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Urinary concentration and dilution.


Discuss the role of the kidney in urinary concentration and dilution.


1. Describe the process by which a concentrated urine is formed.

2. Explain the process by which a dilute urine is formed.

3. Discuss the mechanism by which vasopressin increases the water permeability of the collecting tubule.

Editor's Note: This article, a continuation of the renal physiology series being published in the Nephrology Nursing Journal, covers urinary concentration and dilution and is adapted from an article published in the August 1992 issue of ANNA Journal, volume 19, number 4.

Since water is the major component of all living cells, the ability to absorb and release water is a fundamental aspect of life. In humans 60%-70% of body weight is water, which equilibrates across the lipid bilayer in cell membranes throughout the body. Because we live on land, the human body is exposed to constant, daily unregulated losses of water through the feces, sweat, and lungs. Without fluid replacement, these losses would ultimately dehydrate the body. Water balance is tightly regulated by the kidneys, because they are the only organs capable of regulating total body water balance based on their ability to concentrate urine (thus saving body water) or dilute it (thus ridding the body of excess water). This paper reviews the mechanisms involved in urinary concentration and dilution.

An Evolutionary Perspective

It is theorized that the kidneys evolved from early excretory structures in primitive multicellular sea organisms. As these organisms developed increasingly complex cellular structures, simple diffusion of solutes

and water through the skin became impossible. Thus, a single tubular structure evolved that secreted or reabsorbed solutes (primarily sodium chloride [NaCl]) and water and opened at one end to the sea, enabling the organism to maintain an internal osmotically favorable environment. This earliest form of kidney, analogous to the tubule structures present in human kidneys, provides the basis for the additional structures and processes present in the human kidneys.

When early vertebrates were exposed to freshwater, the kidney evolved further. The simple tubular kidney was no longer adequate to maintain the internal osmotic environment--it could not eliminate enough water, and too much solute was lost, so the organism succumbed to extreme hypo-osmolality. Thus, the glomerulus evolved. This structure rapidly dumped the contents of the extracellular fluid into the tubule, thus solving the problem of water elimination. However, since a significant amount of valuable solutes were also discarded at the glomerulus, a mechanism for recapturing solutes and some water evolved along the tubular structures.

The kidneys' ability to regulate solute and water balance probably did not achieve present day potential until animals emerged permanently onto dry land. Then, within the tubular structure, mechanisms continued to evolve that recaptured solutes, allowing for the excretion of dilute urine. Hormonal regulation and the collecting duct system evolved, allowing the kidneys to produce urine that was more concentrated than body fluids. This conservation of body water was refined in the mammalian kidneys with the loop of Henle, which is a countercurrent mechanism to further concentrate urine and conserve body water. With these water conservation mechanisms, mammals could leave pools of water for extended periods.

Anatomy of the Mammalian Kidney

Tubular structure and orientation. The ability of the kidney to concentrate or dilute urine is structurally based on the orientation of the nephron within the three layers of the kidney. These layers are (at the cortical layer, the most superficial layer; (b) the outer medullary layer, medial to the cortical layer; and (c) the inner medullary layer, the deepest layer. As shown on the left side of Figure 1, each layer has a higher osmotic gradient than the one external to it. The osmolality rises from 300 mOsm/kg H20 in the cortical layer (similar to that of plasma) to 1200 mOsm/kg [H.sub.2]O in the inner medullary layer. These different gradients are important in establishing the various solute and water properties present in different segments of the tubule and collecting ducts.


The tubules of the nephron extend perpendicularly through all three layers of the kidney; however, each layer houses different tubule segments (see Figure 1). The proximal convoluted tubule, receiving tubular fluid from the Bowman's capsule, resides in the cortical layer. It connects to the proximal straight tubule, which begins in the cortical layer and joins the descending limb of the loop of Henle in the outer medullary layer.

Two different types of nephrons receive output from the proximal tubule, conduct it through the medullary layer via the loop of Henle, and pass it on to the distal convoluted tubule. Superficial nephrons have short loops of Henle that extend only to the outer medullary layer, and their efferent arterioles brandl into peritubular capillaries that surround the nephron segments. Juxtamedullary nephrons (see Figure 1) have longer loops of Henle that extend to the deep layers of the inner medulla, and their efferent arterioles form both a network of peritubular capillaries and a series of vascular loops called the vasa recta.

Upon exit from the loop of Henle, tubule fluid enters the distal convoluted tubule (DCT) in the cortical layer. Severn DCTs merge to form a connecting tubule, which in turn, joins other collecting tubules to conduct tubule fluid to a cortical collecting duct. Arranged parallel to the loops of Henle, the collecting ducts extend from the superficial layer of the cortical layer to the deepest inner medullary layer. Similar to the loop of Henle, the passage of the collecting duct through different layers of the kidney permits differentiation in water and solute transport.

Tubule vasculature. The blood vessels that carry blood in and out of the renal medulla, collectively called the vasa recta, lie in close proximity to the loops of Henle and collecting ducts. A dense capillary bed projects within the medulla between the afferent (descending) and efferent (ascending) vasa recta. More capillary beds exist in the outer medullary layer than in the inner medullary layer.

The arrangement of the tubule vasculature helps the nephrons concentrate or dilute fluid by creating a countercurrent exchange between the solute and water-rich fluid within the tubule (coming from the Bowman's capsule) and the solute-and water poor descending vasa recta (and proximal capillaries) coming from the glomerulus. There is a reverse relationship in the osmolality between the tubule fluid and the interstitium and vasa recta plasma. That is, as the tubular fluid becomes more concentrated, the surrounding interstitium and plasma within the vasa recta become more dilute. The arrangement of the tubule vasculature in the medulla creates a low flow/high perfusion state (by having dense capillary beds) that facilitates efficient countercurrent exchange and maintains the differentiation of solute concentrations within the interstitium of the medulla. High flow rates would wash out this difference. In contrast to the medulla, the cortical layer has a high flow rate of blood through its capillaries, which facilitates the rapid return of solutes and water from the nephron to the blood.

Water Regulation Along the Tubule Segments

The key factors that allow the kidneys to produce either a concentrated urine or a dilute urine, depending on our body's fluid needs are: (a) tubular segments with different permeability to water, NaCl, and urine (see Table 1); (b) an increase in the osmolality of the interstitial space from the cortical to the inner medullary layer (see Figure 1); and (c) the presence of vasopressin, which alters the water permeability of the distal tubule and collecting ducts. Thus, water transport in each of the nephron segments differs markedly.

Proximal tubule. The proximal tubule wall reabsorbs approximately 67% of tubular fluid water as well as sodium, potassium, and other ions. These components move through the cortical layer interstitium where high vasa recta flow rates cause rapid reabsorption into the plasma. Solute movement (mainly sodium) into the interstitial space occurs through active and facilitative transport mechanisms, creating an osmotic gradient that is higher in the interstitium than in the tubular fluid. Water diffuses through the tubular wall to dilute the higher interstitial concentration, so that the tubular fluid that ultimately exits the proximal tubule (and enters the descending loop of Henle) is relatively isosmotic with respect to the vasa recta plasma. Because simple dig fusion across or between tubular wall cells is too slow to account for the rapidity of water movement across the tubule wall, specialized water channels in the cells of the tubular walls allow for the rapid movement of water. At the end of the proximal tubule, the tubular fluid is isosmotic to that of plasma (300 mOsm/kg [H.sub.2]O).

Loop of Henle. In the loop of Henle, 25% of the filtered NaCl is rapidly absorbed by active transport into the medullary interstitium and, ultimately, into the vasa recta plasma. The descending limb is highly permeable to water and much less so to solutes such as NaCl and urea. Consequently, as the fluid descends into the medulla, water is reabsorbed because of the osmotic gradient between the tubular and interstitial fluid. Thus, at the tip of the loop, the tubular fluid has an osmolality equal to that of the surrounding interstitial fluid. However, the NaCl concentration is greater than the surrounding interstitial fluid, while the urea concentration is less than that of the surrounding interstitial fluid.

The thin ascending limb is impermeable to water, but permeable to NaCl and urea. Consequently, as tubular fluid moves up the ascending limb, NaCl is passively reabsorbed because the tubular fluid NaCl concentration is greater than that of the surrounding interstitial fluid. In contrast, urea passively diffuses into the lumen because the tubular fluid urea concentration is less than that of the surrounding interstitial fluid. The net movement of urea is less than that of NaCl, and the tubular fluid becomes hypo-osmolar. The net effect is that while the volume of fluid remains unchanged along the thin ascending limb, the NaCl concentration decreases and the urea concentration increases.

The fluid becomes more dilute as it moves into the thick ascending limb, which is impermeable to water and urea, but actively reabsorbs NaCl. Fluid leaving this segment is hypo osmotic with respect to plasma (approximately 150 mOsm/kg [H.sub.2]O).

The processes by which the kidney makes concentrated or dilute urine are the same up to this point. The major distinguishing factor occurs with the presence of vasopressin (antidiuretic hormone [ADH]). Vasopressin is made in the cell bodies of the hypo thalamus. When plasma osmolality rises, it stimulates osmoreceptors located in the hypothalamus, which, in turn, sends signals to the vasopressin synthesizing cells located in the supraoptic and paraventricular nuclei of the hypothalamus. Vasopressin is transported along the axons for release in the posterior pituitary gland.

Distal tubule axon collecting duct. The same processes that regulate water and solute movement in the distal tubule also do so in the cortical portion of the collecting duct. At the beginning of the distal tubule, the tubular fluid is hypo-osmotic to that of plasma. In the absence of vasopressin, this hypotonicity is maintained throughout the distal tubule and collecting duct system, as these segments are impermeable to water. The distal tubule and the cortical portion of the collecting duct actively reabsorb NaCl but are impermeable to urea. Thus, the urine is made more dilute and hypo-osmotic with respect to plasma. The sodium concentration in the cortex remains close to the plasma concentration due to the high flow rate of blood within the vasa recta in this area. As the collecting duct extends into the medullary layers, NaCl is still actively reabsorbed, increasing the osmolality of the medullary interstitium. In the medullary layer, the collecting duct becomes slightly permeable to water and urea, thereby allowing a small amount of urea into the collecting duct and a small amount of water into the medullary interstitium. Under diuretic conditions, the volume of urine excreted can be as much as 18 L/day or approximately 10% of the glomerular filtration rate (GFR).

In contrast, a rise in the vasopressin level increases water permeability in the distal tubule and collecting ducts. Water flows towards the higher concentration in the interstitium and plasma; the high flow rate within the vasa recta in the cortex maintains the cortical osmolality close to the plasma osmolality. The cortical collecting duct, however, can only concentrate urine to an osmolality that is no higher than the plasma osmolality (approximately 300 mOsm/kg [H.sub.2]O). Urine becomes more concentrated as passes down the collecting duct from the cortical layer through the medullary layers. Due to the hyperosmolality of the interstitium in these layers (up to 1200 mOsm/kg [H.sub.2]O in the inner medullary layer), water is reabsorbed into the interstitium. The resulting urine is concentrated more than the plasma and the primary remaining solute is urea. Urine volume under this condition can be as low as .5 L/day.

Mechanism of Water Movement Across the Walls of the Tubules

Aquaporins. Now that we have reviewed the fundamentals of urinary concentration and dilution in the kidneys, let us take a closer look at the mechanisms underlying water movement through the tubule walls. Over the past decade, experiments have demonstrated that the velocity of water traveling from inside the tubular lumen to the surrounding interstitium cannot be explained by simple diffusion through the cells' lipid bilayers or between cell junctions in the tubule wall. It was theorized that specialized water channels existed within the cells that allowed the rapid movement of water from the lumen into the interstitium.

This water channel theory was supported by the discovery of Aquaporin-1 in the proximal tubule, which is highly permeable to water. Aquaporin-1 is a channel composed of protein that spans the cell membrane and is specific for water only. Water passes more rapidly through this channel than through the lipid bilayer or between cell junctions. There are many Aquaporin-1 channels on the tubular lumen side and the interstitial side of the tubule wall cells. In healthy individuals, the Aquaporin-1 channels remain an ever-present structure in the luminal wall cells of the proximal tubule and the descending limb of the loop of Henle. Therefore, these two segments are always permeable to water. Aquaporin-1 is not located in the distal tubule or the collecting duct, other sites with well-known water movement. This makes sense, since the "always open" nature of the Aquaporin-1 channels would make them unsuitable for regulation. Indeed, a second aquaporin channel, Aquaporin-2, was discovered. These water channels are removed from the membrane of the distal tubules and the collecting ducts and are stored within vesicles within the cells during urinary dilution. As a result, the water is kept in the collecting duct lumen. Once activated by an increase in vasopressin, these vesicles move towards and integrate themselves within the cell membranes of the distal tubules and collecting ducts. This movement leads to greater water permeability and, therefore, greater water absorption. Surprisingly, while short bursts of vasopressin liberate Aquaporin-2 channels from storage vesicles, chronic exposure to vasopressin produces new Aquaporin-2 channels that have never been stored.

While Aquaporin-2 are integrated into the luminal side of the cells in the distal tubule and collecting duct, Aquaporin-3 and Aquaporin-4 are integrated into the interstitial side of the cell. These water channels have the same function as Aquaporin-2; that is, as water flows through the channels at one side of the cell, they conduct it out of the cell at the other side. As always, the direction of water movement still depends on the solute concentration gradient on either side of the tubule lumen. Although the list of known aquaporins has grown to 10, many of them have unclear roles; however, experimental studies have discovered a correlation between expression and integration of aquaporin channels (mostly type 2) and human disorders (see Table 2).

Role of vasopressin. Vasopressin affects the expression of aquaporin channels, mainly the Aquaporin-2 channels. When vasopressin activity is low, water permeability is low in the collecting ducts, and relatively little water is absorbed in this segment. The dilute fluid exiting the loop of Henle remains hypotonic all the way to the final urine. With high vaso pressin, more water channels exist; water exits the tubular lumen and urine becomes more hypertonic. Only the distal tubules and the collecting ducts exhibit vasopressin regulated water transport.

During water diuresis, when vaso pressin levels are low, a small amount of water is still reabsorbed, primarily at the inner medullary layer where the medullary osmotic gradient is highest and the basal water permeability is also highest. This results in a reduction of the inner medullary osmolality. Vasopressin also increases urea permeability in the collecting duct within the inner medullary layer and increases the rate of active NaCl absorption from the loop of Henle. Urea and NaCl absorption contribute to increasing the hypertonicity of the inner medullary layer. In the cortical layer section of the collecting duct, vasopressin increases water absorption where rapid blood flow can return it to the circulation.


The mammalian kidneys have evolved into a structure capable of regulating several complex mechanisms simultaneously. The link between structure and function is exemplified by the perpendicular orientation of the tubule structures within the layers of the kidney. The nephrons could not produce both a concentrated or dilute urine without traveling through these layers of differing osmolality. The anatomical structure of the kidney serves one important function: to maintain total body water balance.

Additional Readings

Agre, P. (2000). Aquaporin water channels in kidney: Homer W. Smith award lecture. Journal of the American Society of Nephrology, 11(4), 764-777.

Grantham, J.J., & Wallace, D.P. (2002). Return of the secretory kidney. American Journal of Physiology: Renal Physiology, 282, F1-F9.

Inoue, T., Nonoguchi, H., & Tomita, K. (2001). Physiological effects of vasopressin and atrial natriuretic peptide in the collecting duct. Cardiovascular Research, 59, 470-480.

Koeppen, B.M., & Stanton, B.A. (2003). Renal physiology (3rd ed.) (pp. 75-92). St. Louis: Mosby, Inc.

Kishore, B.K., Krane, C.M., Reif, M., & Menon, A.G. (2001). Molecular physiology of urinary concentration defect in elderly population. International Urology and Nephrology, 33, 235-248.

Masilamani, S., Knepper, M.A., & Burg, M.B. (2000). Urine concentration and dilution. In B.M. Brenner (Ed.), Brenner and Rector's the kidney (6th ed.) (pp. 595 635). Philadelphia: Saunders.

Schrier, R.W., & Cadnapaphornchai, M.A. (2002). Renal aquaporin channels: From molecules to human disease. Progress in Biophysics and Molecular Biology, 81, 117-131.

Stanton, B.A., & Koeppen, B.M. (1998). Control of body fluid osmolality and volume. In R.M. Berne & M.N. Levy (Eds.), Physiology (4th ed.) (pp. 715-743). St. Louis: Mosby, Inc.

Verkman, A.S. (1999). Lessons on renal physiology from transgenic mice lacking aquaporin channels. Journal of the American Society of Nephrology, 10, 1126-1135.

Urinary Concentration and Dilution David Guthrie, MS, ARNP and Carolyn Yucha, PhD, RN

Posttest--1.5 Contact Hours Posttest Questions

(See posttest instructions on the answer form, on page 303.)

1. Which of the following nephron segments creates an isomotic fluid and is not directly involved in the formation of a concentrated or dilute urine?

A. Proximal tubul

B. Loop of Henle

C. Distal tubule

D. Collecting tubule

2. The arrangement of the tubular vasculature in the medulla helps to produce a concentrated or dilute urine by creating a counter current exchange. The arrangement creates a

A. high flow, high perfusion state.

B. high flow, low perfusion state.

C. low flow, high perfusion state.

D. low flow, low perfusion state.

3. Which of the following contribute to the progressive increase in filtrate osmolality as the filtrate passes along the descending limb of Henle's loop?

A. Reabsorption of solutes

B. Reabsorption of water

C. Secretion of solutes

D. Secretion of water

4.The thin ascending limb contributes to the generation of the hypertonic medullary interstitium by

A. passive reabsorption of sodium.

B. active reabsorption of sodium.

C. passive reabsorption of urea.

D. active reabsorption of urea.

5. The medullary collecting tubules contribute to the generation of the hypertonic medullary interstitium by

A. passive reabsorption of sodium.

B. active reabsorption of sodium.

C. passive reabsorption of urea.

D. active reabsorption of urea.

6. Vasopressin is released from the

A. distal and collecting tubule cells.

B. osmoreceptors in the hypothalamus.

C. posterior pituitary.

D. supraoptic and paraventricular nuclei in the hypothalamus.

7. Vasopressin regulates the water permeability of the

A. vasa recta.

B. descending limb of Henle's loop.

C. thin ascending limb of Henle's loop.

D. cortical and medullary collecting tubules.

8. Vasopressin increases the water permeability by mediating the insertion of

A. aquaperin-1 into the proximal tubule.

B. aquaporin-2 into the proximal tubule.

C. aquaporin-1 into the collecting duct.

D. aquaporin-2 into the collecting duct.

9. You work in the ICU. You would expect diuresis in a patient with which diagnosis?

A. Diabetes insipidus only

B. Diabetes insipidus and hypokalemia only

C. Diabetes insipidus, hypokalemia, and congestive heart failure only

D. Diabetes insipidus, hypokalemia, congestive heart failure, and cirrhosis

10. A key factor that allows the kidney to produce concentrated or dilute urine is

A. tubule segments with similar permeability.

B. decrease in osmolality of the interstitial space.

C. the presence of vasopressin.

D. aquaproin 1 channels.

David Guthrie, MN, ARNP, is Doctoral Student, University of Florida College of Nursing, Gainesville, FL

Carolyn Yucha, PhD, RN, is Professor and Dean, University of Nevada at Las Vegas, Las Vegas, NV.

Acknowledgement: This article was adapted from the original written by Patricia Preisig, PhD, RN, published in the ANNA Journal, Volume 19, Number 4, in August 1992. The author and Nephrology Nursing Journal would like to thank Dr. Preisig for her excellent work in the original article.
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Title Annotation:Continuing Education
Author:Guthrie, David; Yucha, Carolyn
Publication:Nephrology Nursing Journal
Date:May 1, 2004
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