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Researchers discover promising treatment for the most common cause of inherited nephrotic syndrome

03 January 2024

In a recent study, funded by Kidney Research UK and the Nephrotic Syndrome Trust and published in the journal Kidney International, Professors Moin Saleem and Gavin Welsh and their team at Bristol Renal have shown that a drug can restore the function of a protein that is disrupted in the most common form of inherited nephrotic syndrome (NS).

Main wearing black jumper and blue jacket
Professor Moin Saleem

What is nephrotic syndrome?

Nephrotic syndrome is a condition where the filtering structure of the kidneys, known as the glomerular filtration barrier, becomes damaged and allows proteins that should remain in the bloodstream to leak into urine. This can lead to swelling, particularly in the eyes and legs, and increased risk of infections and blood clots. 

Unravelling the genetic roots of nephrotic syndrome

The most common genetic cause of NS is a change in the gene responsible for making podocin - a crucial protein found in podocytes (specialised cells in the kidneys that are responsible for filtering blood). When a cell produces a protein, it must then fold it into the appropriate shape. This genetic change means that podocin doesn’t fold properly. Although the protein should still work, the folding problem stops it from being transported to the outer covering of the cell, called the cell membrane, where it needs to be to perform its job. Instead, the misfolded podocin stays inside the cell where it cannot function. 

Patients with this genetic change develop NS at an early age; while current treatments aim to manage symptoms, there is no permanent cure. As the illness progresses, dialysis or kidney transplantation may be required.

“There are more than 30 known mutations in podocin that can cause steroid-resistant nephrotic syndrome. The R138Q mutation is the most common and accounts for nearly 60% of cases. Patients with this mutation develop symptoms of NS early in childhood and rapidly progress to end-stage renal disease.” Professor Moin saleem

Helping proteins get to the right place: learning from cystic fibrosis research 

Cystic fibrosis can also be caused by genetic changes resulting in misfolded proteins that cannot reach the cell membrane. Researchers have found that this is because a protein called keratin 8 (K8) binds to the misfolded protein, stopping it from being delivered to the cell membrane. A drug known as c407 was shown to interfere with this system in cystic fibrosis. 

The Bristol team wondered if K8 might also be the reason that the misfolded podocin protein cannot reach the cell membrane. Using their lab models of NS, they showed for the first time that the misfolded podocin protein does in fact bind to K8. 

They then discovered that when they used the new drug in their lab models, the misfolded podocin moved to the cell membrane, where it began to function properly.  

What might this mean for patients?

More research is now needed, but this work suggests that medications that disrupt the interaction between K8 and misfolded podocin protein could provide a treatment option for patients with the most common inherited form of NS. 

“Current treatment is focussed on slowing the progression of the disease and controlling the symptoms, though they don’t deal with the root cause of the problem. Here we have a potential treatment that could restore kidney function by getting the misfolded protein to the cell membrane where it can do its job. This way we can stop the progression of the disease and stop patients needing dialysis or transplant.” Moin added. 

Elaine Davies, director of research operations at Kidney Research UK said: "We have supported the team at Bristol Renal for many years and we are delighted to share this breakthrough that could transform the treatment of the most common form of inherited NS. We look forward to the next steps for this exciting discovery." 

Meet the researchers  

Moin Saleem is a professor of renal medicine at the University of Bristol and a paediatric nephrologist at the Bristol Royal Hospital for Children. He leads a highly successful team of multidisciplinary kidney researchers at Bristol Renal. Moin's research focuses on understanding the mechanisms of NS. He is internationally recognised for developing the world's first podocyte cell line, which has become an invaluable tool for kidney researchers worldwide.  

Moin highlighted that research breakthroughs such as these take time and require a lot of support. "We have been fortunate enough to receive several grants from Kidney Research UK over the years that have supported this work. This research is a great example of how impactful pieces of work that push the boundaries of our knowledge and develop exciting new therapies sometimes take multiple sources of funding but can generate life changing results for patients.”

Moin collaborates closely with Gavin Welsh, a professor of renal cell biology to try to understand the molecular basis of NS and to develop potential new treatments for this devastating disease. The work described above was carried out by Dr Valeryia Kuzmuk in the team who was funded by a Kidney Research UK PhD studentship. 

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