Beat only by the brain in their structural complexity, the kidneys are the unsung heroes of the human body. The shell of these bean-shaped organs is called the renal cortex, which is an intricate network of blood vessels and nephrons (the basic functional unit that filters your blood). Proper kidney function leads directly to the proper function of the entire body. Without a working kidney, things like blood pH, red blood cell count, and electrolyte balance cannot support homeostasis. The pair of organs delicately balance body chemistry, depending beautifully on miniscule interactions in even smaller spaces. Injury or illness to an organ this vital is a crisis in medicine, killing over 50,000 people per year in the United States. Doctors and scientists are aware of the issue, but how can we even begin to address it? As it turns out, the astonishing complexity of the kidney makes it very difficult to mimic in a research setting.

The pair of organs delicately balance body chemistry, depending beautifully on miniscule interactions in even smaller spaces.

Organoids are essentially miniscule organs, commonly made from stem cells to mimic a particular part of the human body for fields such as drug development, disease research, and regenerative medicine. Tumor organoids, for example, have been used to determine which chemotherapies are most effective on various tumor types. But creating a complex kidney in comparison to a mass of cells is a much harder feat to accomplish in vitro. Previous models derived from stem cells have loosely resembled a kidney but have lacked the complicated structural organization that makes it so unique. That is, until a team of scientists based at the University of Southern California shared their method, which led to the most accurate kidney replicas ever made.

The team of researchers working out of USC described why they find kidney research incredibly important. Kidneys wash the blood, receiving a liter per minute through the renal artery and separating small molecules like water and electrolytes from larger proteins and blood cells. These small molecules are reabsorbed by the body, and toxins (like urea and creatinine) and excess water collect as urine and exit through the ureters. Balance of critical molecules is just one of the duties of the kidneys. Oddly similar to organs of the endocrine system, they also possess the ability to respond to and produce hormonal signals. Dysfunction of this whole system is, for a lack of better words, catastrophic. As kidney failure progresses, swelling in the limbs begins while the balance of intracellular and extracellular fluids is thrown off. The oxygen-carrying abilities of the blood suffer due to a lack of the hormone erythropoietin. At the same time, toxin presence in the bloodstream leads to neurologic symptoms, resulting in seizures and comas in many end-stage kidney failure patients. The only option in most cases is dialysis for symptom management, and kidney transplant if you’re lucky enough to find one. These scientists want to change that.

The team explained this past September that they began by exploring various mouse progenitor cell types (similar to stem cells, but more specialized). They tested different growth mediums until they found an environment in which the millimeter-sized creations thrived. What makes the new method so exciting is the extent to which the organoids develop — rather than halting development at a stage akin to an embryonic kidney, the organoids at USC appeared as postnatal kidneys, complete with organized networks of nephrons. At three weeks, the miniature organs appeared to have at least 150 nephrons and a plethora of other kidney-associated cells. Even more astonishing? These mouse organoids actually expressed genes such as AQP1 and UMOD, which are expressed in live mouse pup kidneys. When implanted into mice, the organoids promptly connected to the circulatory system and actually filtered blood. Some urine was produced, but it was considerably more dilute than typical kidney excretions. This points out that despite the strides the USC team made in terms of structural complexity, there is still much work to be done.

In an additional experiment intended to apply this study towards human health, the researchers designed organoids with a genetic defect that’s common in polycystic kidney disease. The team explained that autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, making it an excellent model to explore the potential for clinical research. In the mutant organoids, dramatic cyst development was observed. The progression of the disease in mouse models closely followed that of human ADPKD patients, eventually leading to nonfunctional kidneys. Functional kidneys are essential to maintaining homeostasis, meaning that illnesses such as ADPKD are detrimental to patients. The beauty of the organs lie in how complexly they’re organized — which is also what makes them so incredibly difficult to study. The research by Huang and his team aimed to create organoids that successfully convey this complexity. Organoids have become increasingly popular in recent years to study the ways in which pathogens or genetic defects impact the body. Some have even been grown from patients’ stem cells to study their specific biology! Despite the prevalence of organoid use in research and clinical applications, it’s been hard to develop any that accurately model the kidneys. What the team from the University of Southern California shared is a major breakthrough. Not only do we have the most precise modeling of the human kidney to date, but there is also proof that its use in clinical research is feasible. According to a review by science writer Mitch Leslie, lab-grown kidneys aren’t out of the realm of possibility. For an organ this amazing, it only makes sense that its research is equally as remarkable.

While acknowledging that their organoids aren’t functional to the extent of an actual kidney, the scientists at Southern California can revel in the fact that their creations are the closest anyone has gotten to a lab-grown kidney.

While acknowledging that their organoids aren’t functional to the extent of an actual kidney, the scientists at Southern California can revel in the fact that their creations are the closest anyone has gotten to a lab-grown kidney. After the success of the mouse kidney organoids, they attempted a similar experiment with human-derived progenitor cells. The resulting organoids lacked some of the organization that the mouse organoids had but did demonstrate the ability to filter blood when implanted into mice. Contrary to the mouse-derived organoids, however, no dilute urine could be collected from this experiment. Despite the fact that human models need to be further developed, the considerable progress made in this study can still be applied to current research about human kidney illnesses.