CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 1, January/February 2010
AFRICA
5
ally reversible with restoration of cardiac function.
It is often a delicate juggling act to prevent pulmonary
congestion and maintain renal perfusion with optimal doses of
loop diuretics, aldosterone antagonists, beta-blockers and ACEIs.
Renal function must be carefully monitored as well as serum
potassium (K
+
) levels. Therefore, for Onuigbo, in his critical
re-appraisal of the evidence for RAS blockade on renal outcomes,
to use cardiac failure studies to conclude that these agents may
not be renoprotective is extremely difficult to understand.
8
Do RAS inhibitors improve cardiovascular out-
comes in patients with CKD and proteinuria?
Balamuthusamy
et al
. conducted a meta-analysis of cardiovas-
cular outcomes in patients with CKD and proteinuria receiving
RAS blockers. They showed a significant reduction in risk of
myocardial infarction, heart failure and total cardiovascular
outcomes compared with placebo, and reduced cardiovascular
outcomes and heart failure when compared to control treatment.
31
Are there safety concerns about RAS inhibitors
in patients with CKD and cardiovascular
disease?
Not unlike any pharmaceutical agents, RAS inhibitors need to be
used with due diligence. RAS inhibitors are contraindicated in
pregnancy and may cause hyperkalaemia, especially in patients
with severe cardiac disease or advanced CKD, particularly if
combined with aldosterone anatagonists. Careful monitoring of
the serum K
+
is required.
It is also well established that RAS inhibitors may cause an
acute deterioration in renal function. Patients at risk are those
with severe cardiac failure, bilateral renal artery stenosis, normo-
tensive patients with CKD, and patients with CKD or cardiac
failure who become pre-renal due to overuse of diuretics or
inter-current illnesses such as acute gastroenteritis. On the other
hand, from a physiological perspective, RAS inhibitors cause a
rise in creatinine due to a reduction in GC pressure. One of the
most frequently asked questions of nephrologists is ‘What degree
of rise in creatinine level is acceptable after introducing an RAS
inhibitor?’
Bakris and Weir found that in most trials there was minimal
or no rise in creatinine levels with initiation of ACEIs in patients
with normal renal function, but if there was pre-existing renal
insufficiency (creatinine
≥
124
µ
mol/l), up to a 30% decline
in creatinine levels may be acceptable and the ACE inhibitor
continued, provided there was no further deterioration and the
serum K
+
concentration was not above 5.6 mmol/l.
32
In fact, this
finding predicted a long-term preservation of renal function. In
my opinion, any rise in creatinine above 20% should prompt the
physician to consider renal artery stenosis or pre-renal insuffi-
ciency. Because of these safety concerns, RAS inhibitors should
preferably be initiated and monitored by specialists in patients
with abnormal renal function, especially if estimated GFR is
below 45 ml/min, whereas the general practitioner can safely
handle patients with normal renal function.
Conclusion
There is unequivocal evidence that RAS inhibitors protect the
kidney in patients with diabetes, in non-diabetics with CKD,
particularly if urinary protein is above 0.5 g/day, and improve
cardiovascular outcomes in patients with proteinuric CKD. There
is suggestive evidence that ACEIs may preserve renal function
in patients with hypertension, especially if there is established
hypertensive nephrosclerosis. The role of RAS inhibitors in the
general protection of the kidney in patients at high cardiovascular
risk remains unproven, but this must be interpreted in the context
that these trials are not powered to make any positive or nega-
tive conclusions. RAS inhibitors may cause acute deterioration
in renal function in patients with bilateral renal artery stenosis
and severe cardiac failure. Initiation of RAS inhibition in any
patient who has CKD with elevated creatinine must be carefully
monitored.
BRIAN RAYNER
Division of Nephrology and Hypertension,
University of Cape Town
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