First name
Benjamin
Middle name
L
Last name
Laskin

Title

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

Year of Publication

2022

Date Published

08/2022

ISSN Number

1592-8721

DOI

10.3324/haematol.2022.280788

Alternate Title

Haematologica

PMID

35979718

Title

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

Year of Publication

2020

Number of Pages

6051-6063

Date Published

2020 12 08

ISSN Number

2473-9537

Abstract

<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>

DOI

10.1182/bloodadvances.2020003471

Alternate Title

Blood Adv

PMID

33290544

Title

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

Year of Publication

2020

Date Published

2020 Mar 09

ISSN Number

1523-6536

Abstract

<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>

DOI

10.1016/j.bbmt.2020.02.024

Alternate Title

Biol. Blood Marrow Transplant.

PMID

32165324

Title

The natural history of BK polyomavirus and the host immune response after stem cell transplantation.

Year of Publication

2019

Date Published

2019 Dec 18

ISSN Number

1537-6591

Abstract

<p><strong>BACKGROUND: </strong>BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function.</p>

<p><strong>METHODS: </strong>In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at months 1-4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (eGFR) and overall survival for two years post-transplant. We examined factors associated with viral clearance by month 4 including BKPyV-specific T cells by enzyme-linked immune absorbent spot (ELISPOT) at month 3 and cidofovir use.</p>

<p><strong>RESULTS: </strong>We prospectively enrolled 193 participants (median age 10 years). 18% had viremia ≥10 000 copies/mL, and 45% had viruria ≥109 copies/mL in the first three months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR two years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1-4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and viremia &lt;10 000 copies/mL, but not cidofovir exposure.</p>

<p><strong>CONCLUSIONS: </strong>Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication.</p>

DOI

10.1093/cid/ciz1194

Alternate Title

Clin. Infect. Dis.

PMID

31851312

Title

Major Adverse Kidney Events in Pediatric Sepsis.

Year of Publication

2019

Date Published

2019 Apr 18

ISSN Number

1555-905X

Abstract

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Major adverse kidney events, a composite of death, new kidney replacement therapy, or persistent kidney dysfunction, is a potential patient-centered outcome for clinical trials in sepsis-associated kidney injury. We sought to determine the incidence of major adverse kidney events within 30 days and validate this end point in pediatric sepsis.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: </strong>We conducted a retrospective observational study using the Pediatric Health Information Systems Plus database of patients &gt;6 months to &lt;18 years old with a diagnosis of severe sepsis/septic shock; orders for bacterial blood culture, antibiotics, and at least one fluid bolus on hospital day 0/1; and known hospital disposition between January 2007 and December 2011. The primary outcome was incidence of major adverse kidney events within 30 days. Major adverse kidney events within 30 days were validated against all-cause mortality at hospital discharge, hospital length of stay, total hospital costs, hospital readmission within 30 days and 1 year, and lowest eGFR between 3 months and 1 year after discharge. We reported incidence of major adverse kidney events within 30 days with 95% confidence intervals using robust SEM and used multivariable logistic regression to test the association of major adverse kidney events within 30 days with hospital costs and mortality.</p>

<p><strong>RESULTS: </strong>Of 1685 admissions, incidence of major adverse kidney events within 30 days was 9.6% (95% confidence interval, 8.1% to 11.0%), including 4.5% (95% confidence interval, 3.5% to 5.4%) death, 1.7% (95% confidence interval, 1.1% to 2.3%) kidney replacement therapy, and 5.8% (95% confidence interval, 4.7% to 6.9%) persistent kidney dysfunction. Patients with versus without major adverse kidney events within 30 days had higher all-cause mortality at hospital discharge (28% versus 1%; &lt;0.001), higher total hospital costs ($61,188; interquartile range, $21,272-140,356 versus $28,107; interquartile range, $13,056-72,697; &lt;0.001), and higher proportion with eGFR&lt;60 ml/min per 1.73 m between 3 months and 1 year after discharge (19% versus 4%; =0.001). Major adverse kidney events within 30 days was not associated with length of stay or readmissions.</p>

<p><strong>CONCLUSIONS: </strong>In children with sepsis, major adverse kidney events within 30 days are common, feasible to measure, and a promising end point for future clinical trials.</p>

<p><strong>PODCAST: </strong>This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_04_18_CJASNPodcast_…;

DOI

10.2215/CJN.12201018

Alternate Title

Clin J Am Soc Nephrol

PMID

31000518

Title

The Cost of Vancomycin and Piperacillin/Tazobactam Treatment-Reply.

Year of Publication

2018

Date Published

2018 Mar 05

ISSN Number

2168-6211

DOI

10.1001/jamapediatrics.2018.0038

Alternate Title

JAMA Pediatr

PMID

29507935

Title

Association of Acute Kidney Injury With Concomitant Vancomycin and Piperacillin/Tazobactam Treatment Among Hospitalized Children.

Year of Publication

2017

Number of Pages

e173219

Date Published

2017 Oct 02

ISSN Number

2168-6211

Abstract

<p><strong>Importance: </strong>β-Lactam antibiotics are often coadministered with intravenous (IV) vancomycin hydrochloride for children with suspected serious infections. For adults, the combination of IV vancomycin plus piperacillin sodium/tazobactam sodium is associated with a higher risk of acute kidney injury (AKI) compared with vancomycin plus 1 other β-lactam antibiotic. However, few studies have evaluated the safety of this combination for children.</p>

<p><strong>Objective: </strong>To assess the risk of AKI in children during concomitant therapy with vancomycin and 1 antipseudomonal β-lactam antibiotic throughout the first week of hospitalization.</p>

<p><strong>Design, Setting, and Participants: </strong>This retrospective cohort study focused on children hospitalized for 3 or more days who received IV vancomycin plus 1 other antipseudomonal β-lactam combination therapy at 1 of 6 large children's hospitals from January 1, 2007, through December 31, 2012. The study used the Pediatric Health Information System Plus database, which contains administrative and laboratory data from 6 pediatric hospitals in the United States. Patients with underlying kidney disease or abnormal serum creatinine levels on hospital days 0 to 2 were among those excluded. Patients 6 months to 18 years of age who were admitted through the emergency department of the hospital were included. Data were collected from July 2015 to March 2016. Data analysis took place from April 2016 through July 2017. (Exact dates are not available because the data collection and analysis processes were iterative.).</p>

<p><strong>Main Outcomes and Measures: </strong>The primary outcome was AKI on hospital days 3 to 7 and within 2 days of receiving combination therapy. Acute kidney injury was defined using KDIGO criteria and was based on changes in serum creatinine level from hospital days 0 to 2 through hospital days 3 to 7. Multiple logistic regression was performed using a discrete-time failure model to test the association between AKI and receipt of IV vancomycin plus piperacillin/tazobactam or vancomycin plus 1 other antipseudomonal β-lactam antibiotic.</p>

<p><strong>Results: </strong>A total of 1915 hospitalized children who received combination therapy were identified. Of the 1915 patients, a total of 866 (45.2%) were female and 1049 (54.8%) were male, 1049 (54.8%) were identified as white in race/ethnicity, and the median (interquartile range) age was 56 (2.1-12.7) years. Among the cohort who received IV vancomycin plus 1 other antipseudomonal β-lactam antibiotic, 157 patients (8.2%) had antibiotic-associated AKI. This number included 117 of 1009 patients (11.7%) who received IV vancomycin plus piperacillin/tazobactam combination therapy. After adjustment for age, intensive care unit level of care, receipt of nephrotoxins, and hospital, IV vancomycin plus piperacillin/tazobactam combination therapy was associated with higher odds of AKI each hospital day compared with vancomycin plus 1 other antipseudomonal β-lactam antibiotic combination (adjusted odds ratio, 3.40; 95% CI, 2.26-5.14).</p>

<p><strong>Conclusions and Relevance: </strong>Coadministration of IV vancomycin and piperacillin/tazobactam may increase the risk of AKI in hospitalized children. Pediatricians must be cognizant of the potential added risk of this combination therapy when making empirical antibiotic choices.</p>

DOI

10.1001/jamapediatrics.2017.3219

Alternate Title

JAMA Pediatr

PMID

28973124

Title

The Effects of Tacrolimus on T-Cell Proliferation Are Short-Lived: A Pilot Analysis of Immune Function Testing.

Year of Publication

2017

Number of Pages

e199

Date Published

2017 Aug

ISSN Number

2373-8731

Abstract

<p><strong>BACKGROUND: </strong>Optimal immunosuppression after organ transplant should balance the risks of rejection, infection, and malignancy while minimizing barriers to adherence including frequent or time-sensitive dosing. There is currently no reliable immune function assay to directly measure the degree of immunosuppression after transplantation.</p>

<p><strong>METHODS: </strong>We developed an immune function assay to mea//sure T-cell proliferation after exposure to immunosuppression in vivo. We tested the assay in mice, and then piloted the approach using single time point samples, 11 pediatric kidney transplant recipients prescribed tacrolimus, mycophenolate, and prednisone 6 months to 5 years posttransplant, with no history of rejection, opportunistic infection, or cancer. Twelve healthy adults were controls.</p>

<p><strong>RESULTS: </strong>We demonstrated that our assay can quantify suppression of murine T-cell proliferation after tacrolimus treatment in vivo. In humans, we found a mean 25% reduction in CD4 and CD8 T-cell proliferation in pediatric renal transplant recipients on triple immunosuppression compared with adult healthy controls, but the pilot results were not statistically significant nor correlated with serum tacrolimus levels. We observed that cell processing and washing reduced the effects of tacrolimus on T-cell proliferation, as did discontinuation of tacrolimus treatment shortly before sampling.</p>

<p><strong>CONCLUSIONS: </strong>T-cell proliferation is currently not suitable to measure immunosuppression because sample processing diminishes observable effects. Future immune function testing should focus on fresh samples with minimal washing steps. Our results also emphasize the importance of adherence to immunosuppressive treatment, because T-cell proliferation recovered substantially after even brief discontinuation of tacrolimus.</p>

DOI

10.1097/TXD.0000000000000715

Alternate Title

Transplant Direct

PMID

28795150

Title

Outcomes Among Children Who Received a Kidney Transplant in the United States From a Hepatitis B Core Antibody-Positive Donor, 1995-2010.

Year of Publication

2015

Date Published

2015 Oct 14

ISSN Number

2048-7207

Abstract

<p><strong>BACKGROUND: </strong>Accepting kidneys for transplant from donors with a history of hepatitis B virus infection may increase the availability of organs for those with end-stage kidney disease. In adult recipients, kidney transplants from hepatitis B virus core antibody-positive donors have resulted in favorable graft and patient survival rates. However, pediatric organ transplant recipients have developing immune systems and a higher risk of infectious complications than adults. Accordingly, little is known about the outcomes of children who have received a kidney transplant from a hepatitis B virus core antibody-positive donor.</p>

<p><strong>METHODS: </strong>We included 11 898 children ≤18 years of age who received a first kidney transplant in the United States between January 1, 1995, and December 31, 2010, and who were recorded in the Scientific Registry of Transplant Recipients. We examined differences in graft and patient survival rates among children who received a kidney transplant from a hepatitis B virus core antibody-positive donor.</p>

<p><strong>RESULTS: </strong>There were 199 children (1.7%) who received a kidney transplant from a hepatitis B virus core antibody-positive donor. More than 80% of these transplants occurred in recipients who were hepatitis B virus core antibody and surface antigen negative. After a median follow-up of 7.9 years, there were no significant differences in the adjusted graft (hazard ratio [HR], 1.03 [95% confidence interval (CI), 0.80-1.31]) or patient (HR, 1.12 [95% CI, 0.73-1.73]) survival rates according to donor core antibody status.</p>

<p><strong>CONCLUSIONS: </strong>It may be acceptable, on a case-by-case basis, to consider hepatitis B virus core antibody-positive donors for kidney transplants to seroprotected children with end-stage kidney disease.</p>

DOI

10.1093/jpids/piv070

Alternate Title

J Pediatric Infect Dis Soc

PMID

26501473

Title

Longer interdialytic interval and cause-specific hospitalization in children receiving chronic dialysis.

Year of Publication

2013

Number of Pages

2628-36

Date Published

2013 Oct

ISSN Number

1460-2385

Abstract

<p><strong>BACKGROUND: </strong>Previous studies have demonstrated a relationship between longer interdialytic intervals and hospitalization for cardiovascular causes in adults maintained on hemodialysis (HD). This association has not been previously demonstrated in children. We hypothesized that the risk of hospitalization for hypertension (HTN), fluid overload or electrolyte abnormalities would be increased on the days following a longer interdialytic interval in children.</p>

<p><strong>METHODS: </strong>We queried the Pediatric Hospital Information System for all admissions of patients with chronic kidney disease stage V or V-D who received dialysis during the hospitalization. Admissions were divided into two categories: admissions for HTN, fluid overload or electrolyte abnormalities and admissions for all other causes. We assumed that HD patients did not receive dialysis on weekends, and therefore any admission on Monday occurred following a longer interval from the last dialysis. We assumed that all peritoneal dialysis (PD) patients received dialysis on a daily basis. We used mixed effects logistic regression, clustering by patient within each hospital, to assess the increased odds for cause-specific admission on Monday versus other days of the week. We stratified the analysis by dialysis modality, HD or PD.</p>

<p><strong>RESULTS: </strong>Among HD patients, the odds ratio of admission for HTN, fluid overload or electrolyte abnormalities was 2.6 (95% CI = 1.4-4.7, P = 0.003) if the admission occurred on a Monday versus other days of the week. The odds of cause-specific admission among PD patients was not significantly different on Monday compared with other days of the week (95% CI =0.5-1.3, P = 0.8).</p>

<p><strong>CONCLUSION: </strong>Children receiving chronic HD are more likely to be hospitalized for HTN, fluid overload or electrolyte abnormalities following a longer interdialytic interval. Changes to the frequency of outpatient dialysis treatments may decrease admissions in this population and decrease resource utilization in this high-risk population.</p>

DOI

10.1093/ndt/gft276

Alternate Title

Nephrol. Dial. Transplant.

PMID

23861468

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