Demonstrating an Integrated and Functional Kidney Organoid

Researchers have recently demonstrated in pigs the integration of an engineered kidney organoid, a few centimeters of kidney tissue grown from stem cells. The tissue functions as a kidney should, but it is far from full size, and does not bear all of the hallmarks of the real thing. However, enough of the normal suite of additional connections were also produced by the researchers involved to allow surgical integration of the organoid with the excretory system, and thus demonstrate generation of urine.

This work well illustrates the nature of the challenges that lie ahead for the field of tissue engineering. It isn't enough to build correctly functioning organ tissue, challenging as that is and still very much a work in progress. Connections to circulatory and other systems in the body must also exist, and each of these is its own distinct engineering task. A replacement organ whose principal job is chemical processing or filtration of one sort or another doesn't have to be shaped or structured in exactly the same way as the evolved version we're all equipped with at birth, but it does have to integrate with all of the surrounding organs and systems. That places constraints on the development of engineered organs, and presents a set of intricate challenges akin to those involved in carrying out an organ transplant.

The kidney organoids demonstrated in pigs in the research linked below are a step ahead of the first prototypes to get the tissue structure and functionality correct, but they are still many incremental steps removed from something that could replace the need for human kidney donors. Still, things are headed in the right direction, and quite rapidly at that. It was only three years ago that the first kidney organoids were unveiled, so it doesn't seem unreasonable to predict that the first practical proto-kidneys that are medically useful in humans might enter clinical trials in the early 2020s.

Lab-grown kidneys work in animals

Scientists say they are a step closer to growing fully functioning replacement kidneys, after promising results in animals. When transplanted into pigs and rats, the kidneys worked, passing urine just like natural ones. The researchers used a stem cell method, but instead of just growing a kidney for the host animal, they set about growing a drainage tube too, along with a bladder to collect and store the urine. They used rats as the incubators for the growing embryonic tissue. When they connected up the new kidney and its plumbing to the animal's existing bladder, the system worked. Urine passed from the transplanted kidney into the transplanted bladder and then into the rat bladder. And the transplant was still working well when they checked again eight weeks later. They then repeated the procedure on a much larger mammal - a pig - and achieved the same results.

Urine excretion strategy for stem cell-generated embryonic kidneys

There have been several recent attempts to generate, de novo, a functional whole kidney from stem cells using the organogenic niche or blastocyst complementation methods. However, none of these attempts succeeded in constructing a urinary excretion pathway for the stem cell-generated embryonic kidney.

First, we transplanted metanephroi from cloned pig fetuses into gilts; the metanephroi grew to about 3 cm and produced urine, although hydronephrosis eventually was observed because of the lack of an excretion pathway. Second, we demonstrated the construction of urine excretion pathways in rats. Rat metanephroi or metanephroi with bladders (developed from cloacas) were transplanted into host rats. Histopathologic analysis showed that tubular lumina dilation and interstitial fibrosis were reduced in kidneys developed from cloacal transplants compared with metanephroi transplantation. Then we connected the host animal's ureter to the cloacal-developed bladder, a technique we called the "stepwise peristaltic ureter" (SWPU) system. The application of the SWPU system avoided hydronephrosis and permitted the cloacas to differentiate well, with cloacal urine being excreted persistently through the recipient ureter.

Finally, we demonstrated a viable preclinical application of the SWPU system in cloned pigs. The SWPU system also inhibited hydronephrosis in the pig study. To our knowledge, this is the first report showing that the SWPU system may resolve two important problems in the generation of kidneys from stem cells: construction of a urine excretion pathway and continued growth of the newly generated kidney.

Comments

"but they are still many incremental steps removed from something that could replace the need for human kidney donors."

Anyone have any idea what the remaining incremental steps are?

Posted by: Jim at September 23rd, 2015 5:52 PM

@Jim: (1) making the organoid much bigger, which means solving the blood vessel situation, (2) pull up a good anatomy book picture of the kidney and look at all the various labelled incoming and outgoing vessels for fluid transport, each of which needs to be built, and (3) coming up with a set of surgical procedures for integration that are applicable to the particular final structure of the organoid and less Rube Goldberg than the extra bladder method used for this demonstration.

Posted by: Reason at September 23rd, 2015 6:21 PM

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