Search

Author(s): Hayton Chui [sup.1] [sup.2] , Kelly R. McMahon [sup.3] , Shahrad Rod Rassekh [sup.4] , Kirk R. Schultz [sup.4] , Tom D. Blydt-Hansen [sup.5] , Cherry Mammen [sup.5] , [...], Background Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) may be early cisplatin-AKI biomarkers. Methods We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013-December 2017). Blood and urine (measured for TIMP-2, IGFBP-7) were collected pre-cisplatin, 24-h post-cisplatin, and near hospital discharge during the first or second cisplatin cycle (early visit (EV)) and during second-to-last or last cisplatin cycle (late visit (LV)). Primary outcome: serum creatinine (SCr)-defined AKI ([greater than or equal to] stage 1). Results At EV (median (interquartile (IQR)) age: 6 (2-12) years; 78 (50%) female), 46/156 (29%) developed AKI; at LV, 22/127 (17%) experienced AKI. At EV, TIMP-2, IGFBP-7, and TIMP-2*IGFBP-7 pre-cisplatin infusion concentrations were significantly higher in participants with vs. those without AKI. At EV and LV, biomarker concentrations were significantly lower in participants with vs. those without AKI at post-infusion and near-hospital discharge. Biomarker values normalized to urine creatinine were higher in patients with AKI compared to without (LV post-infusion, median (IQR): TIMP-2*IGFBP-7: 0.28 (0.08-0.56) vs. 0.04 (0.02-0.12) (ng/mg creatinine).sup.2/1000; P < .001). At EV, pre-infusion biomarker concentrations had the highest area under the curves (AUC) (range: 0.61-0.62) for AKI diagnosis; at LV, biomarkers measured post-infusion and near discharge yielded the highest AUCs (range: 0.64-0.70). Conclusions TIMP-2*IGFBP-7 were poor to modest at detecting AKI post-cisplatin. Additional studies are needed to determine whether raw biomarker values or biomarker values normalized to urinary creatinine are more strongly associated with patient outcomes. Graphical abstract

Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production-dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3-4 (ClinicalTrials.gov Identifier NCT04741646).

Author(s): Alexandra Franiek [sup.1] , Atul Sharma [sup.2] , Vedran Cockovski [sup.3] , David S. Wishart [sup.4] , Michael Zappitelli [sup.5] , Tom D. Blydt-Hansen [sup.6] Author Affiliations: (1) grid.4305.2, [...], Background Acute kidney injury (AKI) is characterized by an abrupt decline in glomerular filtration rate (GFR). We sought to identify separate early urinary metabolomic signatures at AKI onset (with-AKI) and prior to onset of functional impairment (pre-AKI). Methods Pre-AKI (n=15), AKI (n=22), and respective controls (n=30) from two prospective PICU cohort studies provided urine samples which were analyzed by GC-MS and DI-MS mass spectrometry (193 metabolites). The cohort (n=58) was 8.7±6.4 years old and 66% male. AKI patients had longer PICU stays, higher PRISM scores, vasopressors requirement, and respiratory diagnosis and less commonly had trauma or post-operative diagnosis. Urine was collected within 2-3 days after admission and daily until day 5 or 14. Results The metabolite classifiers for pre-AKI samples (1.5±1.1 days prior to AKI onset) had a cross-validated area under receiver operator curve (AUC)=0.93 (95%CI 0.85-1.0); with-AKI samples had an AUC=0.94 (95%CI 0.87-1.0). A parsimonious pre-AKI classifier with 13 metabolites was similarly robust (AUC=0.96, 95%CI 0.89-1.0). Both classifiers were similar and showed modest correlation of high-ranking metabolites (tau=0.47, p Conclusions This exploratory study demonstrates the potential of a urine metabolite classifier to detect AKI-risk in pediatric populations earlier than the current standard of diagnosis with the need for external validation. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information with inner reference to ESM for GA

Background: Life with end‐stage organ failure is accompanied by an accumulation of traumatic medical or surgical experiences. Despite recovery after solid organ transplantation (SOT), many children and adolescents develop post‐traumatic stress symptoms (PTSS). PTSS remain underappreciated as a major comorbidity in SOT programs, despite their association with decreased quality of life. Methods: We conducted a retrospective, cross‐sectional study of 86 pediatric SOT recipients (17 heart, 44 kidney, and 25 liver) to evaluate potential determinants of PTSS. Trauma symptoms were measured by the Child Trauma Screening Questionnaire (CTSQ). Demographic, baseline, and contemporaneous factors were tested for independent association with CTSQ scores. Results: The median post‐transplant CTSQ score was 2 (IQR 1–4), and 22% were identified as high risk (score ≥5) for PTSD. Higher CTSQ scores were independently associated with the number of ICU days within the previous 12 months, the number of medications (complexity), and involvement with foster care in the primary model (R2 [adj.] = 0.26). The addition of the Family Impact Module improved the overall model (R2 [adj.] = 0.33), wherein higher family functioning was independently associated with lower CTSQ scores. An exploratory analysis of pre‐transplant patients (n = 34) found a median pre‐transplant CTSQ of 2 (IQR 1–6), suggesting that PTSS are onset before transplant and persist afterward. Conclusions: PTSS are highly prevalent in the SOT population. Risk factors include recent adverse medical experiences and complexity, whereas family stability may be protective. Additional research is needed to improve early ascertainment and support for patients at high risk of developing PTSS throughout their transplant journey. [ABSTRACT FROM AUTHOR]

Aim: Cisplatin causes acute kidney injury (AKI) in approximately one third of patients. Serum creatinine and urinary output are poor markers of cisplatin‐induced AKI. Metabolomics was utilized to identify predictive or early diagnostic biomarkers of cisplatin‐induced AKI. Methods: Thirty‐one adult head and neck cancer patients receiving cisplatin (dose ≥70 mg/m2) were recruited for metabolomics analysis. Urine and serum samples were collected prior to cisplatin (pre), 24–48 h after cisplatin (24–48 h) and 5–14 days (post) after cisplatin. Based on serum creatinine concentrations measured at the post timepoint, 11/31 patients were classified with clinical AKI. Untargeted metabolomics was performed using liquid chromatography‐mass spectrometry (LC‐MS). Results: Metabolic discrimination was observed between "AKI" patients and "no AKI" patients at all timepoints. Urinary glycine, hippuric acid sulfate, 3‐hydroxydecanedioc acid and suberate were significantly different between AKI patients and no AKI patients prior to cisplatin infusion. Urinary glycine and hippuric acid sulfate were lower (−2.22‐fold and −8.85‐fold), whereas 3‐hydroxydecanedioc acid and suberate were higher (3.62‐fold and 1.91‐fold) in AKI patients relative to no AKI patients. Several urine and serum metabolites were found to be altered 24–48 h following cisplatin infusion, particularly metabolites involved with mitochondrial energetics. Conclusions: We propose glycine, hippuric acid sulfate, 3‐hydroxydecanedioc acid and suberate as predictive biomarkers of predisposition to cisplatin‐induced AKI. Metabolites indicative of mitochondrial dysfunction may serve as early markers of subclinical AKI. [ABSTRACT FROM AUTHOR]

Background: Incomplete resolution of T cell‐mediated rejection (TCMR) after treatment may not be detected with serum creatinine monitoring and is associated with donor‐specific antibodies and chronic rejection. We evaluate the utility of follow‐up biopsies (FUB) to identify and characterize rates of persistent TCMR after treatment in pediatric kidney transplant patients. Methods: Patients from two pediatric transplant centers performing standard of care FUB at 1.5–2 months after treatment for TCMR were included. FUB were evaluated for extent of rejection resolution (complete vs. incomplete) and grade. Clinical data at time of FUB and later were reported, where available. Results: Fifty‐eight patients underwent FUB, at mean of 1.7 months (SD 0.7) post‐index biopsy. Rejection grade on index biopsy was Banff borderline (≥i1t1 and

Background: Live attenuated varicella vaccine (LAVV) has historically been contraindicated in children who are immunocompromised due to solid organ transplant (SOT) because of safety concerns. Recently, clinical guidelines were developed that support post‐transplant varicella vaccination in selected SOT recipients based on emerging evidence of LAVV safety. This qualitative study sought to explore barriers and facilitators to implementing the new guidelines, as well as acceptability of LAVV among healthcare providers (HCPs) and parents. Methods: HCPs and parents of transplant recipients were recruited from four sites using purposive sampling. Data from semi‐structured interviews were analyzed using an Interpretive Description approach that incorporated data from the interviews, academic knowledge and clinical experience, and drew from Grounded Theory and Thematic Analysis. The theoretical framework used was Adaptive Leadership. Results: Thirty‐four participants (16 HCPs and 18 parents) were included in the analysis. Parents developed skills in adaptive leadership that included strategies to protect their child against infectious diseases. Foundational information that live vaccines were absolutely contraindicated post‐transplant "stuck" with parents and led them to develop strategies other than vaccination to keep their child safe. Some parents struggled to understand that information previously presented as a certainty (contraindication of LAVV) could change. Their approach to adaptive leadership informed their appraisal of the new vaccination guidelines and willingness to accept vaccination. Conclusions: HCPs should adopt a family‐centered approach to communicating changing guidelines that considers parents' approach to adaptive leadership and discusses the changing nature of medical evidence. Trust between HCPs and parents can facilitate these conversations. [ABSTRACT FROM AUTHOR]

Nonanonymized direct contact between organ recipients and donor families is a topic of international interest in the adult context. However, there is limited discussion about whether direct contact should be extended to pediatric settings due to clinician and researcher concerns of the potential harms to pediatric patients. We interviewed pediatric organ recipients, their families, and donorfamilies in British Columbia, Canada, to determine their views on direct contact. Interviews were conducted in two stages, with those who were further removed from the transplant process informing the approach to interviews with those who more recently went throughthe transplant process. Twenty-nine individuals participated in twenty in-depth interviews. The study included participants from three major organ systems: kidney, heart, and liver. Only five participants expressed that direct contact might cause harm or discomfort, while twenty-three indicated they saw significant potential for benefits. Nearly half focused on the harms to others rather than themselves, and nearly two-thirds focused on the benefits for others rather than themselves. There appears to be a community desire for direct contact in pediatric organ transplant programs among those living in British Columbia, Canada. These results suggest a need to revisit the medical community's assumptions around protection and paternalism in our practice as clinicians and researchers. [ABSTRACT FROM AUTHOR]

Background: Despite the common use of mycophenolate in pediatric renal transplantation, lack of effective therapeuic drug monitoring increases uncertainty over optimal drug exposure and risk for adverse reactions. This study aims to develop a novel urine test to estimate MPA exposure based using metabolomics. Methods: Urine samples obtained on the same day of MPA pharmacokinetic testing from two prospective cohorts of pediatric kidney transplant recipients were assayed for 133 unique metabolites by mass spectrometry. Partial least squares (PLS) discriminate analysis was used to develop a top 10 urinary metabolite classifier that estimates MPA exposure. An independent cohort was used to test pharmacodynamic validity for allograft inflammation (urinary CXCL10 levels) and eGFR ratio (12mo/1mo eGFR) at 1 year. Results: Fifty‐two urine samples from separate children (36.5% female, 12.0 ± 5.3 years at transplant) were evaluated at 1.6 ± 2.5 years post‐transplant. Using all detected metabolites (n = 90), the classifier exhibited strong association with MPA AUC by principal component regression (r = 0.56, p <.001) and PLS (r = 0.75, p <.001). A practical classifier (top 10 metabolites; r = 0.64, p <.001) retained similar accuracy after cross‐validation (LOOCV; r = 0.52, p <.001). When applied to an independent cohort (n = 97 patients, 1053 samples), estimated mean MPA exposure over Year 1 was inversely associated with mean urinary CXCL10:Cr (r = −0.28, 95% CI −0.45, −0.08) and exhibited a trend for association with eGFR ratio (r = 0.35, p =.07), over the same time period. Conclusions: This urinary metabolite classifier can estimate MPA exposure and correlates with allograft inflammation. Future studies with larger samples are required to validate and evaluate its clinical application. [ABSTRACT FROM AUTHOR]

Introduction: Hypervitaminosis D is a relatively uncommon etiology of hypercalcemia. Toxicity is usually caused by very high doses, mostly secondary to erroneous prescription or administration of vitamin D, and less commonly, contaminated foods or manufacturing errors of vitamin D-containing supplements. Case Presentation: A 16-year-old male, previously healthy, presented with 2-week history of nonspecific symptoms (fatigue, gastrointestinal complaints). Investigations showed acute kidney injury and hypercalcemia (total calcium 3.81 mmol/L). Further diagnostic workup revealed markedly elevated 25-hydroxyvitamin D levels (1,910 nmol/L). He denied taking any vitamin D supplements; however, he reported consumption of creatine and protein supplements. Mass spectrometry analysis of the creatine supplement estimated a vitamin D content of 425,000 IU per serving (100 times the upper tolerable daily dose). A few months later, another previously healthy adolescent presented with severe hypercalcemia and acute kidney injury secondary to hypervitaminosis D. He was also using a creatine supplement, from the same manufacturer brand and lot. Both patients were treated with intravenous hydration, calcitonin, and pamidronate. They maintained normocalcemia after their initial presentation but required low-calcium diets and laboratory testing for months after this exposure. Discussion/Conclusion: We present 2 cases of hypervitaminosis D caused by a manufacturing error of a natural health product which did not claim to contain vitamin D. The use of dietary supplements is highly prevalent; this should be incorporated while taking medical history, and considered a potential source of toxicity when an alternative source cannot be found, regardless of the product label. [ABSTRACT FROM AUTHOR]

Background: Identification of differences in medication adherence by sex or organ type may help in planning interventions to optimize outcomes. We compared immunosuppressive medication adherence between males and females, and between kidney, liver and heart transplant recipients. Methods: This multicenter study of prevalent kidney, liver and heart transplant recipients 14–25 years assessed adherence 3 times (0, 3, 6 months post‐enrollment) with the BAASIS self‐report tool. At each visit, participants were classified as adherent if they missed no doses in the prior 4 weeks and non‐adherent otherwise. Adherence was also assessed using the coefficient of variation (CV) of tacrolimus trough levels; CV < 30% was classified as adherent. We used multivariable mixed effects logistic regression models adjusted for potential confounders to compare adherence by sex and by organ. Results: Across all visits, males (n = 150, median age 20.4 years, IQR 17.2–23.3) had lower odds of self‐reported adherence than females (n = 120, median age 19.8 years, IQR 17.1–22.7) (OR 0.41, 95% CI 0.21–0.80) but higher odds of adherence by tacrolimus CV (OR 2.50, 95% CI 1.30–4.82). No significant differences in adherence (by self‐report or tacrolimus CV) were noted between the 184 kidney, 58 liver, and 28 heart recipients. Conclusion: Females show better self‐reported adherence than males but greater variability in tacrolimus levels. Social desirability bias, more common in females than males, may contribute to better self‐reported adherence among females. Higher tacrolimus variability among females may reflect biologic differences in tacrolimus metabolism between males and females rather than sex differences in adherence. There were no significant differences in adherence by organ type. [ABSTRACT FROM AUTHOR]

Background: Urinary CXCL10/Cr is a promising diagnostic tool for early detection of TCMR in pediatric transplant recipients, and most studies focus on its utility in the context of localized allograft inflammation thus far. Other sources of inflammation that may be detected by CXCL10 are less clear. Methods: We present a case review of a patient with BL, who was enrolled in a prospective trial of urinary CXCL10 monitoring. To evaluate the potential confounding, we tested for association of CXCL10/Cr and EBV viral load in a prospective cohort of pediatric transplant recipients with serial testing for urinary CXCL10/Cr. Results: This report describes a 15‐year‐old boy, 3.5 years post‐transplant with chronic EBV viremia, stable kidney function and no history of rejection. Urinary CXCL10/Cr level increased acutely to 79.43 ng/mmol, 0.8 months prior to onset of BL, identified by a surge in EBV viral load. In a national cohort of 97 pediatric kidney transplant recipients, there was no association between urinary CXCL10/Cr with EBV viral loads when comparing periods of pre‐viremia (5.8 ± 9.2 ng/mmol) to active viremia (4.0 ± 5.3 ng/mmol) and periods of active viremia (7.1 ± 8.9 ng/mmol) to post‐viremia (4.4 ± 9.8 ng/mmol). Conclusions: Acute rise in urinary CXCL10/Cr was associated with onset of graft‐associated BL. We were not able to confirm a general association of EBV viral load and urinary CXCL10. As non‐invasive monitoring is implemented using biomarkers like CXCL10 in the clinic, attention will be needed to identify other uncommon, potential sources of CXCL10 elevation. [ABSTRACT FROM AUTHOR]