Quinn, CT; Saraf, SL; Gordeuk, VR; Fitzhugh, CD; Creary, SE; Bodas, P; George, A; Raj, AB; Nero, AC; Terrell, CE; McCord, L; Lane, A; Ackerman, HC; Yang, Y; Niss, O; Taylor, MD; Devarajan, P; Malik, P. Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial. American Journal of Hematology. 2017; 92(9):E520-E528.
Nephropathy (kidney disease) is a common and progressive complication of sickle cell anemia (SCA), one feature of which is the loss of protein in the urine (albuminuria). Based on positive findings in a mouse model of SCA treated with losartan, an angiotensin receptor blocker, we studied the effects of losartan in children and adults with SCA in a phase-2 clinical trial. We found that losartan decreased urinary albumin excretion in most participants with albuminuria. Those with the highest amounts of albuminuria had the greatest benefit. The medication was also tolerated well. This study forms the basis for a phase-3, randomized, placebo-controlled trial of losartan that we are currently designing, which we hope will conclusively demonstrate its therapeutic benefits.
Tarango, C; Kumar, R; Patel, M; Blackmore, A; Warren, P; Palumbo, JS. Inferior vena cava atresia predisposing to acute lower extremity deep vein thrombosis in children: A descriptive dual-center study. Pediatric Blood and Cancer. 2018; 65(2):e26785-e26785.
This retrospective study suggests that inferior vena cava (IVC) atresia is a risk factor for unprovoked lower extremity deep vein thrombosis (LE DVT), pulmonary embolism, and recurrent thrombosis in otherwise healthy children. This study also highlights the importance of dedicated imaging of the IVC in young patients with unprovoked LE DVT. While the optimal long-term treatment of IVC atresia-associated thrombosis is unclear, indefinite anticoagulation may be something to consider in pediatric patients presenting with unprovoked thrombosis secondary to an atretic IVC.
Opoka, RO; Ndugwa, CM; Latham, TS; Lane, A; Hume, HA; Kasirye, P; Hodges, JS; Ware, RE; John, CC. Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia. Blood. 2017; 130(24):blood-2017-06-788935-blood-2017-06-788935.
Hydroxyurea has proven laboratory and clinical efficacy for children with sickle cell anemia, but almost all studies conducted to date have been in high-resource settings like the United States and Europe. In sub-Saharan Africa, where the burden of sickle cell anemia is the highest, there is very little experience with hydroxyurea treatment. Since special co-morbidities in Africa, such as malnutrition and malaria, could have important influences on the hydroxyurea treatment effects, we designed a prospective research trial of hydroxyurea versus placebo for very young children with sickle cell anemia living in Uganda. A total of 208 children received treatment for one year, and hydroxyurea treatment was not associated with worse malaria events, either by the number of infections of their severity. Hydroxyurea did have the expected laboratory and clinical benefits, however, suggesting that it may be a safe and effective drug for sickle cell anemia in sub-Saharan Africa.
Smart, LR; Ambrose, EE; Raphael, KC; Hokororo, A; Kamugisha, E; Tyburski, EA; Lam, WA; Ware, RE; McGann, PT. Simultaneous point-of-care detection of anemia and sickle cell disease in Tanzania: the RAPID study. Annals of Hematology. 2018; 97(2):239-246.
Anemia is a common cause of global morbidity and mortality, disproportionately affecting women and children living in resource-limited settings, and sickle cell disease (SCD) is one of the most important causes. RAPID was a prospective study performed at Bugando Medical Centre, a busy referral hospital in northwest Tanzania, that investigated the accuracy and feasibility of two novel point-of-care (POC) assays for the diagnosis of anemia and SCD in a real-world field evaluation within sub-Saharan Africa. The sickle cell disease POC test was highly sensitive and specific compared to the laboratory result, even when interpreted by numerous minimally trained personnel with variable expertise in clinical medicine. The first generation, color-based point-of-care anemia assay demonstrated good correlation with the laboratory result, showed excellent interobserver agreement, and will use results to refine the next generation of the assay. RAPID provides important pilot data for the implementation of these POC assays in limited resource settings where needed the most.
Lesmana, H; Dyer, L; Li, X; Denton, J; Griffiths, J; Chonat, S; Seu, KG; Heeney, MM; Zhang, K; Hopkin, RJ; Kalfa, TA. Alu element insertion in PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients. Human Mutation. 2018; 39(3):389-393.
Pyruvate kinase deficiency (PKD) is the most frequent cause of hereditary nonspherocytic hemolytic anemia, caused by mutations in the PKLR-gene. We discovered a novel type of PKLR mutation caused by an Alu retrotransposon insertion in PKLR in a young male patient of Middle-Eastern descent with transfusion-dependent chronic hemolytic anemia born to consanguineous parents. The mutation detected by Next Generation Sequencing utilizing our hereditary hemolytic anemia gene panel (developed and offered as a clinical test in Cincinnati Children’s). Further sequence analysis identified AluYb9 within exon 6 of the PKLR gene. A second unrelated patient from Middle East has the same mutation, indicating the possibility of a founder Alu-insertion event in PKLR in the Arab population.