Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

ABCF2 expression may predict the prognosis of cervical cancer

5045 Background: ABCF2 is a new member of the ATP-binding cassette transporter superfamily gene. We previously reported that ABCF2 protein is new biomarker in clear cell adenocarcinoma (CC) of the ovary and its expression may predict the response to chemotherapy and survival of CC patients (Proc ASCO 2005, Clin Cancer Res 2005). In this study, we examined ABCF2 expression in cervical cancer (CACX) and evaluated the relationship between ABCF2 expression and clinical factor. Methods: Formalin-fixed surgical samples from one hundred fourty CACX were included in this study. ABCF2 expression was investigated by immunohistochemistry. Positive expression of ABCF2 was &gt;10% based on the cytoplasmic staining. Results: One hundred fourty patients were included in this study. The clinical stage was I in 86 patients, II in 38 patients, III in 10 patients, and IV in 6 patients. Histologic types were squamous cell carcinoma (SC) in 101 patients and non-squamous cell carcinoma (NSC) in 39 patients. The positive rate of ABCF2 in advanced stage (III + IV) was significantly higher than it in early stage (I + II) (p = 0.03). However, histologic type was not related with ABCF2 expression (SC 49.5% vs NSC 59.0%, p = 0.35). ABCF2-negative tumors had longer overall survival (OS) than ABCF2-positive tumors (p = 0.0014). The ABCF2 expression were correlated with further biological variables such as age, tumor stage, and histologic type for OS rate by univariate and multivariate Cox regression analysis. Multivariate analysis revealed that stage and ABCF2 were independent prognostic factor (Hazards ratio (HR) = 4.66, p = 0.0005; HR = 0.34, p = 0.025). Conclusions: The role of ABCF2 protein may predict the prognosis of CACX. [Table: see text] No significant financial relationships to disclose. </jats:p

ABCF2 expression in endometrial cancer and breast cancer

5035 Background: ABCF2 is a new member of the ATP-binding cassette transporter superfamily gene. We previously reported that ABCF2 protein is new biomarker in clear cell adenocarcinoma (CC) of the ovary and its expression may predict the response to chemotherapy and survival of CC patients (Proc ASCO 2005, Clin Cancer Res 2005). Both breast cancer (BC) and endometorial cancer (EC) are estrogen-dependent tumors, however, their biological behavior differ. In this study, we examined ABCF2 expression in EMCA and BC and evaluated the relationship between ABCF2 expression and clinical factor. Methods: Formalin-fixed surgical samples from 100 EMCA and 191 BC patients were included in this study. ABCF2 expression was investigated by immunohistochemistry. Positive expression of ABCF2 was &gt; 10% based on the cytoplasmic staining. Results: Histologic types and stage were as followed: EMCA: (Endometrioid (EM): 92; Adenosquamous (AS): 8), (I: 63; II: 5; III: 30; IV: 2). BC: (Papillo tu (PP): 60; Solid tub (SL): 38; Scirrhous (SC): 77; Other (OT): 15). Breast cancer was sub-classified into 3 types according to the criteria of the Japanese Breast Cancer Society. The relationship between ABCF2 expression and histologic type was shown in table. In EMCA and BC, there were no significant relationship between ABCF2 expression and clinical factor like stage, histologic type, grade and estrogen receptor (ER). In EMCA, ABCF2 expression was not related with disease free survival (DFS). However, in BC, ABCF2-positive tumors had longer DFS than ABCF2-negative tumors (p = 0.03). The ABCF2 expression were correlated with further biological variables such as tumor stage, lympho node metastasis, nuclear grade and ER status for DFS by univariate and multivariate Cox regression analysis. Multivariate analysis revealed that ABCF2 was an independent prognostic factor (HR 0.46; p = 0.018). Conclusion: The role of ABCF2 protein may differ between EMCA and BC. [Table: see text] No significant financial relationships to disclose. </jats:p

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease