Homeostasis, the milieu intérieur, and the wisdom of the nephron

Abstract

The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to maintain the "internal milieu" and allow organisms the "physiologic freedom" to move into varying environments and take in varying diets and fluids. Early ingenious, albeit rudimentary, experiments unlocked a wealth of secrets on the mechanisms involved in the formation of urine and renal handling of the gamut of electrolytes, as well as that of water, acid, and protein. Recent scientific advances have confirmed these prescient postulates such that the modern clinician is the beneficiary of a rich understanding of the nephron and the kidney's critical role in homeostasis down to the molecular level. This review summarizes those early achievements and provides a framework and introduction for the new CJASN series on renal physiology.

Keywords: kidney; nephron; renal physiology.

Figure 1.

Study of the kidney requires consideration of both the role of each segment and the three-dimensional architecture. (A) Homer Smith’s rectilinear nephron mimics the straight trajectory of the fish nephron. (B) The human nephron is more intricate; the distal nephron greets its own glomerulus before it returns to the environs established by the loop of Henle. TX, treatment. A is modified from reference 1, with permission.

Figure 2.

Micropuncture and “stop flow” techniques were used to help define the role of each segment of the nephron. (A) The proximal tubule from the kidney of the aquatic salamander is illustrated here. A micropipette removes the filtrate at a point just proximal to a “plug” of mineral oil. To determine the role of the tubule in handling of individual constituents (reabsorption, secretion, or diffusion), fluid was injected into the tubule at different locations and then collected distally. This “artificial” fluid could be altered to differ from the normal filtrate by one or more constituents. (B) A sketch of a camara lucida drawing of a guinea pig nephron after microdissection (these drawings were created with the aid of a light projector because photomicrographs were not readily available at the time). Oil or mercury blocks could be inserted at various points along the nephron and fluid from the lumen could be collected and studied. A is modified from reference 17, with permission; B is modified from reference 16, with permission.

Figure 3.

The Ussing Chamber can be used to measure ion transport between the two sides of an epithelial cell membrane by polarized cells. Here, a monolayer of epithelial cells separates two compartments. Fluid in the two compartments is identical to eliminate the contribution of passive paracellular diffusion driven by differences in concentration, osmotic pressure, or hydrostatic pressure. Voltage electrodes placed near the epithelial membrane maintain the potential difference at zero so that the current measured by the current electrodes reflects the movement of ions by active transport through the epithelial cells.

Figure 4.

Study of isolated perfused tubular segments allowed study of each of the different nephron segments independently. (A) A photomicrograph of a portion of a rabbit proximal convoluted tubule during perfusion. (B) A schematic diagram of the technique. One end of the dissected tubule was connected to a micropipette, which was used to perfuse the lumen, and the other end was connected to a collection micropipette. Both the luminal fluid and the peritubular fluid could be controlled to assess tubular transport characteristics. A is reprinted with permission from Burg MB: Perfusion of isolated renal tubules. Yale J Biol Med 45: 321–326, 1972.

Figure 5.

The unique transporters and cell structure of each segment of the nephron work in concert to maintain homeostasis. ENaC, epithelial sodium channel; NKCC2, Na⁺-K⁺-2Cl cotransporter; ROMK, renal outer medullary potassium.