Prevalence of kidney health genetic variants in adults with sickle cell nephropathy.

The pathophysiology and genetic risk for sickle cell disease (SCD)-related chronic kidney disease (CKD) are not well understood. In 70 adults with SCD-related CKD and without APOL1 inherited in a high-risk pattern, 24 (34%) had pathogenic variants in candidate genes using KidneySeq™. A moderate impact INF2 variant was observed in 20 (29%) patients and those with 3 versus 0-2 pathogenic or moderate impact glomerular genetic variants had higher albuminuria and lower estimated glomerular filtration rate (adjusted p ≤ 0.015). Using a panel of preselected genes implicated in kidney health, we observed several variants in people with sickle cell nephropathy.

Soluble urokinase plasminogen activator receptor is associated with kidney disease and its progression in sickle cell anemia.

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Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease.

Etavopivat is an investigational, once-daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study (https://clinicaltrials.gov/study/NCT03815695) was conducted to characterize the safety and clinical activity of etavopivat. Thirty-six patients with sickle cell disease (SCD) were enrolled into 4 cohorts: one single-dose; two multiple ascending doses; one open-label [OL]. In the OL cohort, 15 patients (median age 33.0 [range, 17‒55] years received 400-mg etavopivat once daily for 12 weeks; 14 completed treatment. Consistent with the mechanism of PKR activation, increases in ATP and decreases in 2,3 diphosphoglycerate were observed and sustained over 12 weeks' treatment. This translated clinically to an increase in hemoglobin (mean maximal increase 1.6 [range, 0.8‒2.8] g/dL), with >1 g/dL increase in 11 (73%) patients during treatment. Additionally, oxygen tension at which hemoglobin is 50% saturated was reduced (P=.0007) with concomitant shift in point-of-sickling (P=.0034) to lower oxygen tension in oxygen-gradient ektacytometry. Hemolysis markers (absolute reticulocyte count, indirect bilirubin, lactate dehydrogenase) decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events (AEs) were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n=7) in the OL cohort. In this first study of etavopivat in SCD, 400 mg once daily for 12 weeks was well-tolerated, resulting in rapid and sustained increases in hemoglobin, improved RBC physiology, and decreased hemolysis.

Mental health, pain and likelihood of opioid misuse among adults with sickle cell disease.

Depressive symptoms are prevalent in individuals living with sickle cell disease (SCD) and may exacerbate pain. This study examines whether higher depressive symptoms are associated with pain outcomes, pain catastrophizing, interference and potential opioid misuse in a large cohort of adults with SCD. The study utilized baseline data from the 'CaRISMA' trial, which involved 357 SCD adults with chronic pain. Baseline assessments included pain intensity, daily mood, the Patient Health Questionnaire (PHQ), the Generalized Anxiety Disorders scale, PROMIS Pain Interference, Pain Catastrophizing Scale, the Adult Sickle Cell Quality of Life Measurement Information System and the Current Opioid Misuse Measure. Participants were categorized into 'high' or 'low' depression groups based on PHQ scores. Higher depressive symptoms were significantly associated with increased daily pain intensity, negative daily mood, higher pain interference and catastrophizing, poorer quality of life and a higher likelihood of opioid misuse (all p < 0.01). SCD patients with more severe depressive symptoms experienced poorer pain outcomes, lower quality of life and increased risk of opioid misuse. Longitudinal data from this trial will determine whether addressing depressive symptoms may potentially reduce pain frequency and severity in SCD.

Sickle Cell Disease and CKD: An Update.

BACKGROUND: Sickle cell disease is an inherited red blood cell disorder that affects approximately 100,000 people in the USA and 25 million people worldwide. Vaso-occlusion and chronic hemolysis lead to dysfunction of vital organ systems, with the kidneys being among the most commonly affected organs. SUMMARY: Early renal manifestations include medullary ischemia with the loss of urine-concentrating ability and hyperfiltration. This can be followed by progressive damage characterized by persistent albuminuria and a decline in the estimated glomerular filtration rate. The risk of sickle nephropathy is greater in those with the APOL1 G1 and G2 kidney risk variants and variants in HMOX1 and lower in those that coinherit α-thalassemia. Therapies to treat sickle cell disease-related kidney damage focus on sickle cell disease-modifying therapies (e.g., hydroxyurea) or those adopted from the nonsickle cell disease kidney literature (e.g., renin-angiotensin-aldosterone system inhibitors), although data on their clinical efficacy are limited to small studies with short follow-up periods. Kidney transplantation for end-stage kidney disease improves survival compared to hemodialysis but is underutilized in this patient population. KEY MESSAGES: Kidney disease is a major contributor to early mortality, and more research is needed to understand the pathophysiology and develop targeted therapies to improve kidney health in sickle cell disease.

Gene expression changes in sickle cell reticulocytes and their clinical associations.

Transcriptional changes in compensatory erythropoiesis in sickle cell anemia (SCA) and their disease modulation are unclear. We detected 1226 differentially expressed genes in hemoglobin SS reticulocytes compared to non-anemic hemoglobin AA controls. Assessing developmental expression changes in hemoglobin AA erythroblasts for these genes suggests heightened terminal differentiation in early erythroblasts in SCA that diminishes toward the polychromatic to orthochromatic stage transition. Comparison of reticulocyte gene expression changes in SCA with that in Chuvash erythrocytosis, a non-anemic disorder of increased erythropoiesis due to constitutive activation of hypoxia inducible factors, identified 453 SCA-specific changes attributable to compensatory erythropoiesis. Peripheral blood mononuclear cells (PBMCs) in SCA contain elevated proportions of erythroid progenitors due to heightened erythropoiesis. Deconvolution analysis in PBMCs from 131 SCA patients detected 54 genes whose erythroid expression correlated with erythropoiesis efficiency, which were enriched with SCA-specific changes (OR = 2.9, P = 0.00063) and annotation keyword "ubiquitin-dependent protein catabolic process", "protein ubiquitination", and "protein polyubiquitination" (OR = 4.2, P = 7.5 × 10-5). An erythroid expression quantitative trait locus of one of these genes, LNX2 encoding an E3 ubiquitin ligase, associated with severe pain episodes in 774 SCA patients (OR = 1.7, P = 3.9 × 10-5). Thus, erythroid gene transcription responds to unique conditions within SCA erythroblasts and these changes potentially correspond to vaso-occlusive manifestations.

Vaccination in sickle cell disease: Immunocompromised or immunocompetent?

Sickle cell disease (SCD) is an immunocompromised condition and patients with SCD may have a reduced immune response to certain vaccinations. The report by Nakahara et al. demonstrated that SCD patients exhibited elevated and more sustained IgG production following COVID-19 vaccination, when compared to healthy controls. This suggests that the immune response to vaccinations may vary among different types of vaccines in individuals with SCD. Commentary on: Nakahara et al. Enhanced IgG immune response to COVID-19 vaccination in patients with sickle cell disease. Br J Haematol 2023;202:937-941.

Community-level socioeconomic distress is associated with nutritional status in adults with sickle cell anemia.

Sickle cell anemia (SCA) negatively impacts the ability to achieve educational and occupational goals increasing vulnerability to socioeconomic challenges. In a cross-sectional analysis of 332 SCA adults, we investigated whether the distressed community index (DCI) was associated with SCA-related complications and nutritional status. More patients with higher DCI had Medicaid insurance. A higher DCI was independently associated with tobacco use and lower body mass index, serum albumin, and vitamin D 25-OH levels after adjusting for insurance status but was not associated with SCA-related complications. Future studies investigating access to healthy foods may help improve health equity in patients with SCA.

Proteomic cardiovascular risk assessment in chronic kidney disease.

AIMS: Chronic kidney disease (CKD) is widely prevalent and independently increases cardiovascular risk. Cardiovascular risk prediction tools derived in the general population perform poorly in CKD. Through large-scale proteomics discovery, this study aimed to create more accurate cardiovascular risk models. METHODS AND RESULTS: Elastic net regression was used to derive a proteomic risk model for incident cardiovascular risk in 2182 participants from the Chronic Renal Insufficiency Cohort. The model was then validated in 485 participants from the Atherosclerosis Risk in Communities cohort. All participants had CKD and no history of cardiovascular disease at study baseline when ∼5000 proteins were measured. The proteomic risk model, which consisted of 32 proteins, was superior to both the 2013 ACC/AHA Pooled Cohort Equation and a modified Pooled Cohort Equation that included estimated glomerular filtrate rate. The Chronic Renal Insufficiency Cohort internal validation set demonstrated annualized receiver operating characteristic area under the curve values from 1 to 10 years ranging between 0.84 and 0.89 for the protein and 0.70 and 0.73 for the clinical models. Similar findings were observed in the Atherosclerosis Risk in Communities validation cohort. For nearly half of the individual proteins independently associated with cardiovascular risk, Mendelian randomization suggested a causal link to cardiovascular events or risk factors. Pathway analyses revealed enrichment of proteins involved in immunologic function, vascular and neuronal development, and hepatic fibrosis. CONCLUSION: In two sizeable populations with CKD, a proteomic risk model for incident cardiovascular disease surpassed clinical risk models recommended in clinical practice, even after including estimated glomerular filtration rate. New biological insights may prioritize the development of therapeutic strategies for cardiovascular risk reduction in the CKD population.

Predictors and clinical complications associated with antiphospholipid antibodies in sickle cell disease.

Although a higher prevalence of antiphospholipid autoantibodies (aPL) has been observed in some cohorts of sickle cell disease (SCD) patients, the clinical risk factors for the development of aPL and its associated complications remain unclear. In a retrospective study of 63 SCD patients, a lower hemoglobin concentration and higher white blood cell count were independently associated with an elevated aPL. SCD patients with elevated aPL had increased pregnancy complications (≥3 miscarriages, preterm delivery, pre-eclampsia) and venous thrombotic events. Our findings suggest that SCD may predispose to the generation of aPL and that aPL itself may contribute to the vasculopathy of SCD. Prospective testing for aPL is warranted in patients with SCD.

Associations of hemolysis and anemia with cardiopulmonary dysfunction in an adult sickle cell disease cohort.

BACKGROUND: Hemolysis contributes to the anemia of sickle cell disease (SCD). Hemolysis and anemia are distinct but inter-related pathophysiological processes that underlie end-organ dysfunction in this condition. We hypothesized that real-world medical tests would reveal distinct contributions of hemolysis and anemia to certain cardiopulmonary changes in adults with SCD. METHODS: We assessed laboratory and clinical tests of cardiopulmonary function obtained during routine delivery of care in 442 adult SCD patients. We characterized hemolysis by the first principal component (PC1) of reticulocyte percent, lactate dehydrogenase (LDH), aspartate amino transferase (AST) and total bilirubin- the hemolytic component. The relationships of hemoglobin concentration and hemolysis to organ dysfunction were analyzed by multiple regression and path analysis to identify independent associations. RESULTS: Degree of hemolysis and degree of anemia both associated independently with elevated values for left atrial diameter (LAD) and left ventricular end-diastolic diameter (LVED), and with lower percent predicted forced expiratory volume in first second (FEV1). Degree of hemolysis, but not anemia, associated independently with low values for oxygen saturation, forced vital capacity (FVC), and total lung capacity (TLC)]. Path analysis reinforced the trend by multiple regression for association of both degree of hemolysis and anemia with elevated TRV but not with lower diastolic blood pressure. DISCUSSION: Analysis of real-world clinical tests suggest that, although they are inter-related, the degrees of hemolysis and of anemia make independent contributions to cardiopulmonary dysfunction and that treatments that specifically target both aspects of sickle cell disease may be of maximal benefit.

Treatment patterns and burden of complications associated with sickle cell disease: A US retrospective claims analysis.

Complications associated with sickle cell disease (SCD) that are highly impactful for patients but until recently have been less understood include priapism, nephropathy, and neurologic injury. We conducted a retrospective study using US administrative claims data from July 01, 2013 through March 31, 2020 to analyze incidence of these complications, SCD treatment patterns, and healthcare resource utilization (HCRU) and costs among 2524 pediatric and adult patients with SCD (mean [SD] age 43.4 [22.4] years). The most common treatments during follow-up were short-acting opioids (54.0% of patients), red blood cell transfusion (15.9%), and hydroxyurea (11.0%). SCD complications occurred frequently; in the overall population, the highest follow-up incidences per 1000 person-years were for acute kidney injury (53.1), chronic kidney disease (40.6), and stroke (39.0). Complications occurred across all age groups but increased in frequency with age; notably, acute kidney injury was 69.7 times more frequent among ages 65+ than ages 0-15 (p < 0.001). Follow-up per-patient-per-month HCRU also increased with age; however, all-cause healthcare costs were similarly high for all age groups and were driven primarily by inpatient stays. Patients with SCD across the age spectrum have a high burden of complications with the use of current treatments, suggesting unmet needs for treatment management.