BK Polyomavirus Diversity After Hematopoietic Stem Cell Transplantation.

2023

04/2023

1537-6613

BK polyomavirus (BKPyV) infection is common after hematopoietic stem cell transplantation (HSCT) and is associated with the development of hemorrhagic cystitis (HC). The role that BKPyV plays in the pathogenesis of HC is not well characterized. We investigated the impact of BKPyV diversity on the development of HC using a previously established cohort of pediatric HSCT patients. There were 147 urine samples with quantifiable BKPyV at month 1 after HSCT; 137 (93.2%) were amplified using our in-house polymerase chain reaction approach and sent for next-generation sequencing. Subtype Ia was most frequent (61.3%), followed by subtype Ib1 (31.4%). The median viral load of subtype Ia samples was higher than for subtype Ib1 at month 1. Across the protein coding regions, APOBEC-induced mutations and signature patterns associated with HC were identified. This is the largest sequencing study of a single cohort of HSCT patients, providing a vast resource of sequence data for future analyses.

10.1093/infdis/jiad117

J Infect Dis

37165301

Hypertension in Wilms tumor.

2023

05/2023

1432-198X

Wilms tumor (WT) represents over 90% of all pediatric kidney tumors. Children with WT often present acutely with hypertension which resolves in the short term after nephrectomy. However, WT survivors have increased long-term risk of hypertension, primarily due to decreased nephron mass after nephrectomy, with additional insults from possible exposure to abdominal radiation and nephrotoxic therapies. The diagnosis of hypertension may be improved by ambulatory blood pressure monitoring (ABPM), as several recent single-center studies have shown a substantial proportion of WT survivors with masked hypertension. Current gaps in knowledge include determining which WT patients may benefit from routine screening with ABPM, correlation of casual and ABPM parameters with cardiac abnormalities, and longitudinal assessment of cardiovascular and kidney parameters in relation to appropriate treatment of hypertension. This review aims to summarize the most recent literature on hypertension presentation and management at the time of WT diagnosis as well as the long-term hypertension risk and impact on kidney and cardiovascular outcomes in WT survivors.

10.1007/s00467-023-06011-y

Pediatr Nephrol

37178208

Long-Term Kidney and Cardiovascular Complications in Pediatric Cancer Survivors.

2023

89-97.e1

04/2023

1097-6833

OBJECTIVE: The objective of this study was to describe the burden of adverse kidney and hypertension outcomes in patients evaluated by pediatric nephrology in a multidisciplinary survivorship clinic.

STUDY DESIGN: Retrospective chart review of all patients followed up by nephrology in our multidisciplinary survivorship clinic from August 2013 to June 2021. Data included clinic blood pressure, longitudinal ambulatory blood pressure monitoring (ABPM), echocardiography, serum creatinine, and first-morning urine protein/creatinine ratios. For patients with multiple ABPMs, results of initial and most recent ABPMs were compared.

RESULTS: Of 422 patients followed in the multidisciplinary cancer survivorship clinic, 130 were seen by nephrology. The median time after therapy completion to first nephrology visit was 8 years. The most common diagnoses were leukemia/myelodysplastic syndrome (27%), neuroblastoma (24%), and Wilms tumor (15%). At the last follow-up, 68% had impaired kidney function, 38% had a clinical diagnosis of hypertension, and 12% had proteinuria. There were 91 ABPMs performed in 55 (42%) patients. Patients with multiple ABPMs (n = 21) had statistically significant reductions in overall median blood pressure loads: systolic initial load 37% vs most recent 10% (P = .005) and diastolic load 36% vs 14% (P = .017). Patients with impaired kidney function were more likely to have received ifosfamide. Patients with hypertension were more likely to have received total body irradiation or allogeneic stem cell transplant.

CONCLUSIONS: History of leukemia/myelodysplastic syndrome, neuroblastoma, and Wilms tumor was frequent among survivors seen by nephrology. There was significant improvement in cardiovascular measures with increased recognition of hypertension and subsequent treatment.

10.1016/j.jpeds.2022.10.029

J Pediatr

36336006

Predicting psychosocial risk in pediatric kidney transplantation: An exploratory cluster analysis of a revised Pediatric Transplant Rating Instrument.

2023

e14454

03/2023

1399-3046

BACKGROUND: The Pediatric Transplant Rating Instrument (P-TRI) is a 17-item scale developed to assess psychosocial risk factors for poor outcomes after solid organ transplantation. Research has identified the limitations of the original instrument and proposed revisions to improve clinical utility. This project examined patterns of risk in children being evaluated for kidney transplant using a revised P-TRI.

METHODS: A multidisciplinary kidney transplant team revised the P-TRI. A social worker and a psychologist collaboratively completed the modified instrument for 37 children after the psychosocial pretransplant evaluation. Electronic medical records were reviewed for transplant status (transplanted, active waitlist, inactive) 1 year later. Exploratory cluster analyses and chi-square tests examined patterns of risk and correlates with cluster membership.

RESULTS: Three clusters were identified. The high-risk group (29.7%) had difficulties with medication and appointment adherence, strained relationships with the medical team, and the presence of parent psychiatric history. The medium-risk group (35.1%) had difficulties with parent knowledge, financial strain, and risk factors for medication nonadherence. The low-risk group (35.1%) demonstrated no difficulties with adherence or financial strain. Clusters were prospectively associated with transplant status, such that those in the high-risk group were less likely to be transplanted within 1 year post-evaluation.

CONCLUSIONS: The revised P-TRI demonstrated good construct validity as risk level appeared to be associated with transplant listing status 1 year post-evaluation. These results suggest that standardized pretransplant psychosocial risk assessment tools may have value in optimizing transplant access if they can be paired with targeted, multidisciplinary interventions to address concerns early in the transplant process.

10.1111/petr.14454

Pediatr Transplant

36518059

Long-term kidney and cardiovascular complications in pediatric cancer survivors.

2022

11/2022

1097-6833

OBJECTIVE: To describe the burden of adverse kidney and cardiovascular outcomes in patients evaluated by pediatric nephrology in a multidisciplinary survivorship clinic.

STUDY DESIGN: Retrospective chart review of all patients followed by nephrology in our multidisciplinary survivorship clinic from 8/2013-6/2021. Data included clinic blood pressure (BP), longitudinal ambulatory blood pressure monitoring (ABPM), echocardiography, serum creatinine, and first-morning urine protein/creatinine ratios. For patients with multiple ABPMs, results of initial and most recent ABPMs were compared.

RESULTS: Of 422 patients followed in the multidisciplinary cancer survivorship clinic, 130 were seen by nephrology. Median time after therapy completion to first nephrology visit was 8 years. The most common diagnoses were leukemia/myelodysplastic syndrome (27%), neuroblastoma (24%), and Wilms tumor (15%). At last follow-up, 68% had impaired kidney function, 38% had a clinical diagnosis of hypertension, and 12% had proteinuria. There were 91 ABPMs performed in 55 (42%) patients. Patients with multiple ABPMs (n=21) had statistically significant reductions in overall median BP loads: systolic initial load 37% vs. most recent 10% (p=0.005) and diastolic load 36% vs. 14% (p=0.017). Patients with impaired kidney function were more likely to have received ifosfamide. Patients with hypertension were more likely to have received total body irradiation or allogeneic stem cell transplant.

CONCLUSIONS: History of leukemia/myelodysplastic syndrome, neuroblastoma, and Wilms tumor were frequent among survivors seen by nephrology. There was significant improvement in cardiovascular measures with increased recognition of hypertension and subsequent treatment.

10.1016/j.jpeds.2022.10.029

J Pediatr

36336006

Circulating endothelial cells and the study of vascular injury in children undergoing hematopoietic stem cell transplant.

2022

08/2022

1592-8721

10.3324/haematol.2022.280788

Haematologica

35979718

Late effects in survivors of high-risk neuroblastoma following stem cell transplant with and without total body irradiation.

2021

e29537

2021 Dec 31

1545-5017

<p><strong>BACKGROUND: </strong>Neuroblastoma is the most common extracranial solid tumor in children. Those with high-risk disease are treated with multimodal therapy, including high-dose chemotherapy, stem cell transplant, radiation, and immunotherapy that have led to multiple long-term complications in survivors. In the late 1990s, consolidation therapy involved myeloablative conditioning including total body irradiation (TBI) with autologous stem cell rescue. Recognizing the significant long-term toxicities of exposure to TBI, more contemporary treatment protocols have removed this from conditioning regimens. This study examines an expanded cohort of 48 high-risk neuroblastoma patients to identify differences in the late effect profiles for those treated with TBI and those treated without TBI.</p>

<p><strong>PROCEDURE: </strong>Data on the study cohort were collected from clinic charts, provider documentation in the electronic medical record of visits to survivorship clinic, including all subspecialists, and ancillary reports of laboratory and diagnostic tests done as part of risk-based screening at each visit.</p>

<p><strong>RESULTS: </strong>All 48 survivors of BMT for high-risk neuroblastoma had numerous late effects of therapy, with 73% having between five and 10 late effects. TBI impacted some late effects significantly, including growth hormone deficiency (GHD), bone outcomes, and cataracts.</p>

<p><strong>CONCLUSION: </strong>Although high-risk neuroblastoma survivors treated with TBI have significant late effects, those treated without TBI also continue to have significant morbidity related to high-dose chemotherapy and local radiation. A multidisciplinary care team assists in providing comprehensive care to those survivors who are at highest risk for significant late effects.</p>

10.1002/pbc.29537

Pediatr Blood Cancer

34971017

Acute Kidney Injury Associated with Late-Onset Neonatal Sepsis: A Matched Cohort Study.

2020

2020 Dec 16

1097-6833

<p><strong>OBJECTIVES: </strong>To determine incidence and severity of acute kidney injury (AKI) within 7 days of sepsis evaluation and to assess AKI duration and the association between AKI and 30-day mortality.</p>

<p><strong>STUDY DESIGN: </strong>Retrospective, matched cohort study in a single-center level IV NICU. Eligible infants underwent sepsis evaluations at ≥72 hours of age during calendar years 2013-2018. Exposed infants ("cases") were those with culture-proven sepsis and antimicrobial duration ≥5 days. Non-exposed infants ("controls") were matched 1:1 to exposed infants based on gestational and corrected gestational age, and had negative sepsis evaluations with antibiotic durations &lt;48 hours. AKI was defined by modified neonatal Kidney Disease Improving Global Outcomes criteria. Statistical analysis included Mann-Whitney and Chi-square tests, multivariable logistic regression, and Kaplan-Meier time-to-event analysis.</p>

<p><strong>RESULTS: </strong>Among 203 episodes of late-onset sepsis, 40 (20%) developed AKI within 7 days following evaluation, and among 193 episodes with negative cultures, 16 (8%) resulted in AKI (p=0.001). Episodes of sepsis also led to greater AKI severity, compared with non-septic episodes (P = .007). The timing of AKI onset and AKI duration did not differ between groups. Sepsis was associated with increased odds of developing AKI (aOR 3.0, 95% CI 1.5-6.2, p=0.002). AKI was associated with increased 30-day mortality (aOR 4.5, 95% CI 1.3-15.6, p=0.017).</p>

<p><strong>CONCLUSIONS: </strong>Infants with late-onset sepsis had increased odds of AKI and greater AKI severity within 7 days of sepsis evaluation, compared with age-matched infants without sepsis. AKI was independently associated with increased 30-day mortality. Strategies to mitigate AKI in critically ill neonates with sepsis may improve outcomes.</p>

10.1016/j.jpeds.2020.12.023

J Pediatr

33340552

Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.

2020

6051-6063

2020 12 08

2473-9537

<p>Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P &lt; .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.</p>

10.1182/bloodadvances.2020003471

Blood Adv

33290544

Acute kidney injury in children after hematopoietic cell transplantation is associated with elevated urine CXCL10 and CXCL9.

2020

2020 Mar 09

1523-6536

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Acute kidney injury (AKI) is nearly universally associated with worse outcomes, especially among children after hematopoietic stem cell transplant (HCT). Our objective was to examine urinary immune biomarkers of AKI after HCT to provide insights into novel mechanisms of kidney injury in this population. Studying patients undergoing allogeneic (HCT) provides a unique opportunity to examine immune markers of AKI because the risk of AKI is high and the immune system newly develops after transplant.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS: </strong>Children (&gt;2 years old) and young adults undergoing their first allogeneic HCT and enrolled in a prospective, observational cohort study at two large children's hospitals had urine collected pre-HCT and monthly for the first 4 months after HCT. Urine samples at each monthly time point were assayed for 8 immune-related biomarkers. AKI was defined as a 1.5-fold increase in the monthly serum creatinine value which was recorded ±1 day from when the research urine sample was obtained, as compared to the pre-HCT baseline. Generalized estimating equation regression analysis evaluated the association between the monthly repeated measures (urinary biomarkers and AKI).</p>

<p><strong>RESULTS: </strong>A total of 176 patients were included from two pediatric centers. Thirty-six subjects from one center were analyzed as a discovery cohort and the remaining 140 subjects from the second center were analyzed as a validation cohort. AKI rates were 18-35% depending on the monthly time point after HCT. Urine CXCL10 and CXCL9 concentrations were significantly higher among children who developed AKI compared with children who did not (p&lt;0.01) in both cohorts. In order to gain a better understanding of the cellular source for these biomarkers in the urine, we also analyzed in vitro expression of CXCL10 and CXCL9 in kidney cell lines after stimulation with interferon-gamma and interferon-alpha. HEK293-epithelial kidney cells demonstrated interferon-induced expression of CXCL10 and CXCL9, suggesting a potential mechanism driving the key finding.</p>

<p><strong>CONCLUSIONS: </strong>CXCL10 and CXCL9 are associated with AKI after HCT and are therefore promising biomarkers to guide improved diagnostic and treatment strategies for AKI in this high-risk population.</p>

10.1016/j.bbmt.2020.02.024

Biol. Blood Marrow Transplant.

32165324