Our kidneys serve our body by continuously cleaning out all kinds of impurities from the bloodstream to prevent waste, salt, and excess fluid from building up inside our body. The process by which they do this is not selective. Anything in the bloodstream, good and bad, gets removed.
The part of the kidneys responsible for removal are glomeruli – a group of approximately one million filtration units (capillaries) at the end of kidney tubules. These glomeruli remove everything, both waste products, and precious nutrients from the bloodstream. The part of the kidneys responsible for returning the good, wanted nutrients back into the bloodstream are specialized structures known as the proximal tubules.
The purity and essence of our natural fluids are insured when the glomeruli and proximal tubules work well together by properly filtering everything, then accurately re-absorbing only the good molecules. There are two ways things can go wrong with kidneys: poor filtration is one kind of problem and the other is a failure to reabsorb needed nutrients.
It is known that the reabsorptive functions of the proximal tubule can be compromised by drugs, chemicals, or genetic and blood-borne diseases. The thing that is unclear is how these effects occur. It is a very important subject to understand but studying how proximal tubules fail on a cellular level is a complicated science, normally requiring animal studies… until now.
Researchers at Harvard’s Wyss Institute and Roche Innovation Center Basel in Switzerland have developed a vascularized model that closely mimics natural proximal tubules using 3D printing. This will enable the study of renal reabsorption outside the human body and without the need to use animals. This work builds upon a previous study done in 2016 when they first created a continuously perfused 3D proximal tubule model. That model, however, lacked a functional blood vessel compartment, this new one does not.
This time they created a 3D vascularized proximal tubule model in which independently perfusable tubules and blood vessels are printed adjacent to one another within an engineered extracellular matrix. Using their next-generation device, the team has so far measured the transport of glucose from the proximal tubule to the blood vessels and analyzed the effects of hyperglycemia. Their study is published in the Proceedings of the National Academy of Sciences (PNAS).
Neil Lin, Ph.D., who is a Roche Fellow and Postdoctoral Fellow on Lewis’ team, and first author of the study, said:
“We construct these living renal devices in a few days and they can remain stable and functional for months. Importantly, these 3D vascularized proximal tubules exhibit the desired epithelial and endothelial cell morphologies and luminal architectures, as well as the expression and correct localization of key structural and transport proteins, and factors that allow the tubular and vascular compartments to communicate with each other.”
The first experiment they conducted was induced hyperglycemia – a high-glucose condition typical of diabetes and a known risk factor for vascular disease. They did this by circulating a four-fold higher than normal glucose concentration through the proximal tubule compartment.
Kimberly Homan, Ph.D., a co-author on the study and Research Associate in Lewis’ group at the Wyss Institute and SEAS, said:
“We found that high levels of glucose transported to endothelial cells in the vascular compartment caused cell damage. By circulating a drug through the tubule that specifically inhibits a major glucose transporter in proximal tubule epithelial cells, we prevented those harmful changes from happening to the endothelial cells in the adjacent vessels.”
What’s next? The team is currently focused on scaling up these models for use in pharmaceutical applications.
Annie Moisan, Ph.D., a co-author and industry collaborator on the study, and Principal Scientist at Roche Innovation Center Basel, said:
“Our system could enable the screening of focused drug libraries for renal toxicity and thus help reduce animal experiments. I am thrilled by the continued efforts from us and others to increase the physiological relevance of such models, for example by incorporating patient-specific and diseased cells, since personalized efficacy and safety are the ultimate goals of predicting clinical responses to drugs.”
Lewis added:
“Our new 3D kidney model is an exciting advance as it more fully recapitulates the proximal tubule segments found in native kidney tissue. Beyond its immediate applications for drug screening and disease modelling, we are also exploring whether these living devices can be used to augment kidney dialysis.”
At the moment, life-saving dialysis machines filter blood, but they are unable to retrieve precious nutrients and other species from the filtrate that the body needs for many of its functions, which can cause specific deficiencies and complications down the line. They are confident that 3D bioprinted vascularized tubules may lead to improved renal replacement therapies.
Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at SEAS, said:
“This study presents a significant step forward in human kidney engineering that enables human disease and drug-related studies to be carried out over extended periods of time in vitro. It also represents a major step forward for the Wyss Institute’s 3D Organ Engineering Initiative, which aims to generate functional organ replacements with enhanced functionalities for patients in need.”
