13 mei 2022 – 08:13
Kidney organoids provide knowledge about leaking kidney filters
Kidney organoids, tiny mini-kidneys grown in the lab using stem cells, are the best contributor to understanding the cause and possible treatments for nephrotic syndrome, a rare kidney disease. Researchers from Radboudumc, among others, show that these organoids can also serve as a basis for research into other rare kidney diseases.
Nephrotic syndrome is a rare kidney disease in which the filters in the kidneys do not work properly. As a result, the body loses important proteins. These end up in the urine and are passed out. Little is known about the origin of the disease. Researchers are trying to learn more about the cause of this rare disease through tiny mini-kidneys being developed in the lab.
A mini-kidney, called a renal organoid, has a composition that resembles a real kidney, but in miniature: it is a very small piece of tissue, about two millimeters in diameter. Researchers at Radboudumc use stem cells to develop these mini-kidneys. Lead researcher Jitske Jansen: ‘We have used a specific type of stem cell, which has grown into a kidney organoid by means of an advanced ‘culture recipe’. Here we can look at molecular processes that lead to damage to kidney cells.’
Organoid ‘make sick’
The researchers were particularly curious about the cells that play an important role in the nephrotic syndrome: the kidney filter cells, or podocytes. These cells ensure that proteins remain in the body. If something goes wrong in those cells, proteins leak away and the nephrotic syndrome develops. The researchers wanted to mimic this in the kidney organoid. ‘We wanted to make the organoid sick, and we succeeded. The diseased podocytes in the kidney organoid looked similar to the kidneys of patients with the nephrotic syndrome’, says Jansen. Now she and fellow researcher and group leader Bart Smeets can better study the development of nephrotic syndrome. Jansen: ‘This means examining the entire ice floe, rather than just the tip of the iceberg.’ As far as Jansen is concerned, this animal-free research method can also be used in the long term for other rare kidney diseases.
With the help of organoids, Jansen can determine the underlying cause of the nephrotic syndrome in individual patients and possibly remedy it. ‘We can make mini-kidneys from healthy stem cells, but also from stem cells derived from patients’ blood. The cells in those mini-kidneys then have the same abnormality as the kidney cells in the patient, which gives us much more insight into how the condition develops. Because we do know that it is the podocyte that plays a major role in it, but how it is that the podocyte does not work can differ per patient. Using a technique with which DNA can be repaired, CRISPR-Cas9, the researchers succeeded in correcting the abnormality. Jansen: ‘With this knowledge, we can develop and apply better treatments within our Expertise Center for Rare Kidney Diseases than we have hitherto.’
Alternative to prednisone
And new treatments are desperately needed. Until now, the only effective drug for children with nephrotic syndrome is prednisone, but that has serious and unpleasant side effects. Alternatives to this are very welcome, agrees Michiel Schreuder, professor of Pediatric Nephrology. He sees many patients in the Radboudumc Amalia Children’s Hospital, which is at the forefront of care for and research into rare and serious kidney diseases in children. ‘To date, not much is known about the development of the nephrotic syndrome. The disease affects about 500 people every year, of which 55-60 are children. So we see for whom we are doing this research.’ c
About the publication in Development: Human pluripotent stem cell-derived kidney organoids for personalized congenital and idiopathic nephrotic syndrome modeling – Jitske Jansen, Bartholomeus T van den Berge, Martijn van den Broek, Rutger J Maas, […] Michiel F Schreuder, Bart Smeets. DOI: 10.1242/dev.200198.