Long-Term Effects of Spironolactone on Kidney Function and Hyperkalemia-Associated Hospitalization in Patients with Chronic Kidney Disease

Abstract

Background: Spironolactone, a non-selective mineralocorticoid receptor antagonist, can protect against cardiac fibrosis and left ventricular dysfunction, and improve endothelial dysfunction and proteinuria. However, the safety and effects of spironolactone on patient-centered cardiovascular and renal endpoints remain unclear.

Methods: We identified predialysis stage 3⁻4 chronic kidney disease (CKD) patients between 2000 and 2013 from the Longitudinal Health Insurance Database 2005 (LHID 2005). The outcomes of interest were end-stage renal disease (ESRD), major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), hyperkalemia-associated hospitalization (HKAH), all-cause mortality and cardiovascular mortality. The Fine and Gray sub-distribution hazards approach was adopted to adjust for the competing risk of death.

Results: After the propensity score matching, 693 patients with stage 3⁻4 CKD were spironolactone users and 1386 were nonusers. During the follow-up period, spironolactone users had a lower incidence rate for ESRD than spironolactone non-users (39.2 vs. 53.69 per 1000 person-years) and a higher incidence rate for HKAH (54.79 vs. 18.57 per 1000 person-years). The adjusted hazard ratios for ESRD of spironolactone users versus non-users were 0.66 (95% CI, 0.51⁻0.84; p value < 0.001) and 3.17 (95% CI, 2.41⁻4.17; p value < 0.001) for HKAH. A dose-response relationship was found between spironolactone use and risk of ESRD and HKAH. There were no statistical differences in MACE, HHF, all-cause mortality and cardiovascular mortality between spironolactone users and non-users.

Conclusion: Spironolactone represented a promising treatment option to retard CKD progression to ESRD amongst stage 3⁻4 CKD patients, but strategic treatments to prevent hyperkalemia should be enforced.

Keywords: chronic kidney disease (CKD); end-stage renal disease (ESRD); major adverse cardiovascular events (MACE); mortality; spironolactone.

Figure 1

Flowchart of patient selection processes for stage 3–4 chronic kidney disease CKD with or without spironolactone use.

Figure 2

Cumulative incidence rate of progression to end-stage renal disease between spironolactone users and non-users. (p-value < 0.001, Grey’s test).

Figure 3

Cumulative incidence rate of hyperkalemia-associated hospitalization between spironolactone users and non-users. (p-value < 0.001, Grey’s test).

Figure 4

Cumulative incidence rate of hospitalization for heart failure (p-value = 0.2554, Grey’s test) and major adverse cardiovascular events (p-value = 0.7052, Grey’s test) between spironolactone users and non-users between spironolactone users and non-users.

Figure 5

Cumulative incidence rate of all-cause mortality (p-value = 0.439, Grey’s test) and cardiovascular disease-mortality (p-value = 0.9408, Grey’s test) between spironolactone users and non-users.

Figure 6

Hazard ratios of end-stage renal disease associated with spironolactone use in subgroup analyses.

Figure 7

Hazard ratios of progression to hyperkalemia-associated hospitalization associated with spironolactone use in subgroup analyses.