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BackgroundWe report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC).MethodsPatient-level data from the IROC registry were combined with testing, indication, and outcomes data collected to describe the epidemiology of COVID testing, treatment, and clinical outcomes; determine the incidence of a positive COVID-19 test; describe rates of COVID-19 testing; and assess for clinical predictors of a positive COVID-19 test.ResultsFrom September 2020 to February 2021, 21 centers that care for 2690 patients submitted data from 648 COVID-19 tests on 465 patients. Most patients required supportive care only and were treated as outpatients, 16% experienced inpatient care, and 5% experienced intensive care. Allograft complications were rare, with acute kidney injury most common (7%). There was 1 case of respiratory failure and 1 death attributed to COVID-19. Twelve centers that care for 1730 patients submitted complete testing data on 351 patients. The incidence of COVID-19 among patients at these centers was 4%, whereas the incidence among tested patients was 19%. Risk factors to predict a positive COVID-19 test included age > 12 years, symptoms consistent with COVID-19, and close contact with a confirmed case of COVID-19.ConclusionsDespite the increase in testing and positive tests over this study period, the incidence of allograft loss or death related to COVID-19 remained extremely low, with allograft loss or death each occurring in

Learning health systems (LHS) align science, informatics, incentives, and culture for continuous improvement and innovation. In this organizational system, best practices are seamlessly embedded in the delivery process, and new knowledge is captured as an integral byproduct of the care delivery experience aimed to transform clinical practice and improve patient outcomes. The objective of this review is to describe how building better health systems that integrate clinical care, improvement, and research as part of an LHS can improve care within pediatric nephrology. This review will provide real-world examples of how this system can be established in a single center and across multiple centers as learning health networks., Author(s): Charles D. Jr Varnell [sup.1] [sup.2] [sup.3] , Peter Margolis [sup.1] [sup.3] , Jens Goebel [sup.4] [sup.5] , David K. Hooper [sup.1] [sup.2] [sup.3] Author Affiliations: (1) grid.24827.3b, 0000 [...]

Background Nonadherence to immunosuppression is common among pediatric, adolescent, and young adult kidney transplant recipients and a leading cause of graft loss. Assessing barriers to medication adherence in clinical practice may identify patients at risk for rejection and provide therapeutic targets. Methods Kidney transplant patients and/or their caregivers were assessed for 14 barriers to medication adherence using the barriers assessment tool. We compared rejection rates between patients with at least one reported adherence barrier to those without reported adherence barriers using a Kaplan-Meier estimator and Cox proportional hazard models to adjust for other mediators of acute rejection at 2 years following barriers assessment. Results Ninety-eight patients were assessed for barriers to adherence. Over the 2-year observation period, 22 patients developed biopsy-proven acute rejection (BPAR). Kaplan-Meier estimates show that patients with an identified barrier to adherence were more likely to have BPAR (p = 0.02) than patients without an identified barrier in the 24 months following barriers assessment. The median time to rejection for patients who experienced acute rejection was 175.5 days (IQR 63-276 days) from the time of barriers assessment. An identified barrier to adherence remained the only statistically significant predictor of BPAR with Cox modeling (HR 2.6, p = 0.04), after accounting for age, sex, and race. Conclusions Pediatric and adolescent kidney transplant recipients with identified adherence barriers are at increased risk for acute rejection. Barriers to adherence provide a potentially modifiable therapeutic target that can be assessed in clinic to guide targeted interventions., Author(s): Charles D. Jr Varnell [sup.1] [sup.2] [sup.3] , Kristin L. Rich [sup.3] [sup.4] , Bin Zhang [sup.3] [sup.5] , Adam C. Carle [sup.2] [sup.6] , Ahna L. H. Pai [...]

Background: To date, the evidence for proteasome‐inhibitor (PI) based antibody mediated rejection (AMR) therapy has been with the first‐generation PI bortezomib. Results have demonstrated encouraging efficacy for early AMR with lesser efficacy for late AMR. Unfortunately, bortezomib is associated with dose‐limiting adverse effects in some patients. We report use of the second generation proteosome inhibitor carfilzomib for AMR treatment in two pediatric patients with a kidney transplant. Methods: The clinical data on two patients who experienced dose limiting toxicities from bortezomib were collected along with their short‐ and long‐term outcomes. Results: A two‐year‐old female with simultaneous AMR, multiple de novo DSAs (DR53 MFI 3900, DQ9 MFI 6600, DR15 2200, DR51 MFI 1900) and T‐cell mediated rejection (TCMR) completed three carfilzomib cycles and experienced stage 1 acute kidney injury after the first two cycles. At 1 year follow up, all DSAs resolved, and her kidney function returned to baseline without recurrence. A 17‐year‐old female also developed AMR with multiple de novo DSAs (DQ5 MFI 9900, DQ6 MFI 9800, DQA*01 MFI 9900). She completed two carfilzomib cycles, which were associated with acute kidney injury. She had resolution of rejection on biopsy and decreased but persistent DSAs on follow‐up. Conclusions: Carfilzomib treatment for bortezomib‐refractory rejection and/or bortezomib toxicity may provide DSA elimination or reduction, but also appears to be associated with nephrotoxicity. Clinical development of carfilzomib for AMR will require a better understanding of efficacy and development of approaches to mitigate nephrotoxicity. [ABSTRACT FROM AUTHOR]

Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. CYP3A5 intermediate and normal metabolizers (*1 allele carriers; IM/NM) demonstrate faster tacrolimus metabolism than poor metabolizers (PM). We analyzed the electronic health records of 93 patients aged <21 years for the first 8 weeks after a kidney transplant between January 2010 and December 2021. The target tacrolimus trough was 10–15 ng/mL in the first 4 weeks and 7–10 ng/mL in the next 4 weeks. Banked DNA was collected and genotyped for CYP3A5*3, *6, *7, and *8 alleles. We found that CYP3A5 IM/NM (n = 21) took longer than PM (n = 72) to reach the therapeutic range (7 vs. 4 days, p = 0.048). IM/NM had more dose adjustments (8 vs. 6, p = 0.025) and needed >150% of the required daily dose compared with PM. The concentration/dose ratio was influenced by age and concomitant fluconazole (p = 0.0003, p = 0.034, respectively) and the average daily dose decreases with age in CYP3A5 PM (p = 0.001). Tremors were more common in patients who ever had a trough concentration >15 ng/mL compared with those who never had a trough concentration >15 ng/mL (OR 3.31, 95% CI 1.03–8.98, p = 0.038). Using standard dosing, CYP3A5 IM/NM took longer to reach the goal range and require more dose adjustments and higher doses than PM. Preemptive genotyping could decrease the number of dose changes necessary to reach a therapeutic dose. We have implemented pre‐transplant CYP3A5 testing at our institution. [ABSTRACT FROM AUTHOR]

Pri-mary cilia sense environmental conditions, including osmolality, butwhether cilia participate in the osmotic response in renal epithelialcells is not known. The transient receptor potential (TRP) channelsTRPV4 and TRPM3 are osmoresponsive. TRPV4 localizes to cilia incertain cell types, while renal subcellular localization of TRPM3 is notknown. We hypothesized that primary cilia are required for maximalactivation of the osmotic response of renal epithelial cells and thatciliary TRPM3 and TRPV4 mediate that response. Ciliated [murineepithelial cells from the renal inner medullary collecting duct(mIMCD-3) and 176-5] and nonciliated (176-5Δ) renal cells ex-pressedTrpv4andTrpm3. Ciliary expression of TRPM3 was observedin mIMCD-3 and 176-5 cells and in wild-type mouse kidney tissue.TRPV4 was identified in cilia and apical membrane of mIMCD-3cells by electrophysiology and in the cell body by immunofluores-cence. Hyperosmolal stress at 500 mOsm/kg (via NaCl addition)induced the osmotic response genes betaine/GABA transporter (Bgt1)and aldose reductase (Akr1b3) in all ciliated cell lines. This inductionwas attenuated in nonciliated cells. A TRPV4 agonist abrogatedBgt1andAkr1b3induction in ciliated and nonciliated cells. A TRPM3agonist attenuatedBgt1andAkr1b3induction in ciliated cells only.TRPM3 knockout attenuatedAkr1b3induction. Viability under os-motic stress was greater in ciliated than nonciliated cells.Akr1b3induction was also less in nonciliated than ciliated cells when man-nitol was used to induce hyperosmolal stress. These findings suggestthat primary cilia are required for the maximal osmotic response inrenal epithelial cells and that TRPM3 is involved in this mechanism.TRPV4 appears to modulate the osmotic response independent ofcilia. [ABSTRACT FROM AUTHOR]

Abstract: Catatonia is a distinct neuropsychiatric syndrome with prominent motor manifestations. Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic syndrome usually precipitated by malignant hypertension. Given the overlapping neuropathology in both syndromes, we present a case of catatonia precipitated by PRES, with full resolution of the former after successful treatment of the latter. [Copyright &y& Elsevier]

Background: Abnormal serum magnesium (Mg) concentrations are common and associated with worse mortality in kidney-transplant recipients. Many kidney and transplant-related factors affect Mg homeostasis. The concentration of the active form, ionized Mg (iMg), is not measured clinically, and total Mg (tMg) and iMg correlations have conflicted. We hypothesized that iMg and tMg concentrations show poor categorical agreement (i.e., low, normal, and high) in kidney-transplant recipients but that ionized calcium (iCa) correlates with iMg., Methods: We retrospectively evaluated hypomagnesemia in kidney-transplant recipients over a 2-yr period. We prospectively collected blood at 0-28 days post-transplant to measure correlations between iMg and iCa/tMg. iMg and iCa concentrations in the reference ranges of 0.44-0.65 and 1.0-1.3 mmol/L, respectively, were considered normal. Fisher's exact test and unweighted kappa statistics revealed category agreements. Pearson's correlation coefficients and linear regression measured correlations., Results: Among 58 retrospective kidney-transplant recipients, 54 (93%) had tMg<0.66 mmol/L, 28/58 (48%) received Mg supplementation, and 20/28 (71%) had tacrolimus dose adjustments during supplementation. In 13 prospective transplant recipients (N=43 samples), iMg and tMg showed strong category agreement ( P =0.0003) and correlation (r=0.71, P <0.001), whereas iMg and iCa did not ( P =0.7; r=-0.25, P =0.103, respectively)., Conclusions: tMg and iMg exhibited strong correlation following kidney transplantation. However, iCa may not be an accurate surrogate for iMg. Determining the effect of Mg supplementation and the Mg concentration where supplementation is clinically necessary are important next steps.

Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. CYP3A5 intermediate and normal metabolizers (*1 allele carriers; IM/NM) demonstrate faster tacrolimus metabolism than poor metabolizers (PM). We analyzed the electronic health records of 93 patients aged <21 years for the first 8 weeks after a kidney transplant between January 2010 and December 2021. The target tacrolimus trough was 10-15 ng/mL in the first 4 weeks and 7-10 ng/mL in the next 4 weeks. Banked DNA was collected and genotyped for CYP3A5*3, *6, *7, and *8 alleles. We found that CYP3A5 IM/NM (n = 21) took longer than PM (n = 72) to reach the therapeutic range (7 vs. 4 days, p = 0.048). IM/NM had more dose adjustments (8 vs. 6, p = 0.025) and needed >150% of the required daily dose compared with PM. The concentration/dose ratio was influenced by age and concomitant fluconazole (p = 0.0003, p = 0.034, respectively) and the average daily dose decreases with age in CYP3A5 PM (p = 0.001). Tremors were more common in patients who ever had a trough concentration >15 ng/mL compared with those who never had a trough concentration >15 ng/mL (OR 3.31, 95% CI 1.03-8.98, p = 0.038). Using standard dosing, CYP3A5 IM/NM took longer to reach the goal range and require more dose adjustments and higher doses than PM. Preemptive genotyping could decrease the number of dose changes necessary to reach a therapeutic dose. We have implemented pre-transplant CYP3A5 testing at our institution., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Assessing barriers to adherence provides helpful information to clinicians. The objective of this study was to describe the clinical utility of the Barriers Assessment Tool (BAT) using clinical data for a large, midwestern U.S. pediatric kidney transplant program., Methods: Focus group and clinical data were obtained during post-transplant medical visits. Qualitative and quantitative assessment methods were utilized to describe patient and caregiver feedback on the BAT, clinical utility, concordance between reporters, and the effect of interventions on subsequent assessment and electronically measured adherence., Results: Patients were willing to discuss adherence issues with their care team. There was substantial agreement between patients and caregivers at two timepoints. If a barrier was not addressed, 89.6% (43/48) of patients and 85.9% (67/78) of caregivers reported the same BAT scores from the first to second assessment. When barriers were addressed with a clinic-based intervention, 82% of caregivers reported no adherence barriers. No significant change was found for patient-reported barriers., Conclusions: Standardized assessment of barriers to medication adherence provides actionable information to clinicians. Standardized assessment of adherence barriers may give clinicians opportunities to help patients and caregivers overcome these barriers which can decrease risk of rejection.

Rationale & Objective: Nonadherence to medical regimens increases the risk of graft loss among adolescent and young adult recipients of kidney transplants. Interventions that improve adherence may decrease rejection rates, but their perceived costs are a barrier to clinical implementation. We developed a model to assess the cost-effectiveness of an adherence promotion strategy, the Medication Adherence Promotion System (MAPS)., Study Design: Simulation-based. Data sources included published articles indexed in Medline or referenced in bibliographies of relevant English-language articles. Data on costs and outcomes were taken from a single clinical center., Setting & Population: US adolescent patients after their first kidney transplant., Intervention: Usual posttransplant care versus usual care plus MAPS., Outcome: Effectiveness measured in quality-adjusted life years (QALYs) and costs measured in 2020 US dollars., Model, Perspective, & Timeframe: Markov state transition decision model. We used a health care system perspective with a lifelong time horizon., Results: In the base-case analysis, MAPS was more effective and less costly than usual care. MAPS cost $9,106 per patient less than usual care and resulted in a gain of 0.32 QALYs. In probabilistic sensitivity analyses, MAPS was cost saving 100% of the time. Extending results to a program level with 100 patients, any adherence promotion intervention similar in effectiveness to MAPS would cost less than $50,000/QALY if the start-up costs were <$2.5 million and annual costs <$188,000. Strategies with costs similar to MAPS that reduce the risk of rejection by as little as 3% would also have similar cost-effectiveness., Limitations: Estimates of components and costs for MAPS were based on a single center., Conclusions: Adherence promotion strategies with costs similar to MAPS can be cost-effective as long as they reduce rejection rates by at least 3%. This model can be applied to study the cost-effectiveness of adherence promotion strategies with varying costs and outcomes., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

There are limited data on the impact of COVID-19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID-19 in pediatric KT patients. Twenty-two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS-CoV-2 by PCR. Testing indications included symptoms and/or potential exposures to COVID-19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID-19-positive patients, 16 were managed as outpatients, six received non-ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID-19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID-19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID-19 disease and excellent short-term outcomes., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background and Objectives: Kidney biopsy is an essential tool for the diagnosis and treatment of patients with kidney disease; however, because of its invasive nature, bleeding complications may arise., Design, Setting, Participants, & Measurements: We performed a meta-analysis of prospective or retrospective observational studies and randomized, controlled trials in pediatric patients undergoing native or transplant kidney biopsy in an inpatient or outpatient setting in MEDLINE-indexed studies from January 1998 to November 1, 2017 to determine the proportion of patients who develop hematoma, need blood transfusion, or need an additional intervention due to a complication after kidney biopsy., Results: Twenty-three studies of 5504 biopsies met inclusion criteria. The proportion of patients developing hematoma after biopsy was between 11% (95% confidence interval, 7% to 17%) and 18% (95% confidence interval, 9% to 35%) using two analyses that included different time periods. The proportion needing blood transfusion was 0.9% (95% confidence interval, 0.5% to 1.4%). The proportion needing an additional intervention due to postbiopsy complication was 0.7% (95% confidence interval, 0.4% to 1.1%). Secondary analysis was not possible due to lack of data in the original manuscripts on laboratory values, needle gauges, number of needle passes, age of patient, or performer (attending versus trainee). Analysis with metaregression found that use of real-time ultrasound during biopsy did not modify the risk for hematoma, requirement of a blood products transfusion, or requirement of an additional procedure after biopsy. Analysis with metaregression comparing native biopsies with transplant biopsies did not reveal that biopsy type (native kidney biopsy versus transplant kidney biopsy) was associated with the need for a blood transfusion or requirement of an additional intervention after biopsy., Conclusions: The development of perinephric hematoma after kidney biopsy is not an infrequent finding. The proportion of patients requiring blood transfusion or needing an additional intervention as a result of kidney biopsy in pediatric patients is significantly smaller., (Copyright © 2019 by the American Society of Nephrology.)

Pediatric kidney transplant recipients must follow a complicated regimen of timely adherence to immunosuppressant medication, routine blood work, and medical follow-up visits. Failure to adhere to the recommended regimen can result in medical complications and costly treatment. We developed a novel risk score to identify patients at risk for poor adherence behaviors and evaluated whether it would predict future health care utilization and charges. Our risk stratification score combined three simple pass/fail metrics of adherence derived directly from the electronic health record including standard deviation of immunosuppression drug levels, timely laboratory monitoring, and timely clinic visits as indicated by our clinical protocol. Risk for poor adherence was assessed over a three-month period. Linear regression was used to predict subsequent health care charges and utilization. Greater than 75% of patients had some degree of nonadherence risk during the study period, but there were no significant differences found on any outcomes for the overall score. However, when the individual components of the overall risk score were evaluated independently, patients with tacrolimus drug level standard deviation ≥2 (e.g., a marker of poor adherence) had greater health care utilization (e.g., hospitalizations) and increased total charges. Additionally, patients who did not follow up in clinic at least every 4 months had more ED visits and ED-related charges, but fewer hospitalizations. Regular clinic visits and minimizing drug level variation may deter future costly ED visits and hospitalizations.