Frontiers in Renal and Epithelial Physiology – Grand Challenges

The kidneys are one of two organ systems (the other being the lungs) that had to undergo major evolutionary changes to allow vertebrates to survive in a terrestrial environment. As Homer Smith pointed out almost 60 years ago (Weder, 2007) from the perspective of evolution, the kidneys of vertebrates evolved to control blood volume, and, thereby, control blood pressure (BP) in an environment where water and salt ingestion were sporadic and generally uncoupled from one another. In ancestral marine teleosts, the primary requirement of their kidneys was to excrete a large volume of nutrient-free, isotonic urine with an electrolyte composition similar to blood. This function remains as the current day primary function of the proximal convoluted tubule in all vertebrates. As fish colonized fresh water, the requirement to prevent dilution of blood electrolytes required the kidneys to conserve salt and led to the evolution of the proximal straight tubule and the distal convoluted tubule's ability to reabsorb salt with little water reabsorption. The advent of terrestrial vertebrates required conservation of both salt and water and mechanisms for the separate control of salt and water balance since salt and water were often ingested separately. These requirements in mammals promoted the evolution of the loop of Henle, the collecting duct system, and renal medulla. In this evolutionary context, the kidney represents one of the major locations in which the inside world of the body communicates with the external world. At the center of all this communication is the nephron, the functional unit of the kidney; and within the nephron the barrier across which communication occurs are the various epithelial cell types and tissues within the nephron. Epithelial tissues are certainly not restricted to the kidney, but the kidney represents a classic example of the function of epithelial tissue. The initial step in renal function is the separation of a very large volume (180 L/day) of blood ultrafiltrate that is delivered to the lumen of the nephrons. The epithelial tissue of the nephrons forms a barrier between this filtrate and the interstitial space of the body. The epithelium is a selective barrier promoting conservation (reabsorption) of materials in the nephron lumen that are necessary to the body while preventing reabsorption or even promoting secretion of materials that are not needed or even harmful to the body. In the process, the volume of fluid in the lumen of all the nephrons is reduced from about 180 L of fluid to about 1 L of fluid/day with a composition of electrolytes and non-electrolytes that exactly matches the generally poorly controlled input from other parts of the body. Thus, the kidney maintains the homeostatic balance critical for all organisms, but particularly terrestrial vertebrates. It is in the pathologies of mechanisms for maintaining this homeostatic balance that the grand challenges for renal physiology lay. But, because of the central role of epithelial tissue in renal physiology, the grand challenges will include understanding the mechanisms by which epithelial tissues can act as a selective barrier between the blood and the outside world and how this barrier can go awry. In considering the pathologies that lead to grand challenges in renal physiology, it is useful to keep the kidney's evolution in mind because evolution provides a rationale for renal regulatory and transport mechanisms which otherwise might appear to be a willy nilly collection of transporters and hormonal control mechanisms with little systematic integration.