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

United States of America

Hand-colored engraving of the eastern two-thirds of the United States. States are shaded in various colors and Mexican states are outlined in color. Some settlements, roads, and geographic features are noted, with relief shown by hachures

Ohio map

Map of Ohio drawn by John Melish in 1818. John Melish was born in Scotland in 1771 and died in 1822. His early American maps were some of the best to be published

Baltimore, Annapolis and Adjacent Country

Description from Mapping Maryland: "Melish, a Scot working in Philadelphia and engaged primarily in the general map and atlas trade, produced this map for inclusion in his "Traveller's Dictionary Through the United States".1 map; 15 x 10 cm.; Scale: ca. 1:330,000

Franklin Spencer Spalding, man and bishop.

Mode of access: Internet

United States 1813

Shows boundaries, proposed canals, roads and distances ; Relief shown by hachures ; "Entered as the act directs and published by John Melish, Philadelphia June 1813 ; Accompanied by text: A Statistical account of the United States, with topographical tables of the counties, towns, population, &c. from the census of 1810 intended as an accompaniment to the portable map of the United States by John Melish printed by G. Palmer, 1813, 35 p ; 13 cmColor1:6,000,00

Map of Illinoise [sic] /

Includes references to the township and range rectangular survey system.Prime meridians: Washington and London.Annotated on verso: No. 960. Title page of "Map of Illinois." Deposited 16 April 1818 by John Melish as proprietor. DLCMounted on cloth. DLCDiscolored with darkening along center fold. DL