Aldosterone Blockade and Mineralocorticoid Receptor in CKD
Aldosterone Blockade and Mineralocorticoid Receptor in CKD
There was a significant reduction in 24-h proteinuria with SPL plus ACEi and/or ARB (9 clinical trials, 424 patients) compared with ACEi and/or ARB alone. A significant reduction in proteinuria was detected also with the use of EPL plus ACEi in comparison with ACEi plus placebo at the end of 12-week period (1 trial, 268 patients).
Data for end of treatment GFR was available in 8 studies (6 randomized controlled trials, 326 patients with SPL, 1 randomized controlled trial, 268 patients with EPL, 1 retrospective study, 36 patients). There was no significant difference in GFR with either SPL or EPL plus ACEi and/or ARB compared with ACEi and/or ARB alone. However, the retrospective study on subjects with resistant hypertension and CKD stage 3 revealed statistically significant increment of serum creatinine (from 1.5±0.3 to 1.8±0.5 mg/dl) and decrement of eGFR (from 48.6±8.7 to 41.2±11.5 ml/min per 1.73 m) because of use of MRAs.
There was a significant reduction in systolic BP with SPL along with ACEi and/or ARB compared with ACEi and/or ARB alone (7 randomized controlled trials, 372 patients). At 12 weeks, there was a significant reduction in end of treatment systolic and diastolic BP with EPL plus ACEi in comparison with ACEi plus placebo arm. In patients with resistant hypertension, MRAs induced a significant decrease in systolic and diastolic BP (from 162±22 to 138±14 mm Hg and from 87±17 to 74±12 mm Hg, respectively).
Although all the studies reported data on the changes in serum K, only one study specified the frequency for measurements for serum K. On the one hand, nine studies (472 patients) reported a significant increase in the risk of hyperkalemia with MRAs administered in combination with ACEi and/or ARB compared with ACEi and/or ARB alone. In contrast, the study of Epstein et al. carefully assessed the incidence of hyperkalemia by determining serum K at baseline and every 2 weeks during the 12-week study. They determined the incidences of both sustained hyperkalemia (serum K >5.5 mmol/l on two consecutive occasions 1- to 3-day apart) and severe hyperkalemia (serum K >6.0 mmol/l on any occasion). No significant effect on serum K with EPL plus ACEi compared with ACEi alone was demonstrated in 268 diabetic patients. Recent post hoc analysis of this study revealed only 5 separate instances in 1260 separate K determinations in the EPL groups with either severe or sustained hyperkalemia. Furthermore, hyperkalemia did not correlate with eGFR.
Gynecomastia was an infrequent complication in both patients on low-dose SPL or placebo groups. Bianchi et al. reported that 6 out of 83 patients developed gynecomastia (only 1 patient warranting discontinuation of medication and 5 patients with mild gynecomastia) in the SPL group but none (out of 82 patients) in the placebo arm. Furamatsu et al. reported 1 of 15 patients who developed gynecomastia in the SPL group that did not require discontinuation of therapy. Pisoni et al. reported two patients with breast tenderness without gynecomastia or impotence.
Trial Outcomes
End of Treatment 24-h Proteinuria
There was a significant reduction in 24-h proteinuria with SPL plus ACEi and/or ARB (9 clinical trials, 424 patients) compared with ACEi and/or ARB alone. A significant reduction in proteinuria was detected also with the use of EPL plus ACEi in comparison with ACEi plus placebo at the end of 12-week period (1 trial, 268 patients).
End of Treatment GFR
Data for end of treatment GFR was available in 8 studies (6 randomized controlled trials, 326 patients with SPL, 1 randomized controlled trial, 268 patients with EPL, 1 retrospective study, 36 patients). There was no significant difference in GFR with either SPL or EPL plus ACEi and/or ARB compared with ACEi and/or ARB alone. However, the retrospective study on subjects with resistant hypertension and CKD stage 3 revealed statistically significant increment of serum creatinine (from 1.5±0.3 to 1.8±0.5 mg/dl) and decrement of eGFR (from 48.6±8.7 to 41.2±11.5 ml/min per 1.73 m) because of use of MRAs.
End of Treatment BP
There was a significant reduction in systolic BP with SPL along with ACEi and/or ARB compared with ACEi and/or ARB alone (7 randomized controlled trials, 372 patients). At 12 weeks, there was a significant reduction in end of treatment systolic and diastolic BP with EPL plus ACEi in comparison with ACEi plus placebo arm. In patients with resistant hypertension, MRAs induced a significant decrease in systolic and diastolic BP (from 162±22 to 138±14 mm Hg and from 87±17 to 74±12 mm Hg, respectively).
Hyperkalemia
Although all the studies reported data on the changes in serum K, only one study specified the frequency for measurements for serum K. On the one hand, nine studies (472 patients) reported a significant increase in the risk of hyperkalemia with MRAs administered in combination with ACEi and/or ARB compared with ACEi and/or ARB alone. In contrast, the study of Epstein et al. carefully assessed the incidence of hyperkalemia by determining serum K at baseline and every 2 weeks during the 12-week study. They determined the incidences of both sustained hyperkalemia (serum K >5.5 mmol/l on two consecutive occasions 1- to 3-day apart) and severe hyperkalemia (serum K >6.0 mmol/l on any occasion). No significant effect on serum K with EPL plus ACEi compared with ACEi alone was demonstrated in 268 diabetic patients. Recent post hoc analysis of this study revealed only 5 separate instances in 1260 separate K determinations in the EPL groups with either severe or sustained hyperkalemia. Furthermore, hyperkalemia did not correlate with eGFR.
Gynecomastia
Gynecomastia was an infrequent complication in both patients on low-dose SPL or placebo groups. Bianchi et al. reported that 6 out of 83 patients developed gynecomastia (only 1 patient warranting discontinuation of medication and 5 patients with mild gynecomastia) in the SPL group but none (out of 82 patients) in the placebo arm. Furamatsu et al. reported 1 of 15 patients who developed gynecomastia in the SPL group that did not require discontinuation of therapy. Pisoni et al. reported two patients with breast tenderness without gynecomastia or impotence.