Effect of pre-emptive rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder in pediatric kidney transplant recipients: A case series from the pediatric nephrology research consortium.

BACKGROUND: There are scant data on the effect of rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder (PTLD) in pediatric kidney transplant recipients with EBV DNAemia. METHODS: Kidney transplant recipients with EBV DNAemia treated with rituximab to prevent PTLD between 7/1999 and 7/2019 at five pediatric centers were included. Those with confirmed PTLD at the onset of rituximab were excluded. Primary outcomes included percentage change in EBV DNAemia and occurrence of PTLD post rituximab. RESULTS: Twenty-six pediatric kidney transplant recipients were included. Median age at transplant was 4 years (IQR 2.1-10.3). EBV DNA load monitoring by qPCR was performed at 1-3 month intervals. EBV DNAemia onset occurred at a median of 73 days post-transplant (IQR 52-307), followed by DNAemia peak at a median of 268 days (IQR 112-536). Rituximab was administered at a median of 9 days post peak (IQR 0-118). Rituximab regimens varied; median dose 375 mg/m2 (IQR 375-439) weekly for 1-4 doses per course. Following rituximab, EBV DNA load decreased to <10% of baseline at 120 days in 20/26 patients; however, only 30% achieved complete resolution at last follow-up (median 2094 days post-transplant [IQR 1538-3463]). Two (7%) developed PTLD at 915 and 1713 days post rituximab. All recipients had functioning grafts. One death occurred in a child with PTLD following remission due to unrelated reasons. CONCLUSIONS: In the largest pediatric kidney transplant recipient case series with EBV DNAemia given rituximab to prevent PTLD, rituximab achieved a short-term reduction in DNA load; however, recurrent DNAemia is common.

Preparing for kidney replacement therapy in pediatric advanced CKD: a review of literature and defining a multi-disciplinary clinical approach to patient-caregiver education.

Pediatric patients with progressive chronic kidney disease (CKD) approaching kidney replacement therapy (KRT) make up a small population but carry significant morbidity and mortality. Patients and caregivers require comprehensive kidney failure education to ensure a smooth start to KRT. Choice of KRT modality can be influenced by medical comorbidities, patient/caregiver comprehension, and comfort with a particular modality, social and economic factors, and/or implicit bias of the health care team. As KRT modality can influence morbidity, mortality, and quality of life, we created a pediatric advanced CKD clinic to provide comprehensive KRT education and to promote informed decision-making for our advanced CKD patients and their caregivers.

Renal oximetry for early acute kidney injury detection in neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia.

BACKGROUND: Neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia are at high risk of acute kidney injury (AKI). METHODS: We performed a two-site prospective observational study from 2018 to 2019 to evaluate the utility of renal near-infrared spectroscopy (NIRS) in detecting AKI in 38 neonates with HIE receiving therapeutic hypothermia. AKI was defined by a delayed rate of serum creatinine decline (< 33% on day 3 of life, < 40% on day 5, and < 46% on day 7). Renal saturation (Rsat) and systemic oxygen saturation (SpO2) were continuously measured for the first 96 h of life (HOL). Renal fractional tissue oxygen extraction (RFTOE) was calculated as (SpO2 - Rsat)/(SpO2). Using renal NIRS, urine biomarkers, and perinatal factors, logistic regression was performed to develop a model that predicted AKI. RESULTS: AKI occurred in 20 of 38 neonates (53%). During the first 96 HOL, Rsat was higher, and RFTOE was lower in the AKI group vs. the no AKI group (P < 0.001). Rsat > 70% had a fair predictive performance for AKI at 48-84 HOL (AUC 0.71-0.79). RFTOE ≤ 25 had a good predictive performance for AKI at 42-66 HOL (AUC 0.8-0.83). The final statistical model with the best fit to predict AKI (AUC = 0.88) included RFTOE at 48 HOL (P = 0.012) and pH of the infants' first postnatal blood gas (P = 0.025). CONCLUSIONS: Lower RFTOE on renal NIRS and pH on infant first blood gas may be early predictors for AKI in neonates with HIE receiving therapeutic hypothermia. A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

Utilization Pattern for Eculizumab Among Children With Hemolytic Uremic Syndrome.

Background: Hemolytic uremic syndrome (HUS) is a complex disease with multi-organ involvement. Eculizumab therapy is recommended for treatment of complement mediated hemolytic uremic syndrome (cHUS). However, there are few studies evaluating eculizumab therapy among children with HUS. The primary objectives of the study were to describe and identify factors associated with eculizumab therapy in children with HUS. Design/Methods: This large, retrospective, multi-center, cohort study used the Pediatric Health Information System (PHIS) database to identify the index HUS-related hospitalization among patients ≤18 years of age from September 23, 2011 (Food and Drug Administration approval date of eculizumab) through December 31, 2018. Multivariate analysis was used to identify independent factors associated with eculizumab therapy during or after the index hospitalization. Results: Among 1,885 children included in the study, eculizumab therapy was noted in 167 children with a median age of 3.99 years (SD ± 4.7 years). Eculizumab therapy was administered early (within the first 7 days of hospitalization) among 65% of children who received the drug. Mortality during the index hospitalization among children with eculizumab therapy was 4.2 vs. 3.0% without eculizumab therapy (p = 0.309). Clinical factors independently associated with eculizumab therapy were encephalopathy [odds ratio (OR) = 3.09; p ≤ 0.001], seizure disorder (OR = 2.37; p = 0.006), and cardiac involvement (OR = 6.36, p < 0.001). Conclusion(s): Only 8.9% of children received eculizumab therapy. Children who presented with neurological and cardiac involvement with severe disease were more likely to receive eculizumab therapy, and children who received therapy received it early during their index hospitalization. Further prospective studies are suggested to confirm these findings.

Industry Payments to Nephrologists in the United States.

Background Industry payments to physicians raise concerns about conflicts of interest that have the potential to impact patient care. In this study, we explored nonresearch and nonownership payments from industry to nephrologists to identify trends in compensation. Methodology Using data from the Centers for Medicare and Medicaid Services (CMS), we explored financial relationships between industry and US nephrologists from 2014 to 2018. We analyzed payment characteristics including payment categories, payment distribution among physicians, regional trends, and biomedical manufacturers. Results In this retrospective study, a total of $75,174,999 was paid to nephrologists in the United States during the study period (i.e., 2014-2018). The number of board-certified nephrologists receiving payment from the industry increased from 11,642 in 2014 to 13,297 in 2018. Among board-certified nephrologists, 56% to 63% received industry payments during the study period. The total payments to nephrologists increased from $13,113,512 in 2014 to $16,467,945 in 2017, with consulting fees (24%) and compensation for services other than consulting (35%) being the highest-paid categories. The top 10% of physician beneficiaries collected 90% of the total industry payments. Conclusions A small proportion of US nephrologists consistently received the majority of industry payments, the value of which grew over the study period.

Association of Anemia and Blood Pressure With Novel Markers of Diastolic Function in Pediatric Sickle Cell Disease.

Diastolic dysfunction is a known cause of mortality in adults with sickle cell disease (SCD). Left atrial function (LAf) and strain (LAS) are novel echocardiographic parameters to assess early diastolic dysfunction, which have not been assessed in pediatric SCD. Through a retrospective single-center study, we describe echocardiographic parameters of diastology in children with SCD and evaluate their relationship with clinical variables including anemia and blood pressure. Baseline clinical data, 24-hour ambulatory blood pressure monitoring data and echocardiography results were collected. LAf and LAS were measured using volumetric data and speckle-tracking echocardiography, respectively. Sixty-seven children with SCD (13.5±7 y, 47% male, 7% hypertensive) with a mean hemoglobin of 8.8±1.3 g/dL, LAf of 61±8% (n=53) and LAS of 46.3±7.4% (n=28) were included. LAS was significantly associated with hemoglobin (ρ=0.43, P=0.022) but not with maximal left atrial (LA) volume (ρ=-0.05, P=0.79) or any blood pressure parameters. On multivariate analysis, LAS decreased by 3.2% (1.3, 5.1) and LA volume increased by 1.6 mL/m2 (3.1, 0.08) for every 1 g/dL decrease in hemoglobin. Thus, severity of baseline anemia in pediatric SCD correlates with diastolic function as measured by LAS, independent of LA dilation.

Nocturnal hypertension associated with stroke and silent cerebral infarcts in children with sickle cell disease.

BACKGROUND: Strokes and silent cerebral infarcts (SCIs) lead to significant morbidity and mortality in children with sickle cell disease (SCD). Higher systolic blood pressures increase risk for stroke and SCIs; however, patients with SCD often have lower clinic blood pressures than the general population. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) allows for more robust examination of blood pressures. This study evaluated associations between abnormal ABPM measurements with stroke and SCIs. PROCEDURE: A cross-sectional study was performed. Children with SCD completed 24-hour ABPMs. Children with a documented magnetic resonance imaging (MRI) brain within a year of the ABPM were included in the analysis. Bivariate analyses were performed to identify associations between ABPM parameters with cerebrovascular outcomes. RESULTS: Forty-two children with a median age of 13 years (10, 17) were included in the analysis. Seven (17%) had history of stroke and seven (17%) had SCIs. Nocturnal hypertension, elucidated via 24-hour ABPM, was noted in 25% of subjects. The presence of nocturnal hypertension was significantly higher in the SCI/stroke group (55% vs 12%, P = .01). Sensitivity analyses were performed during which stroke patients were removed from analysis. Nocturnal hypertension remained significantly associated with the presence of SCIs (P = .006). CONCLUSIONS: This study reveals an association between nocturnal hypertension and a higher prevalence of SCI and stroke in children with SCD. Larger, prospective studies are needed to confirm these findings and evaluate the contributory nature of blood pressure abnormalities to cerebrovascular events in children with SCD.

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.

Outcomes of COVID-19 in Solid Organ Transplants.

The novel coronavirus disease 2019 (COVID-19) is a global pandemic affecting millions of people worldwide. Solid organ transplant (SOT) recipients are probably at higher risk of severe infection and associated complications from COVID-19. Data on clinical outcomes of COVID-19 infection in SOT recipients are limited. Using the TriNetX database, patients with laboratory-confirmed COVID-19 from January 20, 2020, to July 7, 2020, were included in the study. We compared clinical outcomes comprising hospitalization, need for critical care services, intubation, and mortality among SOT recipients and patients without SOT. Of 30,573 laboratory-confirmed COVID-19 patients, 288 had SOT. Patients with SOT were more likely to be hospitalized (37.2% vs. 12.2%; p < 0.0001), needed critical care services (6.9% vs. 2.3%; p < 0.0001), needed intubation (7.9% vs. 2.0%; p < 0.0001), and had a higher 30-day mortality (11.1% vs. 3.8%; p < 0.0001). Patients in the transplant group were older (55.4 vs. 47.6 years; p < 0.0001) and had a higher prevalence of medical co-morbidities. SOT recipients are at significant risk of adverse COVID-19 related outcomes, including hospitalization, need for critical care services, and 30-day mortality, likely due to multiple co-morbid conditions.

Use of direct oral anticoagulants in cerebral venous thrombosis: a systematic review.

: We are here to review the efficacy and safety of direct oral anticoagulants (DOACs) in the treatment of Cerebral Venous Thrombosis (CVT). A search strategy was developed with a research librarian. All published articles including trials, studies, case series, and case reports were reviewed from NCBI/PubMed up to May 2019 by two independent reviewers. A total of 11 studies were identified, which included 70 patients with CVT on DOACs. After 6 months follow-up more than 86.7% of these patients had a good outcome on the Modified Rankin Scale (mRS) of 0--1 at 6 months and no recurrence of venous thromboembolic events (VTE) at 12 months. Recanalization rate at 6 months varied from 55 to 100%. Only two patients had a side effect of minor bleeding because of DOAC usage. Although the current American Heart Association/American Stroke Association and European Stroke Organization guidelines do not endorse the use of DOACs for treatment of CVT because of lack of evidence from large randomized clinical trials, Use of DOACs in CVT appears to be well tolerated and efficacious with favorable outcomes. Further evidence is needed to establish their use in CVT.

Industry Payment to Vascular Neurologists: A 6-Year Analysis of the Open Payments Program From 2013 Through 2018.

Background and Purpose- Industry payments to physicians raise concerns regarding conflicts of interest that could impact patient care. We explored nonresearch and nonownership payments from industry to vascular neurologists to identify trends in compensation. Methods- Using Centers for Medicare and Medicaid Services and American Board of Psychiatry and Neurology data, we explored financial relationships between industry and US vascular neurologists from 2013 to 2018. We analyzed payment characteristics, including payment categories, payment distribution among physicians, regional trends, and biomedical manufacturers. Furthermore, we analyzed the top 1% (by compensation) of vascular neurologists with detailed payment categories, their position, and their contribution to stroke guidelines. Results- The number of board certified vascular neurologist increased from 1169 in 2013 to 1746 in 2018. The total payments to vascular neurologist increased from $99 749 in 2013 to $1 032 302 in 2018. During the study period, 16% to 17% of vascular neurologists received industry payments. Total payments from industry and mean physician payments increased yearly over this period, with consulting fee (31.1%) and compensation for services other than consulting (30.7%) being the highest paid categories. The top 10 manufacturers made the majority of the payments, and the top 10 products changed from drug or biological products to devices. Physicians from south region of the United States received the highest total payment (38.72%), which steadily increased. Payments to top 1% vascular neurologists increased from 64% to 79% over the period as payments became less evenly distributed. Among the top 1%, 42% specialized in neuro intervention, 11% contributed to American Heart Association/American Stroke Association guidelines, and around 75% were key leaders in the field. Conclusions- A small proportion of US vascular neurologists consistently received the majority of industry payments, the value of which grew over the study period. Only 11% of the top 1% receiving industry payments have authored American Heart Association/American Stroke Association guidelines, but ≈75% seem to be key leaders in the field. Whether this influences clinical practice and behavior requires further investigation.

Ambulatory Hypertension in Pediatric Patients With Sickle Cell Disease and Its Association With End-Organ Damage.

Background Sickle cell disease (SCD), a chronic hemolytic disorder, results in cumulative end-organ damage affecting major organs such as the cardiovascular, renal, and central nervous systems. Effects of modifiable risk factors, such as blood pressure (BP), on the development of end-organ complications in SCD have not been well studied, particularly among the pediatric population. Relative hypertension in patients with SCD increases their risks of stroke, cardiovascular complications, and death. The primary hypothesis of this study was that abnormal BP patterns are common among patients with SCD and they impact end-organ complications. Methods Patients with SCD (HbSS, HbSß0) were enrolled from the Children's Hospital at Montefiore (N = 100). For each patient, demographic data were collected, biochemical variables in urine and blood samples were analyzed, BP was determined with ambulatory blood pressure monitoring (ABPM), and an echocardiogram was performed. The prevalence of abnormalities in BP parameters was defined, and their relationships with measures of SCD severity and end-organ damage were assessed. Results Sufficient ABPM data were available for 67 patients. Enrolled children were 13 ± 4 years (40% were males). Assessment of diurnal variation demonstrated that 81% of patients had abnormal systolic nocturnal dipping and 61% had abnormal diastolic nocturnal dipping. Abnormalities in the diurnal pattern were associated with reticulocytosis and hyperfiltration. Microalbuminuria was present in 19% (n = 13) of patients, of which 77% (n = 10) were females (p = 0.014). Diastolic load and abnormal nocturnal dipping were associated with hyperfiltration but not with microalbuminuria. Conclusions BP abnormalities detected with ABPM in SCD patients are prevalent and perhaps are a risk factor for end-organ complications. Further studies are required to identify the mechanisms underlying these relationships and their longitudinal changes.

Why are acute ischemic stroke patients not receiving thrombolysis in a telestroke network?

OBJECTIVE: The purpose of this study was to determine reasons for not giving intravenous tissue plasminogen activator to eligible patients with acute ischemic stroke in a telestroke network. METHODS: We performed a retrospective analysis of prospectively collected data of patients who were seen as a telestroke consultation during 2015 and 2016 with the Arkansas Stroke Assistance through Virtual Emergency Support programme for possible acute ischemic stroke. RESULTS: Total consultations seen were 809 in 2015 and 744 in 2016, out of which 238 patients in 2015 and 247 patients in 2016 received intravenous tissue plasminogen activator. In 2015 and 2016, out of the remaining 571 and 497 patients, 294 and 200 patients respectively were thought to be cases of acute stroke based on clinical evaluation. The most common reasons for not being treated in 2015 and 2016, respectively, were; (a) minimal deficits in 42.17% and 49.5% cases, (b) falling out of the 4.5-hour time window in 22.44% and 22% cases, (c) patient/next of kin refusal in 18.02% and 16.5% cases. Less common reasons included limited functional status, abnormal labs (thrombocytopenia, elevated international normalised ratio (INR)/prothrombin time (PT)/partial thromboplastin time (PTT), hypo or hyperglycemia etc), recent surgery and symptoms being too severe etc. CONCLUSION: 'Minimal deficits' and 'out of time window' continue to be the major causes for not receiving thrombolysis during acute ischemic stroke in both traditional and telestroke systems. Patient/next of kin refusal was high in our telestroke system when compared to traditional practices. Considering the increasing utility of telestroke this needs to be further looked into, along with the ways to address it.

Author Correction: Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways.

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

Fabry's disease and stroke: Effectiveness of enzyme replacement therapy (ERT) in stroke prevention, a review with meta-analysis.

BACK GROUND AND OBJECTIVE: Fabry's disease, is the most prevalent lysosomal storage disorder and is notorious for its early multi-organ involvement leading to complications, including ischemic strokes and transient ischemic attacks. Since 2001, enzyme replacement therapy (ERT) has become the mainstay treatment for Fabry's patients but the indications are not clearly defined. We did a meta-analysis of the available data to review the benefit of ERT for stroke prevention in Fabry's patients. METHODS: A literature search was performed from National Center for Biotechnology information (NCBI)/PubMed database without restriction of years for systematic review purposes. A systematic review of clinical cohort studies and trials was performed with pooled analysis of proportions. The pooled proportions and the confidence intervals (CI) for stroke recurrence ratio were calculated for both ERT treatment group and native treatment groups. RESULT: A total of 7 cohort studies and 2 RCTs involving 7513 participants (1471 on ERT vs 6042 on native treatment) met inclusion criteria. The pooled proportions analysis showed that the stroke recurrence ratio in the ERT treatment group was 8.2% [95% CI 0.038, 0.126] and in native-treatment group was 16% [95% CI; 0.102, 0.217]. Effect differences favored ERT treatment group over native treatment group (p = 0.03). CONCLUSION: Our meta-analysis based on the currently available data showed that ERT for Fabry's disease has beneficial effect on stroke prevention. Female carriers and atypically affected males could be started on ERT as soon as diagnosis is made. Further studies are warranted to support the role of ERT in stroke prevention.