300
not ETA/ETB receptor antagonist bosentan, prevented the aggravation of hyperten-
sion in renal failure rats treated with erythropoietin-stimulating agents [ 73 ].
Administration of a selective ETA receptor antagonist to hypertensive patients with
CKD produced a substantial reduction in BP (10 mmHg) and increased renal blood
flow [ 74 ]. In addition, chronic treatment with the mixed ETA/ETB receptor antago-
nist, avosentan [ 75 ], and the selective ETA receptor antagonist, atrasentan [ 76 ], in
addition to standard ACEI/ARB treatment, substantially decreased albumin excre-
tion in patients with diabetic nephropathy.
While ET receptor antagonists are generally well tolerated in clinical trials, the
major adverse effects are peripheral edema, a mild decrease in hemoglobin (thought
to be related to hemodilution secondary to increased extracellular fluid), headache,
and flushing. As these drugs are primarily metabolized and eliminated by the liver,
one significant adverse effect is hepatic dysfunction, which is dose dependent and
reversible upon discontinuation of the drug [ 47 ].
Conclusions and Recommendations
In patients requiring a triple therapy, this should consist of an ACEI or
ARB + CCB + diuretic (ACD regimen) for most patients. This regimen is thought
to be effective and well tolerated in CKD. It should be tried in optimum doses as
the first therapeutic step in patients with CKD and RH, in the absence of
contraindications.
ACEIs and ARBs are especially preferred in patients with CKD and heart failure,
post-myocardial infarction, and proteinuria. Adverse effects include hypotension,
acute kidney injury, and hyperkalemia. Monitoring of serum creatinine and potas-
sium is indicated after starting treatment. If strategies to minimize hyperkalemia fail
to maintain serum potassium concentrations <5.6 mEq/l, the RAS inhibitor should
be discontinued, and another class of antihypertensive drugs should be used instead.
In patients with advanced CKD (stages 4 and 5), consideration should be given to
stopping ACEIs/ARBs when there are no other compelling indications for these
agents and especially when there is high risk of hyperkalemia and/or acute kidney
injury, which may precipitate dialysis initiation. Dual therapy ACEI + ARB or
ACEI/ARB + DRI is not indicated, because of increased risk of adverse events and
lack of proven benefits.
Diuretics are the cornerstone of hypertension treatment in CKD and, by defini-
tion, a component of any antihypertensive drug combination for RH. The combina-
tion of diuretics with RAS inhibitors, CCBs, and BBs is synergistic and very
effective. In patients with CKD stage 4 (GFR <30 ml/min/1.73 m^2 ) or with signifi-
cant edema, thiazide diuretics should be replaced or combined with loop diuretics.
CCBs are particularly useful in hypertensive patients who also have angina and/
or supraventricular tachycardia. Most CCBs do not accumulate in patients with
impaired renal function. Dihydropyridines may induce fluid retention, which can be
L. Segall