Kidneys work to constantly filter blood and remove toxins from the body. Conditions such as chronic kidney disease (CKD) are characterized by a reduced ability to perform this essential function. CKD incidence is growing and more than 1.4 million individuals depend on dialysis or kidney transplant for survival. Development of new treatments requires an understanding of the mechanisms of the disease progression, but scientists have not been able to accurately model kidney filtration in vitro - until now.
In a landmark study published in Nature Communications, scientists demonstrate an in vitro kidney model that could change the course of research for diseases like CKD.
The kidney contains specialized structures called glomeruli. Within each glomerulus is a filtration barrier made up of two thin layers of highly specialized cells and a membrane that acts as a selective filter. As blood moves through each glomerulus, toxins and small molecules can pass through, while proteins and other important components are kept in the bloodstream. "This filtration process breaks down in patients with kidney disorders," explains co-senior author on the study. "But because we haven't had a good in vitro model, we still don't know the mechanisms of injury to the glomerulus in CKD."
A model glomerulus that functions nearly identically to that found in real kidneys. They are calling this model, which is derived entirely from healthy, human kidney tissue, a glomerulus on a chip.
On one side of the cells, investigators add fluid and, on the other side, they collect what the 'glomerulus' filters, which is called the filtrate. In their experiment, the scientists added blood serum from healthy individuals. Without the use of a manufactured filter, the team's in vitro glomerulus behaved as human kidneys are expected to act: proteins remained in the serum while smaller molecules passed into the filtrate. "The barrier that our cells naturally formed is selective, just as it would be in a fully-functioning kidney," says the author. "It is remarkable."
This model represents a substantial leap forward from the current standard of in vitro kidney research. While this seemed a distant goal in the past, the authors are already recreating and studying the disease state in their model. When the investigators added serum from patients with CKD, they found that the glomerulus exhibited the same type of damage observed clinically: proteins began to leak through the compromised filter. Protein levels measured in the experimental filtrate matched patient clinical filtrate samples with a correlation of approximately 90%.
The authors also show its applicability for renal disease modeling and drug testing. A total of 2000 independent chips were analyzed, supporting high reproducibility and validation of the system for high-throughput screening of therapeutic compounds.
This breakthrough paves the way for numerous clinical applications. In the burgeoning era of personalized medicine, a preparation such as this can be used to examine molecular mechanisms of kidney damage in individual patients. Disease progression can then be monitored over time using serial blood sampling. The model could also be used for screening new drugs prior to human clinical testing.