Shivi Jain

APOL1,α-thalassemia, and BCL11A variants as a genetic risk profile for progression of chronic kidney disease in sickle cell anemia

Sickle cell anemia (SCA) is caused by a mutation in the β-globin gene that results in hemoglobin polymerization and affects approximately 1 in 500 African Americans and 25 million people worldwide. Chronic kidney disease (CKD) is observed in up to 58% of adults, and is associated with a 3-fold increased risk for early mortality in SCA. Multiple genetic modifiers of clinical complications in SCA have been reported, and combining these genetic factors into a risk profile may strengthen the predictive value as compared to the individual factors alone. Homozygosity or compound heterozygosity for APOL1 G1/G2 (G1=S342G/I384M substitutions, G2=N388/Y389 deletions) is observed in 10-15% of African Americans, and is the strongest genetic association for CKD in African Americans in general. APOL1 G1/G2 is also associated with proteinuria and albumin-

Patterns of opioid use in sickle cell disease

Pain, the hallmark complication of sickle cell disease (SCD), is largely managed with opioid analgesics in the United States, but comprehensive data regarding the long‐term use of opioids in this patient population is lacking. The pain medication prescription records from a cohort of 203 SCD patients were analyzed. Twenty‐five percent were not prescribed opioid medications while 47% took only short‐acting opioids, 1% took only long‐acting opioids, and 27% took a combination of short‐acting and long‐acting opioids. The median (interquartile range) daily opioid dose was 6.1 mg (1.7–26.3 mg) of oral morphine equivalents, which is lower than the published opioid use among patients with other pain syndromes. The dose of opioids correlated with the number of admissions due to vaso‐occlusive crisis (VOC) (r = 0.53, P < 0.001). When the patients were grouped into quartiles based on daily dose opioid use, a logistic regression model showed that history of avascular necrosis (AVN) (OR: 2.87, 95% CI: 1.37–6.02, P = 0.005), 25‐OHD levels (OR: 0.59, 95% CI: 0.38–0.93, P = 0.024) and total bilirubin concentration (OR: 0.64, 95% CI: 0.42–0.99, P = 0.043) were independently associated with opioid use quartiles. In conclusion, doses and types of opioid medications used by adult SCD patients vary widely. Our findings implicate AVN and lower vitamin D levels as factors associated with higher opioid use. They also suggest an association of higher bilirubin levels, possibly suggesting higher hemolytic rate, with lower opioid use. Am. J. Hematol. 91:1102–1106, 2016.

Risk factors for vitamin D deficiency in sickle cell disease

Vitamin D deficiency (VDD), 25‐OHD levels <20 ng/ml, is prevalent among patients with sickle cell disease (SCD) and is linked to acute and chronic pain and bone fracture in this population. There is limited literature regarding VDD‐associated risk factors for SCD. We examined potential clinical and genomic parameters associated with VDD in 335 adults with SCD in a cross‐sectional study. VDD was present in 65% of adult SCD patients, and 25‐OHD levels independently and positively correlated with older age (P < 0·001) and vitamin D supplementation (P < 0·001). 25‐OHD levels were higher in SCD patients over 40 years of age compared to the general African‐American population. Both lower 25‐OHD levels and increased pain frequency were associated with increased expression of SLC6A5 encoding glycine transporter‐2 (GlyT2), a protein involved in neuronal pain pathways. Lower 25‐OHD levels were also associated with increased expression of CYP3A4, and with decreased expression of GC (also termed DBP) and VDR, three genes involved in vitamin D metabolism. We conclude that vitamin D supplementation should be an almost universal feature of the care of young adults with SCD, and that further research is warranted into genomic factors that regulate vitamin D metabolism in SCD.

Erythropoiesis-stimulating agents in sickle cell anaemia

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Nadeu, F., Delgado, J., Royo, C., Baumann, T., Stankovic, T., Pinyol, M., Jares, P., Navarro, A., Martin-Garcia, D., Bea, S., Salaverria, I., Oldreive, C., Aymerich, M., Suarez-Cisneros, H., Rozman, M., Villamor, N., Colomer, D., Lopez-Guillermo, A., Gonzalez, M., Alcoceba, M., Terol, M.J., Colado, E., Puente, X.S., Lopez-Otin, C., Enjuanes, A. & Campo, E. (2016) Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1 and ATM mutations in chronic lymphocytic leukemia. Blood, 127, 2122–2130. Pozzo, F., Bittolo, T., Arruga, F., Bulian, P., Macor, P., Tissino, E., Gizdic, B., Rossi, F.M., Bomben, R., Zucchetto, A., Benedetti, D., Degan, M., D’Arena, G., Chiarenza, A., Zaja, F., Pozzato, G., Rossi, D., Gaidano, G., Del, P.G., Deaglio, S., Gattei, V. & Dal, B.M. (2016) NOTCH1 mutations associate with low CD20 level in chronic lymphocytic leukemia: evidence for a NOTCH1 mutation-driven epigenetic dysregulation. Leukemia, 30, 182–189. 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Puente, X.S., Bea, S., Valdes-Mas, R., Villamor, N., Gutierrez-Abril, J., Martin-Subero, J.I., Munar, M., Rubio-Perez, C., Jares, P., Aymerich, M., Baumann, T., Beekman, R., Belver, L., Carrio, A., Castellano, G., Clot, G., Colado, E., Colomer, D., Costa, D., Delgado, J., Enjuanes, A., Estivill, X., Ferrando, A.A., Gelpi, J.L., Gonzalez, B., Gonzalez, S., Gonzalez, M., Gut, M., Hernandez-Rivas, J.M., Lopez-Guerra, M., Martin-Garcia, D., Navarro, A., Nicolas, P., Orozco, M., Payer, A.R., Pinyol, M., Pisano, D.G., Puente, D.A., Queiros, A.C., Quesada, V., Romeo-Casabona, C.M., Royo, C., Royo, R., Rozman, M., Russinol, N., Salaverria, I., Stamatopoulos, K., Stunnenberg, H.G., Tamborero, D., Terol, M.J., Valencia, A., Lopez-Bigas, N., Torrents, D., Gut, I., Lopez-Guillermo, A., Lopez-Otin, C. & Campo, E. (2015) Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature, 526, 519–524. Rasi, S., Khiabanian, H., Ciardullo, C., Terzi-diBergamo, L., Monti, S., Spina, V., Bruscaggin, A., Cerri, M., Deambrogi, C., Martuscelli, L., Biasi, A., Spaccarotella, E., De, P.L., Gattei, V., Foa’, R., Rabadan, R., Gaidano, G. & Rossi, D. (2016) Clinical impact of small subclones harboring NOTCH1, SF3B1 OR BIRC3 mutations in chronic lymphocytic leukemia. Haematologica, 101, e135–e138. Sportoletti, P., Baldoni, S., Del, P.B., Aureli, P., Dorillo, E., Ruggeri, L., Plebani, S., Amico, V., Di Tommaso, A., Rosati, E., Marconi, P., Di Ianni, M. & Falzetti, F. (2014) A revised NOTCH1 mutation frequency still impacts survival while the allele burden predicts early progression in chronic lymphocytic leukemia. Leukemia, 28, 436–439. Stilgenbauer, S., Schnaiter, A., Paschka, P., Zenz, T., Rossi, M., Dohner, K., Buhler, A., Bottcher, S., Ritgen, M., Kneba, M., Winkler, D., Tausch, E., Hoth, P., Edelmann, J., Mertens, D., Bullinger, L., Bergmann, M., Kless, S., Mack, S., Jager, U., Patten, N., Wu, L., Wenger, M.K., FingerleRowson, G., Lichter, P., Cazzola, M., Wendtner, C.M., Fink, A.M., Fischer, K., Busch, R., Hallek, M. & Dohner, H. (2014) Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood, 123, 3247–3254.

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

Abstract We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 109/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.

Program expansion of a day hospital dedicated to manage sickle cell pain

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High Inpatient Dose of Opioid at Discharge Compared to Home Dose Predicts Readmission Risk in Sickle Cell Disease

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Increased vancomycin dosing requirements in sickle cell disease due to hyperfiltration-dependent and independent pathways

Glomerular hyperfiltration is common among patients with sickle cell disease (SCD), likely driven by increased renal blood flow and glomerular hyperperfusion. In other conditions, hyperfiltration is associated with increased renal clearance of drugs, especially antibiotics, but evidence in SCD patients is lacking. Vancomycin, an antibiotic primarily excreted via glomerular filtration, is commonly used to treat gram-positive pathogens. The drug level is frequently measured to optimize the dosing regimen. We studied vancomycin as a model to show that patients with SCD had increasing drug dosing requirements. Pathway analysis and gene profiling analysis demonstrated that both hyperfiltration-dependent and -independent mechanisms appear to contribute to increased drug clearance in this patient population. Using a pharmacy order reporting system, we conducted a retrospective cohort study of SCD adults with a creatinine clearance (CrCl) of 80 mL/min or more, as calculated by the Cockcroft-Gault equation, who were treated with intravenous vancomycin in an academic medical center from 2011 to 2015 and had a vancomycin trough level drawn at steady state after at least three doses. A control group of age(± 5 years), gender-, weight(± 10%), and race-matched non-SCD patients with CrCl of 80 mL/min or more were identified using the same pharmacy order reporting method. CrCl of 80 mL/min or more is a commonly used cut off for standard versus renaladjusted vancomycin dosing regimens. The SCD patients excluded for a CrCl less than 80 mL/min accounted for approximately 10% of the patients meeting the other inclusion criteria. Vancomycin doses, trough level at steady state, and other clinical variables were collected through retrospective chart review. The study was approved by the Institutional Review Board. We identified 104 unique patients meeting the inclusion criteria in the SCD and control groups, providing a study population of 208. Ninety-two percent of the patients (n=96) in the SCD group were hemoglobin SS (HgbSS) genotype and 8% were HgbSC genotype. HgbSS and HgbSC genotypes were compared to their respective HgbAA controls (Table 1). In the HgbSS versus HgbAA comparison, median age was 29 and 30 years, respectively, and 53% were males in both groups (Table 1). Patient weight was also comparable (69 kg vs. 70 kg). In 76% of the HgbSS patients, the indication for vancomycin was acute chest syndrome (ACS). The most common indications for vancomycin treatment in the control group included fever (21%), sepsis (13%), pneumonia (11%), abscess (9%), cellulitis (7%), wound infection (7%), and meningitis (5%). For the majority of the indications in both groups, the target vancomycin trough level was 15-20 mg/L. The HgbSS patients had higher CrCl and eGFR, as estimated using the Chronic Kidney Disease Epidemiology Collaboration formula, compared to the HgbAA group (Table 1). The first vancomycin trough level at steady state was comparable between the two groups (8.7 vs. 8.8 mg/L). The median vancomycin dose and weight-based dose at the trough level were approximately 20% higher in the HgbSS patients (Table 1). The incidence of acute kidney injury was comparable between the HgbSS and HgbAA groups. The HgbSC and matched controls had 8 subjects in each group, and the comparisons failed to show statistical significance, likely due to the small numbers of subjects. A linear regression analysis of the vancomycin trough level was performed in a multivariate analysis that adjusted for age, gender, SCD genotype (HgbAA, HgbSC, and HgbSS coded as 0, 1, and 2), and weight-based vancomycin dose. SCD genotype was an independent correlate of lower trough level (β = -0.083, 95%CI: -0.023 to 0.144; P=0.007) (Figure 1A). We hypothesized that increased renal clearance due to glomerular hyperfiltration could be one of the mechanisms causing the higher dosing requirements in the SCD group. Consistent with our hypothesis, CrCl or eGFR was an independent, significant predictor of the trough level (P<0.001) when added to this model, whereas SCD genotype was less significant (P=0.036 and P=0.112, respectively). We also performed pathway analysis of vancomycin trough level using structural equation modeling. The fit-

Utility of the Revised Cardiac Risk Index for Predicting Postsurgical Morbidity in Hb SC and Hb Sβ+‐thalassemia Sickle Cell Disease

reviews in the majority of cases [6]. The cohort is also representative of pediatric patients in routine care settings in the southeastern USA states and other small states with predominantly small-city and rural populations in terms of age, sex, racial demographics, and Medicaid eligibility, but these results may not be generalizable to other patient groups. These findings update the existing literature on the musculoskeletal manifestations of SCD in youth and the knowledge base of pediatric practitioners to better anticipate their clinical care needs and to provide them more effective care.