Targeting the body clock to improve outcomes for glomerular disease and optimise treatment timings?

09 December 2024

In recent results published in Kidney International, Dr Rebecca Preston and the team from the University of Manchester, found that the glomerulus (the filtering unit of the kidney), has its own biological clock, in addition to the master clock in the brain.

One of the most common causes of kidney failure is glomerular disease, which affects the tiny filters in the kidney called glomeruli. These filters usually keep important proteins in the blood, but in glomerular disease, tiny blood vessels in the filters are damaged allowing proteins to leak into the urine.

We know that urine protein levels and kidney filtration rates vary throughout the day and night, and this pattern reflects our circadian rhythm, or body clock. We also know that other parts of the kidney respond to circadian rhythms, but little was previously understood about how this worked in the kidney filters or what that might mean for treatment of glomerular disease.

“Circadian rhythms are very understudied in the glomerulus. With support from Kidney Research UK, I was able to explore this in more detail and see whether there were any links between glomerular disease and genes in the kidney that were controlled by their own circadian clock.” Dr Rebecca Preston

Circadian rhythm

This is the daily rhythm generated by the 24-hour internal body clock in our brain that regulates processes within the body by responding to light changes in our environment. The most well-known body clock is the sleep-wake cycle but there are other biological clocks too.

Key findings for kidney disease patients

In this study, Rebecca and the team explored healthy kidneys to find out whether the kidney filters have their own circadian rhythm.

Using laboratory models, the team identified a link between the body clock and activity of genes in the glomerulus and podocytes (a type of cell in the glomerulus). Further analysis of the genes involved, using a technique called transcriptomics, showed that they were involved in regulating the thickness (and therefore function) of the glomerular membrane. In particular, they found that the glomerular membrane gets thinner when collagen IV, the protein involved in Alport syndrome, is less abundant.

Red pattern, that is almost brain like in shape, which is the stain of collegen.

Immunofluorescence staining of collagen IV (shown in red) in the glomerular basement membrane of normal human kidney.

The second part of this study looked closely at podocyte genes that are associated with a type of glomerular disease that does not respond to glucocorticoids (known as steroid-resistance). Rebecca and her colleagues found that the changes in these genes which we know can cause steroid resistance in podocytes are also linked to problems in responding to circadian rhythms, offering a new explanation for a lack of treatment response in patients with a kidney condition called nephrotic syndrome.

What does this mean for kidney patients?

Rebecca’s work has improved our understanding of why some patients do not respond well to certain treatments and may also lead to new ways to manage glomerular diseases in the future.

“We have found a mechanism which links the body clock to treatment response in the kidney. This allows us to test the possibility of targeting this pathway to help restore the glomerular filters in some types of kidney disease. Exploring links between the circadian clock, glomerular disease and chronotherapy (administering drugs according to the time of day) could offer promising new options for patients in the future.” Dr Rebecca Preston.

What’s next?

Rebecca will now look further into how these discoveries might improve patient outcomes.

“I am extremely grateful for my clinical research training fellowship with Kidney Research UK, which has allowed me to show the important role that the body clock plays in the health and function of kidney filters. I will now build on this research work, while continuing my role as a kidney doctor for children." Dr Rebecca Preston.