The salt concentration gradient within the kidney is known as the corticopapillary osmotic gradient. In simple terms, near the cortex (the outer part of the kidney), the salt concentration matches plasma levels (280–300 mOsm/L), while near the pelvis (the innermost part of the kidney), it is much higher than 300 mOsm/L depending on one’s level of hydration. During severe dehydration, it can rise up to 1200–1400 mOsm/L.

To form the urine, the filtrate from the blood needs to pass through a structure called the collecting duct extending from the cortex to the medulla. When the salt concentration in the medulla is high (1200–1400 mOsm/L) and you’re thirsty, the collecting duct becomes highly water-permeable. Water moves from the duct into the medullary interstitial space by osmosis and is reabsorbed into the bloodstream, relieving dehydration. If you drink excess water, the medullary salt concentration drops (down to 600 mOsm/L), and the duct becomes less permeable or impermeable to water. As a result, the water stays in the duct and is excreted as diluted urine.

The above explanation illustrates that our kidneys possess a highly sensitive and powerful ability to regulate water balance in the body.

So, you might wonder: how is this corticopapillary osmotic gradient created? CCM has been the widely accepted mechanism since the 1950s. After blood is filtered in the kidney, the filtrate passes through a U-shaped structure called the Loop of Henle before reaching the collecting duct. The ascending limb of the Loop of Henle has a thin lower part and a thick upper part. The thick ascending limb contains NKCC2 co-transporters, which are small protein structures that actively move salts from the filtrate into the surrounding interstitial space. This salt buildup is crucial for water reabsorption later in the collecting duct. When dehydrated, the high salt concentration in the medulla helps to draw water out of the collecting duct and back into the bloodstream by osmosis.

Although the U-shaped Loop of Henle generates countercurrent flow, and it’s widely known that the NKCC2 proteins in the thick ascending limb actively transport salts from inside the tubule to the surrounding interstitial space, the question remains: how are these accumulated salts distributed to form the corticopapillary osmotic gradient? The explanations found in textbooks and scientific literature are vague and contain logical issues, making the teaching of the CCM mechanism quite challenging and difficult to clearly explain.

However, a theoretical breakthrough came with Dr. Kuang’s 2013 publication, which solved this problem. In particular, Dr. Kuang identified a crucial missing logical link in the current explanations of CCM. Once this key piece was added, the entire mechanism became clear and coherent. The key is that the activity or transport rate of the NKCC2 proteins should follow a gradient, referred to as the NKCC2 protein activity gradient. This gradient, with the highest activity at the bottom of the thick ascending limb and the lowest at the top, is key to the process. The NKCC2 proteins create an osmotic gradient inside the thick ascending limb, which in turn generates the NKCC2 protein activity gradient. This protein activity gradient directly leads to the formation of the corticopapillary osmotic gradient in the renal medulla.

Simultaneously, concurrent looping processes illustrate how the results of the vertical processes (i.e., the formation and function of the three gradients) are augmented cycle by cycle during countercurrent flow.

With this new understanding, a refined model explaining detailed CCM processes has been developed. Moreover, a set of mathematical formulas governing CCM has been established in a supplemental Excel file accompanying Dr. Kuang’s publication, providing a more precise and quantitative explanation of CCM. Teachers can use the model to generate their own data set to teach CCM and students can play with the model to have hands-on experience to understand the details of the topic.

Another important contribution of this paper is the formal introduction of the concept of equilibrium in the countercurrent system. This is significant because CCM cannot continue endlessly; it is merely a transient process. After a series of countercurrent flow cycles, CCM reaches an endpoint. This termination signifies that the system has shifted from its previous equilibrium to a new equilibrium state.

For instance, when a person feels thirsty, the original equilibrium is disrupted, and CCM occurs. After several cycles, the corticopapillary osmotic gradient becomes amplified, and a new equilibrium is established. At this point, the collecting duct can reabsorb more water to correct the body’s dehydration, allowing the system to return to its original equilibrium state. In some patients, however, the collecting duct may not function properly in reabsorbing water. As a result, their countercurrent flow system will reach an equilibrium at a different level compared to that of healthy individuals.

So, you might be wondering: what mechanism controls when CCM begins and when it stops? The following knowledge is well-known: during dehydration, ADH levels rise, making the collecting duct more water-permeable and boosting NKCC2 activity, which increases the corticopapillary osmotic gradient for more water reabsorption. When hydrated, ADH levels drop or are even absent, reducing water reabsorption in the collecting duct and NKCC2 activity, lowering the corticopapillary osmotic gradient. This allows the kidneys to adjust water reabsorption based on hydration levels. Based on Dr. Kuang’s publication, if the ADH level becomes stable, CCM ceases, i.e., the system reaches equilibrium.

Dr. Kuang’s new CCM model also holds significant potential for future research, serving as a foundational functional platform for research into the nephron. On this platform, various fields, such as physiology, pathophysiology, pharmacology, toxicology, integrative physiology, systems physiology, network physiology, clinical research, and bioengineering, can conduct experiments or develop and expand mathematical models.

Therefore, Dr. Kuang’s model opens up new horizons for future research and collaborations, providing a comprehensive framework for advancing understanding in many areas of kidney function and beyond. She is also keen on finding multidisciplinary collaborators to continue driving research forward in this area.