Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure.

Department of Internal Medicine, Women's L3623-0271, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA.
American heart journal (Impact Factor: 4.56). 12/2004; 148(6):971-8. DOI: 10.1016/j.ahj.2004.10.005
Source: PubMed

ABSTRACT A previous randomized controlled trial evaluating the use of spironolactone in heart failure patients reported a low risk of hyperkalemia (2%) and renal insufficiency (0%). Because treatments for heart failure have changed since the benefits of spironolactone were reported, the prevalence of these complications may differ in current clinical practice. We therefore sought to determine the prevalence and clinical associations of hyperkalemia and renal insufficiency in heart failure patients treated with spironolactone.
We performed a case control study of heart failure patients treated with spironolactone in our clinical practice. Cases were patients who developed hyperkalemia (K(+) >5.0 mEq/L) or renal insufficiency (Cr >or=2.5 mg/dL), and they were compared to 2 randomly selected controls per case. Clinical characteristics, medications, and serum chemistries at baseline and follow-up time periods were compared.
Sixty-seven of 926 patients (7.2%) required discontinuation of spironolactone due to hyperkalemia (n = 33) or renal failure (n = 34). Patients who developed hyperkalemia were older and more likely to have diabetes, had higher baseline serum potassium levels and lower baseline potassium supplement doses, and were more likely to be treated with beta-blockers than controls (n = 134). Patients who developed renal insufficiency had lower baseline body weight and higher baseline serum creatinine, required higher doses of loop diuretics, and were more likely to be treated with thiazide diuretics than controls.
Spironolactone-induced hyperkalemia and renal insufficiency are more common in our clinical experience than reported previously. This difference is explained by patient comorbidities and more frequent use of beta-blockers.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aldosterone-receptor antagonists dose-dependently reduce both the epithelial and nonepithelial actions of aldosterone. These compounds are used commonly in the treatment of hypertension, with or without aldosteronism, and in the volume-overload periods of various forms of heart failure, cirrhosis, and renal failure. In this regard, the relevant site of action for these compounds is compartmentalized to the distal nephron. The cardiac benefits of aldosterone-receptor blockade now are sufficiently well established to warrant routine use of these compounds for their survival benefits in moderate to advanced stages of heart failure. Aldosterone-receptor antagonists spironolactone and eplerenone commonly are used in the treatment of resistant forms of hypertension. Spironolactone, but not eplerenone, is a commonly used add-on diuretic that provides incremental benefit for salt-and-water excretion in excess of what may be seen with a loop diuretic given together with a thiazide-type diuretic. The dose-response relationship for natriuresis with spironolactone has not been explored completely as to its combination therapy responses. The quite high doses of spironolactone used in patients with cirrhosis and ascites would infer that the overall treatment effect with this compound exceeds simple receptor blockade and may include a nervous system effect that operationally reduces renal sympathetic nerve traffic. The adverse electrolyte and renal function side effects with aldosterone-receptor antagonists are not uncommon in at-risk patients, such as those with chronic kidney disease, and require that dosing be mindful of the tendency of these drugs to importantly increase serum potassium levels.
    Seminars in Nephrology 05/2014; · 2.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyperkalemia, a condition in which serum potassium ions (K+) exceed 5.0 mmol/L, is a common electrolyte disorder associated with substantial morbidity. Current methods of managing hyperkalemia, including organic polymer resins such as sodium polystyrene sulfonate (SPS), are poorly tolerated and/or not effective. Sodium zirconium cyclosilicate (ZS-9) is under clinical development as an orally administered, non-absorbed, novel, inorganic microporous zirconium silicate compound that selectively removes excess K+ in vivo. The development, structure and ion exchange properties of ZS-9 and its hypothesized mechanism of action are described. Based on calculation of the interatomic distances between the atoms forming the ZS-9 micropores, the size of the pore opening was determined to be ∼3 Å (∼diameter of unhydrated K+). Unlike nonspecific organic polymer resins like SPS, the ZS-9 K+ exchange capacity (KEC) was unaffected by the presence of calcium (Ca2+) or magnesium ions (Mg2+) and showed>25-fold selectivity for K+ over either Ca2+ or Mg2+. Conversely, the selectivity of SPS for K+ was only 0.2-0.3 times its selectivity for Ca2+ or Mg2+in mixed ionic media. It is hypothesized that the high K+ specificity of ZS-9 is attributable to the chemical composition and diameter of the micropores, which possibly act in an analogous manner to the selectivity filter utilized by physiologic K+ channels. This hypothesized mechanism of action is supported by the multi-ion exchange studies. The effect of pH on the KEC of ZS-9 was tested in different media buffered to mimic different portions of the human gastrointestinal tract. Rapid K+ uptake was observed within 5 minutes - mainly in the simulated small intestinal and large intestinal fluids, an effect that was sustained for up to 1 hour. If approved, ZS-9 will represent a novel, first-in-class therapy for hyperkalemia with improved capacity, selectivity, and speed for entrapping K+ when compared to currently available options.
    PLoS ONE 12/2014; 9(12):e114686. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: While randomized controlled trials have demonstrated benefits of aldosterone antagonists for patients with heart failure and reduced ejection fraction (HFrEF), they excluded patients with serum creatinine >2.5mg/dl and their use is contraindicated in those with advanced chronic kidney disease (CKD). In the current analysis, we examined the association of spironolactone use with readmission in hospitalized Medicare beneficiaries with HFrEF and advanced CKD. Of the 1140 patients with HFrEF (EF <45%) and advanced CKD (estimated glomerular filtration rate {eGFR} <45 ml/min/1.73m2), 207 received discharge prescriptions for spironolactone. Using propensity scores (PS) for the receipt of discharge prescriptions for spironolactone we estimated PS-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for spironolactone-associated outcomes. Patients (mean age 76 years, 49% women, 25% African American) had mean EF 28%, mean eGFR 31 ml/min/1.73m2, and mean potassium 4.5 mEq/L. Spironolactone use had significant PS-adjusted association with higher risk of 30-day (HR, 1.41; 95% CI: 1.04–1.90) and 1-year (HR, 1.36; 95% CI: 1.13–1.63) all-cause readmission. The risk of 1-year all-cause readmission was higher among 106 patients with eGFR <15 ml/min/1.73m2 (HR, 4.75; 95% CI: 1.84–12.28) than among those with eGFR 15–45 ml/min/1.73m2 (HR, 1.34; 95% CI, 1.11–1.61; p for interaction, 0.003). Spironolactone use had no association with HF readmission and all-cause mortality. In conclusion, among hospitalized patients with HFrEF and advanced CKD, spironolactone use was associated with higher all-cause readmission but had no association with all-cause mortality or HF readmission.
    The American Journal of Cardiology 07/2014; · 3.43 Impact Factor