The Barriers Assessment Tool-A Patient-Centered Measure of Adherence Barriers in Pediatric Kidney Transplantation.

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.

Tacrolimus pharmacokinetics are influenced by CYP3A5, age, and concomitant fluconazole in pediatric kidney transplant patients.

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.

Carfilzomib-based antibody mediated rejection therapy in pediatric kidney transplant recipients.

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.

COVID-19 in pediatric kidney transplantation: a follow-up report of the Improving Renal Outcomes Collaborative.

BACKGROUND: We report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC). METHODS: Patient-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. RESULTS: From 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. CONCLUSIONS: Despite 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 < 1% of COVID-19-positive patients and in less than < 0.1% of all transplant patients within the IROC cohort. A higher resolution version of the Graphical abstract is available as Supplementary information.

The learning health system for pediatric nephrology: building better systems to improve health.

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.

Impact of the COVID-19 pandemic on the kidney community: lessons learned and future directions.

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected patients with kidney disease, causing significant challenges in disease management, kidney research and trainee education. For patients, increased infection risk and disease severity, often complicated by acute kidney injury, have contributed to high mortality. Clinicians were faced with high clinical demands, resource shortages and novel ethical dilemmas in providing patient care. In this review, we address the impact of COVID-19 on the entire spectrum of kidney care, including acute kidney injury, chronic kidney disease, dialysis and transplantation, trainee education, disparities in health care, changes in health care policies, moral distress and the patient perspective. Based on current evidence, we provide a framework for the management and support of patients with kidney disease, infection mitigation strategies, resource allocation and support systems for the nephrology workforce.

A Cost-effectiveness Analysis of Adherence Promotion Strategies to Improve Rejection Rates in Adolescent Kidney Transplant Recipients.

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.

Hypervitaminosis A in Pediatric Patients With Advanced Chronic Kidney Disease.

OBJECTIVE: Hypervitaminosis A is well-described but overlooked in chronic kidney disease (CKD) and has been associated with hypercalcemia, contributing to mineral bone disease. Our objective is to assess prevalence of hypervitaminosis A and its association with bone health in an advanced-CKD population. METHODS: We performed a retrospective review of 58 children with CKD 4-5 to examine the association between vitamin A levels and bone health and compared these values between a primarily formula-fed (FF) and nonprimarily formula-fed cohort (NFF). RESULTS: Fifty-six of 58 patients (97%) had hypervitaminosis A with a mean vitamin A level of 1,475 ± 597 mcg/dL. When compared with the upper limit of normal vitamin A level for age, the FF group's vitamin A level was 2.9x upper limit of normal and the NFF group's vitamin A level was 2.2x upper limit of normal (P = .02). The mean calcium level was 10.3 mg/dL in the FF group and 9.8 mg/dL in the NFF group (P = .057). Percent of patients lower than, within, or greater than goal parathyroid hormone range was statistically significant with 15 (62%) of the FF group lower than goal and 16 (72%) of the NFF cohort greater than goal (P = .006). CONCLUSIONS: We concluded vitamin A and calcium levels are higher in the FF versus the NFF population. FF patients are more likely to have parathyroid hormone levels lower than the goal range, placing them at risk for adynamic bone disease. We recommend monitoring vitamin A levels as part of routine nutritional assessments and dietary interventions to prevent hypervitaminosis A to improve bone health in late CKD.

A Medication Adherence Promotion System to Reduce Late Kidney Allograft Rejection: A Quality Improvement Study.

RATIONALE & OBJECTIVE: Adolescent and young adult kidney transplant recipients have a high risk of rejection related to suboptimal adherence. Multicomponent interventions improve adherence in controlled trials, but clinical implementation is lacking. We describe an initiative to reduce allograft rejection using evidence-based adherence promotion strategies. STUDY DESIGN: Interrupted time series. SETTING & PARTICIPANTS: Kidney transplant recipients cared for at Cincinnati Children's Hospital ≥ 1 year after transplant and taking ≥1 immunosuppressive medication(s) from 2014 through 2017. QUALITY IMPROVEMENT ACTIVITIES: The following interventions, collectively called MAPS (Medication Adherence Promotion System), were implemented over 14 months: (1) adherence promotion training for clinical staff, 2) electronic health record-supported adherence risk screening, (3) systematic assessment of medication adherence barriers, (4) designation of specific staff to address adherence barriers, (5) shared decision-making with the patients to overcome adherence barriers, (6) follow-up evaluation to assess progress, and (7) optional electronic medication monitoring. OUTCOMES: Primary Outcome: Late acute rejection. Process measures were conducted to assess barriers, identify barriers, and perform interventions. The secondary outcomes/balancing measures were de novo donor-specific antibodies (DSA), biopsy rate, and rejections per biopsy. ANALYTICAL APPROACH: Time series analysis using statistical process control evaluated patient-days between acute rejections as well as monthly rejections per 100 patient-months before and after implementation. To control for known rejection risk factors including changes in treatment and case mix, multivariable analyses were performed. RESULTS: The monthly rejection rate fell from 1.61 rejections per 100 patient-months in the 26 months before implementation to 0.88 rejections per 100 patient-months in the 22 months after implementation. In the multivariable analysis, MAPS was associated with a 50% reduction in rejection incidence (incidence rate ratio, 0.50 [95% CI, 0.27-0.91]; P = 0.02). DSA and time since transplant (per each additional year) were also associated with rejection incidence (incidence rate ratio, 2.27 [P = 0.02] and 0.87 [P = 0.02], respectively). LIMITATIONS: Single-center study, and potential confounding by unmeasured variables. CONCLUSIONS: Clinical implementation of evidence-based adherence-promotion strategies was associated with a 50% reduction in acute rejection incidence over 2 years.

Primary hyperoxaluria diagnosed after kidney transplant: A review of the literature and case report of aggressive renal replacement therapy and lumasiran to prevent allograft loss.

Primary hyperoxaluria type 1 is a rare inherited disorder caused by abnormal liver glyoxalate metabolism leading to overproduction of oxalate, progressive kidney disease, and systemic oxalosis. While the disorder typically presents with nephrocalcinosis, recurrent nephrolithiasis, and/or early chronic kidney disease, the diagnosis is occasionally missed until it recurs after kidney transplant. Allograft outcomes in these cases are typically very poor, often with early graft loss. Here we present the case of a child diagnosed with primary hyperoxaluria type 1 after kidney transplant who was able to maintain kidney function, thanks to aggressive renal replacement therapy as well as initiation of a new targeted therapy for this disease. This case highlights the importance of having a high index of suspicion for primary hyperoxaluria in patients with chronic kidney disease and nephrocalcinosis/nephrolithiasis or with end stage kidney disease of uncertain etiology, as initiating therapies early on may prevent poor outcomes.

Predicting acute rejection in children, adolescents, and young adults with a kidney transplant by assessing barriers to taking medication.

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.

COVID-19 in pediatric kidney transplantation: The Improving Renal Outcomes Collaborative.

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.

Bleeding Complications after Pediatric Kidney Biopsy: A Systematic Review and Meta-Analysis.

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.

Predicting Health Care Utilization and Charges Using a Risk Score for Poor Adherence in Pediatric Kidney Transplant Recipients.

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.

Mycophenolate mofetil-related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs.

MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant.

Assessing barriers to adherence in routine clinical care for pediatric kidney transplant patients.

Patient-identified barriers to immunosuppressive medications are associated with poor adherence and negative clinical outcomes in transplant patients. Assessment of adherence barriers is not part of routine post-transplant care, and studies regarding implementing such a process in a reliable way are lacking. Using the Model for Improvement and PDSA cycles, we implemented a system to identify adherence barriers, including patient-centered design of a barriers assessment tool, identification of eligible patients, clear roles for clinic staff, and creating a culture of non-judgmental discussion around adherence. We performed time-series analysis of our process measure. Secondary analyses examined the endorsement and concordance of adherence barriers between patient-caregiver dyads. After three methods of testing, the most reliable delivery system was an EHR-integrated tablet that alerted staff of patient eligibility for assessment. Barriers were endorsed by 35% of caregivers (n=85) and 43% of patients (n=60). The most frequently patient-endorsed barriers were forgetting, poor taste, and side effects. Caregivers endorsed forgetting and side effects. Concordance between patient-caregiver dyads was fair (k=0.299). Standardized adherence barriers assessment is feasible in the clinical care of pediatric kidney transplant patients. Features necessary for success included automation, redundant systems with designated staff to identify and mitigate failures, aligned reporting structures, and reliable measurement approaches. Future studies will examine whether barriers predict clinical outcomes (eg, organ rejection, graft loss).

Primary cilia regulate the osmotic stress response of renal epithelial cells through TRPM3.

Primary cilia sense environmental conditions, including osmolality, but whether cilia participate in the osmotic response in renal epithelial cells is not known. The transient receptor potential (TRP) channels TRPV4 and TRPM3 are osmoresponsive. TRPV4 localizes to cilia in certain cell types, while renal subcellular localization of TRPM3 is not known. We hypothesized that primary cilia are required for maximal activation of the osmotic response of renal epithelial cells and that ciliary TRPM3 and TRPV4 mediate that response. Ciliated [murine epithelial cells from the renal inner medullary collecting duct (mIMCD-3) and 176-5] and nonciliated (176-5Δ) renal cells expressed Trpv4 and Trpm3 Ciliary expression of TRPM3 was observed in mIMCD-3 and 176-5 cells and in wild-type mouse kidney tissue. TRPV4 was identified in cilia and apical membrane of mIMCD-3 cells by electrophysiology and in the cell body by immunofluorescence. 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 induction was attenuated in nonciliated cells. A TRPV4 agonist abrogated Bgt1 and Akr1b3 induction in ciliated and nonciliated cells. A TRPM3 agonist attenuated Bgt1 and Akr1b3 induction in ciliated cells only. TRPM3 knockout attenuated Akr1b3 induction. Viability under osmotic stress was greater in ciliated than nonciliated cells. Akr1b3 induction was also less in nonciliated than ciliated cells when mannitol was used to induce hyperosmolal stress. These findings suggest that primary cilia are required for the maximal osmotic response in renal epithelial cells and that TRPM3 is involved in this mechanism. TRPV4 appears to modulate the osmotic response independent of cilia.