ALBERT

Description: Background: Nephropathy in sickle cell anemia (SCA) begins in childhood and portends chronic kidney disease, renal failure, and early mortality among affected adults. Individuals of African descent have disproportionately higher rates of developing non-diabetic renal disease. Several candidate genetic variants have been identified, including some specific to African Americans, which are associated with the development of albuminuria and renal disease. The influence of genetic polymorphisms on albuminuria and elevated glomerular filtration rate (GFR) in children with SCA, both early signs of sickle nephropathy, has not been investigated. Objectives: To determine the influence of selected single nucleotide polymorphisms (SNPs) on the development of albuminuria and elevated GFR in children with SCA; to identify novel genetic variants influencing albuminuria and GFR by whole exome sequencing (WES). Design/Methods: Genomic DNA was collected on children with SCA enrolled in two prospective studies with pre-hydroxyurea renal assessments (n=185): (1) Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175, n=79) with no prior disease-modifying therapy; and (2) Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH, NCT 01425307, n=106) on chronic transfusions for abnormal TCD velocities. Albuminuria was defined as ≥30mg albumin/gm creatinine on the pre-hydroxyurea urine specimen. GFR was measured in HUSTLE using plasma DTPA (technetium 99m-labeled diethylenetriaminepentaacetic acid) clearance, and estimated GFR (eGFR) in TWiTCH based on serum creatinine. DNA samples were genotyped for 8 candidate SNPs previously associated with renal disease, using PCR-based allelic discrimination, bidirectional Sanger sequencing, and analysis of variable number tandem repeats (VNTR). Associations between albuminuria and genetic polymorphisms were tested using an additive model and correlation trend test. Linked WES data from the same patients were analyzed to identify other variants associated with albuminuria and GFR. Results: Albuminuria was present in 13.1% of patients, including 16.3% in HUSTLE and 11.0% in TWiTCH. APOL1 genetic variants were common (G1 allele frequency = 21.9%, G2 allele = 16.0%, Table) and similar to published cohorts. Children with two APOL1 G1 alleles had an increased risk of albuminuria that approached statistical significance (p=0.053). Conversely, the presence of the DARC SNP that confers Duffy antigen expression had a protective effect (p=.038). WES analysis did not identify additional non-synonymous APOL1 variants linked with albuminuria. However, 93 non-synonymous variants were associated with DTPA GFR (p

Description: Transcranial Doppler (TCD) screening in children with sickle cell anemia (SCA) identifies abnormally elevated cerebral artery flow velocities that confer an elevated risk for primary stroke. Chronic transfusions offer effective stroke prophylaxis in this setting, but must be continued indefinitely and lead to transfusional iron overload. An alternative treatment strategy that offers similar effective protection against primary stroke, and provides control of iron overload, is needed. TCD With Transfusions Changing to Hydroxyurea (TWiTCH, NCT01425307) was an NHLBI-funded Phase III multicenter randomized clinical trial comparing 24-months of standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with SCA and abnormal TCD velocities. All eligible children had received at least 12 months of transfusions. TWiTCH had a non-inferiority trial design; the primary study endpoint was the 24-month TCD velocity obtained from a linear mixed model, controlling for baseline (enrollment) values, with a non-inferiority margin of 15 cm/sec. The transfusion arm maintained children at HbS

Description: Introduction: The TCD with Transfusions Changing to Hydroxyurea (TWiTCH) trial was an NHLBI-funded multicenter phase 3 randomized trial that demonstrated non-inferiority of hydroxyurea versus continued transfusion therapy in children with sickle cell anemia and abnormal TCD velocities but no severe vasculopathy. Children who were randomized to continue transfusions (Standard Arm) received conventional iron chelation therapy with deferasirox, while children receiving hydroxyurea (Alternative Arm) received serial phlebotomy (10 mL/kg, maximum 500 mL) every 4 weeks. Extrahepatic iron burden was monitored by R2* MRI in the kidney, pancreas, and spleen to monitor the changes in iron overload phenotype between the two groups. Methods: R2* MRI of the abdomen was performed at baseline, 1 year, and 2 years following enrollment. Liver, spleen, pancreas, and kidney R2* were measured from axial and coronal multiecho, gradient echo images. Images were analyzed centrally at an experienced core laboratory using an exponential plus constant model for signal decay. Iron burden in the different organs was assessed using repeated measures analysis of variance (ANOVA) using JMP 11.0. Results: 120 patients underwent baseline R2* assessment, 83 completed the midpoint, and 89 patients completed the endpoint examination. Figure 1 (left) summarizes the changes in kidney R2* across the three time points. Kidney R2* was elevated at baseline in both treatment arms and correlated with LDH (r2 =0.28, p 100 Hz) was only observed in two patients at the mid timepoint. Spleen R2* was markedly elevated at baseline (503 ± 396 Hz), but did not change systematically over time in either group. The change in spleen R2* was correlated with the change in liver iron (r2=0.21, p=0.003), regardless of the treatment group, suggesting that the spleen iron stores are part of the dynamic iron storage pool. 37% of the patients had no MRI-detectable spleen (surgical + autosplenectomy). The change of liver iron was not different in patients with or without a spleen. Conclusion: Hydroxyurea therapy was associated with lower intravascular hemolysis and kidney iron deposition. Further studies are necessary to determine whether these changes are associated with decreased proteinuria or improved renal function. Splenic iron burden remained high but stable in all patients, and its role in iron unloading needs further investigation. Pancreas iron loading remained rare, consistent with the low prevalence of endocrinopathies in SCD. Figure 1 Figure 1. Disclosures Wood: Apopharma: Consultancy; Ionis Pharmaceuticals: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Biomed Informatics: Consultancy; AMAG: Consultancy; Biomed Informatics: Consultancy; Ionis Pharmaceuticals: Consultancy; World Care Clinical: Consultancy; World Care Clinical: Consultancy; Celgene: Consultancy; Apopharma: Consultancy; Celgene: Consultancy; AMAG: Consultancy. Heeney:Sancilio and Company: Consultancy, Research Funding; Eli Lilly and Company: Research Funding; Pfizer: Research Funding. Ware:Global Blood Therapeutics: Consultancy; Nova Laboratories: Consultancy; Biomedomics: Research Funding; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Bayer Pharmaceuticals: Consultancy.

Description: Introduction Biopsychosocial models of illness suggest that a combination of disease-related and psychosocial factors influence outcomes for patients. In pediatric sickle cell disease (SCD), caregivers play a significant role in helping children to manage pain, including during home-based management of episodes as well as during the decision-making process for seeking health care services for severe episodes. Few previous studies have examined the extent to which caregiver psychological functioning is related to health outcomes for pediatric patients with SCD. The purpose of the present study was to determine how two specific aspects of psychological functioning (caregiver coping style and mood) impact pain outcomes for this population. Methods Caregivers (N = 70) and their children with SCD (N = 76) were recruited at routine hematological visits to participate in a study of pain in pediatric SCD. Caregivers completed ratings of coping style (active versus passive coping) using the Coping Strategies Questionnaire, Revised. Caregivers also completed ratings of positive and negative mood using the Positive and Negative Affect Scale, Revised. Information on recent pain history was collected using the Structured Pain Interview for SCD. Both caregivers and children completed the interviews and their ratings were averaged to produce final pain ratings. Information was collected on pain frequency (total over the past 12 months) and pain intensity and duration (average over the past 12 months). Medical record review was used to collect information on health care utilization for pain over the past 24 months, including total number of emergency room visits, hospitalizations, and outpatient contacts for pain. A structured coding method was used to examine medical records and a second rater independently verified the information. The medical record was also used to confirm the child’s SCD subtype. Multiple hierarchical regressions were used to determine the effects of caregiver coping style and mood on pain and health care utilization. All models controlled for child age, gender, and disease subtype (high versus low risk). Results Multiple hierarchical regression analysis suggested that caregiver psychological functioning was associated with pain duration and health care utilization. Specifically, caregiver negative mood contributed a significant amount of variance to the model for pain duration (F (1, 65) = 8.01, p = .006, R2 = .11). In addition, caregiver active and passive coping contributed a significant amount of variance to the model for health care utilization (F (2, 64) = 3.91, p = .025, R2 = .10) and passive coping was a significant individual predictor of utilization (p = .041). Caregiver psychological variables were not significantly related to pain frequency or intensity. Conclusion Caregivers of children with SCD play an important role in helping children to manage pain. The present study suggests that improving caregiver psychological functioning may help to improve pain outcomes for children with SCD. In particular, negative mood and passive coping were most related to poorer pain outcomes in terms of duration and health care utilization. Negative mood tends to be associated with poorer psychological functioning, including higher ratings of anxiety and depression, whereas passive coping tends to reflect negative beliefs about pain and less reliance on active approaches to pain management. Clinicians working with caregivers may benefit from focusing on the aspects of pain that are more controllable for families, such as preventative approaches to pain episodes or adherence with existing home-based protocols. Referrals for additional psychosocial supports may also be beneficial for caregivers presenting with poorer psychological functioning. Limitations of the present study include the cross-sectional design and the use of retrospective pain ratings. Understanding the temporal precedence of pain and caregiver psychological functioning would be beneficial in future studies. Disclosures No relevant conflicts of interest to declare.