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Ofelia Alvarez,
Scott T Miller,
Winfred C Wang,
Zhaoyu Luo,
M Beth McCarville,
George J Schwartz,
Bruce Thompson,
Thomas Howard,
Rathi V Iyer,
Sohail R Rana,
Zora R Rogers, Sharada A Sarnaik,
Courtney D Thornburg,
Russell E Ware
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ABSTRACT: Children with sickle cell anemia (SCA) often develop hyposthenuria and renal hyperfiltration at an early age, possibly contributing to the glomerular injury and renal insufficiency commonly seen later in life. The Phase III randomized double-blinded Clinical Trial of Hydroxyurea in Infants with SCA (BABY HUG) tested the hypothesis that hydroxyurea can prevent kidney dysfunction by reducing hyperfiltration.
193 infants with SCA (mean age 13.8 months) received hydroxyurea 20 mg/kg/day or placebo for 24 months. (99m) Tc diethylenetriaminepentaacetic acid (DTPA) clearance, serum creatinine, serum cystatin C, urinalysis, serum and urine osmolality after parent-supervised fluid deprivation, and renal ultrasonography were obtained at baseline and at exit to measure treatment effects on renal function.
At exit children treated with hydroxyurea had significantly higher urine osmolality (mean 495 mOsm/kg H(2) O compared to 452 in the placebo group, P = 0.007) and a larger percentage of subjects taking hydroxyurea achieved urine osmolality >500 mOsm/kg H(2) O. Moreover, children treated with hydroxyurea had smaller renal volumes (P = 0.007). DTPA-derived glomerular filtration rate (GFR) was not significantly different between the two treatment groups, but was significantly higher than published norms. GFR estimated by the Chronic Kidney Disease in Children (CKiD) Schwartz formula was the best non-invasive method to estimate GFR in these children, as it was the closest to the DTPA-derived GFR.
Treatment with hydroxyurea for 24 months did not influence GFR in young children with SCA. However, hydroxyurea was associated with better urine concentrating ability and less renal enlargement, suggesting some benefit to renal function.
Pediatric Blood & Cancer 01/2012; 59(4):668-74. · 1.89 Impact Factor
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Michael R DeBaun, Sharada A Sarnaik,
Mark J Rodeghier,
Caterina P Minniti,
Thomas H Howard,
Rathi V Iyer,
Baba Inusa,
Paul T Telfer,
Melanie Kirby-Allen,
Charles T Quinn, [......],
Corina E Gonzalez,
Suzanne L Saccente,
Karen A Kalinyak,
John J Strouse,
Jason M Fixler,
Mae O Gordon,
J Phillip Miller,
Michael J Noetzel,
Rebecca N Ichord,
James F Casella
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ABSTRACT: The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.
Blood 11/2011; 119(16):3684-90. · 9.90 Impact Factor
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ABSTRACT: We report a rare case of juvenile cobalamin deficiency who presented at the age of 17 years. He was underweight and had skin changes, normocytic anemia, and autonomic dysfunction, which led to adynamic ileus and acute postrenal failure. The expected macrocytosis was masked by an underlying alpha-thalassemia trait. The patient had an excellent response to parenteral cobalamin treatment.
Journal of Pediatric Hematology/Oncology 11/2011; 34(2):140-2. · 1.16 Impact Factor
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Winfred C Wang,
Russell E Ware,
Scott T Miller,
Rathi V Iyer,
James F Casella,
Caterina P Minniti,
Sohail Rana,
Courtney D Thornburg,
Zora R Rogers,
Ram V Kalpatthi, [......], Sharada A Sarnaik,
Thomas H Howard,
Lynn W Wynn,
Abdullah Kutlar,
F Daniel Armstrong,
Beatrice A Files,
Jonathan C Goldsmith,
Myron A Waclawiw,
Xiangke Huang,
Bruce W Thompson
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ABSTRACT: Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects.
This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ(0)thalassaemia, were aged 9-18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on (99)Tc spleen scan) and renal function (glomerular filtration rate by (99m)Tc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2-4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400.
96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m(2), p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia.
On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia.
The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.
The Lancet 05/2011; 377(9778):1663-72. · 38.28 Impact Factor
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Monica L Hulbert,
Robert C McKinstry,
JoAnne L Lacey,
Christopher J Moran,
Julie A Panepinto,
Alexis A Thompson, Sharada A Sarnaik,
Gerald M Woods,
James F Casella,
Baba Inusa,
Jo Howard,
Fenella J Kirkham,
Kofi A Anie,
Jonathan E Mullin,
Rebecca Ichord,
Michael Noetzel,
Yan Yan,
Mark Rodeghier,
Michael R Debaun
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ABSTRACT: Children with sickle cell disease (SCD) and strokes receive blood transfusion therapy for secondary stroke prevention; despite this, approximately 20% experience second overt strokes. Given this rate of second overt strokes and the clinical significance of silent cerebral infarcts, we tested the hypothesis that silent cerebral infarcts occur among children with SCD being transfused for secondary stroke prevention. A prospective cohort enrolled children with SCD and overt strokes at 7 academic centers. Magnetic resonance imaging and magnetic resonance angiography of the brain were scheduled approximately every 1 to 2 years; studies were reviewed by a panel of neuroradiologists. Eligibility criteria included regularly scheduled blood transfusion therapy. Forty children were included; mean pretransfusion hemoglobin S concentration was 29%. Progressive cerebral infarcts occurred in 45% (18 of 40 children) while receiving chronic blood transfusion therapy; 7 had second overt strokes and 11 had new silent cerebral infarcts. Worsening cerebral vasculopathy was associated with new cerebral infarction (overt or silent; relative risk = 12.7; 95% confidence interval, 2.65-60.5, P = .001). Children with SCD and overt strokes receiving regular blood transfusion therapy experience silent cerebral infarcts at a higher rate than previously recognized. Additional therapies are needed for secondary stroke prevention in children with SCD.
Blood 10/2010; 117(3):772-9. · 9.90 Impact Factor
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Russell E Ware,
Renee C Rees, Sharada A Sarnaik,
Rathi V Iyer,
Ofelia A Alvarez,
James F Casella,
Barry L Shulkin,
Eglal Shalaby-Rana,
C Frederic Strife,
John H Miller,
Peter A Lane,
Winfred C Wang,
Scott T Miller
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ABSTRACT: To examine the feasibility and accuracy of glomerular filtration rate (GFR) measurements in infants with sickle cell anemia (SCA).
The NHLBI/NICHD-sponsored Phase III randomized double-blinded placebo-controlled trial (BABY HUG) tests the hypothesis that hydroxyurea can prevent chronic organ damage in SCA. GFR elevation is a coprimary endpoint, measured quantitatively by technetium 99m-labeled diethylenetriaminepentaacetic acid (DTPA) plasma clearance and estimated by the Schwartz equation with height and creatinine.
Baseline DTPA GFR measurement was attempted in 191 infants; 176 of 184 completed studies (96%) were interpretable. Average age (mean +/- 1SD) was 13.7 +/- 2.6 months. Average DTPA GFR was 125.2 +/- 34.4 (range 40.2-300.9, normal 91.5 +/- 17.8 mL/min/1.73m(2)), while Schwartz estimates were higher at 184.4 +/- 55.5 mL/min/1.73m(2). DTPA GFR was correlated with Schwartz GFR (r(2) = 0.0658, P = .0012); also with age, weight, height, and kidney volume (all P < .002); but not with hemoglobin, HbF, white blood cell count, reticulocytes, medical events, or splenic function.
Quantitative GFR measurement is feasible but variable among infants with SCA. Schwartz GFR estimates are not highly correlated with quantitative DTPA GFR values. Baseline GFR measurements suggest that renal dysfunction in SCA, evidenced by glomerular hyperfiltration, begins during infancy.
The Journal of pediatrics 10/2009; 156(1):66-70.e1. · 4.02 Impact Factor
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Sharada A. Sarnaik,
James F. Casella,
Bruce A Barton,
Michele Afif,
Gladstone Airewele,
Brian W. Berman,
Francoise Bernaudin,
Thomas Coates,
Beng Fuh,
Helge Hartung, [......],
Charles T. Quinn,
Rupa Redding-Lallinger,
Melissa M. Rhodes,
Hernan Sabio,
Suzanne Saccente,
Charles Scher,
Paul Telfer,
Alexis A Thompson,
Gerald M Woods,
Michael R. DeBaun
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ABSTRACT: Abstract 262 IntroductionThe most common cause of neurological injury in sickle cell anemia is silent cerebral infarcts (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial) cohort, we sought to identify risk factors associated with SCI. Patients and MethodsIn this cross-sectional study, we evaluated the clinical history, baseline laboratory values and performed magnetic resonance imaging of the brain. For those children with SCI-like lesions, a pediatric neurologist examined the child and neuroradiology and neurology committees adjudicated the presence of SCI. Children between the ages of 5 and 15 years with hemoglobin SS or S-beta{degrees} thalassemia and no history of overt strokes or seizure were evaluated. ResultsA total of 542 children were evaluated; 173 (31.9%) had SCI. The mean age of the children was 9.3 years, with 280 males (51.7%). In a multivariate logistic analysis, two covariates were significant: a single systolic blood pressure (SBP) obtained during a baseline well-visit, p = 0.015 and hemoglobin F (Hgb F) level obtained after three years of age, p = 0.038. Higher values of SBP and lower values of Hgb F increased the odds of SCI; Figure. Baseline values of white blood cell count, hemoglobin level, oxygen saturation, reticulocytes, pain, or ACS event rates were not associated with SCI. [IMG] /small/bld0010900030002.gif" ALT="Figure 1"> Figure. Joint effect of fetal hemoglobin and systolic blood -pressure on odds of silent cerebral infarct in 542 children with hemoglobin SS or S-beta{degrees}-thalassemia between 5 and 15 years of age. ConclusionSBP and Hgb F level are two previously unidentified risk factors for SCI in children with sickle cell disease. Modulation of SBP and Hgb F levels might decrease the risk of SCI. DisclosuresNo relevant conflicts of interest to declare.
Blood (ASH Annual Meeting Abstracts). 01/2009; 114(22):262-.
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ABSTRACT: Although cardiac involvement is common in adult sickle cell disease (SCD) patients, it is unknown when cardiac dysfunction appears in the course of SCD. Diastolic function has not been comprehensively analyzed in children with SCD. Thus, our aim was to evaluate diastolic function in pediatric SCD patients. Echocardiograms were performed in 156 (73 SC and 81 control) patients. Left ventricular and left atrial volumes, left ventricular mass, mitral inflow, and tissue Doppler indices (TDI) were obtained. The right ventricular pressures (RVP) were calculated. For each SCD patient, mean hemoglobin (Hb), fetal hemoglobin (HbF) levels, and blood transfusion encounters were recorded. Data were analyzed using t-test, univariate and multivariate regression, and Spearman correlation analyses. SCD patients had significantly larger left ventricular and atrial volumes than controls. Mitral inflow velocities were significantly higher in the SCD group. Of 73 SCD subjects, 32 had left ventricular dilatation, 11 had hypertrophy, and 25 had elevated RVP. Left ventricular size was inversely related to Hb, but unrelated to HbF or age. The early mitral inflow velocity was correlated negatively with Hb and positively with left ventricular sizes. TDI indices did not differ between the SCD and control groups. They were unrelated to Hg, HgF, transfusion history, or ventricular size; however, Doppler indices of left ventricular stiffness were increased in SCD patients. Pediatric SCD patients demonstrate increased left ventricular stiffness, and a significant percentage of them have left ventricular hypertrophy. There are strong positive relations between left ventricular hypertrophy and right ventricular pressure in these patients. TDI should be employed in the evaluation of SCD patients.
American Journal of Hematology 07/2007; 82(6):433-8. · 4.67 Impact Factor
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ABSTRACT: Localized Langerhans cell histiocytosis (LCH) of bone often presents as a diagnostic challenge. Magnetic resonance imaging (MRI) is frequently used to better delineate most solitary bony lesions. The authors present two cases that illustrate and better define the role of MRI in the evaluation of solitary bone lesions of LCH. In a 3-year-old boy with left-sided hip pain, MRI showed a focal lesion involving the proximal left femur with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. A tumor was suspected because of the overall imaging characteristics and increased uptake on three-phase nuclear scintigraphy. In a 6-year-old boy with right thigh pain, MRI showed a fluid-containing lesion in the mid-diaphysis of the right femur, suggestive of chronic osteomyelitis and Brodie abscess. MRI was instrumental in showing the extent of the lesions in both cases; however, the final diagnosis of LCH was achieved only with histopathologic confirmation, illustrating the limited diagnostic power of this imaging tool.
Journal of Pediatric Hematology/Oncology 09/2005; 27(8):432-5. · 1.16 Impact Factor
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Sharada A Sarnaik
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ABSTRACT: Hemoglobinopathies are the most common single gene disorders in man. There are several hundred of these disorders though the thalassemias -- alpha and beta and the sickling disorders make up the vast majority. Recent advances in the understanding of the hemoglobin structure and the genetics of its synthesis has contributed significantly to the understanding of these diseases. Disorders include those with reduced globin synthesis, abnormal globin chains and failure to switch globin chain synthesis at the appropriate age. This review focuses on the clinical features, diagnosis and management strategies of the alpha and beta thalassemias, the sickling disorders and touches on a few rarer hemoglobinopathies. It also emphasizes prevention strategies and chronic transfusion safety in countries like India where there are limited resources.
The Indian Journal of Pediatrics 05/2005; 72(4):319-24. · 0.52 Impact Factor
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Sharada A Sarnaik
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ABSTRACT: Sickle cell disease is an important and common hemoglobinopathy that is highly prevalent worldwide. Recent clinical research has clarified the natural history, and newer, exciting therapeutic maneuvers have been developed, including stem cell transplantation, a curative, albeit toxic strategy. There is a need for early identification of a severe disease profile so that these newer therapeutic interventions can be offered before severe organ damage occurs. Investigative methodologic research by radiologists to discover early organ damage can be important to successful planning of treatment protocols. Stroke is one complication, which, if diagnosed early, can be satisfactorily managed with more aggressive therapy. The advent of transcranial Doppler and MRI have greatly increased the ability to detect early CNS disease.
Pediatric Radiology 04/2005; 35(3):223-8. · 1.67 Impact Factor
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Journal of Pediatric Hematology/Oncology 24(6):509-10. · 1.16 Impact Factor
