294
Mineralocorticoid Receptor Antagonists
Aldosterone may mediate CKD progression, independently of its BP-increasing
effect. Animal studies suggest that MR antagonists reduce proteinuria in diabetic
nephropathy. MR antagonists may also ameliorate early renal injury and prevent
renal fibrosis, presumably via the inhibition of macrophage infiltration, reduction
in local oxidative stress, and the decreased expression of fibronectin, plasminogen
activator inhibitor-1, and transforming growth factor-β1 [ 12 ].
In CKD, MR antagonists have been tried for anti-proteinuric and renoprotective
purposes, as well as for the treatment of RH. In the largest relevant RCT [ 45 ] involv-
ing CKD patients with proteinuria and type 2 diabetes, the addition of eplerenone to
enalapril resulted in a significant decrease in albuminuria, as compared to placebo,
without an increase in the risk of hyperkalemia. The PATHWAY-2 study [ 15 ] unfor-
tunately excluded patients with eGFR <45 ml/min. Based on current data, the long-
term effects of MR antagonists on renal and cardiovascular outcomes, mortality,
and safety in patients with CKD are unknown [ 24 ].
Because of the risk of hyperkalemia and acute kidney injury, MR antagonists
should be used with caution in CKD patients. Plasma potassium levels and kidney
function should be monitored closely during the introduction of these agents and
during intercurrent illnesses, such as dehydration. Great care should be taken when
MR antagonists are combined with ACEIs, ARBs, or NSAIDs. Caution is also
advised when used together with other cytochrome P450-metabolized agents, such
as verapamil [ 24 ]. Predictors of hyperkalemia include baseline renal function, serum
potassium levels, the dose of MR antagonists, and the use of other RAS blockers or
drugs that interfere with renal potassium handling [ 12 ]. MR antagonists are usually
combined with thiazide or loop diuretics, which enhance potassium loss in the urine.
The ESH/ESC guidelines [ 6 ] suggest the addition of a MR antagonist as fourth-
line therapy for RH (12.5–25 mg/day spironolactone or 25–50 mg/day eplerenone,
to be adapted according to eGFR level) in patients with GFR ≥30 ml/min and
plasma potassium concentrations ≤4–5 mmol/L or in patients with other indica-
tions, such as heart failure. However, the ESH guidelines do not recommend the
routine use of MR antagonists in patients with CKD, especially in combination with
RAS blockers, because of the risk of further renal impairment and hyperkalemia.
The KDIGO [ 24 ] and ERBP [ 35 ] guidelines only state that the place of MR antago-
nists as an add-on therapy in hypertensive patients with CKD needs to be explored
in further studies.
Beta-Blockers
BBs are one of the most extensively investigated drug classes, having been used to
treat hypertension, as well as coronary artery disease, heart failure, and cardiac
arrhythmias, for over 40 years. Although all BBs are effective for reducing BP, other
issues may influence their indication in a given patient and which specific drug is
L. Segall