI following cardiac surgery. METHODS: A nested case-control study was performed. FGF23 levels were measured pre- and post-operatively in 19 children without chronic kidney disease (CKD) who underwent cardiopulmonary bypass. Five patients developed AKI and 14 patients served as controls. RESULTS: FGF23 levels in patients who developed AKI following cardiac surgery were elevated above normal levels, both pre-operatively and post-operatively compared with those patients who did not develop AKI. Relative risk of developing AKI when the pre-operative FGF23 level was >86 RU/mL was 2.0 (p = 0.033). Preoperative FGF23 levels correlated with post-operative fluid gain (correlation coefficient 0.607, p = 0.0059). CONCLUSIONS: FGF23 may serve as a pre-operative prognostic indicator of the development of AKI following cardiopulmonary bypass surgery in pediatric patients without CKD. Identifying patients more likely to have AKI following surgery provides a means of achieving closer clinical management of AKI and fluid balance.

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BKVN leads to allograft dysfunction following kidney transplantation and is preceded by BK viremia. Studies in pediatric kidney transplant recipients reveal an incidence of viruria ranging from 18% to 33%, viremia 6-16%, and BKVN 2-8%. Specific risk factors have not been clearly elucidated. Retrospective chart review of pediatric kidney transplants performed from January 2005 through December 2009; to identify risk factors associated with BK viremia in pediatric kidney transplant recipients from a single center. Of the 93 patients who received kidney transplants in the study period, 22 (24%) developed BK viruria, including 12 (13%) who developed viremia. One patient with viremia (1.6%) had BKVN. Obstructive uropathy was identified as the cause of ESKD in 22 (24%) of all recipients. 27% (n = 6) of these 22 patients developed viremia, while only 8.5% (6/71) with ESKD from another cause had viremia (p = 0.001). No other examined variable differed between the two groups. Although the overall incidence was no higher than other reported series, we identified that BK disease was more frequent in children with OU. A higher index of suspicion for invasive BK disease is necessary in patients with OU who receive kidney allografts. Transplant protocols may need to consider underlying cause of ESKD when designing screening protocols for BK disease in children after kidney transplantation.

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INTRODUCTION: During continuous renal replacement therapy (CRRT), hemofiltration circuits ideally are changed after 72 h since tubing integrity and flow rates are not guaranteed after this time interval. This potential risk must be weighed against the risk of hypotension during elective circuit changes in the unstable patient. The aim of this study was to examine the safety of circuits used beyond 72 h in pediatric CRRT. METHODS: A retrospective chart review of all patients who underwent CRRT at our institution from January 2003 to October 2005 was performed. Procedures were divided into standard (≤72 h) and extended (>72 h) circuit duration groups. Patients who had more than one CRRT procedure (n=13) were excluded from study. RESULTS: 71 CRRT procedures were performed for 71 patients. A total of 254 circuits were used, of which 64 (25%) were used for >72 h. For circuits >72 h, the mean duration of use was 5.5 days ± 1.8 (range 4-11). There were no differences between the groups in age (p=0.12), weight (p=0.48), diagnosis (p=0.21), CRRT indication (p=0.07), CRRT mode (p=0.37), anticoagulation (p=0.53), blood flow rate (p=0.06), replacement rate (p=0.50) or dialysate rate (p=0.89). There were no incidents of membrane or tubing rupture in either group. CONCLUSIONS: Use of hemofiltration circuits beyond 72 h may be safe in pediatric patients undergoing CRRT without increased risk of tubing rupture. Our data suggest a need to redefine the limits of prolonged circuit use in pediatric CRRT.

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BACKGROUND AND OBJECTIVES: This study characterizes the pathologic and clinical relationships of thrombotic microangiopathy (TMA) to antibody-mediated rejection (AMR) in renal allograft biopsies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Consecutive renal allograft biopsies, routinely stained for C4d over a period of 51 months (n=1101), were reviewed. For comparative analysis of histology and clinical features, additional patients with TMA and peritubular capillary (PTC) C4d (n=5) were combined with those identified in the 51-month period of review (n=6). RESULTS: One hundred eighty-two of 1073 adequate biopsies from 563 allografts had PTC C4d in the study period. Six of 37 biopsies with TMA had PTC C4d (five at ≤90 days and one at 213 days). Early (≤90 days) C4d+ biopsies (n=5) had more frequent TMA (11.9% C4d+ versus 3.4% C4d-; odds ratio, 3.84; P=0.03). Graft loss was significantly greater in an early C4d+TMA+ group (n=5 study+2 archival patients) than in C4d+ controls without TMA (n=21) (57% versus 9.5%; P=0.02). Early TMA+C4d+ biopsies had more severe glomerulopathy and less severe arteriolopathy than TMA+C4d- and had more frequent neutrophilic capillaritis than TMA-C4d+ biopsies. CONCLUSIONS: TMA was infrequent in this series of unselected, consecutive, renal allograft biopsies (3.4%). PTC C4d may be a significant risk factor for early TMA, and TMA is associated with glomerular thrombi and neutrophilic capillaritis. TMA in allografts with suspected AMR may portend a higher risk of graft loss.

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BK viral nephropathy is a well-documented clinical entity in kidney transplant recipients and a significant cause of morbidity and allograft loss in affected patients. BK viral nephropathy in native kidneys of non-kidney transplant recipients is relatively uncommon, but has been reported in adult patients. We report the occurrence of BK viral nephropathy in a pediatric heart transplant recipient. A 10-yr-old boy with past history of Ewing's sarcoma underwent heart transplantation for dilated cardiomyopathy induced by previous chemotherapy with doxorubicin. Post-transplant course was complicated by grade 3A rejection and CMV colitis. He was diagnosed with native BK viral nephropathy approximately 18 months post-transplant due to mild, but persistent, elevation in serum creatinine associated with proteinuria. BK viral nephropathy affects non-kidney transplant recipients, and a high index of suspicion is necessary for early diagnosis and management of this condition.

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CONTEXT: Factors associated with the high prevalence of vitamin D deficiency in China are not well described, especially among Chinese adolescents. OBJECTIVES: The aim of the study was to examine important environmental or sociodemographic factors influencing 25-hydroxyvitamin D [25(OH)D] levels and estimate its heritability. DESIGN: A sample of 226 male and female adolescent twins aged 13-20 yr from a large prospective twin cohort of rural Chinese children and adolescents that has been followed for 6 yr were evaluated. MAIN OUTCOME MEASURE(S): Blood level of 25(OH)D was measured using tandem mass spectrometry methodology. RESULTS: The overall mean (SD) 25(OH)D level was 18.0 (9.4) ng/ml, with wide variation by gender and season. In males (47.4% of subjects), the mean (SD) 25(OH)D level was 12.1 (4.2) ng/ml in non-summer and 27.4 (8.8) ng/ml in summer; in females, it was 10.1 (4.1) ng/ml in non-summer and 19.5 (6.3) ng/ml in summer. A multivariate model that included gender, age, season, physical activity, and student status demonstrated that male gender, summer season, and high physical activity significantly increased 25(OH)D levels. Summer season and male gender also significantly decreased the risk of being in the lowest 25(OH)D tertile. Overall, 68.9% of the variability in 25(OH)D level was attributable to additive genetic influence. Stratification by gender found that in males, 85.9% of the variability in 25(OH)D level was attributable to such influence, but in females, it was only 17%. CONCLUSION: In this sample of rural Chinese adolescents, 25(OH)D level was influenced by gender, season, and physical activity level. There was a strong genetic influence on 25(OH)D level in males only.

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BACKGROUND: Vitamin D deficiency in children adversely affects bone development by reducing mineralization. Children with chronic kidney disease are at risk for altered bone development from renal osteodystrophy and concomitant vitamin D deficiency. The pediatric Kidney Disease Outcomes Quality Initiative guidelines suggest measuring serum 25-hydroxyvitamin D (25[OH]D) levels if serum parathyroid hormone levels are above the target range for chronic kidney disease stages 2 and beyond, but the magnitude of vitamin D deficiency in children with chronic kidney disease is not well studied. OBJECTIVES: The purpose of this work was to determine whether children with chronic kidney disease had vitamin D deficiency, to evaluate whether the prevalence of vitamin D deficiency changed over time, and to examine seasonal and ethnic differences in 25(OH)D levels. METHODS: 25(OH)D levels in children with chronic kidney disease (stages 1-5) were measured over a 10-year period from 1987 to 1996. Data were also collected for a contemporary group of patients from 2005 to 2006. RESULTS. The prevalence of vitamin D deficiency ranged from 20% to 75% in the decade studied. There was a significant trend for decreasing 25(OH)D levels over the decade, both at the group and individual levels. Seasonal variation was noted. In our contemporary population with chronic kidney disease, the mean 25(OH)D level was 21.8 ng/mL; we found a prevalence of vitamin D deficiency of 39%. Black and Hispanic patients had lower levels of 25(OH)D than white patients. CONCLUSIONS: Children with chronic kidney disease have great risk for vitamin D deficiency, and its prevalence was increasing yearly in the studied decade. Contemporary data show that vitamin D deficiency remains a problem in these children. Sunlight exposure and ethnicity play a role in levels of 25(OH)D. Our data support the recent pediatric Kidney Disease Outcomes Quality Initiative guidelines for measurement of 25(OH)D levels in children with chronic kidney disease and secondary hyperparathyroidism.

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OBJECTIVE: Aprotinin, a serine protease inhibitor, decreases transfusion requirements and inflammatory response after cardiopulmonary bypass. This study was done to determine whether aprotinin is associated with adverse outcomes, particularly mortality and acute kidney failure, in pediatric patients (<18 years of age) undergoing cardiopulmonary bypass. METHODS: We compared a cohort of all pediatric cardiopulmonary bypass operations from 1994-1999, when aprotinin was not used (n = 1230), with a cohort from 2000-2006, when all patients received high-dose aprotinin (n = 1251). Primary end points were operative and late mortality, acute kidney failure, need for dialysis, and neurologic complications. Association of aprotinin with primary end points was assessed by means of univariate analysis, multivariate logistic regression, and Cox regression analysis, where appropriate. RESULTS: The aprotinin group was younger (mean age, 3.49 +/- 1.84 vs 3.64 +/- 4.75 years; P = .019) and had a higher Aristotle score (7.8 +/- 2.3 vs 7.2 +/- 2.6, P < .001). Univariate and multivariate analysis showed no significant difference between the no-aprotinin and aprotinin groups for operative mortality (55 [4.5%] vs 47 [3.8%], P = .508), acute kidney failure (68 [6.0%] vs 69 [5.7%], P = .77), need for temporary dialysis (6 [0.49%] vs 12 [0.96%], P = .17), or neurologic complications (14 [1.1%] vs 17 [1.4%], P = .62). By means of Cox regression analysis, aprotinin had no influence on late mortality (24 vs 10 deaths, P = .078). CONCLUSION: In this retrospective cohort study of pediatric patients undergoing cardiopulmonary bypass, there was no association between the use of aprotinin and acute kidney failure, need for dialysis, neurologic complications, and operative or late mortality. We continue to use aprotinin for all pediatric patients undergoing cardiopulmonary bypass.

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