CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 1, January/February 2010
AFRICA
3
Editorial
Do inhibitors of the renin–angiotensin system prevent
chronic kidney disease?
The world is facing an epidemic of chronic kidney disease
(CKD) and in South Africa, death rates from end-stage renal
disease (ESRD) have risen by 68% from 1999 to 2006.
1
The
major drivers of this epidemic are type 2 diabetes (T2D) and/or
hypertension.
2
All major guidelines recommend ACE inhibitors
(ACEIs) or angiotensin receptor blockers (ARBs) for the preven-
tion of CKD.
3-5
Recently, two important studies have reported no
benefit on renal outcome in patients at high cardiovascular risk
or in patients with type 1 diabetes receiving renin–angiotensin
system (RAS) inhibitors,
6,7
and commentators have questioned
the validity of the guideline recommendations.
8,9
To improve our interpretation of studies of renal disease there
needs to be a better understanding of renal physiology and ‘hard’
renal versus surrogate endpoints.
Basic renal physiology
Single nephron glomerular filtration rate (SNGFR) is deter-
mined by the following equation:
K
f
[(
P
gc
–
P
bs
) – (
π
gc
–
π
bs
)]
where
K
f
is the ultrafiltration coefficient,
P
gc
is the glomerular
capillary hydrostatic pressure,
P
bs
the Bowman’s space hydro-
static pressure,
π
gc
the glomerular capillary oncotic pressure
and
π
bs
the Bowman’s space oncotic pressure.
10
Total GFR is
determined by the sum of all SNGFRs. Short-term changes in
GFR are largely determined by changes in GC pressure, which
is dependent on blood pressure (BP) and tone of the afferent and
efferent renal arterioles.
In patients with CKD, there is progressive nephron loss.
Overall, GFR is maintained by increasing SNGFR by raising
GC pressure via afferent arteriolar dilatation and efferent vaso-
constriction, largely mediated by angiotensin II. Raised GC pres-
sure is harmful in the long term, causing progressive proteinuria
and glomerulosclerosis. Therefore, BP lowering and especially
lowering GC pressure by RAS inhibition has been experimen-
tally shown to prevent glomerulosclerosis, but at the expense of
short-term reduction in GFR.
In diabetes, there is evidence of GC hypertension prior to the
onset of overt renal disease, and angiotensin II plays a crucial
role in the pathogenesis of diabetic nephropathy.
By contrast, in patients with heart failure, there is under-
perfusion of the kidney, resulting in reduction of GC pressure and
hence GFR. To compensate, the kidney responds by constrict-
ing the efferent arteriole and dilating the afferent arteriole to
maintain GC pressure (and GFR) through tubular glomerular
feedback and angiotensin II. This is termed renal autoregula-
tion. Therefore, the use of RAS inhibitors in patients with severe
cardiac failure may cause acute reduction in GFR unless there is
compensatory improvement in cardiac output.
Interpreting hard renal endpoints
In most studies, doubling in serum creatinine or ESRD is used as
a hard renal endpoint. However, it is important to understand that
GFR is inversely proportional to serum creatinine. Therefore,
if the renal function is normal, a doubling in serum creatinine
will represent a loss of 50% of renal function, i.e. 50 ml/min.
However, if the GFR is 25 ml/min, a doubling in serum creatinine
will also represent a loss of 50% of renal function but in absolute
terms, a reduction of 12.5 ml/min. Therefore in advanced CKD,
small changes in GFR may result in large increases in creatinine,
giving a spurious appearance of accelerated deterioration and
greater opportunity to achieve hard renal endpoints.
In most cases of CKD there is a constant, progressive loss of
function of approximately 5 to 10 ml/min/year. Therefore it will
take five to 10 years to demonstrate a doubling in creatinine, and
10 to 20 years for ESRD in patients with normal renal function.
By contrast, in patients with reduced GFR, the time period of
doubling of creatinine is considerably reduced and in the bounds
of a conventional trial. Therefore trials of advanced CKD disease
are usually powered to show reductions in hard renal endpoints,
whereas a trial of patients with preserved renal function is not,
and surrogate endpoints such as microalbuminuria and proteinu-
ria by necessity are used.
In patients with CKD, proteinuria is an excellent surrogate
marker for progression of the disease.
11
Microalbuminuria is a
predictor of incipient nephropathy in diabetics
12
but its relation-
ship to CKD and progression of renal disease in hypertensive
patients and patients at high cardiovascular risk is less well
defined and may be more of a marker of endothelial dysfunction
rather than early CKD.
13
Therefore trials reporting microalbu-
minuria results as an index of CKD outside diabetes must be
interpreted with caution.
In patients with cardiac disease, the endpoint of doubling of
serum creatinine must be seen in a different perspective, and
is more an issue of safety. This may occur rapidly over hours
to days due to acute reductions in renal perfusion, leading to
pre-renal failure and rapidly rising creatinine, which is generally
reversible if cardiac function is improved.
Preventing kidney disease: the evidence for
RAS inhibitors
Diabetes
The natural history of diabetic nephropathy is well documented
and follows a predictable course. There is usually approximately
five years of hyperfiltration, 10 years of microalbuminuria with
preserved renal function (or incipient nephropathy), and 10
years of overt proteinuria with declining renal function (or overt
nephropathy), reaching ESRD approximately 20 to 25 years after
