Sickle-Cell Trait: Novel Clinical Significance

There is a long-standing controversy in the literature as to whether sickle-cell trait (SCT) should be viewed as a benign carrier state or as an intermediate disease phenotype. Because SCT is routinely detected by neonatal screening for sickle-cell disease, it becomes imperative that consensus on this issue be achieved in order to provide the best medical advice to affected individuals. The issue of selective screening in the post-neonatal period was thrust into the limelight recently by the National Collegiate Athletic Association’s recommendation that its member colleges and universities test student-athletes to confirm their carrier status if not already known. The stated goal of this recommendation was to prevent exercise-related sudden death in athletes with SCT. We review some of the reported complications of SCT for which new information has emerged, focusing particularly on venous thromboembolism and renal manifestations

DUET: A phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS

Background: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. Methods: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 yearswith biopsy-proven FSGS, eGFR>30ml/min per 1.73m2, and urinary protein-to-creatinine ratio (UP/C)≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300mg/d) for 8 weeks, followed by open-label sparsentan only. End points atweek 8 were reduction from baseline inUP/C(primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C:≤1.5 g/g and>40%reduction [secondary]). Results: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients didwhen all doses (45%versus 19%; P=0.006) or the 400 and 800mg doses (47%versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. Conclusions: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated

Sugar-sweetened soda consumption, hyperuricemia, and kidney disease

The metabolism of high-fructose corn syrup used to sweeten soda drinks may lead to elevations in uric acid levels. Here we determined whether soda drinking is associated with hyperuricemia and, as a potential consequence, reduced kidney function. At baseline, 15,745 patients in the Atherosclerosis Risk in Communities Study completed a dietary questionnaire and had measurements of their serum creatinine and uric acid. After 3 and 9 years of follow-up, multivariate odds ratios from logistic regressions for binary outcome of hyperuricemia and chronic kidney disease (eGFR less than 60 ml/min per 1.73 m2) were evaluated. Compared to participants who drank less, consumption of over one soda per day was associated with increased odds of prevalent hyperuricemia and chronic kidney disease. The odds ratio for chronic kidney disease significantly increased to 2.59 among participants who drank more than one soda per day and had a serum uric acid level over 9.0 mg/dl. In longitudinal analyses, however, drinking more than one soda per day was not associated with hyperuricemia or chronic kidney disease. Neither preexistent hyperuricemia nor development of hyperuricemia modified the lack of association between soda drinking and incident chronic kidney disease. Thus our study shows that high consumption of sugar-sweetened soda was associated with prevalent but not incident hyperuricemia and chronic kidney disease

Sickle Cell Trait and Incident Ischemic Stroke in the Atherosclerosis Risk in Communities Study

Numerous case reports describe stroke in individuals with sickle cell trait (SCT) in the absence of traditional risk factors for cerebrovascular disease. To date, no prospective epidemiological studies have investigated this association

Prospective study of sickle cell trait and venous thromboembolism incidence

Sickle cell trait may increase risk of venous thromboembolism, but this is not fully established

Proceedings of a Sickle Cell Disease Ontology workshop - Towards the first comprehensive ontology for Sickle Cell Disease

Sickle cell disease (SCD) is a debilitating single gene disorder caused by a single point mutation that results in physical deformation (i.e. sickling) of erythrocytes at reduced oxygen tensions. Up to 75% of SCD in newborns world-wide occurs in sub-Saharan Africa, where neonatal and childhood mortality from sickle cell related complications is high. While SCD research across the globe is tackling the disease on multiple fronts, advances have yet to significantly impact on the health and quality of life of SCD patients, due to lack of coordination of these disparate efforts. Ensuring data across studies is directly comparable through standardization is a necessary step towards realizing this goal. Such a standardization requires the development and implementation of a disease-specific ontology for SCD that is applicable globally. Ontology development is best achieved by bringing together experts in the domain to contribute their knowledge. The SCD community and H3ABioNet members joined forces at a recent SCD Ontology workshop to develop an ontology covering aspects of SCD under the classes: phenotype, diagnostics, therapeutics, quality of life, disease modifiers and disease stage. The aim of the workshop was for participants to contribute their expertise to development of the structure and contents of the SCD ontology. Here we describe the proceedings of the Sickle Cell Disease Ontology Workshop held in Cape Town South Africa in February 2016 and its outcomes. The objective of the workshop was to bring together experts in SCD from around the world to contribute their expertise to the development of various aspects of the SCD ontology

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Association of Sickle Cell Trait With Chronic Kidney Disease and Albuminuria in African Americans

The association between sickle cell trait (SCT) and chronic kidney disease (CKD) is uncertain