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.

Altered cardiac reserve is a determinant of exercise intolerance in sickle cell anaemia patients.

BACKGROUND: The underlying mechanisms of exercise intolerance in sickle cell anaemia (SCA) patients are complex and not yet completely understood. While latent heart failure at rest could be unmasked upon exercise, most previous studies assessed cardiac function at rest. We aimed to investigate exercise cardiovascular reserve as a potential contributor to exercise intolerance in adult SCA patients. METHODS: In this observational prospective study, we compared prospectively 60 SCA patients (median age 31 years, 60% women) to 20 matched controls. All subjects underwent symptom-limited combined exercise echocardiography and oxygen uptake (VO2 ) measurements. Differences between arterial and venous oxygen content (C(a-v)O2 ) were calculated. Cardiac reserve was defined as the absolute change in cardiac index (Ci) from baseline to peak exercise. RESULTS: Compared to controls, SCA patients demonstrated severe exercise intolerance (median peakVO2 , 34.3 vs. 19.7 ml/min/kg, respectively, p < .0001). SCA patients displayed heterogeneously increased Ci from rest to peak exercise (median +5.8, range 2.6 to 10.6 L/min/m²) which correlated with peakVO2 (r = 0.71, p < .0001). In contrast, the C(a-v)O2 exercise reserve was homogenously reduced and did not correlate with peakVO2 (r = 0.18, p = .16). While haemoglobin level and C(a-v)O2 were similar in SCA subgroups, SCA patients in the lower VO2 tertile had chronotropic incompetence and left ventricular diastolic dysfunction (left atrial peak longitudinal strain was reduced, and both E/e' ratio and left atrial volume index were increased) and were characterized by a reduced cardiac reserve, +5.0[4.2-5.5] compared to +6.7[5.5-7.8] L/min/m² for the rest of the patient cohort, p < .0001. CONCLUSIONS: Altered cardiac reserve due to chronotropic incompetence and left ventricular diastolic dysfunction seems to be an important determinant of exercise intolerance in adult SCA patients.

Pulmonary Blastomycosis: A Rare Cause of Acute Chest Syndrome and Prolonged Fevers in a Pediatric Patient With Sickle Cell Disease.

Blastomyces is a fungus found in the soil of regions of North America including the Mississippi and Ohio River Valleys. It can be inhaled into the lungs and cause pneumonia and disseminated disease. Although blastomycosis is not widely reported in the sickle cell literature, sickle cell patients may be at increased risk of complications from blastomycosis pneumonia due to their immune compromise and risk of developing acute chest syndrome. We describe the case of a 13-year-old female with homozygous sickle cell disease who presented with pneumonia and acute chest syndrome and was found to have pulmonary blastomycosis.

Sickle cell disease in sub-Saharan Africa: transferable strategies for prevention and care.

Sickle cell disease can be life-threatening or chronically debilitating for both children and adults. Worldwide, more than 300 000 children are born with sickle cell disease every year, over 75% of whom in sub-Saharan Africa. Increased awareness and early interventions, such as neonate screening and comprehensive care, have led to considerable reductions in mortality in children younger than 5 years in high-income countries. However, sickle cell disease prevention and care have largely been neglected in Africa. Without intervention, 50-90% of affected children in many sub-Saharan African countries die before their fifth birthday. Fortunately, increasing initiatives in sub-Saharan Africa are piloting interventions such as neonate screening and comprehensive care, and as mortality declines, quality of life and increased life expectancy become major targets for interventions. Hydroxyurea (hydroxycarbamide) and haematopoietic stem-cell transplantation have already been shown to be effective therapies in high-income countries, but are either not widely accessible or too expensive for most African populations. These challenges are being alleviated by numerous networks evolving through international collaborations that are positively changing the outlook of sickle cell disease management in sub-Saharan Africa. In this Series paper, we describe the epidemiology, pathophysiology, clinicobiological profile, and psychosocial effects of sickle cell disease in sub-Saharan Africa. We highlight transferable strategies already used for the successful management of the condition and key strategies and recommendations for affordable and comprehensive care on the continent. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Longitudinal study of glomerular hyperfiltration and normalization of estimated glomerular filtration in adults with sickle cell disease.

Glomerular hyperfiltration is common in sickle cell disease (SCD) and precedes proteinuria and declining kidney function. We evaluated hyperfiltration in SCD patients and its "normalization." Routine visit data were collected retrospectively from adult SCD patients in a single centre from 2004 to 2013. Baseline was defined as first available serum creatinine and hyperfiltration as estimated glomerular filtration rates (eGFR) >130 ml/min/1·73 m2 for women and >140 ml/min/1·73 m2 for men. Normalization of hyperfiltration was eGFR reduction to 90-130 ml/min/1·73 m2 for women or 90-140 ml/min/1·73 m2 for men. Among 292 patients, median age was 27 years [interquartile range (IQR):20·0-38·0], and 56·8% had baseline hyperfiltration. Baseline hyperfiltration was inversely associated with age [odds ratio (OR):0·86, 95% confidence interval (CI): 0·82-0·90; P < 0·0001], male sex (OR:0·16, 95% CI: 0·07-0·41; P = 0·0001), haemoglobin (OR:0·76, 95% CI 0·61-0·94; P = 0·01), weight (OR:0·96, 95% CI: 0·93-0·99; P = 0·004), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACE-I/ARB) use (OR:0·08, 95% CI: 0·01-0·75; P = 0·03), and positively with hydroxycarbamide use (OR:2·99, 95% CI: 1·18-7·56; P = 0·02). Of 89 hyperfiltration patients without baseline proteinuria, 10 (11·2%) developed new-onset proteinuria [median 1·05 years (IQR:0·63-2·09)]. Normalization of hyperfiltration was less likely with higher baseline eGFR [hazard ratio (HR):0·90, 95% CI: 0·86-0·95; P < 0·0001] and more likely in males (HR:6·35, 95% CI:2·71-14·86, <0·0001). Hyperfiltration is common in adult SCD patients, particularly when younger. Decline to normal values is more likely in males, possibly representing kidney function loss rather than improvement in hyperfiltration.

Reliability of different estimated glomerular filtration rate as measures of renal function in children with sickle cell disease.

BACKGROUND: There is no reliable marker for detecting early renal disease in early children with sickle cell disease (SCD). Estimation of glomerular filtration rate (eGFR) as derived from the height/plasma creatinine formula is dependent on the accuracy of the creatinine analytical method used. The aim of this study was to evaluate different equations for eGFR. METHODS: Children aged 5-16 years recruited. mGFR was obtained using plasma disappearance of Inutest/Iohexol, serum creatinine (SCr) was measured either by standard laboratory method or by tandem mass spectrometry (MSMS). Estimated GFR was then calculated either by "Bedside Schwartz method" or by the full-age spectrum (FAS) equation. FINDINGS: A total of 79 patients (mean age 9.8 ± 4.0 years). A revised eGFR constant was calculated for Schwartz equation from the slope of the plot of height/plasma creatinine versus mGFR. Mean values for mGFR (132.7 ± 32.1 ml/min/1.73m2) and eGFR methods compared: eGFR from standard SCr was significantly higher (144.2 ± 37.3 ml/min/1.73m2, p = 0.008). The MSMS eGFR showed the lowest SD (SD = 27.5), while both FAS eGFR and FAS-height eGFR showed the highest correlation coefficient (r = 0.67). INTERPRETATION: eGFR calculation based on height and SCr determined with MSMS traceable creatinine is more reliable than Schwartz formula using jaffe/enzymatic methods in SCD children.

Effects of hydroxyurea on brain function in children with sickle cell anemia.

INTRODUCTION: Sickle cell anemia (SCA) results in numerous adverse effects on the brain, including neurocognitive dysfunction. Hydroxyurea has been utilized extensively for management of SCA, but its effects on brain function have not been established. METHODS: We examined prospectively the effects of 1 year of treatment with hydroxyurea on brain function in children with SCA (HbSS/HbSß0 -thalassemia) by baseline and exit evaluations, including comprehensive neurocognitive testing, transcranial Doppler ultrasound (TCD), and brain MRI (silent cerebral infarcts [SCI], gray matter cerebral blood flow [GM-CBF], and blood oxygen level-dependent [BOLD] signal from visual stimulation). RESULTS: Nineteen patients with SCA, mean age 12.4 years (range 7.2-17.8), were evaluated. At baseline, subjects had these mean values: full-scale IQ (FSIQ) 82.8, TCD velocity 133 cm/s, GM-CBF 64.4 ml/100 g/min, BOLD signal 2.34% increase, and frequency of SCI 47%. After 1 year of hydroxyurea, there were increases in FSIQ (+2, p = .059) and reading passage comprehension (+4, p = .033), a significant decrease in TCD velocity (-11 cm/s, p = .007), and no significant changes in GM-CBF, BOLD, or SCI frequency. Hemoglobin F (HbF) was associated with passage comprehension, hemoglobin with lower TCD velocity, and lower GM-CBF with greater working memory. Higher BOLD signal was associated with higher processing speed and lower TCD velocity with higher math fluency. DISCUSSION: Improvements in neurocognition and decreased TCD velocity following 1 year of treatment support hydroxyurea use for improving neurocognitive outcomes in SCA. Understanding the mechanisms of benefit, as indicated by relationships of neurocognitive function with HbF, hemoglobin, and CBF, requires further evaluation.

Impact of pre-eclampsia on renal outcome in sickle cell disease patients.

The long-term consequences of pre-eclampsia (PrE) for renal function have never been determined in patients with sickle cell disease (SCD). Between 2008 and 2015, we screened 306 pregnancies in women with SCD and identified 40 with PrE (13%). The control group consisted of 65 pregnant SCD patients without PrE. In multivariable analysis, PrE events were associated with an increase of 1 log of lactate dehydrogenase level (adjusted odds ratio, aOR = 3·83, P = 0·05), a decrease of 10 g/l of haemoglobin levels (aOR = 2·48, P = 0·006) and one or more vaso-occlusive crisis during pregnancy (aOR = 16·68, P = 0·002). Estimated glomerular filtration rate (eGFR) was similar in the two groups at steady state but was significantly lower in the PrE group after one year of follow-up and at last follow-up (130 vs 148 ml/min/1·73 m2 , P < 0·001 and 120 vs 130 ml/min/1·73 m2 , P < 0·001, respectively). In multivariable analysis, eGFR had returned to steady-state levels one year after pregnancy in patients without PrE but continued to decrease in patients with PrE (ß = -18·15 ml/min/1·73 m2 , P < 0·001). This decline was more marked at the end of follow-up (ß = -31·15 ml/min, P < 0·001). In conclusion, PrE episodes are associated with a significant risk of subsequent renal function decline in SCD patients.

P-selectin deficiency promotes liver senescence in sickle cell disease mice.

Sickle cell disease (SCD) is caused by a homozygous mutation in the ß-globin gene, which leads to erythrocyte sickling, vasoocclusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vasoocclusive events in patients with SCD; however, the chronic effect of P-selectin inhibition in SCD remains to be determined. Here, we used quantitative liver intravital microscopy in our recently generated P-selectin-deficient SCD mice to show that chronic P-selectin deficiency attenuates liver ischemia but fails to prevent hepatobiliary injury. Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin-deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance of investigating the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in patients with SCD.

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.

Cognitive Functioning and Educational Support Plans in Youth With Sickle Cell Disease.

Children with sickle cell disease (SCD) face academic challenges because of direct and indirect disease-related events. This study examined the proportion of youth with SCD with educational plans and whether cognitive functioning is associated with educational support. Ninety-one youth (7 to 16 y) with SCD completed the WISC-V; caregivers reported educational support (504 Plan/Individualized Education Program) and completed the Behavior Rating Inventory of Executive Function. χ2 square and t test analyses explored whether overall intelligence (full-scale intelligence quotient [FSIQ]), relative weaknesses in processing speed and working memory (> 1SD below FSIQ), and parent-reported executive functioning were associated with educational plans. Participants with a FSIQ<90 were more likely to have support (74%) compared with youth with a FSIQ≥90 (47%; P=0.012). Those with FSIQ≥90 and FSIQ=80 to 89 were less likely to have support (47%, 58%, respectively) compared with those with FSIQ≤79 (89%; P=0.004). Relative weaknesses in processing speed were associated with educational support (83% vs. 52%, P=0.018) as well as behavioral aspects of executive functioning (Ps<0.05). Despite universal eligibility for a 504 Plan, 42% of youth with SCD in our sample did not have educational support. Significant deficits in intellectual functioning, processing speed, and parent-observed executive functioning are associated with having a plan, but children with subtle deficits seem less likely to be identified for educational support.

Proteinuric and nonproteinuric chronic kidney disease among patients with sickle cell anaemia (HbSS) attending a tertiary hospital in north-eastern Nigeria.

OBJECTIVE/BACKGROUND: Individuals with sickle cell anaemia (SCA) may manifest various forms of renal abnormalities. Proteinuria is an early marker of renal dysfunction and a strong risk factor for chronic kidney disease (CKD) progression in both patients with SCA and non-SCA population. Currently, the degree of attention given to proteinuric CKD far exceeds that of nonproteinuric CKD, and risk factors that might trigger a progressive decline of the glomerular filtration rate (GFR) in the absence of proteinuria have not been well evaluated in SCA. The aim of this study was to compare the clinical and laboratory parameters among SCA patients with proteinuric and nonproteinuric CKD. METHODS: This was a cross-sectional study conducted at the University of Maiduguri Teaching Hospital in north-eastern Nigeria between January 2013 and April 2018. Clinical variables including age of diagnosis of SCA, frequency of vaso-occlusive crises, number of hospitalizations per annum and transfusion therapy were collected. Laboratory data including haematological profile and renal function test were obtained from routine blood sampling. RESULTS: A total of 257 patients with SCA (HbSS) were enrolled during the study period of which 42 had proteinuric CKD, and 48 had nonproteinuric CKD. The two groups were matched for the number of hospital admission (p = .063) and blood transfusion per year (p = .450), frequency of painful crisis (p = .210), systolic blood pressure (p = .084) and diastolic blood pressure (p = .400). In the proteinuric CKD group, the mean serum creatinine was higher (332.17 µmol/L, p = .001) and the estimated GFR was lower (31.88 mL/min, p = .046). The serum alkaline phosphatase was higher in the nonproteinuric CKD group (81.81 IU/L, p = .012). CONCLUSION: Nonproteinuric CKD was more frequent than proteinuric CKD in our study population; however, the proteinuric group presented with more advanced disease.

Chronic osteo-articular changes in patients with sickle cell disease

Abstract Background: Sickle cell disease (SCD) is an autosomal recessive genetic disease in which a mutation occurs in the β-globin chain gene, resulting in abnormal hemoglobin levels. In an environment with reduced oxygen concentration, red blood cells change their conformation, resulting in chronic hemolysis and consequent anemia and vaso-occlusive crises with injuries to several organs, with a significant impairment of the osteoarticular system. This study aimed to verify the chronic osteoarticular alterations and their association with clinical and laboratory characteristics of patients with SCD with a more severe phenotype (SS and Sβ0), on a steady-state fasis. Methods: Fifty-five patients were referred to a medical consultation with a specialized assessment of the locomotor system, followed by laboratory tests and radiographic examinations. Results: In total, 74.5% patients had hemoglobinopathy SS; 67.3% were female; and 78.2% were non-whites. The mean patient age was 30.5 years. Most patients (61.8%) reported up to three crises per year, with a predominance of high-intensity pain (65.5%). Radiographic alterations were present in 80% patients. A total of 140 lesions were identified, most which were located in the spine, femur, and shoulders. Most lesions were osteonecrosis and osteoarthritis and were statistically associated with the non-use of hydroxyurea. Conclusions: There was a high prevalence of chronic osteoarticular alterations, which was statistically associated only with the non-regular use of hydroxyurea.(AU)

Non-hematopoietic deficiency of proprotein convertase subtilisin/kexin type 9 deficiency leads to more severe anemia in a murine model of sickle cell disease.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency leads to lower cholesterol and is associated with reduced vascular complications in the general population. Cholesterol lowering may also have beneficial effects in sickle cell disease (SCD). The objective of this study was to determine effects of PCSK9 deficiency in a mouse model of SCD. Bone marrow transplantation (BMT) was performed from donor SCD mice to wild-type, PCSK9-deficient, and LDLR-deficient recipients to generate SCD controls (Pcsk9+/+, SCDbmt) with preserved PCSK9 status, SCD mice with deficiency of PCSK9 (Pcsk9-/-, SCDbmt), and SCD mice with deficiency of LDLR (Ldlr-/-, SCDbmt). Although cholesterol levels were lower in Pcsk9-/-, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice, anemia was more severe in Pcsk9-/-, SCDbmt mice. Increased reticulocytosis, enhanced ex vivo erythrocyte sickling, and increased erythrocyte phosphatidylserine exposure was also observed. Livers, spleens, and kidneys contained increased iron in Pcsk9-/-, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice consistent with greater hemolysis. SCD mice with deficiency of LDLR (Ldlr-/-, SCDbmt mice) had similar anemia as Ldlr+/+, SCDbmt mice despite higher serum cholesterol. In conclusion, deficiency of PCSK9 is associated with worsened anemia in SCD mice due to increased hemolysis. These findings may have implications for lipid-lowering strategies in patients with SCD, as well as for potential novel modifiers of anemia severity.