title: Potassium handling with dual renin-angiotensin system inhibition in diabetic nephropathy.
abstract: OBJECTIVE
  Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation.
  
  
  METHODS
  In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models.
  
  
  RESULTS
  Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P<0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P<0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study.
  
  
  CONCLUSIONS
  Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal potassium homeostasis contributes to hyperkalemia in these patients. A better understanding of extrarenal potassium homeostasis will provide an opportunity to use this drug more safely in patients with diabetic nephropathy as well as other patient populations.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, and, †Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Van Buren
authors.forename: Beverley
authors.initials: B
authors.lastname: Adams-Huet
authors.forename: Mark
authors.initials: M
authors.lastname: Nguyen
authors.forename: Christopher
authors.initials: C
authors.lastname: Molina
authors.forename: Robert D
authors.initials: RD
authors.lastname: Toto
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000652:urine; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000652:urine; D004232:Diuretics / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006947:Hyperkalemia / Q000097:blood / Q000139:chemically induced; D017706:Lisinopril / Q000009:adverse effects / Q000627:therapeutic use*; D019808:Losartan / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood* / Q000652:urine*; D011446:Prospective Studies; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012307:Risk Factors; D012964:Sodium / Q000652:urine; D013148:Spironolactone / Q000009:adverse effects / Q000627:therapeutic use*; D013781:Texas; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D004232:Diuretics; D013148:Spironolactone; D000450:Aldosterone; D012964:Sodium; D003404:Creatinine; D017706:Lisinopril; D019808:Losartan; D011188:Potassium