Potassium Handling With Dual Renin-Angiotensin System Inhibition in Diabetic Nephropathy

Clin J Am Soc Nephrol. 2014 Feb;9(2):295-301. doi: 10.2215/CJN.07460713. Epub 2014 Jan 9.


Background and objectives: 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.

Design, setting, participants, & measurements: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00381134.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aldosterone / blood
  • Angiotensin II Type 1 Receptor Blockers / adverse effects
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use*
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Biomarkers / blood
  • Biomarkers / urine
  • Creatinine / urine
  • Diabetic Nephropathies / blood
  • Diabetic Nephropathies / diagnosis
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / urine
  • Diuretics / adverse effects
  • Diuretics / therapeutic use*
  • Drug Therapy, Combination
  • Female
  • Humans
  • Hyperkalemia / blood
  • Hyperkalemia / chemically induced
  • Lisinopril / adverse effects
  • Lisinopril / therapeutic use*
  • Losartan / adverse effects
  • Losartan / therapeutic use*
  • Male
  • Middle Aged
  • Potassium / blood*
  • Potassium / urine*
  • Prospective Studies
  • Renin-Angiotensin System / drug effects*
  • Risk Factors
  • Sodium / urine
  • Spironolactone / adverse effects
  • Spironolactone / therapeutic use*
  • Texas
  • Time Factors
  • Treatment Outcome


  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Biomarkers
  • Diuretics
  • Spironolactone
  • Aldosterone
  • Sodium
  • Creatinine
  • Lisinopril
  • Losartan
  • Potassium

Associated data

  • ClinicalTrials.gov/NCT00381134