Follow-up biopsies identify high rates of persistent rejection in pediatric kidney transplant recipients after treatment of T cell-mediated rejection.

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

Adrenal insufficiency in pediatric kidney transplantation recipients.

BACKGROUND: Immunosuppression of pediatric kidney transplant (PKT) recipients often includes corticosteroids. Prolonged corticosteroid exposure has been associated with secondary adrenal insufficiency (AI); however, little is known about its impact on PKT recipients. METHODS: This was a retrospective cohort review of PKT recipients to evaluate AI prevalence, risk factors, and adverse effects. AI risk was assessed using morning cortisol (MC) and diagnosis confirmed by an ACTH stimulation test. Potential risk factors and adverse effects were tested for associations with MC levels and AI diagnosis. RESULTS: Fifty-one patients (60.8% male, age 7.4 (IQR 3.8, 13.1) years; 1 patient counted twice for repeat transplant) were included. Patients at risk for AI (MC < 240 nmol/L) underwent definitive ACTH stimulation testing, confirming AI in 13/51 (25.5%) patients. Identified risk factors for AI included current prednisone dosage (p = .001), 6-month prednisone exposure (p = .02), daily prednisone administration (p = .002), and rejection episodes since transplant (p = .001). MC level (2.5 years (IQR 1.1, 5.1) post-transplant) was associated with current prednisone dosage (p < .001), 6-month prednisone exposure (p = .001), daily prednisone administration (p = .006), rejection episodes since transplant (p = .003), greater number of medications (ß = -16.3, p < .001), 6-month hospitalization days (ß = -3.3, p = .013), creatinine variability (ß = -2.4, p = .025), and occurrence of acute kidney injury (ß = -70.6, p = .01). CONCLUSION: Greater corticosteroid exposure was associated with a lower MC level and confirmatory diagnosis of AI noted with an ACTH stimulation test. Adverse clinical findings with AI included greater medical complexity and kidney function lability. These data support systematic clinical surveillance for AI in PKT recipients treated with corticosteroids.

Metabolomic identification of predictive and early biomarkers of cisplatin-induced acute kidney injury in adult head and neck cancer patients.

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.

Noninvasive testing for mycophenolate exposure in children with renal transplant using urinary metabolomics.

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.

Parent and healthcare provider views of live varicella vaccination of pediatric solid organ transplant recipients.

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.

Differences in medication adherence by sex and organ type among adolescent and young adult solid organ transplant recipients.

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.

Acute kidney injury during cisplatin therapy and associations with kidney outcomes 2 to 6 months post-cisplatin in children: a multi-centre, prospective observational study.

BACKGROUND: Few studies describe acute kidney injury (AKI) burden during paediatric cisplatin therapy and post-cisplatin kidney outcomes. We determined risk factors for and rate of (1) AKI during cisplatin therapy, (2) chronic kidney disease (CKD) and hypertension 2-6 months post-cisplatin, and (3) whether AKI is associated with 2-6-month outcomes. METHODS: This prospective cohort study enrolled children (aged < 18 years at cancer diagnosis) treated with cisplatin from twelve Canadian hospitals. AKI during cisplatin therapy (primary exposure) was defined based on Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria (≥ stage one). Severe electrolyte abnormalities (secondary exposure) included ≥ grade three hypophosphatemia, hypokalemia, or hypomagnesemia (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0). CKD was albuminuria or decreased kidney function for age (KDIGO guidelines). Hypertension was defined based on the 2017 American Academy of Pediatrics guidelines. RESULTS: Of 159 children (median [interquartile range [IQR]] age: 6 [2-12] years), 73/159 (46%) participants developed AKI and 55/159 (35%) experienced severe electrolyte abnormalities during cisplatin therapy. At median [IQR] 90 [76-110] days post-cisplatin, 53/119 (45%) had CKD and 18/128 (14%) developed hypertension. In multivariable analyses, AKI was not associated with 2-6-month CKD or hypertension. Severe electrolyte abnormalities during cisplatin were associated with having 2-6-month CKD or hypertension (adjusted odds ratio (AdjOR) [95% CI]: 2.65 [1.04-6.74]). Having both AKI and severe electrolyte abnormalities was associated with 2-6-month hypertension (AdjOR [95% CI]: 3.64 [1.05-12.62]). CONCLUSIONS: Severe electrolyte abnormalities were associated with kidney outcomes. Cisplatin dose optimization to reduce toxicity and clear post-cisplatin kidney follow-up guidelines are needed. A higher resolution version of the Graphical abstract is available as Supplementary information.

Child and caregiver perspectives on access to psychosocial and educational support in pediatric chronic kidney disease: a focus group study.

BACKGROUND: Children with chronic kidney disease (CKD) generally have worse educational and psychosocial outcomes compared with their healthy peers. This can impair their ability to manage their treatment, which in turn can have long-term health consequences through to adulthood. We attempted to capture the experiences of children with CKD and to describe the perspectives of their parents and caregivers on access to educational and psychosocial support. METHODS: Children with CKD (n = 34) and their caregivers (n = 62) were sampled via focus groups from pediatric hospitals in Australia, Canada, and the USA. Sixteen focus groups were convened and the transcripts were analyzed thematically. RESULTS: We identified four themes: disruption to self-esteem and identity (emotional turmoil of adolescence, wrestling with the sick self, powerlessness to alleviate child's suffering, balancing normality and protection); disadvantaged by lack of empathy and acceptance (alienated by ignorance, bearing the burden alone); a hidden and inaccessible support system (excluded from formal psychological support, falling behind due to being denied special considerations); and building resilience (finding partners in the journey, moving towards acceptance of the illness, re-establishing childhood). CONCLUSIONS: Children with CKD and their caregivers encountered many barriers in accessing psychosocial and educational support and felt extremely disempowered and isolated as a consequence. Improved availability and access to psychosocial and educational interventions are needed to improve the wellbeing and educational advancement of children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Height-adjusted lean body mass and its associations with physical activity and kidney function in pediatric kidney transplantation.

BACKGROUND: Although LBM is positively associated with health outcomes, studies assessing determinants for the accrual of ht-LBM, such as physical activity, are limited. This study aimed to assess ht-LBM levels in pediatric kidney transplant recipients and test its association with baseline and contemporaneous variables, including physical activity. METHODS: A retrospective cross-sectional review was performed on 46 pediatric kidney transplant recipients, and a longitudinal review was performed on a subset of recipients with serial post-transplant (n = 21) and pre/post-transplant (n = 11) ht-LBM measurements. Ht-LBM measurements were obtained using DXA scans. RESULTS: This cohort was 16.0 (IQR 12.3, 17.7) years old, 56.5% male and 46 ± 45 months post-transplant with a mean ht-LBM of 15.1 ± 2.5 kg/m2 . A median ht-LBM increase of 1.6 kg/m2 (IQR - 0.1, 2.6 kg/m2 ; p < .01) was observed, over 29.2 ± 12.0 months from the earliest post-transplant scan obtained at 46 ± 25 months post-transplant until the most recent post-transplant scan. A 1.7 ± 1.4 kg/m2 (p < .01) increase was observed between pre- and post-transplant DXA scans which were taken at 12 ± 11 months pre-transplant and 13 ± 6 months post-transplant, respectively. In separate adjusted models, lower physical activity questionnaire scores (n = 17, beta = 1.55, p = .02), faster rate of estimated glomerular filtration rate decline (beta = 0.05, p < .048) adjusted for annualized change in BSA, and younger age at scan (beta = 0.32, p < .01) were each significant predictors of lower ht-LBM. CONCLUSIONS: Physical activity and kidney function may influence ht-LBM in the pediatric kidney transplant population.

High urinary CXCL10/Cr with onset of Burkitt lymphoma in a pediatric kidney transplant recipient.

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.

The mental health profiles of pediatric organ transplant recipients.

BACKGROUND: Solid organ transplantation is the indicated treatment for children with end-stage organ failure. Little is known about the impact of organ transplantation on pediatric transplant recipients' mental health. Symptoms of medical procedure and generalized anxiety, post-traumatic stress, and depression may emerge, despite the successful restoration of organ function. METHODS: We examined symptoms of anxiety, depression, trauma, and medical procedure anxiety-specifically, fear and avoidance of needles-in youth who had received a kidney, liver, or heart transplant. Parent-report on child mental health symptoms was also collected. RESULTS: Data were obtained for 56 youth. Most children did not endorse clinically significant symptoms of depression. In contrast, 20% of parents reported symptoms of depression in their child that exceeded clinical cutoffs. Parents also reported higher levels of anxiety in their children than did the children themselves. Indeed, on average, children reported lower levels of depression and anxiety than would be expected in a general population. On a trauma measure, 22.6% of youths' scores were above clinical cutoffs, with girls scoring higher than boys. Finally, 10.9% of children stated that they attempted to avoid needles because of fear. Once again, girls reported higher needle fear scores than boys and younger patients reported experiencing higher levels of needle fear. CONCLUSIONS: Anxiety, depression, post-traumatic stress, and needle fear are important psychological parameters that should be considered in the evaluation of pediatric patients with solid organ transplant, as part of their routine post-transplant care.

Urinary metabolomics to develop predictors for pediatric acute kidney injury.

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<0.001). 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. A higher resolution version of the Graphical abstract is available as Supplementary information with inner reference to ESM for GA.

A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial.

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).

Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients.

Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy-associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety-seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66-0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66-0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first-year eGFR decline (ρ = -0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real-time clinical monitoring in children.

Isolated diastolic high blood pressure: a distinct clinical phenotype in US children.

BACKGROUND: Screening studies have shown that 0.7-4.5% of generally healthy children have isolated diastolic high BP. We therefore studied the characteristics of children with diastolic BP in the elevated and hypertensive ranges according to current guidelines in US children from the National Health and Nutrition Examination Survey (NHANES, 1999-2016). METHODS: We studied 17,362 children (8-18 years) with BP measured by sphygmomanometry. High BP was categorized as isolated systolic (iSH), isolated diastolic (iDH), or Mixed. RESULTS: Overall, 86.0% (95% CI = 85.0-87.0) of the population had normal BP, 8.7% (8.0-9.3) elevated BP, 4.9% (4.4-5.5) Stage 1, and 0.4% (0.4-0.6) Stage 2. Moreover, 11.1% (10.3-12.0) had iSH, 1.9% (1.5-2.2) iDH, and 1.0% (0.8-1.2) Mixed. Children with iDH were more likely to be female, younger, white, and leaner than those with iSH, with lower rates of overweight/obesity. iDH was generally between normals and iSH. Resting heart rate was significantly higher in iDH even after adjustment for known covariates. CONCLUSIONS: Children with iDH may have a distinct clinical picture. A leaner habitus and higher resting heart rate may reflect differences in underlying pathophysiology. Longitudinal follow-up studies are needed to better define the pathogenesis, progression, and long-term prognosis in iDH. IMPACT: Using gold-standard auscultation and 2017 guidelines, isolated diastolic high BP (iDH) is found in 1.9% (95% CI 1.5-2.2) of American children; these children are younger, leaner, more female, and have fewer cardiometabolic risks. Resting heart rate is significantly higher in iDH compared to both normals and iSH even after adjustments for known covariates. Autonomic hyperactivity in iDH may speak to both etiology and therapeutic approaches. iDH appears to be a distinct clinical phenotype characterized by differences in anthropometric measures, sex, age, and resting heart rate. Follow-up studies are clearly needed to clarify its pathogenesis, progression, and prognosis.

Yield and utility of surveillance kidney biopsies in pediatric kidney transplant recipients at various time points post-transplant.

BACKGROUND: Due to a lack of consensus on SB for pediatric kidney transplant recipients, we evaluated the yield and clinical utility of SB findings at various time points post-transplant. METHODS: Patients transplanted at a single institution between 2014 and 2020 with at least one SB at 1.5, 3, 6, 12, and 24 months post-transplant were included. Additional biopsies were done for indication (IB). TCMR was classified by Banff criteria (score ≥i1t1). RESULTS: Forty-seven patients had 142 biopsies (SB = 113, IB = 29); 19 (40.4%) of whom experienced at least one TCMR episode in the first-year post-transplant. The greatest SB yield of any pathologic abnormality was at 6 months (57.1%; P < .001). Six months also had the highest yield for TCMR (42.9%), compared with 3.3%, 20.8%, 15.0%, and 9.1% at 1.5, 3, 12 months, and 24 months, respectively (P = .003). SB instigated intensification of immunosuppression (28.3% cases), reduction of immunosuppression (2.7% cases), and other non-immunosuppressant changes (1.8% cases). The 6-month SB led to the greatest number of changes in management (53.6%), compared with 1.5, 3, 12, and 24 months (13.3, 20.8, 25.0, and 36.4%, respectively; P = .012). There were no major biopsy-related complications. CONCLUSIONS: SBs identify an important burden of subclinical rejection and other pathology leading to changes in clinical management. The greatest yield was at 6 months, whereas the least utility was at the 1.5 months. Selection of SB timing may be tailored such that the optimal yield is balanced against the procedural risk.

Low renal transplantation rates in children with end-stage kidney disease: A study of barriers in a low-resource setting.

After 2 decades as a low-cost transplant centre in India, our rates of kidney transplantation are low compared to the burden of end-stage kidney disease (ESKD). We performed this study to identify possible barriers inhibiting paediatric kidney transplant and to assess the outcomes of paediatric ESKD. A retrospective chart review of ESKD patients (2013 - 2018) at a tertiary paediatric nephrology centre was conducted. Medical/non-medical barriers to transplant were noted. Patient outcomes were classified as "continued treatment," "lost to follow-up (LTFU)" or "died." Of 155 ESKD patients (monthly income 218 USD [146, 365], 94% self-pay), only 30 (19%) were transplanted (28 living donor). Sixty-five (42%) were LTFU, 19 (12%) died, and 71 (46%) continued treatment. LTFU/death was associated with greater travel distance (300 km [60, 400] vs 110 km [20, 250] km, P < .0001) and lower monthly income (145 USD [101, 290] vs 290 USD [159, 681], P < .0001). Among those who continued treatment, 41 proceeded to transplant evaluation of whom 13 had no living donor and remained waitlisted for 27 months (15, 30). The remainder (n = 30) did not proceed to transplant due to unresolved medical issues (n = 10) or a lack of parental interest in pursuing transplant (n = 20). Barriers to transplantation in low-resource setting begin in ESKD. LTFU resulted in withdrawal of care and was associated with low socioeconomic status. Among those who continued treatment, transplant rates were higher but medical challenges and negative attitudes towards transplant and organ donation occurred.

Biomarker implementation: Evaluation of the decision-making impact of CXCL10 testing in a pediatric cohort.

BACKGROUND: Children are at high risk for subclinical rejection, and kidney biopsy is currently used for surveillance. Our objective was to test how novel rejection biomarkers such as urinary CXCL10 may influence clinical decision-making to indicate need for a biopsy. METHODS: A minimum dataset for standard decision-making to indicate a biopsy was established by an expert panel and used to design clinical vignettes for use in a survey. Pediatric nephrologists were recruited to review the vignettes and A) estimate rejection risk and B) decide whether to biopsy; first without and then with urinary CXCL10/Cr level. Accuracy of biopsy decisions was then tested against the biopsy results. IRA was assessed by Fleiss Kappa (κ) for binary choice and ICC for probabilities. RESULTS: Eleven pediatric nephrologists reviewed 15 vignettes each. ICC of probability assessment for rejection improved from poor (0.28, P < .01) to fair (0.48, P < .01) with addition of CXCL10/Cr data. It did not, however, improve the IRA for decision to biopsy (K = 0.48 and K = 0.43, for the comparison). Change in clinician estimated probability of rejection with additional CXCL10/Cr data was correlated with CXCL10/Cr level (r2  = 0.7756, P < .0001). Decision accuracy went from 8/15 (53.3%) cases to 11/15 (73.3%) with CXCL10/Cr, although improvement did not achieve statistical significance. Using CXCL10/Cr alone would have been accurate in 12/15 cases (80%). CONCLUSION: There is high variability in decision-making on biopsy indication. Urinary CXCL10/Cr improves probability estimates for risk of rejection. Training may be needed to assist nephrologists in better integrate biomarker information into clinical decision-making.

Post-traumatic stress as a determinant of quality of life in pediatric solid-organ transplant recipients.

Living with end-stage organ failure is associated with an accumulation of traumatic medical events, and despite recovery after solid-organ transplantation (SOT), many children continue to exhibit lower quality of life (QOL). Few studies have examined the relationship between post-traumatic stress disorder (PTSD) and QOL among pediatric SOT recipients. We conducted a retrospective, cross-sectional review of 61 pediatric SOT recipients (12 heart, 30 kidney, and 19 liver) to evaluate the association of PTSD with self-reported QOL. PTSD was measured by the Child Trauma Screening Questionnaire (CTSQ), and QOL was measured using the PedsQL and PedsQL Transplant Module (PedsQL-TM) surveys. Demographics, baseline, and contemporaneous factors were tested for independent association. SOT recipients were 15.2 (12.1-17.6) years old at survey completion. Median CTSQ score was 2 (1-3), highest in kidney recipients, and 13% were identified as high risk for PTSD. Median PedsQL score was 83 (70-91) and significantly associated with the CTSQ score (r = -.68, p < .001). Median PedsQL Transplant Module score was 89 (83-95) and similarly associated with the CTSQ score (r = -.64, p < .001). Age at time of surveys and presence of any disability were also independently associated with PedsQL and PedsQL-TM, respectively. When adjusted for Emotional Functioning, CTSQ remained associated with PedsQL subscores (r = -.65, p < .001). Trauma symptoms are a major modifiable risk factor for lower self-perceived QOL and represent a potentially important target for post-transplant rehabilitation. Additional research is needed to understand the root contributors to PTSD and potential treatments in this population.

Self-reported physical activity and lack of association with health-related quality of life in a pediatric solid-organ transplant population.

BACKGROUND: Physical activity (PA) has been shown to have benefits, including improving health-related quality of life (HRQOL). However, there are few and conflicting studies assessing PA and its relationship with HRQOL in a pediatric solid-organ transplant (SOT) population. The aim of this study was to assess whether overall HRQOL was associated with PA and to determine whether that association was independent of other baseline and contemporaneous clinical and demographic indicators. METHODS: A retrospective cross-sectional review was performed on 55 pediatric transplant patients (13 heart, 27 kidney, and 15 liver transplant). PA was measured by PAQ-C/PAQ-A, and HRQOL was measured using PedsQL. Demographics, baseline, and contemporaneous data were collected. RESULTS: There were no significant differences in baseline and contemporaneous characteristics between heart, kidney, and liver transplant recipients. SOT recipients were 15.0 (11.0-18.0) years old at completion of surveys. Median PAQ score was 2.3 (1.6-3.2), PedsQL total score was 77 (65-91), and PedsQL physical functioning score was 88 (72-97). The PedsQL total score was not significantly associated with PAQ score. The PAQ score was significantly associated with physical functioning subscore of the PedsQL (r = 0.37, p < 0.01). Higher physical functioning score was associated with time since transplant (r = 0.29, p = 0.031). CONCLUSION: Our SOT cohort has a HRQOL similar to other chronic conditions and higher than previous reported HRQOL in pediatric SOT populations. Higher levels of PA and longer time since transplant are associated with higher physical functioning scores.