Protecting kidney function in diabetic kidney disease
Around 40% of people with diabetes will go on to develop diabetic kidney disease (DKD). Professor Simon Satchell and Dr Matt Butler have been looking at treatments for DKD, how they work and how to improve them.
Both type 1 and type 2 diabetes lead to an inability to control sugar levels in the blood. Sugar levels that are too high can impact on the fine structures within our organs. Within the kidney the layers that make up the filters can become damaged letting protein leak into the urine (known as ‘proteinuria’). If the damage builds up, the kidneys can fail. This may take around 10 years in type 1 diabetes but is often quicker in those with type 2. At this point the only treatment is either transplant or dialysis.
Treatment: with a catch
DKD can be treated with drugs known as mineralocorticoid receptor (MR) antagonists. These medications lower blood pressure and reduce the amount of protein lost into the urine, slowing the progression of DKD. Unfortunately, side-effects caused by MR antagonists can include swelling of the breasts in males, vaginal bleeding and hyperkalaemia (excess levels of potassium in the blood). These side-effects limit their acceptability.
Simon and Matt were funded by Kidney Research UK to look at how MR antagonists act on the kidney, particularly how they improve the filtering ability of the kidney in DKD in the hope that they could find a better drug target.
The impact of DKD on kidney function
As DKD progresses, protein starts to leak into the urine due to damage to the filters in the kidney, known as the glomerulai. These filters are formed from several layers, which together act like a sieve. The first layer is called the ‘glycocalyx’ and is made by the cells of the blood vessels within the kidney.
Simon and Matt found that the glycocalyx is damaged in patients with DKD. However, this damage could be repaired by MR antagonists.
What is the glycocalyx?
The glycocalyx is a gel-like mesh of stringy molecules. It helps to limit how much protein passes into the urine.
To do this Simon and Matt measured the thickness of the glycocalyx and measured how leaky glomeruli (clusters of tiny blood vessels within the kidneys) are following diabetes onset. They found proteins that build up or break down the glycocalyx alter in diabetes and could be great therapeutic targets, avoiding creating the undesirable side-effects of MR antagonists.
Protecting the kidney filters
In this project Simon and Matt used Spironolactone (an MR antagonist that is currently used to treat DKD). They found that this drug acts on a group of enzymes called sheddases. Sheddases break down the glycocalyx, stripping this layer from the glomerular filtration barrier. Spironolactone stops sheddases from working properly and protects the glycocalyx. Other drugs that inhibit sheddases could be just as effective as MR antagonists but without the side effects associated with MR inhibition.
Dr Matt Butler, co-senior author and co-applicant said: “This paper is really exciting for us because it confirms that blocking MR antagonists using spironolactone (a commonly used blood pressure medication) preserves kidney function by acting on the glycocalyx. Moving forward we hope to recreate this effect by using novel alternative therapeutics that will avoid the troublesome side effects associated with MR antagonists.
“Our group are currently working with another promising drug that is in common use but not used to treat kidney disease. We have already confirmed this drug targets glycocalyx damage much more directly than spironolactone and we know it is safe for long-term use in patients. If we can confirm this drug is as effective as MR inhibition in our lab models then we hope to move towards clinical trials in the near future. The advantage of repurposing medication already in use is that we could see changes to clinical practice that could dramatically improve patients care within five years.”
This research was funded by a Kidney Research UK project grant.
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