Invention: ACE inhibitors to stop chronic kidney disease (CKD)
Treatment outcomes have greatly improved over the past decades thanks to the inventions of Italian nephrologist Giuseppe Remuzzi and fellow researchers Carlamaria Zoja and Ariela Benigni. The team's medications use angiotensin-converting-enzyme (ACE) inhibitors to treat chronic kidney disease and complications related to organ transplants.
Over 200 million people suffer from chronic kidney disease
(CKD). Although a simple test can provide early warning - increased protein levels
in the urine signal impaired kidney function - many patients only seek help once
their symptoms are advanced. At that stage, doctors used to be powerless to
stop CKD - or kidney inflammation after organ transplants - from progressing to
organ failure and lifelong dependence on dialysis machines.
Dialysis is no longer inevitable, thanks to the medications developed
by Remuzzi, Zoja and Benigni. The team achieved its breakthrough after Remuzzi
discovered the kidney-saving properties of certain enzyme inhibitors in the
late 1980s. Conventionally used to treat hypertension, these inhibitors
provided the key mechanism behind the team's patent-protected drugs, which are now standard treatments for
CKD worldwide.
Societal benefit
The team's
ACE inhibitor-based medications were not only the first drugs to stop the
progression of CKD: they also proved effective against diabetic nephropathy, a
complication affecting up to 35% of diabetics. One of the team's key drugs, Losartan,
specifically benefits organ transplant patients, since CKD affects 21% of
intestine and 18% of liver recipients. As a result, patients can recover to
lead fully independent lives.
The drugs are powerful
tools in developing countries, where dialysis remains widely unavailable and
prevention is key. Remuzzi founded an international charity, the Global
Advancement Nephrology Project, to bring screening and affordable treatments
for kidney complications to impoverished communities.
Remuzzi is also an advocate of preventive testing. "The
heart beats, the lung breathes - the kidney does not make any noise, and often
people end up being presented with end-stage kidney disease having never
realised anything was wrong," he says. A simple urine test can reveal
kidney dysfunction, and treatment can then start before the damage becomes
irreversible.
Economic benefit
In the 1990s, Remuzzi and his team worked on developing ACE
inhibitor-based drugs specifically for kidney disease. Brought to market by
pharmaceutical company Merck, in 1995 Losartan received US and EU approval for
treating complications from organ transplants, and by 2011 it was generating annual
sales of almost EUR 1.5 billion. Another of their drugs, Irbesartan, was approved
in 1997 and is marketed by Sanofi. It achieved sales of around EUR 775
million in 2015.
Market analysts BCC
Insights valued the US market for kidney-failure treatment at EUR 36 billion
in 2016 and expect it to exceed EUR 41.7 billion by 2021. The global market for
enzyme inhibitors - including the team's
ACE inhibitors - was worth nearly EUR 117 billion in 2016.
As research co-ordinator at the Mario Negri Institute for
Pharmacological Research in Bergamo, Remuzzi encourages "his"
scientists to pursue research for the sake of science. The Institute was
created in Milan in 1963 as a non-profit research institution, and the Bergamo
branch was launched to encourage research into rare and "orphan"
diseases, which are often neglected as "unprofitable" by pharmaceutical companies. The
Institute's policy is not to file patents itself, but to allow other companies
to patent its research.
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Giuseppe Remuzzi, Carlamaria Zoja and Ariela Benigni (from left to right)
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Giuseppe Remuzzi, Ariela Benigni and Carlamaria Zoja (from left to right)
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Carlamaria Zoja (left) and Ariela Benigni
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Giuseppe Remuzzi
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Carlamaria Zoja, Giuseppe Remuzzi and Ariela Benigni (from left to right)
How it works
Doctors identified increased protein output in patients' urine as a warning sign of progressive
kidney disease in the 1890s. High protein levels indicate that glomerular
filtration rates, which reflect the kidney's ability to filter the blood, are
declining.
After ten years of research, Remuzzi made a key discovery: increased
protein traffic to the kidney is not just a symptom
of kidney disease but a cause,
actually increasing damage as it persists.
This discovery led Remuzzi to search for an "off switch" to stop the progression of
kidney disease before it could lead to organ failure. He found it in ACE
inhibitors. This group of drugs was already known to reduce hypertension, a
common complication affecting 70% of lung, heart and liver transplant
recipients.
Remuzzi discovered that the mechanism behind ACE inhibitors
lowered protein levels in the blood, which halted the progression of kidney
disease. He refined the use of ACE compounds into drugs specifically for kidney
disease which block angiotensin II type 1 receptors.
The inventors
After earning his medical degree at University of Pavia in
1974, Giuseppe Remuzzi began working with CKD patients and organ-transplant
recipients at Bergamo Hospital. After publishing his findings on haemolytic uraemic
syndrome (a known cause of CKD) and renal replacement therapy in The Lancet in 1977, he gained international
recognition as an authority in his field.
Today, he is professor
of nephrology at the University of Milan. He has served as director of the
Department of Immunology and Clinical Transplantation (since 1996) and
Department of Medicine (since 2011) at Bergamo Hospital. He has been the director
of the Division of Nephrology and Dialysis at Azienda Ospedaliera Papa Giovanni
XXII in Bergamo since 1999, having become research co-ordinator at the Mario
Negri Institute for Pharmacological Research in Bergamo in 1984.
In a research career
spanning almost four decades, Remuzzi has authored and co-authored some 1 300
scientific articles. His honours include the ISN Jean Hamburger Award (2005),
the John P. Peters Award (2007) and the ISN AMGEN Award (2011).
Carlamaria Zoja and Ariela Benigni both earned their degrees in biological sciences from the
University of Milan and PhDs from the University of Maastricht. Zoja has been working
as a researcher and scientist at the Mario Negri Institute in Bergamo since
1985, where she currently heads the Laboratory of Pathophysiology of
Experimental Renal Disease and Interaction with other Organ Systems in the
Department of Molecular Medicine.
Ariela Benigni
joined the Mario Negri Institute in Bergamo in 1986 and is currently head of
the Department of Molecular Medicine. A renowned expert in the role of blood
pressure and proteins in progressive kidney disease, she has authored over 270
peer-reviewed articles and lectured at more than 140 national and international
meetings. A recipient of the
Citta di Bergamo Merit Award, Benigni has also been consulted by the World
Health Organization as a leading expert on progressive kidney disease.
Did you know?
Conventionally, pharmaceutical research follows a
cardinal rule: one drug for one disease. But although ACE inhibitors were
originally designed to treat hypertension, Remuzzi discovered that they
also had the potential to treat kidney disorders. That made ACE inhibitors part of a select group
of drugs which are designed to treat one condition but can be "repurposed"
to cure other ailments (often without any significant change in their
composition).
Other examples include Tamoxifen (treats breast
cancer, but is also effective against bipolar disorders), Gabapentin (developed
for epilepsy, now a painkiller), Raloxifene (treats osteoporosis and prevents
breast cancer) and even aspirin (a pain killer that prevents heart disease).
Teaching old drugs new tricks offers great
advantages: they have already been approved and therefore don't require costly
animal testing or clinical trials. "Repurposing" existing medications
is a growing trend in research.
