The leading cause of death in people with kidney damage is cardiovascular disease. This is probably due to accumulating calcium phosphate crystals in the blood. With a Kolff+ grant from the Kidney Foundation, Jeroen de Baaij, Joost Hoenderop and Marc Vervloet (Radboud university medical center) are investigating what exactly these crystals do. De Baaij talks about this and looks ahead to solutions.
The serious consequences of kidney failure are often well known. Of every 100 people with chronic kidney damage, some will develop kidney failure. What few people know is that everyone with kidney damage has an increased risk of cardiovascular disease. With moderate kidney damage (still 60% percent kidney function) you are two to three times more likely to develop cardiovascular disease. People with severe kidney damage (maximum 30% kidney function) have a 10 to 15 times higher risk of cardiovascular disease.
As quickly as possible
“Most people with kidney damage never develop end-stage renal failure, because they already die from cardiovascular disease,” says Dr. Jeroen de Baaij, renal physiologist and researcher at Radboud University Medical Center in Nijmegen. “You really have to take that seriously. In order to finally tackle the cause, we will now look at phosphate and calcium in the blood.” He does this together with Radboudumc colleagues nephrologist Prof. Marc Vervloet and laboratory researcher Prof. Joost Hoenderop. De Baaij: “The questions we answer come from the clinic. Our collaboration ensures that the results reach patients as quickly as possible.”
Crystals cause vascular calcification
With kidney damage, phosphate and calcium accumulate in the blood because the kidneys can no longer excrete them properly. They then form calcium phosphate crystals. Previous laboratory research with cultured blood vessels, in which De Baaij was involved, showed that such crystals cause vascular calcification. “That also happens in people with kidney damage. Calcified vessels become stiff, making them more likely to rupture. Moreover, the heart has to work harder. That can lead to heart failure.”
It is not known how calcium phosphate crystals cause vascular calcification. De Baaij can now find out, thanks to a Kolff+ grant from the Kidney Foundation. According to De Baaij, it is special that the Kidney Foundation funds such fundamental research. “It is unique in the world. Without her support, much of the basic research that ultimately leads to solutions would not take place.”
Overloaded
The calcium-phosphate crystal that the Radboudumc researchers will be examining over the next four years is formed when calcium and phosphate bind to a protein from the liver, fetuin-A. In healthy people, fetuin-A acts as a buffer: it removes excess calcium and phosphate. However, people with chronic kidney damage have a deficiency of fetuin-A. And too much phosphate and calcium. De Baaij: “Fetuin-A becomes overloaded as a result. And ordinary calcium phosphate crystals change into a harmful variant, CPP2.”
Harmful substances
So what makes CPP2 so harmful? “That is uncertain. In addition to calcium and phosphate, CPP2 may also contain other harmful substances that cause inflammation in the vessels, after which calcification occurs.” To see whether this is correct, he will compare calcium phosphate crystals from the blood of healthy volunteers with those from the blood of dialysis patients. “We do this before and after dialysis. This way we know immediately whether this has an influence on the crystal variants.” De Baaij will then make CPP2 crystals in the lab, add the harmful substances and see what they do to cultured vessel wall cells.
Food may be a trigger
It is also not clear how and when exactly the crystals are formed. Food may be a trigger because food contains a lot of phosphate. Part of the research therefore involves eating a standard meal by a group of healthy participants. The researchers look at crystal production in their blood before and afterwards. De Baaij: “We also do that for people who have planned a kidney transplant. Before and after the transplant. In this way we measure whether improved kidney function changes the production of good calcium phosphate crystals and CPP2.”
Less CPP2 after medication?
Finally, the researchers will investigate how you get CPP2 from the blood. They will measure, among other things, calcium phosphate crystals and CPP2 in the blood of people without kidney damage who are being treated for osteoporosis. “Bone cells that will then produce bone tissue need a lot of calcium and phosphate,” says De Baaij. “We are going to see whether the bone cells remove calcium phosphate crystals from the blood for this purpose.” Since there are various medications to stimulate bone growth, he also examines whether one medication has more effect than another. A small group of kidney patients who also happen to be treated for osteoporosis are also asked to participate. “That gives an impression of whether poor kidney function has an influence on the change in the crystal quantity that the medication causes.”
Kidney Physiology 