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are associated with better kidney and cardiovascular outcomes [ 24 ]. ACEIs and
ARBs are probably equivalent with respect to renal outcomes [ 26 ]. They should be
considered for use particularly in patients with CKD who also have heart failure,
recent myocardial infarction, a history of stroke, or a high cardiovascular risk,
although this KDIGO recommendation is largely based on data from studies in non-
CKD patients [ 24 ].
The support for the recommendation of ACEIs/ARBs as first-line therapeutic
agents in hypertensive CKD patients is provided by several studies. The KDIGO
recommendations cite five relevant trials: reanalyses of the Heart Outcomes
Prevention Evaluation (HOPE) trial [ 27 ], the Candesartan Antihypertensive Survival
Evaluation in Japan (CASE-J) trial [ 28 ], the Telmisartan Randomised Assessment
Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND)
[ 29 ], as well as the Investigation on Type 2 Diabetic Nephropathy (INNOVATION)
study [ 30 ] and the Irbesartan in Development of Nephropathy in Patients with Type
2 Diabetes (IDNT) trial [ 31 ]. A meta-analysis of 11 RCTs [ 32 ] included studies of
patients with nondiabetic CKD treated with BP-lowering regimens containing
ACEIs to those not containing ACEIs. All trials included in the analysis targeted a
BP <140/90 mmHg, and nearly all patients were hypertensive at baseline. In this
analysis, the use of an ACEI was associated with a significant reduction in the risk
of progression of kidney disease as defined by doubling of serum creatinine or the
need for dialysis. This effect was independent of other important covariates, includ-
ing baseline BP and urinary protein excretion. Of relevance, there was no significant
interaction between current urinary protein excretion and treatment allocation. In
other words, there was no evidence that the degree of protein excretion modified the
relationship between the use of ACEIs and the progression of kidney disease. The
results of the meta-analysis suggest that ACEIs should be the antihypertensive drugs
of choice in individuals with CKD. However, another analysis of the same data set
[ 33 ] suggested that baseline urinary protein excretion was an important effect modi-
fier, in that those with baseline urine protein excretion ≥500 mg/day seemed to have
greater benefits with ACEI therapy. Those with proteinuria <500 mg/day at baseline
appeared to receive little if any benefit compared to other antihypertensive regi-
mens. TRANSCEND [ 34 ] randomized patients at high vascular risk to telmisartan
or placebo. No difference was observed between groups in the primary cardiovascu-
lar endpoint or the secondary renal endpoint of dialysis, doubling of serum creati-
nine, or death. In a reanalysis of TRANSCEND, individuals without microalbuminuria
had an increased risk of the renal endpoint, while there was no significant difference
in those with urinary albumin excretion ≥30 mg/day, although the trend favored
telmisartan.
There are also some other significant controversies between guidelines regarding
ACEIs and ARBs. First, according to the ERBP guideline [ 35 ], it is unclear if the
renoprotective superiority of ACEIs and ARBs is truly a BP-independent effect or
simply a reflection of better BP control. Second, in contrast with the KDIGO guide-
lines, the authors of ERBP recommend that, due to increased risk of side effects,
consideration should be given to stopping ACEIs/ARBs in patients with advanced
CKD (stages 4 and 5) when there are no other compelling indications for these
L. Segall