The physiology of urinary concentration: an update

Abstract

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.

Figure 1

Molecular identities and locations of the sodium, urea, and water transport proteins involved in the passive mechanism hypothesis for urine concentration in the inner medulla [7;8]. The major kidney regions are indicated on the left. NaCl is actively reabsorbed across the thick ascending limb by the apical plasma membrane Na-K-2Cl cotransporter (NKCC2/BSC1), and the basolateral membrane Na/K-ATPase (not shown). Potassium is recycled through an apical plasma membrane channel, ROMK. Water is reabsorbed across the descending limb segments by AQP1 water channels in both apical and basolateral plasma membranes. Water is reabsorbed across the apical plasma membrane of the collecting duct by AQP2 water channels in the presence of vasopressin. Water is reabsorbed across the basolateral plasma membrane by AQP3 water channels in the cortical and outer medullary collecting ducts and by both AQP3 and AQP4 water channels in the inner medullary collecting duct (IMCD). Urea is concentrated within the collecting duct lumen (by water reabsorption) until it reaches the terminal IMCD where it is reabsorbed by the urea transporters UT-A1 and UT-A3. According to the passive mechanism hypothesis (see text), the fluid that enters the thin ascending limb from the contiguous thin descending limb has a higher NaCl and a lower urea concentration than the inner medullary interstitium, resulting in passive NaCl reabsorption and dilution of the fluid within the thin ascending limb. Abbreviations: AQP, aquaporin; UT, urea transporter.

Figure 2

Countercurrent multiplication of a single effect in a diagram of the loop of Henle in the outer medulla. Panel A: process begins with isosmolar fluid throughout both limbs. Panel B: active solute transport establishes a 20 mOsm/kg H₂O transverse gradient (single effect) across the boundary separating the limbs. Panel C: fluid flows half-way down the descending limb and up the ascending limb. Panel D: active transport reestablishes a 20 mOsm/kg H₂O transverse gradient. Note that the luminal fluid near the bend of the loop achieves a higher osmolality than loop-bend fluid in panel B. Panel E: as the processes in C and D are repeated, the bend of the loop achieves a progressively higher osmolality so that the final axial osmotic gradient far exceeds the transverse 20 mOsm/kg H₂O gradient generated at any level.

Figure 3

Urea recycling pathways in the medulla. Diagram shows a long-looped nephron (right) and a short-looped nephron (left). Dotted lines labeled 1, 2, and 3 show urea recycling pathways. Abbreviations: PST, proximal straight tubule; tDL, thin descending limb of Henle's loop; tAL, thin ascending limb of Henle's loop; TAL, thick ascending limb of Henle's loop; and IMCD, inner medullary collecting duct.

Figure 4

Reconstruction of loops of Henle from rat inner medulla (IM). Red indicates expression of aquaporin-1 (AQP1); green, ClC-K1; gray, both AQP1 and ClC-K1 are undetectable. A: Loops that turn within the first millimeter beyond the outer medulla. Descending thin limbs (DTLs) lack detectable AQP1; ClC-K1 is expressed along prebend segments and ascending thin limbs (ATLs). B: Lops that turn beyond the first millimeter of the IM. DTLs express AQP-1 along the initial ∼40%; ClC-K1 is expressed along the prebend segments and ATLs. C: Enlargement of near-bend regions from box in B. Prebend ClC-K1 expression, on average, begins ∼165 μm before the loop bend (arrows). Scale bars: 500 μm (A and B); 100 μm (C). Figure reproduced from reference [26] and used with the permission of the American Physiological Society.