Kidneys are more than simple filtration contraptions that eliminate toxins through urine. In filtering our blood, they perform a number of highly complex and essential tasks in our bodies – and without us ever noticing. For example, they regulate our body’s water levels, and they also maintain the acid-base balance in the blood as well as the balance of electrolytes, including calcium, sodium, magnesium, potassium as well as phosphate, sulfate and chloride.
These kidney functions are vital – literally – and yet, it’s still not fully clear how exactly kidneys carry out their tasks. This is why eight years ago, the Swiss National Science Foundation (SNSF) introduced the National Center of Competence in Research (NCCR) Kidney.CH. The research network includes (university) hospitals and research groups in Zurich, Aarau, Basel, Bern, Fribourg, Lausanne and Geneva. The leading house of Kidney.CH, however, is the University of Zurich, and its funding is provided by the SNSF.
Kidney.CH’s second phase of funding recently came to an end, which is why the SNSF performed an evaluation of the program – with excellent results. The program was thus given the green light to enter its third funding period.
Kidney.CH’s focus is on the two most common kidney diseases: Chronic renal failure and kidney stones. The aim is to investigate these diseases at the biochemical, molecular and genetic levels to be able to prevent renal diseases and improve their treatment options. In particular precision treatment of kidney stones is to be advanced.
Kidney stones are often considered a trivial, albeit painful, disease. You have them removed and get on with it. However, previous research performed as part of a large-scale kidney stone cohort study in Switzerland suggests that kidney stones are worth being investigated systematically.
Normally kidneys easily manage their task of balancing calcium and phosphate. With kidney stones, however, they fail to fully eliminate excess calcium, which then remains in the kidney and over time clings to other minerals such as oxalate to form stones – in fact, between 60 and 80 percent of kidney stones are made up of calcium oxalate.
Most kidney stone patients are of working age and thus still relatively young when they suffer their first kidney stone colic, and at 50 percent the risk of relapse is considerable. Moreover, those repeatedly suffering from kidney stones also have an increased risk of developing chronic renal insufficiency. Such an insufficiency can eventually mean that a dialysis treatment or even renal replacement may become necessary. Kidney stones are thus not a trivial matter and must instead be diagnosed and treated in the long term to ideally prevent them from forming again.
Prof. Olivier Bonny from the Lausanne University Hospital heads up the Swiss Kidney Stone Cohort. His previous research findings support the idea that kidney stones “are a sign of a profound imbalance in the metabolism,” says Bonny.
If the balance of calcium and phosphate in the blood becomes unsettled, the risk of bone loss, blood vessel calcification (arteriosclerosis) and of deposits in the stomach, lungs or kidneys themselves increases.
“Occasionally other diseases contribute to the formation of kidney stones, such as high-blood pressure, osteoporosis, cardiovascular diseases, chronic kidney diseases, and in rare cases also genetic defects,” says Olivier Bonny.
Professor Carsten Wagner and his team at the Institute of Physiology at UZH research the genetic causes of kidney stones as part of the Kidney.CH research program. “According to what we know, the heritability of kidney stones is very high, at around 60 percent. But the genetics are still mostly unknown,” says Wagner.
Why is it so difficult to identify the genes that play a part in the development of kidney stones? – “Because the contributions of individual genes are very small,” explains Wagner. “Kidney stones only develop when several genes interact.” In addition, some of the genes or genetic defects that result in kidney stones are also very rare. Discovering the genes requires very large cohorts or collaboration across various groups – as exemplified by the Kidney.CH research network.
Carsten Wagner is confident that Kidney.CH will go on to discover a number of genes that play a role in the formation of kidney stones. The methods of analysis are becoming quicker, simpler and more affordable with each passing year. “Today we can look at the entire genome, which increases our chances of finding the relevant genes,” says Wagner. It used to be that analyzing an entire genome cost tens or even hundreds of thousands of francs. “Now we can get it for 1,500 francs.” This means that the researchers are getting closer and closer to achieving precision kidney stone treatments that are tailored to the genomes of patients.
A further finding achieved by Kidney.CH shows how the kidney’s various functions are connected: The majority of genes that cause kidney stones aren’t only involved in keeping the balance of calcium and phosphate, but also in maintaining the levels of acids and bases in the blood.
In the long term kidneys play a key part in the regulation of the bloods’ acid-base balance (the lung also plays a part in the short term by discharging CO2). Carsten Wagner describes the process by way of an example: “When we eat steak, our stomach has to produce lots of acid to pre-digest the meat. This means that we then have a surplus of bases in the rest of our body. This surplus can be eliminated very quickly through respiration and the kidneys. When the meat is digested and its components absorbed, they’re further metabolized in the liver, which leads to surplus acids that then have to be neutralized in the kidneys.”
It is not yet known how the kidneys notice that acid levels in the blood are too high. “Some hormones change if they’re exposed to high levels of acidity. They play a role in stimulating the kidneys and stepping up acid elimination. We also believe there are sensors – but these have still not been identified,” says Wagner.
Acid sensors are not only found in the kidneys, but also in immune cells, bones, the brain and other organs, where they have a wide range of tasks. Carsten Wagner and his team are working on a small family of acid sensors: “We were able to show that they’re also involved in regulating breathing and in inflammation processes in other organs.” The scientists are now trying to apply these insights in their kidney research.
The program entering its third phase will allow the Kidney.CH research teams to continue to investigate the complex links between kidney stones, genes, water levels, electrolytes and acid-base levels in the blood for up to four more years. Interesting insights can thus be expected – at the end of the year for example, when a promising study on phosphate regulation will be published.