Goldsmith_EU_Renal 9/7/07 9:51 am Page 41
Cardiovascular Risk
Direct Renin Inhibitors – Nuance or Necessity?
a report by
Liviu Segall,
1
Kerem Atalar
2
and David Goldsmith
3
1. ’C I Parhon’ University Hospital, Romania; 2. St Thomas’ Hospital, London; 3. Guy’s Hospital, London
Renin-angiotensin-aldosterone System Inhibitors in associated with a reduction in glomerular injury and proteinuria, but
Chronic Kidney Disease also with tubulointerstitial abnormalities.
17
These findings support a
The renin-angiotensin-aldosterone system (RAAS) plays an important role direct profibrotic role for renin, independent of its angiotensin-
in the progression of chronic kidney disease (CKD). Angiotensin (Ang) II generating effect.
generates intra-renal haemodynamic and inflammatory changes that
promote proteinuria, growth of glomerular and tubular cells, inhibition of • ACE inhibitors induce an acute decrease in plasma aldosterone. This
nitric oxide (NO) synthesis, stimulation of extracellular matrix synthesis effect, however, is often only transient and followed by a progressive
and induction of chemokines, reactive oxygen species and apoptosis.
1
In rise in aldosterone levels that ultimately, with long-term ACE inhibition,
addition, in animal models of renal diseases aldosterone is involved in can reach normal or even elevated concentrations. This ‘aldosterone
endothelial dysfunction, inflammation, proteinuria and fibrosis.
2
In clinical escape’, which is more often seen in homogenous deletion (DD) ACE
trials, treatment with angiotensin-converting enzyme (ACE) inhibitors and genotype patients,
18
is not well explained, but it might be the result of
Ang II AT1 receptor blockers (ARBs) can retard the evolution of both aldosterone secretion stimulation by high potassium levels induced by
diabetic
3–5
and non-diabetic nephropathies.
6–8
ACE inhibition.
19
Aldosterone breakthrough also occurs during long-
term ARB treatment through an AT2-dependent mechanism.
20
A controversial issue is whether these agents are superior to other
antihypertensive drugs in terms of renoprotection. Findings from animal • The ARBs leave the AT2 receptors unblocked, and some experimental
studies,
9
as well as from other hypertension clinical trials
10,11
and from a data suggest that these receptors are involved in renal inflammation
large meta-analysis,
12
suggested that the benefit seen with ACE inhibitors by activation of NF-κB in mesangial and endothelial cells and
is related to the blood pressure (BP) decrease alone. ACE inhibitors exhibit induction of chemokines.
21,22
a BP-independent renoprotective effect, but only in patients with
proteinuria and advanced kidney disease (i.e. stage 3 or 4); also, the So, from the above we can see that there is at least the potential for
higher the degree of baseline urine protein excretion and proteinuria newer agents to complement the existing ones to achieve a more
decrease, the more pronounced the effect.
13
complete blockade of RAAS.
However, neither ACE inhibitors nor angiotension receptor blockers
Liviu Segall is a Nephrologist working in the Internal
(ARBs) alone can completely suppress the activity of the RAAS, given its Medicine and Nephrology Unit at the ‘C I Parhon’
remarkable complexity (see Figure 1). The main limitations of these
University Hospital in Romania. He is the author or co-
author of 28 medical articles and three books. He qualified
agents can be summarised as follows:
in medicine after graduating from the the Faculty of
Medicine at the University of Medicine and Pharmacy
‘Gr T Popa’ of Iaï in 1991.
• A substantial proportion of Ang II is generated in the kidneys from
Ang I via non-ACE pathways, such as chymase,
14
which are beyond
the control of ACE inhibitors.
Kerem Atalar is a Senior House Officer in Vascular Surgery
working at St Thomas’ Hospital, London. He graduated
• ACE inhibition and angiotension type 1 (AT1) receptor blockade, by
from Guy’s, King’s and St Thomas’ Hospitals Medical
School in 2005.
interrupting negative feedbacks, result in high renin concentrations
and high plasma renin activity (PRA), which may overcome the
effectiveness of the drugs. The reactivation of Ang II (or ‘the Ang II
escape’) has been described with both ACE inhibitors and ARBs. For
David Goldsmith is a Consultant Nephrologist at Guy’s
example, almost half of congestive heart failure patients treated with
Hospital and has had the same role at St Thomas’ Hospital,
long-term ACE inhibitors were found to have elevated Ang II levels.
15
London, since 1998. He was a Royal College of Physicians
Tutor in 2000, an Executive Member, Trustee and Honorary
Secretary of the UK Renal Association (ERA) from 2002 and
• Renin can also bind to specific receptors in the mesangium and in the
was an ERA Council Member between 2004 and 2007. He
has published one book, eight chapters, 190 papers and
subendothelium of the renal arteries. This binding leads, on the one
130 research abstracts and has given 26 international and
hand, to a substantial increase in the catalytic efficiency of conversion 25 national lectures.
of angiotensinogen to Ang I, and, on the other hand, to a stimulation
E: David.Goldsmith@gstt.nhs.uk
of mitogen-activated protein kinases, ERK-1 and ERK-2.
16
In animal
models of nephrotic syndrome, treatment with ACE inhibitors was
© TOUCH BRIEFINGS 2007 41