Targeting drugs to protect blood vessels within the kidney holds the promise of reducing endothelial damage in diabetic nephropathy, and could be a new way to reduce progression of diabetic kidney disease, according to an experimental study led by researchers at the University of Bristol.
Diabetic nephropathy is now the leading cause of renal failure in the UK, with around 20% of people starting dialysis having the condition. This figure is expected to double in the next few years, according to Kidney Research UK. Slowing progression of kidney disease, which affects 40% of people with diabetes, could help to reduce their fourfold risk of needing either dialysis or a kidney transplant.
The researchers noted that recent clinical trials had shown the antihypertensive spironolactone to be effective in preventing the development of albuminuria. However, adverse effects, including hyperkalaemia, have made clinicians reluctant to use it.
Possibilities for Novel Therapeutic Targets
For their study, published in JCI Insight, researchers from Bristol Medical School and colleagues sought to understand the mechanism of spironolactone's protective effects to give a better definition of the mechanisms of glomerular protection mediated by such drugs, and "to identify novel tissue-specific therapeutic targets".
Spironolactone is a mineralocorticoid receptor (MR) antagonist, and the team's previous research had shown that MR activation caused damage to the glomerular endothelial glycocalyx, which forms the first part of the glomerular filtration barrier. The result was albuminuria. So they investigated whether MR antagonism could limit albuminuria in diabetes.
Experiments in rats confirmed that the induction of diabetes led to albuminuria, increased glomerular albumin permeability and increased glomerular matrix metalloproteinase activity, with corresponding glycocalyx loss in the glomerular endothelium. MR antagonism with spironolactone reduced matrix metalloproteinase activity, preserved the endothelial glycocalyx, and prevented the abnormal permeability, so slowing albuminuria and preventing disease progression.
The researchers then took human glomerular endothelial cells and exposed them to a diabetic environment in vitro, which similarly increased matrix metalloproteinase activity and caused glycocalyx damage. Amelioration of these effects confirmed a direct effect of MR antagonism on the human glomerular cells also.
Mechanisms Confirmed in Human Diabetes
To confirm the relevance of their findings to human disease, they used a novel imaging technique on renal biopsy specimens from patients with diabetic nephropathy to measure glycocalyx depth changes. They confirmed loss of the glomerular endothelial glycocalyx in diabetes, and demonstrated that spironolactone prevented this damage.
Finally, in vitro tests with diabetic nephropathy patients randomised to receive an MR antagonist or placebo showed that the active drug yielded reduced urinary metalloproteinase activity and albuminuria compared with both placebo and baseline levels.
"Taken together our work suggests MR antagonists reduce glomerular matrix metalloproteinase activity and, thereby, preserve the glomerular endothelial glycocalyx, resulting in reduced glomerular permeability and albuminuria in diabetes," the team concluded. Using novel alternative therapeutics to slow down glycocalyx layer degradation in diabetes directly could help to recreate the same effect as spironolactone, but without its adverse effects.
They hoped that the research would benefit the 4.8 million people in the UK with diabetes, approximately 1 in 5 of whom will need treatment for diabetic neuropathy during their lifetime. Diabetes accounts for almost half of all new end-stage renal disease cases.
Study Results are 'Really Exciting'
The study's joint senior author, Dr Matthew Butler, consultant senior lecturer and MRC clinician scientist at the University of Bristol, who is also an honorary nephrology consultant at North Bristol NHS Trust, said: "This study is really exciting for us because it confirms that blocking mineralocorticoid receptors using spironolactone preserves kidney function by acting on the glycocalyx.
"Our next steps will be to look at repurposing drugs that target matrix metalloproteases enzymes to see if they could be of benefit in patients with kidney disease and avoid the troublesome side effects associated with mineralocorticoid receptor blockers. If we see that same level of protection using these more specific drugs, then patients will see significant benefits whilst avoiding the risks associated with high blood potassium levels."
Dr Aisling McMahon, executive director of research and policy at Kidney Research UK, commented that the charity congratulated the researchers on their innovative approach and looked forward to seeing further developments from the team. "Improving outcomes for patients is a key priority at Kidney Research UK. This work is an important step that will allow new treatments for diabetic kidney disease to be identified faster," she said.
Asked to comment on the study, Dr Faye Riley, research communications manager at Diabetes UK, told Medscape News UK: "Kidney damage is a common complication for people with diabetes. If spotted early enough, it can be slowed down with treatment – but options are limited once it has advanced.
"By piecing together precisely how an existing medication works to slow down kidney damage, this early-stage research gives us insight into more effective ways to halt kidney damage and prevent kidney failure. We look forward to further research to harness this potential and help people with diabetes to live well and longer."
The study was funded by Kidney Research UK, Diabetes UK, British Heart Foundation, and the Medical Research Council, with support from the University’s Wolfson Bioimaging Facility.
