The Kidney Maintains Water Balance

One of the most important functions of the kidney is maintaining the water content of the body and the tonicity of the plasma. Terrestrial animals must constantly guard against desiccation, thus their kidneys evolved to reabsorb most of the water in the glomerular filtrate. Under normal conditions, a 10-kg beagle that produces 53.3 L of glomerular filtrate every day may reabsorb more than 99% of the water contained in the glomerular filtrate, excreting only 0.2 to 0.25 L of urine. A water-deprived dog with normal renal function can produce urine that is seven to eight times more concentrated than the osmolality of plasma, significantly higher than 2000 milliosmoles per kilogram of water (mOsm/kg H₂O). However, the kidney also can produce hypotonic urine in response to a water overload. After a water load, the same dog can excrete urine with an osmolality as low as 100 mOsm/kg H₂O, approximately one third that of plasma. This chapter discusses how the kidney accomplishes these feats.

The Proximal Tubule Reabsorbs More Than 60% of Filtered Water

The proximal tubule reabsorbs the majority of the glomerular filtrate. It takes up solutes from the tubule fluid by both active and passive means. The sodium-potassium-adenosine triphosphatase (Na⁺,K⁺-ATPase) pump in the basolateral plasma membrane actively transports Na⁺ and drives carrier-mediated secondary active transport and passive uptake of solutes. Removal of solute from the tubule fluid creates a slight gradient favoring the movement of water into the cells and the intercellular spaces. The complex apical brush border and basolateral plasma membrane infoldings create large surface areas that are highly permeable to water primarily because of the water channel, aquaporin-1 (AQP1), in the apical and basolateral plasma membranes throughout the proximal tubule. Thus, the small chemical gradient results in rapid movement of water from the tubule fluid to the interstitial fluid. The high oncotic pressure and low hydrostatic pressure in the peritubular capillaries favor the movement of reabsorbed water and solute from the interstitial fluid to the blood.

The proximal tubules in the kidneys of our 10-kg beagle reabsorb 32 to 37 L of water per day. However, because the water is reabsorbed nearly isotonically with salt, the osmolality of the tubule fluid remains similar from Bowman’s space to the beginning of the thin descending limb of Henle’s loop.

The Kidney Can Produce Either Concentrated or Diluted Urine

An elegant system has evolved in the mammalian kidney that allows excretion of either concentrated or diluted urine as needed. This system has three main components: (1) generation of a hypertonic medullary interstitium, which allows excretion of concentrated urine; (2) dilution of the tubule fluid by the thick ascending limb and the distal convoluted tubule, which allows excretion of dilute urine; and (3) variability in the water permeability of the collecting duct in response to antidiuretic hormone (ADH, vasopressin), which determines the final urine concentration. The beauty of this system is that all the factors necessary for urine concentration and dilution are operative at any given time, so the kidney can respond immediately to changes in ADH levels with corresponding changes in urine osmolality and water excretion.

A Hypertonic Medullary Interstitium Is Needed to Form Concentrated Urine

Terrestrial animals usually produce urine that is concentrated well above the plasma osmolality. Excretion of concentrated wastes conserves water and thus reduces the volume of water that must be consumed to prevent dehydration. Two of the three factors just mentioned are responsible for the formation of concentrated urine: (1) generation of a hypertonic medullary interstitium and (2) enhanced water permeability in the collecting duct in the presence of ADH.

The hypertonicity of the medullary interstitium is produced and maintained primarily by (1) the reabsorption of osmotically active substances by tubules in the medulla and (2) the removal of water from the medullary interstitium by the vasa recta.

Short-Loop and Long-Loop Nephrons Have Different Roles in Urine Concentration

The anatomical arrangement of the renal tubules in the medulla is a crucial element of the urine-concentrating mechanism. The nephrons of the mammalian kidney are subdivided into superficial and juxtamedullary nephrons based on the location of their respective glomeruli (see Figure 41-1). The majority are superficial nephrons, which have short loops of Henle that extend only into the inner stripe of the outer medulla. These short-loop nephrons have a descending thin limb that parallels the thick ascending limb, but they do not have an ascending thin limb; the thin descending limb merges with the thick ascending limb near the hairpin turn (Figure 43-1).

Juxtamedullary nephrons have long loops of Henle that extend deep into the inner medulla. These long-loop nephrons have several segments of descending and ascending thin limbs with specific urea and water transporter expression that contribute to their role in maintaining the medullary hypertonicity and urine concentrating ability. The juxtamedullary nephrons are particularly responsible for the kidney’s ability to concentrate urine at a much higher level than the osmolality of plasma.

In birds, the reptilian-type nephrons have glomeruli that are near the surface in the renal cortex and have no loops of Henle. The mammalian-type nephrons have glomeruli that are deeper in the cortex and have either short or long loops of Henle that extend into the medullary cone. The mammalian-type nephrons have a countercurrent arrangement and are thought to be largely responsible for the ability of birds to excrete hypertonic urine.

Sodium Chloride Reabsorption by the Medullary Thick Ascending Limb Generates Medullary Hypertonicity

The thick ascending limb of Henle’s loop actively reabsorbs sodium chloride (NaCl) but is impermeable to water. Therefore, this segment raises the osmolality of the interstitial fluid, thus generating medullary interstitial hypertonicity and a lumen-to-interstitium osmotic gradient. This process occurs in both short-loop and long-loop nephrons. The hypertonic interstitium allows water to be abstracted from water-permeable descending thin limbs and returned to the circulation.

Urea Reabsorption by the Inner Medullary Collecting Duct and Urea Recycling Enhance Medullary Hypertonicity

The inner medullary collecting duct (IMCD) also actively reabsorbs NaCl, but its more important contribution to the medullary hypertonicity is the reabsorption of urea (see Figure 43-1). Although the cortical and outer medullary collecting ducts are impermeable to urea, the terminal IMCD is highly permeable to urea via specific urea transporters (UT-A1, UT-A3). Thus, urea remains in the tubule fluid until it reaches the terminal IMCD deep in the medulla. Because urea reabsorption by the IMCD is enhanced by ADH, when conditions demand water conservation and ADH is released, urea reabsorption is enhanced and the osmotic gradient for water uptake increases. Because the thin limbs of Henle’s loop are permeable to urea, the high interstitial urea concentration drives urea into the thin limb luminal fluid. The tubule segments that intervene between the thin ascending limb and the terminal IMCD are impermeable to urea, thus urea reabsorbed from the terminal IMCD and taken up by the thin limbs is recycled back to the IMCD. In mammals this system of urea recycling enhances the efficiency of the urine-concentrating mechanism. In birds, however, urea is nearly absent in the medullary interstitium; urates do not contribute appreciably to osmotic pressure because they have low water solubility. Thus, medullary hypertonicity in birds appears to depend on single-solute (NaCl) recycling.

The Countercurrent Mechanism Increases Medullary Interstitial Osmolality with Minimal Energy Expenditure

The prevailing hypothesis for decades has been that a countercurrent mechanism in the thin limbs of Henle’s loop is responsible for the progressive amplification of the medullary hypertonicity initiated by the active reabsorption of salt by the thick ascending limb of Henle’s loop (Figure 43-2). This may be accomplished with minimal energy expenditure because of two characteristics: (1) the anatomical arrangement of the thin limbs of Henle’s loop and (2) the differential water and salt permeabilities of the descending and ascending thin limbs. Although recent data on the specific distribution of water and solute permeabilities and the complex anatomical associations of tubules and vessels in the medulla have raised doubts about the countercurrent multiplier hypothesis, the fundamentals of the concept remain the basis of understanding the mechanisms maintaining medullary hypertonicity.