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control. However, when thiazides and loop diuretics are used together, the incidence
of adverse effects is higher and requires close monitoring [ 12 ]. Knauf and Mutschler
[ 37 ] showed that HCTZ alone or in combination with furosemide increased diuresis
in patients with CKD even at a GFR <30 ml/min/1.73 m^2. Dussol et al. [ 38 ] con-
ducted an RCT involving 23 patients with hypertension and stage 4 or 5 CKD, who
received long-acting furosemide (60 mg) and HCTZ (25 mg) for 3 months, and then
both diuretics for the next 3 months. The authors found no differences between
furosemide and HCTZ with respect to natriuresis and BP control. Another trial [ 39 ]
enrolled 60 CKD patients with a mean eGFR of 39 ml/min/1.73 m^2 and a systolic
BP of 151 mmHg, under 1.8 antihypertensive drugs on average. After a run-in
phase, all patients were treated with chlorthalidone, and at the end of the 8-week
intervention, systolic BP was significantly reduced by 20 mmHg. Notably, the nine
patients with eGFR <30 ml/min/1.73 m^2 had a similar reduction in BP.
Calcium Channel Blockers
The major subclasses of CCBs are the dihydropyridines (e.g., amlodipine, nifedip-
ine, lercanidipine) and the non-dihydropyridines, including benzothiazepines (dil-
tiazem) and phenylalkylamines (verapamil). Dihydropyridines tend to be more
selective for the vascular smooth muscle (vasodilation) than for the myocardium.
Accordingly, the side effects may include fluid retention and ankle edema, which
can be problematic in patients with CKD. Dizziness, headache, and facial flush are
also common. Non-dihydropyridines have direct effects on the myocardium, includ-
ing the sinoatrial and atrioventricular nodes, causing reductions in heart rate and
contractility [ 24 ].
CCBs are widely used in the treatment of hypertension, angina, and supraven-
tricular tachycardia. Non-dihydropyridine CCBs have been shown to reduce pro-
teinuria. In contrast, dihydropyridines completely abolish renal autoregulation,
which is already impaired in CKD, and may thus aggravate proteinuria when used
as monotherapy. Therefore, the use of dihydropyridines is not advisable without
concomitant use of an ACEI or ARB [ 24 , 35 ].
Most CCBs do not accumulate in patients with impaired kidney function, with
the exception of nicardipine and nimodipine. Accumulation of these agents may
also be due to reduced blood flow to the liver in the elderly. Caution is thus advised
when using these two agents in elderly patients with CKD [ 24 ].
The combination of a RAS inhibitor with a dihydropyridine CCB attenuates the
reflex vasoconstriction and tachycardia resulting from increased sympathetic ner-
vous system activity in response to CCB-induced systemic vasodilation [ 25 ]. Fluid
retention, seen particularly with dihydropyridines, can be problematic in patients
with CKD, such that avoiding other vasodilators may be sensible. The combination
of non-dihydropyridines such as verapamil and diltiazem with BBs can lead to
L. Segall