title: Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy.
abstract: Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension and proteinuria compared with conventional RAAS blockade.
authors.affiliation: Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. asb68@columbia.edu
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bomback
authors.forename: Yelena
authors.initials: Y
authors.lastname: Rekhtman
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Klemmer
authors.forename: Pietro A
authors.initials: PA
authors.lastname: Canetta
authors.forename: Jai
authors.initials: J
authors.lastname: Radhakrishnan
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Appel
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000378:metabolism*; D000577:Amides / Q000008:administration & dosage / Q000009:adverse effects; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000009:adverse effects; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects*; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000009:adverse effects; D005919:Glomerular Filtration Rate; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014633:Valine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000068756:Valsartan
chemical_list: D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D005650:Fumarates; D013777:Tetrazoles; D000450:Aldosterone; C446481:aliskiren; D000068756:Valsartan; D014633:Valine