Leflunomide as adjunct therapy for BK viremia management in pediatric kidney transplant recipients.

BACKGROUND: BK viremia after kidney transplantation (KT) poses significant risk for BK virus-associated nephropathy and impacts graft survival. Conventional treatment involves reduction of immunosuppression, which in turn may increase risk for rejection. To address this dilemma, use of anti-viral therapy with immunosuppressive properties such as leflunomide is an attractive option. METHODS: We performed a multi-center, retrospective chart review to report tolerability and effectiveness of leflunomide use for the eradication of BK viremia and prevention of BK virus-associated nephropathy in pediatric KT recipients. RESULTS: Seventy patients prescribed leflunomide were included and were followed up from initiation until 1 year following leflunomide completion. BK viremia was eradicated in 64 (91.4%) patients including 8 of 11 with nephropathy (BKVN) on initial biopsy. Reduced anti-proliferative medication (AP) dosing was not associated with increase in biopsy proven rejection (BPAR). However, complete discontinuation of AP during leflunomide therapy was associated with increase in BPAR in uni- and multivariate logistic regression, as was targeted reduction in calcineurin inhibitor (CNI) trough goals. One graft was lost to BKVN. There was no significant association found between time to BK eradication and leflunomide trough concentration, mycophenolate dose reduction, or steroid use (univariate logistic regression). Few leflunomide adverse drug reactions (ADR) were reported (most commonly: gastrointestinal, hematologic). CONCLUSION: Leflunomide is a promising adjunctive treatment to immunosuppression reduction for BK virus eradication with minimal ADR. AP reduction, not discontinuation, and judicious reduction in CNI trough goals with close monitoring, is a promising strategy for treatment of BK viremia with concomitant use of leflunomide therapy.

Clinical characteristics and favorable treatment responses of recurrent focal segmental glomerulosclerosis or steroid-resistant nephrotic syndrome in children after kidney transplantation.

BACKGROUND: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely. METHODS: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review. RESULTS: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results. CONCLUSIONS: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents.

Successful use of intra-operative continuous renal replacement therapy in pediatric liver transplant recipients: Single center case series.

BACKGROUND: Acute kidney injury (AKI) is common in pediatric patients undergoing liver transplantation (LT), with an incidence 17%-55%. Fluid, metabolic, and acid-base aberrancies are often pronounced pre-operatively and further worsened by events during LT, making intra-operative continuous renal replacement therapy (CRRT) an option for critically ill LT recipients. METHODS: All pediatric LT performed at our institution who underwent intra-operative CRRT between January 2017 and August 2021 were included. Patient demographics and clinical data including graft outcomes, intra-operative findings, and timing and indications for CRRT were collected from the electronic medical record. RESULTS: CRRT was used in nine of the 76 (12%) pediatric LT performed at our center during the study period. Ages at LT ranged from 39 to 17.7 years. Recipients requiring CRRT were more likely to have acute liver failure, status 1A, and higher calculated MELD/PELD scores. CRRT was initiated pre-transplant in three recipients and continued post-transplant in six recipients. Median duration of CRRT was two (range 0-14) days. Indications included hyperammonemia (3/9), acidosis (3/9), fluid overload (6/9), and hyperkalemia (2/9). The CRRT group had a significantly longer post-transplant intensive care unit length of stay in comparison to those that did not require CRRT (median 6, range 3-40 days vs. median 3, range 0-121 days, p = .02], but there were no significant differences in reoperations, hospital length of stay, or recipient or graft survival. CONCLUSIONS: We demonstrate that CRRT can be safely performed in pediatric LT recipients, including young infants through adolescents.

Impact of once-daily ER-Tac on trough concentration variability in a stable AYA renal transplant recipient cohort.

BACKGROUND: Successful renal transplantation requires complex medication regimens that rely on strict adherence to be effective. Variability in immunosuppression exposure, specifically tacrolimus, is associated with poor allograft outcomes. Wide intra-patient variability of tacrolimus trough concentrations (Vtac) is likely, in part, attributable to regimen complexity and poor medication adherence. Once-daily tacrolimus formulations create opportunity to simplify therapeutic regimens, and this study aims to evaluate their impact on Vtac and ultimately transplant outcomes. METHODS: This retrospective cohort study investigated stable (AYA) renal transplant recipients converted from (IR-Tac) to (ER-Tac). Subjects served as their own controls. Vtac was assessed by measuring the (SD) of serial tacrolimus trough concentrations prior to and at four time points post-conversion to ER-Tac over 24-month follow-up. Secondary outcome measures included graft function, infection rates, and effect on modifiable treatment-related factors. RESULTS: Twenty-eight AYA subjects were converted from IR-Tac to ER-Tac. Vtac significantly improved following conversion and was sustained for 24 months (Vtac0 2.32 vs. Vtac24 1.11, p .017). Renal function remained stable, and (BPAR) rates were modest (14%). Mean pill burden was reduced by 15%, and 42.9% of subjects achieved a once-daily medication regimen. CONCLUSIONS: Conversion from IR-Tac to ER-Tac in this AYA population significantly improved Vtac with sustained effect over 2 years. This effect is likely attributable in part to simplification of the medication regimen and presumably improved medication adherence. Such conversion does not appear to compromise graft function for at least 2 years post-conversion.

Caregiver burden in pediatric dialysis: application of the Paediatric Renal Caregiver Burden Scale.

BACKGROUND: Caring for a child with kidney failure on dialysis profoundly impacts caregivers' lives, yet the depth of this burden is not well understood. The Paediatric Renal Caregiver Burden Scale (PR-CBS) is a recently validated instrument used to measure caregiver burden in this population. METHODS: We performed a cross-sectional study of caregiver burden for caregivers of children with kidney failure receiving dialysis at three pediatric centers. Caregivers completed the PR-CBS instrument as part of a larger qualitative study of caregiver experience. We performed descriptive statistics. T-tests were used to examine differences between dialysis modality and within key demographics. Multivariate linear regression was utilized to assess associations between significant factors and total score. RESULTS: Ten caregivers of children receiving peritoneal dialysis (PD) and 21 receiving hemodialysis (HD) participated. Total burden score and mean score for every domain was higher for caregivers of children on HD compared to PD. PR-CBS score was significantly associated with younger child age and married status in caregivers. In adjusted multivariate analysis, dialysis modality and married marital status were significantly associated with PR-CBS score. CONCLUSIONS: This study found that dialysis caregivers experience significant caregiver burden and demonstrates the utility of the PR-CBS in an American population. We found higher burdens among HD caregivers, younger children, and married caregivers. While these findings must be replicated on a larger scale, they suggest possible areas for targeted interventions to improve the quality of life of children with kidney failure and their families. A higher resolution version of the Graphical abstract is available as Supplementary information.

Implications of the 2017 AAP Clinical Practice Guidelines for Management of Hypertension in Children and Adolescents: a Review.

PURPOSE OF REVIEW: To evaluate the impact of the 2017 American Academy of Pediatrics Clinical Practice Guideline (2017 AAP CPG) for Screening and Management of High Blood Pressure in Children and Adolescents. RECENT FINDINGS: The 2017 AAP CPG had several significant changes compared to the 2004 Fourth Report. This review will focus on the emerging evidence from the first studies to apply the 2017 AAP CPG and the simplified table it contains on the overall prevalence of HTN and on recognition among children and adolescents at a higher cardiovascular risk. Recent evidence suggests that use of the 2017 AAP CPG will result in an overall increase in prevalence of HTN, particularly in youth who are obese or who have other cardiovascular risk factors. The change in prevalence likely differs based on sex, age, and height. The ability for the 2017 AAP CPG to detect an association with hypertension and target organ damage requires further study. Continued study is required to assess long-term implications of the 2017 AAP CPG with the goal of a more meaningful HTN definition in the young.

Hypertension in Pediatric Acute Lymphoblastic Leukemia Patients: Prevalence, Impact, and Management Strategies.

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children under the age of 18. While modern diagnostic technologies, risk-stratification, and therapy intensification have led to outstanding outcomes for many children with ALL, the side effects and consequences of therapy are not to be underestimated. Hypertension is a well-known acute and chronic side effect of treatment for childhood ALL, although limited data are available regarding the prevalence of hypertension in children undergoing treatment for ALL. In this review of hypertension in pediatric ALL patients, we examine the existing data on incidence and prevalence during treatment and in pediatric ALL survivors. We describe independent risk factors for development of hypertension along with treatment-related causes. Long-term consequences and the risk to survivors of pediatric ALL are further defined. While many ALL patients require antihypertensive medications during some portion of their treatment, there are no clear guidelines on treating inpatient hypertension given challenges that exist in recognizing and managing hypertension in this setting and in this population. Here, we propose an algorithmic approach to diagnose and treat pediatric ALL patients with HTN, along with monitoring and continuation versus cessation of antihypertensive therapy as an outpatient.

Management and Associated Toxicokinetics of Massive Valproic Acid Ingestion with High Flow Continuous Venovenous Hemodiafiltration.

INTRODUCTION: Valproic acid (VPA) toxicity commonly results in a self-limited state of CNS depression that is managed with supportive care and levocarnitine. In massive overdose, patients can develop toxic encephalopathy, shock, multisystem organ failure, and death. We present a case with relevant toxicokinetics of a patient presenting with a profoundly elevated VPA concentration resulting in survival, treated with supportive care including high-dose continuous venovenous hemodiafiltration (CVVHDF). CASE REPORT: A 17-year-old female presented to an emergency department after being found unresponsive at home with concern for massive VPA ingestion. She arrived obtunded and hypotensive with initial VPA concentration of 2226 mg/L, estimated 9 h post-ingestion. Her early hospital course was marked by hypotension requiring multiple vasopressors, and her workup was notable for multiple severe metabolic derangements. High-dose CVVHDF was initiated upon transfer to a tertiary children's hospital with the aim to enhance VPA removal and normalize metabolic derangements. At that time, her VPA concentration was 1071 mg/L. Apparent half-life of VPA improved modestly with extracorporeal treatment, but her metabolic derangements and hemodynamic instability corrected rapidly. Her clinical course was complicated by necrotizing pancreatitis, pancytopenia requiring transfusions of multiple cell lines, coma, and seizures. She ultimately recovered with normal neurological function.

White Tongue Because of Uremic Stomatitis as a Sign of Advanced Kidney Disease.

We present a case of a previously healthy adolescent male who initially presented to his primary care physician with the chief complaint of a "large and white tongue," who subsequently was diagnosed with end-stage kidney disease (ESKD) and associated uremic stomatitis. This patient required admission to a PICU for acute renal replacement therapy with intermittent hemodialysis, and his hospital course was complicated by generalized tonic-clonic seizures. ESKD is difficult to diagnose in the pediatric population because these patients are often asymptomatic in the early stages given the insidiousness of underlying disorders. Renal disease should be considered in the differential diagnosis of a child with a white tongue not being the result of oral candidiasis.