Kidney diseases kill tens of thousands of people with diabetes globally every year. Danish researchers are searching in blood, urine and the gut to discover ways of inhibiting these deadly complications.
About one third of the people with diabetes do not solely develop diabetes. Many develop various complications such as blindness, cardiovascular diseases, nerve damage or foot ulcers.
One of the most common and, unfortunately, most serious complications of diabetes is kidney disease, in which the kidneys slowly stop functioning. Severe kidney disease can result in dialysis, transplantation or even death because of the increased incidence of blood clots in the brain or heart. In Denmark alone, 200 people annually are treated for kidney failure as a result of diabetes-related kidney disease. Many more than these 200 people die early from diabetes-related kidney disease.
Kidney disease is therefore an ever-present dark cloud on the horizon of people with diabetes, 30% of whom experience kidney problems. An international research team with Danish participation hopes to change this.
“We are constantly aware of kidney disease in our clinical work with people with diabetes. We take urine and blood samples and try to treat those with signs of kidney disease with medicine to reduce their blood pressure or blood glucose. People still develop kidney disease, and we cannot yet explain why some do and others do not,” says a researcher behind the project, Peter Rossing, Clinical Professor, Chief Physician and Head of Complications Research, Department of Clinical Medicine, University of Copenhagen and Steno Diabetes Center Copenhagen.
In 2014, the Novo Nordisk Foundation awarded a 6-year Challenge Programme grant to Peter Rossing and colleagues from Finland, the United States and the Netherlands for improving the methods of identifying and treating people with diabetes who are at high risk of developing kidney disease.
Diabetes damages the capillaries
The connection between diabetes and kidney disease seems very straightforward.
Increased blood glucose damages the capillaries, and the kidneys have many of them. When the capillaries are destroyed, the kidneys begin to stop functioning, becoming worse at purifying the blood over 10–15 years. The blood pressure rises if the blood is not sufficiently purified, leading to an excess of unpleasant cardiovascular diseases such as heart failure and myocardial infarction.
In the final stages of disease, the kidneys cease to function, and kidney failure, dialysis and transplantation become uncomfortably relevant if the person with diabetes has not already died from ever-threatening heart disease.
Understanding kidney disease appears quite simple. However, the human body is rarely simple once you get under someone’s skin. The link between diabetes and kidney disease is no exception.
Who ends up developing serious kidney complications and who does not vary greatly. Various factors influence this, including smoking, genetics, weight, blood pressure, physical activity and blood glucose control. Nevertheless, many people who take good care of themselves end up with severe kidney disease, whereas many people who do not take good care of themselves avoid kidney disease. There is an association, but it is not always consistent.
“For most people, we are not good at predicting whether or not they will develop kidney disease. We therefore want to find biomarkers that can objectively tell us who is at high risk. We are searching in blood, urine, the gut and in the body in general. We already know about some links. For example, high blood pressure is linked to an increased risk of developing kidney disease, but we want to be able to quantify the risk even before blood pressure increases. We can then tailor preventive treatment optimally,” says Peter Rossing.
The researcher says that both high blood pressure and kidney disease can result from various mechanisms, which also indicates that kidney disease should presumably be treated differently depending on the individual.
20 blood biomarkers indicate the risk of kidney disease
Peter Rossing and his colleagues examined many blood and urine samples from people with diabetes collected at a time when the researchers did not yet know which would develop kidney disease.
This enabled them to examine the samples for markers in the form of various molecules for which elevated or reduced concentrations might indicate that kidney disease is developing.
For example, if the researchers find elevated concentrations of various proteins among the people who end up developing severe kidney disease, these are markers that can potentially be used to identify individuals of whom doctors should be especially aware in the future.
“It would be even better if we could find mechanistic markers related to the pathophysiology of kidney disease that we can also use to repair damage so that we can not only identify the people at high risk of developing kidney disease but also do something about it,” says Peter Rossing.
In collaboration with researchers from Boston, the researchers from Steno Diabetes Center Copenhagen have identified 20 markers that might potentially be used to predict the risk of developing kidney disease.
The 20 markers include multiple tumour necrosis factor (TNF) receptors, which are agents that promote inflammation in the body.
“A major highlight of our current research is that we have discovered these markers that we can use to more rapidly identify the people with diabetes who have the greatest risk of developing the most severe form of kidney disease. However, our findings need to be verified in even larger clinical trials before we can be sure that it can also be used in the real world,” explains Peter Rossing.
Prevention of kidney disease should be individualized
Informing people that they have a potentially fatal disease is insufficient if doctors cannot do anything about it.
The researchers are also working on this aspect to help people with diabetes who have kidney disease.
In addition to using the markers to identify which individuals are at higher risk of developing kidney disease, the researchers will also use the variation in these markers to potentially predict whether a given treatment will be effective for a specific individual.
Doctors have various treatment options, but they are only effective for between one third and one half of the people with diabetes. The problem is that medicine that reduces blood pressure and blood glucose work for some individuals but not for others.
To achieve greater clarity about the possibilities individuals have, Peter Rossing’s research group is currently working on a trial in which they give patients with kidney disease different treatments based on their blood profile.
“Clearly we need to get better at predicting who will respond positively and negatively to the various treatment options. We are still not good enough at doing this, but hopefully things will improve once we get the results of our study. In addition, we need access to many more treatment tools so that we can test several things until we find the right ones,” says Peter Rossing.
Imbalance in the gut associated with kidney disease
One of the newest and most interesting things the researchers are examining is the link between diabetes and the composition of gut bacteria and the risk of developing kidney disease.
Animal experiments from the research colleagues in Finland show that inflammation of the gut causes kidney damage and increases the risk of kidney disease.
Inflammation of the gut is often linked to the composition of gut bacteria, in which many less healthy bacteria replace healthy bacteria. This aspect may need to be examined in the future to reduce the risk of a person with diabetes developing kidney disease.
In their animal experiments, the researchers in Finland demonstrated that treating mice with anti-inflammatory medicine increased their kidney function numbers: blood markers that indicate the health of the kidneys.
Experiments involving mice and rats are quite different from those involving humans. The researchers are therefore working on several clinical trials in which they try to influence the gut microbiota of individuals with diabetes by giving them butyric acid, which is otherwise produced by beneficial gut bacteria. Butyric acid is also the primary energy source of the gut’s cells.
“In another experiment, we are giving people with diabetes probiotics: living, healthy bacteria. In parallel, we are conducting an experiment with the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen to identify whether people with kidney disease have a different composition of gut bacteria than healthy people. If we see differences, we can do something about it,” says Peter Rossing.
Bacterial metabolites in the blood are a bad sign
Peter Rossing thinks that the link between gut bacteria and kidney disease may result from an imbalance in the composition of gut bacteria that could make the intestine more permeable to harmful substances that are normally not allowed to pass through the gut wall into the blood. The reason is perhaps the lack of butyric acid to keep the cells in the gut wall healthy.
The kidneys have to filter out any harmful substances that end up in the blood, thereby purifying the blood. However, the excessive strain caused by chronic intestinal infection worsens their function, which means that the kidneys do not purify the blood adequately.
The researchers have already found an association that makes this idea very credible.
Some less healthy gut bacteria secrete the metabolite trimethylamine (TMA) when we eat meat from four-legged animals, and the liver converts TMA to trimethylamine N-oxide (TMAO), which is released into the blood. TMAO in the blood indicates impaired kidney function. TMAO may also be associated with an increased risk of various cardiovascular diseases.
Imbalances in the gut bacteria can thus increase the concentration of TMAO in the blood, and in addition to putting the already burdened kidneys under pressure, TMAO also increases the risk of acquiring cardiovascular disease.
“Although it is too early to make conclusions, some evidence indicates associations between imbalances in the composition of gut bacteria, the uptake of TMAO across the gut wall and the risk of developing severe kidney disease and being affected by the harmful effects of not having fully functional kidneys. TMAO is a marker for other diseases, but it also appears to be involved in diabetes and kidney disease,” says Peter Rossing.
The research group is currently measuring the concentration of TMAO in the blood of people with diabetes. They will do this again later and see whether the concentrations of TMAO in the blood are associated with the health of the individual between measurements.
Some types of diabetes medicine protect the kidneys
Peter Rossing hopes that the research projects will lead to an opportunity to accurately assess the risk that a specific person with diabetes will develop severe kidney disease.
The optimal situation would be if doctors in the future can analyse a blood or urine sample from a person with diabetes and determine their risk of kidney disease while presenting the person with various medicine options or lifestyle measures that can reduce the level of harmful substances in the blood or correct the inappropriate composition of gut bacteria.
Further, various studies indicate that some forms of diabetes medicine can actually protect the kidneys, including the sodium-glucose cotransporter 2 (SGLT2) inhibitor and GLP-1 analogues such as liraglutide and semaglutide.
Thus, people with kidney disease will have better prospects in the future than they have today.
“We need to move from providing good treatment for people with diabetes to ensuring even better treatment so we can hopefully completely prevent people with diabetes from developing kidney disease. The number of people with diabetes globally is increasing, and if we do nothing to address this problem, more people will develop kidney disease and die from it,” says Peter Rossing.
“Utility of plasma concentration of trimethylamine N-oxide in predicting cardiovascular and renal complications in individuals with type 1 diabetes” has been published in Diabetes Care. In 2014, the Novo Nordisk Foundation awarded a grant of DKK 60 million to Peter Rossing, Clinical Professor, Chief Physician and Head of Complications Research, Department of Clinical Medicine, University of Copenhagen and Steno Diabetes Center Copenhagen for the project PROTON – Personalising Treatment of Diabetic Nephropathy.