The renal medulla produces concentrated urine through the generation of an osmotic gradient extending from the cortico-medullary boundary to the inner medullary tip. This gradient is generated in the outer medulla by the countercurrent multiplication of a comparatively small transepithelial difference in osmotic pressure. This small difference, called a single effect, arises from active NaCl reabsorption from thick ascending limbs, which dilutes ascending limb flow relative to flow in vessels and other tubules. In the inner medulla, the gradient may also be generated by the countercurrent multiplication of a single effect, but the single effect has not been definitively identified. There have been important recent advances in our understanding of key components of the urine concentrating mechanism. In particular, the identification and localization of key transport proteins for water, urea, and sodium, the elucidation of the role and regulation of osmoprotective osmolytes, better resolution of the anatomical relationships in the medulla, and improvements in mathematic modeling of the urine concentrating mechanism. Continued experimental investigation of transepithelial transport and its regulation, both in normal animals and in knock-out mice, and incorporation of the resulting information into mathematic simulations, may help to more fully elucidate the inner medullary urine concentrating mechanism.
The mammalian kidney maintains nearly constant blood plasma osmolality and nearly constant blood plasma sodium concentration by means of mechanisms that independently regulate water and sodium excretion. Because many mammals do not have continuous access to water, the ability to vary water excretion can be essential for survival. Because sodium and its anions are the principal osmotic constituents of blood plasma, and stable electrolyte concentrations are also essential, water excretion must be regulated by mechanisms that decouple it from sodium excretion.
The urine concentrating mechanism plays a fundamental role in regulating water and sodium excretion. When water intake is large enough to dilute blood plasma, a urine more dilute than blood plasma is produced; when water intake is so small that blood plasma is concentrated, a urine more concentrated than blood plasma is produced. In both cases, the total urinary solute excretion rate and the urinary sodium excretion rate are small and normally vary within narrow bounds.
In contrast to solute excretion, urine osmolality varies widely in response to changes in water intake. After several hours without water intake, such as occurs overnight during sleep, human urine osmolality may increase to approximately 1,200 mOsm/kg H2O, about 4 times plasma osmolality (290 mOsm/kg H2O). Conversely, urine osmolality may decrease rapidly after the ingestion of large quantities of water, such as commonly occurs at breakfast, at which point human urine osmolality (and that of other mammals) may decrease to approximately 50 mOsm/kg H2O. Most physiologic studies relevant to the urine concentrating mechanism have been conducted in species that can achieve higher maximum urine osmolalities than human beings. For example, rabbits can concentrate to approximately 1,400 mOsm/kg H2O, rats to approximately 3,000 mOsm/kg H2O, mice and hamsters to approximately 4,000 mOsm/kg H2O, and chinchillas to approximately 7,600 mOsm/kg H2O (reviewed by us previously1).
All mammalian kidneys maintain an osmotic gradient that increases from the corticomedullary boundary to the tip of the medulla (papillary tip). This osmotic gradient is sustained even in diuresis, although its magnitude is diminished relative to antidiuresis.2,3 NaCl is the major constituent of the osmotic gradient in the outer medulla, whereas NaCl and urea are the major constituents in the inner medulla.2,3 The cortex is nearly isotonic to plasma, whereas the inner medullary (papillary) tip is hypertonic to plasma, and has osmolality similar to urine during antidiuresis.4 Sodium and potassium, accompanied by univalent anions, and urea are the major urinary solutes; urea is normally the predominant urinary solute during a strong antidiuresis.2,3
The mechanisms for the independent control of water and sodium excretion are contained mostly within the renal medulla. The medullary nephron segments and vasa recta are arranged in complex but specific anatomic relationships, both in terms of 3-dimensional configuration and in terms of which segments connect to which segments. The production of concentrated urine involves complex interactions among the medullary nephron segments5,6 and vasculature. In outer medulla, the thick ascending limbs of the loops of Henle actively reabsorb NaCl. This serves 2 vital functions: it dilutes the luminal fluid, and it provides NaCl to increase the osmolality of the medullary interstitium, pars recta, descending limbs, vasculature, and collecting ducts. Both the nephron segments and vessels are arranged in a countercurrent configuration, thereby facilitating the generation of a medullary osmolality gradient along the corticomedullary axis. In inner medulla, osmolality continues to increase, although the source of the concentrating effect remains controversial. The most widely accepted mechanism remains the passive reabsorption of NaCl, in excess of solute secretion, from the thin ascending limbs of the loops of Henle.7,8
Perfused tubule studies provided the basis for many of the theories of how concentrated urine is produced (reviewed by us previously1). The cloning of many of the proteins that mediate urea, sodium, and water transport in nephron segments that are important for urinary concentration and dilution have provided additional insights into the urine concentrating mechanism (Fig. 1). In general, the urea, sodium, and water transport proteins are highly specific and appear to eliminate a molecular basis for solvent drag; this specifically suggests that the reflection coefficients should be 1.1 For a detailed review of these transport properties, the reader is referred to our previous report.1
GENERAL FEATURES OF THE CONCENTRATING MECHANISM
Countercurrent multiplication refers to the process by which a small osmolality difference, at each level of the outer medulla, between fluid flows in ascending and descending limbs of the loops of Henle, is multiplied by the countercurrent flow configuration to establish a large axial osmolality difference. This axial difference frequently is referred to as the corticomedullary osmolality gradient because it is distributed along the corticomedullary axis. Figure 2 illustrates the principle of countercurrent multiplication. Figure 2 shows a schematic of a short loop of Henle: the left channel represents the descending limb and the right channel represents the thick ascending limb. A water-impermeable barrier separates the 2 channels. Vertical arrows indicate flow down the left channel and up the right channel. Horizontal arrows (left-directed) indicate active transport of solute from the right channel to the left channel. Local fluid osmolality is indicated by the numbers within the channels. Successive panels represent the time course of the multiplication process.
The schematic loop starts with isosmolar fluid throughout (Fig. 2A). In Figure 2B, enough solute has been pumped by an active transport mechanism to establish a 20-mOsm/kg H2O osmolality difference between the ascending and descending flows at each level. This small osmolality difference, transverse to the flow, is called the single effect. Osmolality values after the fluid has convected the solute halfway down the left channel and halfway up the right channel are illustrated in Figure 2C. In Figure 2D, a 20-mOsm/kg H2O osmolality difference has been re-established by the active transport mechanism, and the luminal fluid near the bend of the loop has attained a higher osmolality than in Figure 2A. A progressively higher osmolality is attained at the loop bend by successive iterations of this process. A large osmolality difference is generated along the flow direction, as illustrated in Figure 2E, where the osmolality at the loop bend is nearly 300 mOsm/kg H2O above the osmolality of the fluid entering the loop. Thus, a 20-mOsm/kg H2O difference, the single effect, has been multiplied axially down the length of the loop by the process of countercurrent multiplication.