Treatment options for chronic kidney disease
have been limited so far. The
last 40 years have not seen any progress in drug development and even patients
who receive a transplant ultimately succumb to dialysis and death.
‘Progressive kidney disease can now be treated by a small molecule which prevents the death of filtration cells called podocytes that are responsible for filtering out toxins.’
team from the Broad Institute, MIT and Harvard, Brigham and Women's Hospital
and Harvard Medical School has identified a small molecule which stops the
progression of kidney disease.
Senior author Anna Greka (member of the Broad Institute,
associate physician at Brigham and Women's Hospital and assistant professor at
Harvard Medical School) and her colleagues started their research on the
rare genetic kidney disease FSGS using a mouse model to understand the genes
involved, proteins and molecular pathways occurring in kidney damage and
. In FSGS, scarring of the glomeruli is usually caused by
destruction of cells responsible for the filtering process. These cells known
as podocytes filter toxins and keep proteins out of blood
of podocytes leads to protein leak into the kidneys and into the urine. This
condition known as proteinuria is majorly responsible for destroying the
In FSGS, the investigators knew that a genetic mutation
activates a protein called Rac1 which in turn activates another protein TRPC5
which causes excess calcium flow into the podocytes thereby destroying it
According to Greka, the team was focused on trying to find a drug which
prevents destruction and damage of podocytes and protects kidney function. The
team believes that this therapeutic research is not just beneficial for FSGS
but all patients with chronic kidney disease since the group of kidney
disorders have a shared pathway for kidney failure.
The researchers designed and tested several compounds before
zeroing in on AC1903 which was able to block this process of podocyte
destruction. AC1903 has been named after Anna Greka and
co-author Corey Hopkins (University of Nebraska Medical Center College of
Pharmacy). In the mouse model, AC1903 protected the podocytes, controlled
proteinuria and restored kidney function
. Even in advanced kidney disease,
the compound was able to prevent loss of podocytes and protect kidney function.
The team also successfully tested AC1903 in mouse models
with hypertension where the kidney function again improved. The research
indicated that TRPC5 mechanism which causes damage to podocytes has a role in
other kidney diseases too apart from FSGS. While in FSGS, damage was due to a
genetic mutation; factors like high blood pressure was the trigger in other
chronic kidney diseases. The team believes that TRPC5 inhibitors have a broad
role in a range of kidney disorders.
The research is very encouraging for 10% of the world's
population is affected
with chronic kidney disease. The 2010 Global Burden of Disease study found that
chronic kidney disease ranks 18 in the cause for worldwide
deaths and over 2 million people worldwide either receives dialysis
regularly or a kidney transplant. The discovery of the new molecular compound
AC1903 brings hope to the millions of sufferers globally. This exciting
research now awaits human clinical studies.
progressive kidney disease?
Progressive kidney diseases are caused by damage
to the kidney's filtration process
. The Glomerular Filtration Rate (GFR) is usually
in kidney conditions. The GFR is the rate at which the kidneys
filter the waste and also relate to measuring kidney function. In chronic
kidney disorders, GFR rate slowly comes down leading to renal insufficiency and
ultimately renal failure and death.
One of the rare genetic kidney diseases is a
condition known as Focal Segmental Glomerulosclerosis (FSGS) which attacks the
kidney's filtering units, glomeruli
. This leads to scarring of the kidneys
and ultimately kidney failure. FSGS has a range of symptoms which include
proteinuria where protein leaks into the kidneys and urine, edema or swelling
in the legs, feet and face, high cholesterol and high blood pressure. FSGS is
caused by a rare genetic mutation, side effects of other blood disorders like
sickle cell anemia and other autoimmune disorders.
Currently, there are no targeted drugs for chronic kidney
diseases or FSGS. The only treatment modalities include diuretics and low-sodium
diet; ACE-inhibitors to control blood pressure and reduce proteinuria,
anticoagulants to stem blood clots and statins to lower blood cholesterol.
People with chronic kidney disorders ultimately need dialysis and transplants. References
- Zhou, Greka, Castonguay, Sidhom et al. (2017) "A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models." Science 358(6368), pp. 1332-1336. DOI: 10.1126/science.aal4178
- Ericson, A., and B. Källén. "Congenital malformations in infants born after IVF: a population-based study." Human reproduction 16, no. 3 (2001): 504-509. https://doi.org/10.1093/humrep/16.3.504
- Kidney Internation - (https://nephcure.org/)
- Chronic Kidney Disease Stages - (http://www.nationalkidneycenter.org/chronic-kidney-disease/stages/)
- Global Facts: About Kidney Disease - (https://www.kidney.org/kidneydisease/global-facts-about-kidney-disease)