Soluble urokinase plasminogen activator receptor is associated with kidney disease and its progression in sickle cell anemia.

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Association of elevated tricuspid regurgitation velocity with cerebrovascular and kidney disease in children with sickle cell disease.

BACKGROUND: Tricuspid regurgitation velocity (TRV), measured by echocardiography, is a surrogate marker for pulmonary hypertension. Limited pediatric studies have considered the association between TRV and surrogate markers of end-organ disease. METHODS: We conducted a cross-sectional study that evaluated the prevalence of elevated TRV ≥2.5 m/s and its associations with renal and cerebrovascular outcomes in children with sickle cell disease (SCD) 1-21 years of age in two large sickle cell cohorts, the University of Alabama at Birmingham (UAB) sickle cell cohort, and the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort at St. Jude Children's Research Hospital. We hypothesized that patients with SCD and elevated TRV would have higher odds of having either persistent albuminuria or cerebrovascular disease. RESULTS: We identified 166 children from the UAB cohort (mean age: 13.49 ± 4.47 years) and 325 children from the SCCRIP cohort (mean age: 13.41 ± 3.99 years) with echocardiograms. The prevalence of an elevated TRV was 21% in both UAB and SCCRIP cohorts. Elevated TRV was significantly associated with cerebrovascular disease (odds ratio [OR] 1.88, 95% confidence interval [CI]: 1.12-3.15; p = .017) and persistent albuminuria (OR 1.81, 95% CI: 1.07-3.06; p = .028) after adjusting for age, sex, treatment, and site. CONCLUSION: This cross-sectional, multicenter study identifies associations between surrogate markers of pulmonary hypertension with kidney disease and cerebrovascular disease. A prospective study should be performed to evaluate the longitudinal outcomes for patients with multiple surrogate markers of end-organ disease.

Outcomes of Referrals in Pediatric Patients With Peripheral Lymphadenopathy.

Lymphadenopathy is a common reason for referral to a subspecialist, which may result in significant anxiety for parents. Understanding which patients require a subspecialty referral for lymphadenopathy is key to streamlining health care utilization for this common clinical entity. This is an IRB-approved retrospective study examining pediatric patients consecutively referred to pediatric hematology oncology, otolaryngology, or surgery for lymphadenopathy from 2012 to 2021 at a free-standing tertiary-care children's hospital. Logistic regression was fitted to examine the association between the maximum size of the lymph nodes (LN) and a diagnosis of malignancy. The odds ratio, area under the receiver operator curve, sensitivity, and specificity were estimated. We found a significant association between LN size and cancer diagnosis. For every centimeter increase in the maximal dimension of LN, there was an estimated 2.3 times increase in the odds of malignancy (OR=2.3, 95% CI: 1.65-3.11; P<0.0001). The estimated area under the curve (0.84, 95% CI: 0.78-0.90) indicated that LN size correlated well with cancer diagnosis. A LN cut-off size of 2 cm resulted in an estimated sensitivity of 1.0 (95% CI: 0.87-1.00) and specificity of 0.54 (95% CI: 0.46-0.61). Maximum LN size may be a predictor of malignancy among pediatric patients with lymphadenopathy.

Kidney failure outcomes in children and young adults with sickle cell disease in the United States Renal Data System.

BACKGROUND: Children and young adults with sickle cell disease (SCD) develop kidney disease early in childhood, with some patients progressing to require dialysis and kidney transplantation. The prevalence and outcomes of children with kidney failure (chronic kidney disease stage 5) due to SCD are not well described. This study aimed to assess the outcome of children and young adults with SCD with kidney failure compared to matched children and young adults without SCD with kidney failure in a large national database. METHODS: Utilizing the United States Renal Data System (USRDS), we retrospectively examined kidney failure outcomes in children and young adults with SCD from 1998 to 2019. RESULTS: We identified 97 patients with SCD who developed kidney failure and identified 96 matched controls with a median age of 19 years (IQR 17, 21) at the time of kidney failure diagnosis. SCD patients had significantly shorter survival (8.4 years vs. 14.0 years, p < 0.001) and had a longer waiting time for their first transplant when compared to matched non-SCD kidney failure patients (12.1 years vs. 7.3 years, p < 0.001). CONCLUSIONS: Children and young adults with SCD kidney failure have significantly higher mortality when matched to non-SCD kidney failure children and experience a longer mean time to kidney transplant.

Machine Learning Predicts Acute Kidney Injury in Hospitalized Patients with Sickle Cell Disease.

INTRODUCTION: Acute kidney injury (AKI) is common among hospitalized patients with sickle cell disease (SCD) and contributes to increased morbidity and mortality. Early identification and management of AKI is essential to preventing poor outcomes. We aimed to predict AKI earlier in patients with SCD using a machine-learning model that utilized continuous minute-by-minute physiological data. METHODS: A total of6,278 adult SCD patient encounters were admitted to inpatient units across five regional hospitals in Memphis, TN, over 3 years, from July 2017 to December 2020. From these, 1,178 patients were selected after filtering for data availability. AKI was identified in 82 (7%) patient encounters, using the 2012 Kidney Disease Improving Global Outcomes (KDIGO) criteria. The remaining 1,096 encounters served as controls. Features derived from five physiological data streams, heart rate, respiratory rate, and blood pressure (systolic, diastolic, and mean), captured every minute from bedside monitors were used. An XGBoost classifier was used for classification. RESULTS: Our model accurately predicted AKI up to 12 h before onset with an area under the receiver operator curve (AUROC) of 0.91 (95% CI [0.89-0.93]) and up to 48 h before AKI with an AUROC of 0.82 (95% CI [0.80-0.83]). Patients with AKI were more likely to be female (64.6%) and have history of hypertension, pulmonary hypertension, chronic kidney disease, and pneumonia than the control group. CONCLUSION: XGBoost accurately predicted AKI as early as 12 h before onset in hospitalized SCD patients and may enable the development of innovative prevention strategies.

Corrigendum to ' Recurrent venous thromboembolism in hospitalized children with a history of prior venous thromboembolism: a report from the Children's Hospital-Acquired Thrombosis Consortium' [Research and Practice in Thrombosis and Haemostasis Volume 7, Issue 5, July 2023, 102139].

[This corrects the article DOI: 10.1016/j.rpth.2023.102139.].

Gastrointestinal symptoms, diagnostic evaluations, and abdominal pathology in children with sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) frequently present with acute pain. The abdomen, a common site of acute SCD-related pain, may be present in a variety of gastrointestinal (GI) pathologies. Limited data exist on prevalence and workup of abdominal pain in patients with SCD during acute pain events. OBJECTIVES: Determine prevalence of GI symptoms, GI-specific evaluation and risks of hospitalization in children with SCD presenting to the emergency department (ED) or hospitalized with abdominal pain. METHODS: Retrospective study of children less than 21 years presenting to the ED or hospitalized with pain in our center over 2 years. Descriptive statistics were used to report clinical characteristics, frequency of GI symptoms, workup by age (<5 vs. ≥5 years), and genotype (sickle cell anemia [SCA] vs. non-SCA). Logistic regression models were used to identify risks associated with hospitalization. RESULTS: A total of 1279 encounters in 378 patients were analyzed; 23% (n = 291) encounters were associated with abdominal pain. More abdominal pain-associated hospitalizations occurred in older children, SCA, children with lower mean hemoglobin (8.7 ± 1.9 vs. 9.6 ± 1.6 g/dL, p < .001) and higher mean white blood cell (WBC) count (14.9 ± 6.6 vs. 13.2 ± 5.3 × 103 /µL, p = .02). We identified that less than 50% of patients presenting to the ED with abdominal pain received a GI-specific evaluation. CONCLUSION: Children with SCD frequently present with abdominal pain and other GI symptoms, with limited GI evaluations performed. GI-specific evaluation may increase diagnosis of GI pathologies, rule out GI pathologies, and contribute to the limited knowledge of the abdomen as a primary site of SCD pain.

Natural history and variability in albuminuria in pediatric and murine sickle cell anemia.

It is critical to characterize the natural history of albuminuria in patients with sickle cell anemia (SCA); however, these data are currently lacking and affecting evidence-based guidelines. We performed a natural history study of the development of pediatric albuminuria. We identified participants with hemoglobin SS/SB0 thalassemia ≥5 years with albumin to creatinine ratio (ACR) measurements performed at a steady-state clinic visit. Participants were characterized as either persistent, intermittent, or never albuminuria. We determined the prevalence of persistent albuminuria, use of ACR ≥100 mg/g as a predictor, and variation in ACR measurements. We mirrored this study to determine the variation in albuminuria measurements in the SCA murine model. Among 355 participants with HbSS/SB0 thalassemia with 1728 ACR measurements, we identified 17% with persistent and 13% with intermittent albuminuria. Thirteen percent of participants with persistent albuminuria developed an abnormal ACR before 10 years of age. A single ACR measurement ≥100 mg/g was associated with 55.5 times (95% confidence interval, 12.3-527) higher odds of having persistent albuminuria. Among participants with ACR ≥100 mg/g, we identified significant variability in the results of repeated measurements. The median ACR at the initial and next measurements were 175.8 mg/g (interquartile range [IQR], 135-242) and 117.3 mg/g (IQR, 64-292). The human variability in ACR was mirrored by ∼20% variability in albuminuria in murine model. This evidence suggests adopting standards for repeating ACR measurements, consider screening for ACR before 10 years of age, and using an ACR >100 mg/g as a risk factor for progression. Pediatric and murine renoprotective clinical trials need to consider the high variability in repeated ACR measurements.

End Stage Kidney Disease Outcomes in Children and Young Adults with Sickle Cell Disease in the United States Renal Data System.

Background: Children and young adults with sickle cell disease (SCD) develop kidney disease early in childhood with some patients progressing to require dialysis and kidney transplantation. The prevalence and outcomes of children with end stage kidney disease (ESKD) due to SCD is not well described. This study aimed to assess the burden and outcomes of ESKD in children and young adults with SCD in a large national database. Methods: Utilizing the United States Renal Data System (USRDS) we retrospectively examined ESKD outcomes in children and young adults with SCD from 1998 - 2019. Results: We identified 97 patients with SCD that developed ESKD and identified 96 matched controls with median age of 19 years (IQR 17, 21) at time of ESKD diagnosis. SCD patients had significantly shorter survival (7.0 years vs. 12.4 years, p < 0.001) and had a longer waiting time to their first transplant when compared to matched non-SCD-ESKD patients (10.3 years vs. 5.6 years, p < 0.001). Conclusions: Children and young adults with SCD-ESKD have a significantly higher mortality when matched to non-SCD-ESKD children and experience a longer mean time to kidney transplant.

The relationship between nutrition, gut dysbiosis, and pediatric sickle cell pain outcomes: A pilot study.

BACKGROUND: Nutritional deficiencies are prevalent in sickle cell disease (SCD) and may be associated with worse pain outcomes. Gut dysbiosis has been reported in patients with SCD and may contribute to both nutritional deficiencies and pain. OBJECTIVES: We tested the association of nutrition, fat-soluble vitamin (FSV) deficiency, and gut microbiome composition on clinical outcomes in SCD. Second, we measured the association between diet and exocrine pancreatic function on FSV levels. METHODS: Using case control design, we enrolled children with SCD (n = 24) and matched healthy controls (HC; n = 17, age, sex, race/ethnicity). Descriptive statistics summarized demographic and clinical data. Wilcoxson-rank tests compared FSV levels between cohorts. Regression modeling tested the association between FSV levels and SCD status. Welch's t-test with Satterthwaite adjustment evaluated associations between microbiota profiles, SCD status, and pain outcomes. RESULTS: Vitamin A and D levels were significantly decreased in participants with HbSS as compared to HC (vitamin A, p = < .0001, vitamin D, p = .014) independent of nutritional status. FSV correlated with dietary intake in SCD and HC cohorts. Gut microbial diversity was reduced in hemoglobin SS (HbSS) compared to hemoglobin SC (HbSC) and HC, p = .037 and .059, respectively. The phyla Erysipelotrichaceae and Betaproteobacteria were higher in SCD children reporting the highest quality-of-life (QoL) scores (p = .008 and .049, respectively), while Clostridia were higher in those with lower QoL scores (p = .03). CONCLUSION: FSV deficiencies and gut dysbiosis are prevalent in children with SCA. Gut microbial composition is significantly different in children with SCD with low QoL scores.

Palatability and Acceptability of Flaxseed-Supplemented Foods in Children with Sickle Cell Disease.

Omega-3 fatty acids (w3FAs) have demonstrated benefits in several inflammatory disease states; however, limited research has been conducted in sickle cell disease (SCD). While marine-based w3FAs are used, their strong odor and taste are a barrier to long-term use. Plant-based sources, especially those in whole foods, may circumvent this barrier. We tested whether flaxseed (rich source of w3FAs) was acceptable to children with SCD. A cross-sectional tasting trial of flaxseed added to baked products (cookies, pancakes, brownies) or to readily available foods (applesauce, pudding, yogurt) was conducted among 30 children (median age = 13 years) reporting to a clinic for routine follow-up, sick visits, or transfusion for SCD to determine acceptability. A food preference rank scale (1-7) was used to rank products based on taste, sight, smell, and texture. An average score for each product was computed. Children were also asked to rank their top three products. The top-ranked products were flaxseed baked in brownies and cookies and ground flaxseed added to yogurt. More than 80% of participants indicated willingness to be contacted for a follow-up study in which a flaxseed-supplemented diet would be evaluated for mitigation of SCD-associated pain. In conclusion, flaxseed-enriched products are palatable and acceptable in children with SCD.

Assessing barriers and facilitators to transition in sickle cell disease care prior to implementation of a formalized program.

Over 95% of children with sickle cell disease (SCD) survive into adulthood in the United States. However, early mortality remains a problem, especially in persons between the ages of 18 and 35. One possible explanation for the increased mortality rate in young adults is difficulties in engaging in care during the transition from a heavily contiguous pediatric healthcare model to a more self-reliant adult healthcare model. The goal of this study was to identify potential facilitators and barriers to a successful transfer in care from the pediatric to adult SCD program before the formation of a formal transition program. This is a retrospective cohort study of transition outcomes for 472 individuals with SCD (all genotypes) treated at the University of Alabama at Birmingham (UAB) sickle cell clinic (aged 18-24). The primary outcome was whether the patient continued care in (any) adult SCD program (defined as being seen at least once in an adult hematology/SCD clinic). One hundred eighty-eight (45%) transition age patients successfully transferred to adult care. Facilitators to successful transfer in care included being treated at the same hospital for both pediatric and adult programs, having the genotype HbSS, and/or receiving an SCD-modifying therapy at the time of transition (hydroxyurea and/or red cell transfusion therapy). Of primary interest, many of the patients who failed to transition to an adult clinic were lost to follow-up prior to 15 years of age. Importantly, these patients who had previously been labeled as "transition failures," were lost to follow-up long before the transition age. Early engagement is needed for this population.

The relationship between pain and sleep in pediatric sickle cell disease.

BACKGROUND: Pain and sleep disturbances are prevalent complications experienced by pediatric patients with sickle cell disease (SCD). This study aims to identify associations between pain and sleep, and to characterize sleep chronotype and social jetlag in children and adolescent patients with SCD. METHODS: We performed a cross-sectional survey of 105 pediatric patients with SCD aged 8-17 years using PROMIS (Patient Reported Outcomes Measurement System) pain interference, sleep disturbance, and sleep-related impairment item banks. The µMCTQ (Ultra-short Munich Chronotype Questionnaire) assessed chronotype and social jetlag. Analyses were performed to assess associations between PROMIS measures, sleep patterns, and clinical variables. RESULTS: Female participants reported higher T-scores for sleep-related impairment than males (females: 56.7 ± 10 vs. males 50.2 ± 9.4, p = .0009). Patients with one or more emergency department (ED) visits for pain in the last 12 months reported greater sleep disturbance (55.0 ± 8.5 vs. 50.7 ± 10, p = .046) and sleep-related impairment (57.1 ± 9.3 vs. 52.1 ± 10.2, p = .03) than patients without any ED visits for pain in the last 12 months. Pain interference was significantly associated with both sleep disturbance (r = .49, p < .0001) and sleep-related impairment (r = .46, p < .0001). The average mid-sleep time was 4:14 ± 1:44 a.m. and the average social jetlag (hh:mm) was 2:32 ± 1:35. CONCLUSION: Our study demonstrates that pain interference is associated with both sleep disturbance and sleep-related impairment. PROMIS measures can identify patients that suffer from pain and sleep disturbances and highlights the need to conduct longitudinal prospective studies to define the directionality of pain and sleep in SCD.

Diagnosis and management of isolated neutropenia: A survey of pediatric hematologist oncologists.

BACKGROUND: Isolated neutropenia is a common referral to pediatric hematology oncology (PHO) physicians. There are no established consensus guidelines in the diagnosis and management of patients with isolated, asymptomatic, and incidentally discovered neutropenia. METHODS: A survey was distributed to PHO physicians on the American Society of Pediatric Hematology Oncology member discussion page to determine the common diagnostic and management decisions regarding patients with isolated neutropenia and to explore beliefs regarding the term "benign ethnic neutropenia." RESULTS: One hundred twenty-six PHO attending physicians completed the survey. The most common tests reportedly ordered for this patient population included complete blood cell count (CBC) (98%), peripheral smear (75%), antineutrophil antibody testing (29%), and immunoglobulins (24%). Providers were more likely to order an antineutrophil antibody in toddlers (p = .0085), and antinuclear antibody (ANA) panels in adolescents (p < .001). Half of providers do not request additional CBCs prior to their initial consultation, and most suggest referring patients with mild neutropenia after confirming a declining absolute neutrophil count (ANC) (51%). The three most important factors influencing ongoing follow-up included: history of recurrent/severe infections (98%), family history of blood disorders (98%), and more severe/progressively worsening neutropenia (97%). Seventy percent of respondents have diagnosed patients with "benign ethnic neutropenia," and 75% support replacement of the term to "typical neutrophil count with Fy(a-/b-) status," if confirmed with red cell phenotyping. CONCLUSION: We identified practice patterns of PHO physicians for the diagnosis and management of patients referred for asymptomatic and isolated neutropenia. These data provide the framework to conduct cost-effectiveness studies.

Pediatric refractory immune thrombocytopenia: A systematic review.

Pediatric immune thrombocytopenia (ITP) is an acquired disorder associated with autoimmune destruction and impairment of platelet production in children. Some children exhibit poor or transient response to ITP-directed treatments and are referred to as having refractory ITP (rITP). There is currently no consensus on the definition of rITP, nor evidence-based treatment guidelines for patients with rITP. After a survey of pediatric ITP experts demonstrated lack of consensus on pediatric rITP, we pursued a systematic review to examine the reported clinical phenotypes and treatment outcomes in pediatric rITP. The search identified 253 relevant manuscripts; following review, 11 studies proposed a definition for pediatric rITP with no consensus amongst them. Most definitions included suboptimal response to medical management, while some outlined specific platelet thresholds to define this suboptimal response. Common attributes identified in this study should be used to propose a comprehensive definition, which will facilitate outcome comparisons of future rITP studies.

Consensus definition of essential, optimal, and suggested components of a pediatric sickle cell disease center.

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.

Sickle Cell Disease and the Kidney: Filters Gone Awry.

Throughout the lifespan, the kidney of a person with sickle cell disease is at increased risk of injury to the glomeruli, tubules, and renal vasculature. This injury manifests as urine concentrating defects, enuresis, albuminuria, acute kidney injury, chronic kidney disease, and end-stage kidney disease. The outcomes for patients who progress to end-stage kidney disease are poor and access to organ transplantation is limited. Therefore, identifying risk factors for progression, intervening with renoprotective agents early in life, and improving access to care are vital for sickle cell patients.