SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 7 NUMBER 1 • MARCH 2010
9
arteriole and hence to a decrease in glomerular filtration
pressure reflected in a decreased glomerular filtration rate.
In the setting of marginal renal perfusion, which may occur
in heart failure or with significant renal artery stenosis, such
a reduction in filtration pressure may lead to a significant
reduction in renal function and significant comorbidity. It is
therefore important that patients have blood tests to quantify
renal function before and within two weeks of commencing
renin–angiotensin system blocking agents to ensure their use
is safe in individual patients. A reduction of under 15% of the
baseline glomerular filtration rate is acceptable following the
introduction of an ACE inhibitor or ARB so long as there is no
further fall in renal function on subsequent testing. Patients
should also be advised to stop taking renin–angiotensin
system blocking agents during intercurrent volume depleting
illnesses such as diarrhoea and vomiting.
In Afro-Caribbean patients ACE inhibitors are thought to
be less effective antihypertensive agents than in other ethnic
groups. However, combined with a low salt diet or a thiazide
diuretic these agents can still be very effective. Chronic ACE
inhibitor use leads to decreased effectiveness and also ACE
inhibitors do not block angiotensin II production by non-ACE
pathways such as by chymases and other tissue proteases
which are more upregulated in the kidneys of diabetic than
in non-diabetic patients.
13
This leads to the rationale for
using dual blockade of the renin–angiotensin system with
the combination of ACE inhibitors and ARBs. In this situation
hypotension may occur and hyperkalaemia is a risk, although
in the early stages of renal dysfunction when the kidneys
maintain their ability to excrete potassium this is rarely a
problem. In the more severe stages of renal dysfunction
correcting acidosis and maintaining a low potassium diet
may be required to avoid hyperkalaemia. Patients taking
renin–angiotensin system blocking agents should be advised
to take the first few doses in the evening in case first-dose
hypotension occurs. They should also be advised that the
incidence of dry cough reported with ACE inhibitor use can
be up to 40%. Finally these drugs are unsafe in even the early
stages of pregnancy, which must be made clear to all females
of a child-bearing age to whom they are prescribed.
Microalbuminuria
Once patients have developed persistent microalbuminuria,
they may be considered to have incipient diabetic
nephropathy. It is essential that early detection and treatment
of microalbuminuria are instituted at this stage of diabetic
nephropathy as it may still be reversible with patients reverting
to normoalbuminuira.
Detecting microalbuminuria (
<
300 mg but
>
30 mg
albuminuria per day) in diabetic patients holds significant
importance because microalbuminuria, as well as heralding
the onset of diabetic nephropathy, is a risk factor for
cardiovascular events in both diabetic and non-diabetic
patients. Urinary dipsticks do not detect microalbuminuria
so this must be sought by other means, such as overnight
urinary albumin excretion rate, or more commonly by the
urinary albumin:creatinine ratio.
Once microalbuminuria has been detected, primary
care physicians have to decide whether it is likely to be
the result of diabetic damage to the kidney or from other
renal pathology which may merit referral to a nephrologist
for further evaluation. In patients with diabetic retinopathy
or neuropathy the onset of microalbuminuria may be
thought with some confidence to be a further microvascular
complication of diabetes and renal biopsy unnecessary. This is
often clearer in type 1 diabetes for which retinopathy occurs
in nearly all patients; it is less clear in type 2 diabetes where
retinopathy occurs eventually in 50–60% of patients.
When diabetic patients present with macroscopic
haematuria or have urinary red cell casts, a renal biopsy is
usually indicated. Similarly, diabetic patients who present
with a rapid fall in glomerular filtration rate, renal dysfunction
in the absence of proteinuria or with signs and symptoms
of systemic disease, should be referred for consideration
of a renal biopsy to establish diagnosis. Finally, patients
who develop a significant drop in renal function after the
introduction of a renin–angiotensin system blocking agent
should be referred to a nephrologist for further evaluation.
In the IRMA-2 trial 590 patients with microalbuminuria
were randomised to receive 150 mg or 300 mg irbesartan
or placebo with a two-year follow-up. The blood pressure
achieved in the study was similar for each group (placebo
144/83 mmHg, 150 mg irbesartan 143/83 mmHg and 300
mg irbesartan 141/83 mmHg). However, the hazard ratio
for time to onset of overt nephropathy was reduced in both
the irbesartan groups, significantly in the 300 mg irbesartan
group. There were also significant decreases in the level of
albuminuria in the irbesartan groups which was not observed
in the placebo group and increased numbers of patients
regressed to normoalbuminuria in the irbesartan groups
compared with the placebo group.
14
The benefits of ARBs
in patients with microalbuminuria have been demonstrated
again in the recently published INNOVATION trial of 527
Japanese diabetic patients with microalbuminuria randomised
to 40 or 80 mg of telmisartan or placebo with a short
follow-up of 1.3 years. There was reduced transition to overt
nephropathy and increased remission to normoalbuminuria
seen in both hypertensive and normotensive patients in the
telmisartan treated patient groups.
15
Dual blockade of the renin–angiotensin system with both
ACE inhibitors and ARBs has been shown to be an effective
treatment in diabetic patients with microalbuminuria. The
CALM study randomised 199 patients to receive 12 weeks
of monotherapy with either 16 mg candesartan or 20 mg
lisinopril followed by 12 weeks of combination therapy
with both agents. This study showed that in monotherapy
both agents were equally effective in reducing blood
pressure and microalbuminuria. Combination treatment led
to a further blood pressure reduction and a further fall in
albumin:creatinine ratio.
16
A secondary finding of the CALM
trial was that dual blockade of the renin–angiotensin system
was well tolerated with no excess study withdrawals due to
