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Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

III. Coordinated Body Functions

16. The Kidneys and Regulation of Water and Inorganic Ions

© The McGraw−Hill Companies, 2001

chapterC H A P T E R

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505

Renal Sodium RegulationControl of GFR

Control of Sodium Reabsorption

Renal Water RegulationBaroreceptor Control of Vasopressin

Secretion

Osmoreceptor Control of VasopressinSecretion

A Summary Example: The Response to Sweating

Thirst and Salt AppetitePotassium Regulation

Renal Regulation of Potassium

SECTION B SUMMARY

SECTION B KEY TERMS

SECTION B REVIEW QUESTIONS

SECTION CCALCIUM REGULATIONEffector Sites for Calcium

HomeostasisBone

Kidneys

Gastrointestinal Tract

Hormonal ControlsParathyroid Hormone

1,25-Dihydroxyvitamin D3

Calcitonin

Metabolic Bone DiseasesSECTION C SUMMARY

SECTION C KEY TERMS

SECTION C REVIEW QUESTIONS

SECTION ABASIC PRINCIPLES OF RENAL

PHYSIOLOGYRenal FunctionsStructure of the Kidneys and

Urinary SystemBasic Renal Processes

Glomerular Filtration

Tubular Reabsorption

Tubular Secretion

Metabolism by the Tubules

Regulation of Membrane Channels andTransporters

“Division of Labor” in the Tubules

The Concept of Renal ClearanceMicturition

SECTION A SUMMARY

SECTION A KEY TERMS

SECTION A REVIEW QUESTIONS

SECTION BREGULATION OF SODIUM, WATER,

AND POTASSIUM BALANCETotal-Body Balance of Sodium

and WaterBasic Renal Processes for Sodium

and WaterPrimary Active Sodium Reabsorption

Coupling of Water Reabsorption toSodium Reabsorption

Urine Concentration: TheCountercurrent Multiplier System

SECTION DHYDROGEN-ION REGULATIONSources of Hydrogen-ion Gain

or LossBuffering of Hydrogen Ions

in the BodyIntegration of Homeostatic

ControlsRenal Mechanisms

Bicarbonate Handling

Addition of New Bicarbonate to thePlasma

Renal Responses to Acidosis andAlkalosis

Classification of Acidosis andAlkalosisSECTION D SUMMARY

SECTION D KEY TERMS

SECTION D REVIEW QUESTIONS

SECTION EDIURETICS AND KIDNEY DISEASEDiureticsKidney Disease

Hemodialysis, Peritoneal Dialysis, andTransplantation

SECTION E SUMMARY

CHAPTER 16 CLINICAL TERMS

CHAPTER 16 THOUGHT QUESTIONS

16

The Kidneys and Regulation of Waterand Inorganic Ions





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TThis chapter deals with how the water and inorganic-ion

composition of the internal environment is homeostatically

regulated. The kidneys play the central role in these

processes.

Regulation of the total-body balance of any substance

can be studied in terms of the balance concept described in

Chapter 7. Theoretically, a substance can appear in the body

either as a result of ingestion or as a product of metabolism.

On the loss side of the balance, a substance can be excreted

from the body or can be metabolized. Therefore, if the

quantity of any substance in the body is to be maintained at a

nearly constant level over a period of time, the total amounts

ingested and produced must equal the total amounts excreted

and metabolized.

Reflexes that alter excretion, specifically excretion via the

urine, constitute the major mechanisms that regulate the

body balances of water and many of the inorganic ions that

determine the properties of the extracellular fluid. The

extracellular concentrations of these ions were given in Table

6–1. We will first describe how the kidneys work in general

and then apply this information to how they process specific

substances—sodium, water, potassium, and so on—and

participate in reflexes that regulate these substances.

B A S I C P R I N C I P L E S O F R E N A L P H Y S I O L O G Y

S E C T I O N A

Renal FunctionsThe adjective renal means “pertaining to the kidneys”;thus, for example, we refer to “renal physiology” and“renal functions.”

The kidneys process the plasma portion of bloodby removing substances from it and, in a few cases, byadding substances to it. In so doing, they perform avariety of functions, as summarized in Table 16–1.

First, and very importantly, the kidneys play thecentral role in regulating the water concentration, inorganic-ion composition, and volume of the internalenvironment. They do so by excreting just enough wa-ter and inorganic ions to keep the amounts of thesesubstances in the body relatively constant. For exam-ple, if you start eating a lot of salt (sodium chloride),the kidneys will increase the amount of the salt theyexcrete to match the intake. Alternatively, if there is notenough salt in the body, the kidneys will excrete verylittle salt or virtually none at all.

Second, the kidneys excrete metabolic waste prod-ucts into the urine as fast as they are produced. Thiskeeps waste products, which can be toxic, from accu-

mulating in the body. These metabolic wastes includeurea from the catabolism of protein, uric acid from nu-cleic acids, creatinine from muscle creatine, the endproducts of hemoglobin breakdown (which give urinemuch of its color), and many others.

A third function of the kidneys is the excretion, inthe urine, of some foreign chemicals, such as drugs,pesticides, and food additives, and their metabolites.

A fourth function is gluconeogenesis. During pro-longed fasting, the kidneys synthesize glucose fromamino acids and other precursors and release it intothe blood. The kidneys can supply approximately 20 percent as much glucose as the liver does at suchtimes (Chapter 18).

Finally, the kidneys act as endocrine glands, se-creting at least three hormones: erythropoietin (de-scribed in Chapter 14), renin, and 1,25-dihydroxyvita-min D3. These last two hormones are described in thischapter. (Note that renin is part of a hormonal systemcalled the renin-angiotensin system; although reninfunctions as an enzyme in this system, it is customaryto refer to it as a “hormone.”)

506





Structure of the Kidneys andUrinary SystemThe two kidneys lie in the back of the abdominal wallbut not actually in the abdominal cavity. They areretroperitoneal, meaning they are just behind the peri-toneum, the lining of this cavity. The urine flows fromthe kidneys through the ureters into the bladder, fromwhich it is eliminated via the urethra (Figure 16–1).

Each kidney contains approximately 1 million sim-ilar subunits called nephrons. Each nephron (Figure16–2) consists of (1) an initial filtering componentcalled the renal corpuscle, and (2) a tubule that ex-tends out from the renal corpuscle. The renal corpus-cle forms a filtrate from blood that is free of cells andproteins. This filtrate then leaves the renal corpuscleand enters the tubule. As it flows through the tubule,substances are added to it or removed from it. Ulti-mately the fluid from all the nephrons exits the kid-neys as urine.

Let us look first at the anatomy of the renal cor-puscles—the filters. Each renal corpuscle contains acompact tuft of interconnected capillary loops calledthe glomerulus (plural, glomeruli), or glomerular cap-illaries (Figures 16–2 and 16–3). Each glomerulus issupplied with blood by an arteriole called an afferentarteriole. The glomerulus protrudes into a fluid-filledcapsule called Bowman’s capsule. The combination ofa glomerulus and a Bowman’s capsule constitutes a re-nal corpuscle. As blood flows through the glomerulus,a portion of the plasma filters into Bowman’s capsule.The remaining blood then leaves the glomerulus byanother arteriole, the efferent arteriole.

One way of visualizing the relationships within therenal corpuscle is to imagine a loosely clenched fist—the glomerulus—punched into a balloon—the Bow-man’s capsule. The part of Bowman’s capsule in con-tact with the glomerulus becomes pushed inward butdoes not make contact with the opposite side of the capsule. Accordingly, a fluid-filled space—Bowman’sspace—exists within the capsule, and it is into this spacethat protein-free fluid filters from the glomerulus.

Blood in the glomerulus is separated from the fluidin Bowman’s space by a filtration barrier consisting ofthree layers (Figure 16–3b): (1) the single-celled capil-lary endothelium, (2) a noncellular proteinaceous layerof basement membrane (also termed basal lamina) between the endothelium and the next layer, which is(3) the single-celled epithelial lining of Bowman’s cap-sule. The epithelial cells in this region are quite differ-ent from the simple flattened cells that line the rest ofBowman’s capsule (the part of the “balloon” not incontact with the “fist”) and are called podocytes. Theyhave an octopus-like structure in that they possess alarge number of extensions, or foot processes. Fluid fil-ters first across the endothelial cells, then through thebasement membrane, and finally between the footprocesses of the podocytes.

In addition to the capillary endothelial cells andthe podocytes, there is a third cell type, mesangialcells, which are modified smooth-muscle cells that surround the glomerular capillary loops but are notpart of the filtration pathway. Their function will bedescribed later.

507The Kidneys and Regulation of Water and Inorganic Ions CHAPTER SIXTEEN

1. Regulation of water and inorganic-ion balance

2. Removal of metabolic waste products from the blood andtheir excretion in the urine

3. Removal of foreign chemicals from the blood and theirexcretion in the urine

4. Gluconeogenesis

5. Secretion of hormones:a. Erythropoietin, which controls erythrocyte production

(Chapter 14)b. Renin, which controls formation of angiotensin, which

influences blood pressure and sodium balance (thischapter)

c. 1,25-dihydroxyvitamin D3, which influences calciumbalance (this chapter)

TABLE 16–1 Functions of the Kidneys

Kidney

Ureter

Bladder

Urethra

Diaphragm

FIGURE 16–1Urinary system in a woman. In the male, the urethra passesthrough the penis (Chapter 19).





The renal tubule is continuous with a Bowman’scapsule. It is a very narrow hollow cylinder made upof a single layer of epithelial cells (resting on a base-ment membrane). The epithelial cells differ in struc-ture and function along the tubule’s length, and 10 to12 distinct segments are presently recognized (see Fig-ure 16–2). It is customary, however, to group two or

more contiguous tubular segments when discussingfunction, and we shall follow this practice. Accord-ingly, the segment of the tubule that drains Bowman’scapsule is the proximal tubule (comprising the proxi-mal convoluted tubule and the proximal straighttubule of Figure 16–2). The next portion of the tubuleis the loop of Henle, which is a sharp hairpin-like loop

508 PART THREE Coordinated Body Functions

Glomerulus(glomerular capillaries)

Bowman’s space inBowman’s capsule

Proximal convoluted tubule

Proximal straight tubule

Descending thin limb of Henle’s loop

Ascending thin limb of Henle’s loop

Thick ascending limb of Henle’s loop(contains macula densa at end)

Distal convoluted tubule

Connecting tubule

Cortical collecting duct

Medullary collecting duct

Renal pelvis

Renal tubule

Loop of Henle

Collecting duct system

(a)

(b)

Proximalconvolutedtubule

Proximalstraight tubule

Descendingthin limbof Henle’s loop

Ascendingthin limbof Henle’s loop

Thick ascending limb of Henle’s loop

Renal pelvis

Medullary collectingducts fromother nephrons

Medullary collectingduct

Cortex

Medulla

Corticalcollecting duct

Cortical collectingduct from anothertubule


Connectingtubule

Bowman’s space

Bowman’s capsule

Glomerulus

Afferentarteriole

Renal corpuscle

Efferentarteriole

Maculadensa

Renalcorpuscle


Proximal Tubule

FIGURE 16–2Basic structure of a nephron. (a) Anatomical organization. The macula densa is not a distinct segment but a plaque of cells inthe ascending loop of Henle where the loop passes between the arterioles supplying its renal corpuscle of origin. The outerarea of the kidney is called the cortex and the inner the medulla. The black arrows indicate the direction of urine flow. (b) Consecutive segments of the nephron. All segments in the screened area are parts of the renal tubule; the terms to theright of the brackets are commonly used for several consecutive segments.





consisting of a descending limb coming from the prox-imal tubule and an ascending limb leading to the nexttubular segment, the distal convoluted tubule. Fluidflows from the distal convoluted tubule into the col-lecting duct system, the first portion of which is theconnecting tubule, followed by the cortical collectingduct and then the medullary collecting duct (the rea-sons for the terms “cortical” and “medullary” will beapparent shortly). The connecting tubule is so similarin function to the cortical collecting duct that, in sub-sequent discussions, we will not describe its functionseparately.

From Bowman’s capsule to the collecting-duct sys-tem, each nephron is completely separate from the oth-ers. This separation ends when multiple cortical col-lecting ducts merge. The result of additional mergings

from this point on is that the completed urine drainsinto the kidney’s central cavity, the renal pelvis, viaonly several hundred large medullary collecting ducts.The renal pelvis is continuous with the ureter drain-ing that kidney (Figure 16–4).

There are important regional differences in thekidney (Figures 16–2 and 16–4). The outer portion isthe renal cortex, and the inner portion the renalmedulla. The cortex contains all the renal corpuscles.The loops of Henle extend from the cortex for varyingdistances down into the medulla. The medullary col-lecting ducts pass through the medulla on their wayto the renal pelvis.

All along its length, each tubule is surrounded bycapillaries, called the peritubular capillaries. Note thatwe have now mentioned two sets of capillaries in the


Proximal tubule

Basement membraneof capillary loops

Podocytes(covering capillaries)

Afferentarteriole

Efferentarteriole

Glomerularcapillaryendothelial cell

Basement membrane

Bowman’s space

Bowman’sspace

Podocytes

(a)

(b)

Bowman’scapsuleepithelium

FIGURE 16–3(a) Anatomy of the renal corpuscle. Brown lines in the capillary loops indicate space between adjoining podocytes. (b) Crosssection of the three corpuscular membranes—capillary endothelium, basement membrane, and epithelium (podocytes) ofBowman’s capsule. For simplicity, glomerular mesangial cells are not shown in this figure.





kidneys—the glomerular capillaries (glomeruli) andthe peritubular capillaries. Within each nephron, thetwo sets of capillaries are connected to each other byan efferent arteriole, the vessel by which blood leavesthe glomerulus (see Figures 16–2 and 16–3). Thus therenal circulation is very unusual in that it includes twosets of arterioles and two sets of capillaries. After sup-plying the tubules with blood, the peritubular capil-laries then join together to form the veins by whichblood leaves the kidney.

One additional anatomical detail involving boththe tubule and the arterioles must be mentioned. Nearits end, the ascending limb of each loop of Henle passesbetween the afferent and efferent arterioles of thatloop’s own nephron (see Figure 16–2). At this pointthere is a patch of cells in the wall of the ascendinglimb called the macula densa, and the wall of the afferent arteriole contains secretory cells known as juxtaglomerular (JG) cells. The combination of mac-ula densa and juxtaglomerular cells is known as thejuxtaglomerular apparatus (JGA) (Figure 16–5). Thejuxtaglomerular cells secrete the hormone renin.

Basic Renal ProcessesAs we have said, urine formation begins with the fil-tration of plasma from the glomerular capillaries intoBowman’s space. This process is termed glomerularfiltration, and the filtrate is called the glomerular fil-trate. It is cell-free and except for proteins, contains allthe substances in plasma in virtually the same con-centrations as in plasma; this type of filtrate is alsotermed an ultrafiltrate.

During its passage through the tubules, the fil-trate’s composition is altered by movements of sub-stances from the tubules to the peritubular capillariesand vice versa (Figure 16–6). When the direction ofmovement is from tubular lumen to peritubular capil-lary plasma, the process is called tubular reabsorption,or simply reabsorption. (A more accurate term for thisprocess is absorption, but reabsorption persists, for his-torical reasons, as the term more commonly used byrenal physiologists.) Movement in the opposite direc-tion—that is, from peritubular plasma to tubular lu-men—is called tubular secretion, or simply secretion.Tubular secretion is also used to denote the movementof a solute from the cell interior to the lumen in thecases in which the kidney tubular cells themselves gen-erate the substance.

To summarize: A substance can gain entry to thetubule and be excreted in the urine by glomerular fil-tration or tubular secretion. Once in the tubule, how-ever, the substance need not be excreted but can be re-absorbed. Thus, the amount of any substance excretedin the urine is equal to the amount filtered plus theamount secreted minus the amount reabsorbed.

Amount Amount Amount Amount� � �

excreted filtered secreted reabsorbed


Renalpelvis

Ureter

To urinarybladder

Nephron(enlarged)

Fat deposit

Renal cortex

Renal medulla

FIGURE 16–4Section of a human kidney. For clarity, the nephron illustratedto show nephron orientation is not to scale—its outline wouldnot be clearly visible without a microscope. The outer kidney,which contains all the renal corpuscles, is the cortex, and theinner kidney is the medulla. Note that in the medulla, the loopsof Henle and the collecting ducts run parallel to each other.The medullary collecting ducts drain into the renal pelvis.

Renalcorpuscle

Efferentarteriole

Maculadensa

Juxtaglomerular cells

Afferentarteriole

Renalsympatheticnerve

FIGURE 16–5Anatomy of the juxtaglomerular apparatus.





It should be stressed that not all these processes—filtration, secretion, reabsorption—apply to all sub-stances.

To emphasize general principles, the renal han-dling of three hypothetical substances is illustrated inFigure 16–7. Approximately 20 percent of the plasmathat enters the glomerular capillaries is filtered intoBowman’s space. This filtrate, which contains X, Y, andZ in the same concentrations as in the capillary plasma,

enters the proximal tubule and begins its flow throughthe rest of the tubule. Simultaneously, the remaining80 percent of the plasma, with its X, Y, and Z, leavesthe glomerular capillaries via the efferent arteriole andenters the peritubular capillaries.

Assume that the tubule can secrete 100 percent ofthe peritubular-capillary X into the tubular lumen butcannot reabsorb X. Thus, by the combination of filtra-tion and tubular secretion, all the plasma that origi-nally entered the renal artery loses all of its substanceX, which leaves the body via the urine.

Assume that the tubule can reabsorb, but not se-crete, Y and Z. The amount of Y reabsorption is small,so that much of the filtered material is not reabsorbedand escapes from the body. But for Z the reabsorptivemechanism is so powerful that all the filtered Z istransported back into the plasma. Therefore, no Z is lostfrom the body. Hence, for Z the processes of filtrationand reabsorption have canceled each other out, and thenet result is as though Z had never entered the kidney.

For each substance in plasma, a particular combi-nation of filtration, tubular reabsorption, and tubularsecretion applies. The critical point is that, for manysubstances, the rates at which the processes proceed aresubject to physiological control. By triggering changesin the rate of filtration, reabsorption, or secretion when-ever the body content of a substance goes above or be-low normal, homeostatic mechanisms can regulate thesubstance’s bodily balance. For example, consider whathappens when a normally hydrated person drinks a lotof water: Within 1–2 h all the excess water has been ex-creted in the urine, partly as a result of an increase infiltration but mainly as a result of decreased tubular re-absorption of water. In this example, the kidneys areeffector organs of a reflex that maintains body waterconcentration within very narrow limits.


Artery

Afferentarteriole

Glomerularcapillary

Efferentarteriole

Bowman’sspace

TubulePeritubularcapillary

Vein

Urinaryexcretion

3

2

1

1. Glomerular filtration2. Tubular secretion3. Tubular reabsorption

FIGURE 16–6The three basic components of renal function. This figure isto illustrate only the directions of reabsorption and secretion,not specific sites or order of occurrence. Depending on theparticular substance, reabsorption and secretion can occur atvarious sites along the tubule.

Substance X

Bowman’sspace

Glomerularcapillary

Substance Y Substance Z

Urine Urine Urine

FIGURE 16–7Renal handling of three hypothetical substances X, Y, and Z. X is filtered and secreted but not reabsorbed. Y is filtered, and afraction is then reabsorbed. Z is filtered and completely reabsorbed.





Although renal physiologists traditionally listglomerular filtration, tubular reabsorption, and tubu-lar secretion as the three basic renal processes, a fourthprocess—metabolism by the tubular cells—is also ofconsiderable importance for some substances. In somecases, the renal tubular cells remove substances fromblood or glomerular filtrate and metabolize them, re-sulting in their disappearance from the body. In othercases, the cells produce substances and add them eitherto the blood or tubular fluid; the most important ofthese, as we shall see, are ammonium, hydrogen ion,and bicarbonate.

In summary, one can study the normal renal pro-cessing of any given substance by asking a series ofquestions:

1. To what degree is the substance filterable at therenal corpuscle?

2. Is it reabsorbed?3. Is it secreted?4. What factors homeostatically regulate the

quantities filtered, reabsorbed, or secreted: thatis, what are the pathways by which renalexcretion of the substance is altered to maintainstable body balance?

Glomerular FiltrationAs stated above, the glomerular filtrate—that is, thefluid in Bowman’s space—normally has no cells butcontains all plasma substances except proteins in vir-tually the same concentrations as in plasma. This is be-cause glomerular filtration is a bulk-flow process inwhich water and all low-molecular-weight substancesmove together. The overwhelming majority of plasmaproteins—the albumins and globulins—are excludedalmost entirely from the filtrate. One reason for theirexclusion is that the renal corpuscles restrict the move-ment of such high-molecular-weight substances. A sec-ond reason is that the filtration pathways in the cor-puscular membranes are negatively charged and sooppose the movement of these plasma proteins, mostof which are themselves negatively charged. It shouldbe noted, however, that low-molecular-weight plasmaproteins do filter in varying degrees, but we shall ig-nore this fact.

The only exceptions to the generalization that allnonprotein plasma substances have the same concen-trations in the glomerular filtrate as in the plasma arecertain low-molecular-weight substances that wouldotherwise be filterable but are bound to plasma proteinsand therefore are not filtered. For example, half theplasma calcium and virtually all of the plasma fattyacids are bound to plasma protein and so are not filtered.

Forces Involved in Filtration As described in Chap-ter 14, filtration across capillaries is determined by op-posing forces: The hydrostatic pressure differenceacross the capillary wall favors filtration, while the pro-tein concentration difference across the wall creates anosmotic force that opposes filtration.

This also applies to the glomerular capillaries, assummarized in Figure 16–8. The pressure of the bloodin the glomerular capillaries—the glomerular capillaryhydrostatic pressure (PGC)—is a force favoring filtra-tion. The fluid in Bowman’s space exerts a hydrostaticpressure (PBS) that opposes this filtration. Another op-posing force is the osmotic force (�GC) that results fromthe presence of protein in the glomerular capillaryplasma. Recall that there is virtually no protein in thefiltrate in Bowman’s space. The unequal distributionof protein causes the water concentration of the plasmato be slightly less than that of the fluid in Bowman’sspace, and this difference in water concentration favorsfluid movement by bulk-flow from Bowman’s spaceinto the glomerular capillaries—that is, opposesglomerular filtration.

Note that in Figure 16–8 the value given for thisosmotic force—29 mmHg—is larger than the value—24 mmHg—for the osmotic force given in Chapter 14for plasma in all arteries and nonrenal capillaries. Thereason is that, unlike the situation elsewhere in thebody, so much water (about 20 percent of the plasmasupplying the kidneys) filters out of the glomerularcapillaries that the protein left behind in the plasmabecomes significantly more concentrated than in arte-rial plasma. In other capillaries, in contrast, so little wa-ter filters that the capillary protein concentration re-mains essentially unchanged from its value in arterialplasma. In other words, unlike the situation in othercapillaries, the plasma protein concentration and,hence, the osmotic force, increases from the beginningto the end of the glomerular capillaries. The valuegiven in Figure 16–8 for the osmotic force is the aver-age value along the length of the capillaries.

To summarize, the net glomerular filtration pres-sure is the sum of three relevant forces:

Net glomerular filtration pressure � PGC � PBS � �GC

Normally the net filtration pressure is always pos-itive because the glomerular capillary hydrostatic pres-sure is larger than the sum of the hydrostatic pressurein Bowman’s space and the osmotic force opposing fil-tration. The net glomerular filtration pressure initiatesurine formation by forcing an essentially protein-freefiltrate of plasma out of the glomeruli and into Bow-man’s space and thence down the tubule into the re-nal pelvis.






Rate of Glomerular Filtration The volume of fluidfiltered from the glomeruli into Bowman’s space perunit time is known as the glomerular filtration rate(GFR). GFR is determined not only by the net filtrationpressure but also by the permeability of the corpuscu-lar membranes and the surface area available for filtra-tion (see Chapter 14). In other words, at any given netfiltration pressure, the GFR will be directly proportionalto the membrane permeability and the surface area. Theglomerular capillaries are so much more permeable tofluid than, say muscle or skin capillaries, that the netglomerular filtration pressure causes massive filtration.In a 70-kg person, the GFR averages 180 L/day (125ml/min)! Contrast this number with the net filtrationof fluid across all the other capillaries in the body—4 L/day, as described in Chapter 14.

When we recall that the total volume of plasma inthe cardiovascular system is approximately 3 L, it fol-lows that the entire plasma volume is filtered by thekidneys about 60 times a day. This opportunity toprocess such huge volumes of plasma enables the kid-neys to regulate the constituents of the internal envi-ronment rapidly and to excrete large quantities ofwaste products.

It must be emphasized that the GFR is not a fixedvalue but is subject to physiological regulation. As weshall see, this is achieved mainly by neural and hor-monal input to the afferent and efferent arterioles,which results in changes in net glomerular filtrationpressure.

In this regard it must be emphasized that theglomerular capillaries are unique in that they are situ-ated between two sets of arterioles—the afferent andefferent arterioles. Constriction of the afferent arteri-oles alone has the same effect on the hydrostatic pres-sure in the glomerular capillaries (PGC) as does con-striction of arterioles anywhere in the body on thepressure in the capillaries supplied by those arterioles:Capillary pressure decreases because the increased ar-teriolar resistance causes a greater loss of pressure be-tween the arteries and the capillaries. In contrast, ef-ferent arteriolar constriction alone has precisely theopposite effect on PGC—it increases it. This occurs be-cause the efferent arteriole lies beyond the glomerulus,so that efferent-arteriolar constriction tends to “damback” the blood in the glomerular capillaries, raisingPGC. Finally, simultaneous constriction of both sets ofarterioles tends to leave PGC unchanged because of theopposing effects. The effects of arteriolar dilation arethe reverse of those described for constriction.

In addition to the neuroendocrine input to the ar-terioles, there is also input to the mesangial cells thatsurround the glomerular capillaries. Contraction ofthese cells reduces the surface area of the capillaries,which causes a decrease in GFR at any given net fil-tration pressure.

It is possible to measure the total amount of anynonprotein substance (assuming also that the sub-stance is not bound to protein) filtered into Bowman’sspace by multiplying the GFR by the plasma concen-tration of the substance. This amount is called the fil-tered load of the substance. For example, if the GFR is180 L/day and plasma glucose concentration is 1 g/L,then the filtered load of glucose is 180 L/day �1 g/L � 180 g/day.

Once we know the filtered load of the substance,we can compare it to the amount of the substance ex-creted and tell whether the substance undergoes nettubular reabsorption or net secretion. Whenever thequantity of a substance excreted in the urine is lessthan the filtered load, tubular reabsorption must haveoccurred. Conversely, if the amount excreted in theurine is greater than the filtered load, tubular secretionmust have occurred.

Tubular ReabsorptionTable 16–2, which summarizes data for a few plasmacomponents that undergo filtration and reabsorption,gives an idea of the magnitude and importance of


PGCGlomerularcapillary

PBS

πGC

Bowman’sspace

Forces

60

15

29

16

mmHg

Favoring filtration:

Glomerular capillary blood pressure (PGC)

Opposing filtration:

Fluid pressure in Bowman’s space (PBS)

Osmotic force due to protein in plasma (π GC)

Net glomerular filtration pressure = PGC – PBS – πGC

FIGURE 16–8Forces involved in glomerular filtration. The symbol �denotes the osmotic force due to the presence of protein inglomerular capillary plasma.





reabsorptive mechanisms. The values in this table aretypical for a normal person on an average diet. Thereare at least three important conclusions to be drawnfrom this table: (1) The filtered loads are enormous, gen-erally larger than the amounts of the substances in thebody. For example, the body contains about 40 L of wa-ter, but the volume of water filtered each day is, as wehave seen, 180 L. (2) Reabsorption of waste products isrelatively incomplete (for example, only 44 percent inthe case of urea) so that large fractions of their filteredloads are excreted in the urine. (3) Reabsorption of mostuseful plasma components (for example, water, inor-ganic ions, and organic nutrients) is relatively completeso that the amounts excreted in the urine represent verysmall fractions of their filtered loads.

In this last regard, an important distinction shouldbe made between reabsorptive processes that can becontrolled physiologically and those that cannot. Thereabsorption rates of most organic nutrients (for ex-ample, glucose) are always very high and are not phys-iologically regulated, and so the filtered loads of thesesubstances are normally completely reabsorbed, noneappearing in the urine. For these substances, like sub-stance Z in our earlier example, it is as though the kid-neys do not exist since the kidneys do not eliminatethese substances from the body at all. Therefore, thekidneys do not regulate the plasma concentrations ofthese organic nutrients—that is, they do not minimizechanges from normal plasma levels. Rather, the kid-neys merely maintain whatever plasma concentrationsalready exist. (As described in Chapter 18, these con-centrations are generally the result of hormonal regu-lation of nutrient metabolism.)

In contrast, the reabsorptive rates for water andmany ions, although also very high, are regulatable.Recall, for example, the situation given earlier in whicha person drinks a lot of water, which decreases tubu-lar water reabsorption and thereby leads to increasedwater excretion. The critical point is that the rates atwhich water and many inorganic ions are reabsorbed,

and therefore the rates at which they are excreted, aresubject to physiological control.

In contrast to glomerular filtration, the crucialsteps in tubular reabsorption—those that achievemovement of a substance from tubular lumen to in-terstitial fluid—do not occur by bulk flow (there areinadequate pressure differences across the tubule andpermeability of the tubular membranes). Instead, twoother processes are involved. (1) The reabsorption ofsome substances is by diffusion, often across the tightjunctions connecting the tubular epithelial cells (Fig-ure 16–9). (2) The reabsorption of all other substancesinvolves mediated transport, which requires the par-ticipation of transport proteins in the cell’s plasmamembranes.

Regardless of how a substance being reabsorbedgoes from the lumen to the interstitial fluid, the finalstep in reabsorption—movement from interstitial fluidinto the peritubular capillaries—is by a combinationof diffusion and bulk flow, the latter driven by the cap-illary Starling forces. We will not mention this finalstep again in our discussions of reabsorption, but sim-ply assume it occurs automatically once the substancereaches the interstitial fluid.


Basolateralmembrane

Interstitialfluid

Tight junction

Luminalmembrane

Peritubular capillary

Tubularlumen

Tubularepithelial

cell

FIGURE 16–9Diagrammatic representation of tubular epithelium. In thisand subsequent figures illustrating transport in this chapter,the basement membrane of the tubule—a homogeneousproteinaceous structure that plays no significant role intransport—will not be shown. (Do not confuse thebasement membrane with the basolateral membrane of thetubular cells, as illustrated in this and subsequent figures.)

Amount AmountFiltered Excreted Percent

Substance per Day per Day Reabsorbed

Water, L 180 1.8 99Sodium, g 630 3.2 99.5Glucose, g 180 0 100Urea, g 54 30 44

TABLE 16–2 Average Values for SeveralComponents That UndergoFiltration and Reabsorption





Reabsorption by Diffusion Urea reabsorption by theproximal tubule provides an example of passive reab-sorption by diffusion. An analysis of urea concentra-tions in the proximal tubule will help elucidate themechanism. Because the corpuscular membranes arefreely filterable to urea, the urea concentration in thefluid within Bowman’s space is the same as that in theperitubular-capillary plasma and the interstitial fluidsurrounding the tubule. Then, as the filtered fluidflows through the proximal tubule, water reabsorptionoccurs (by mechanisms to be described later). This re-moval of water increases the concentration of urea inthe tubular fluid above that in the interstitial fluid andperitubular capillaries. Therefore, urea diffuses downthis concentration gradient from tubular lumen to peri-tubular capillary. Urea reabsorption is thus dependentupon the reabsorption of water.

Reabsorption by diffusion in precisely this manneroccurs for a variety of lipid-soluble organic substances,both naturally occurring and foreign (the pesticideDDT, for example).

Reabsorption by Mediated Transport Figure 16–9highlights the fact that a substance reabsorbed by me-diated transport must first cross the luminal mem-brane separating the tubular lumen from the cell inte-rior, then diffuse through the cytosol of the cell, andfinally cross the basolateral membrane, which beginsat the tight junctions and constitutes the plasma mem-brane of the sides and base of the cell. This route istermed transcellular epithelial transport; its mecha-nisms were described in Chapter 6 and this material,particularly Figures 6–23 and 6–24, should be re-viewed at this time.

Note in those two figures that a substance need notbe actively transported across both the luminal and ba-solateral membranes in order to be actively trans-ported across the overall epithelium—that is, to movefrom lumen to interstitial fluid against its electro-chemical gradient. Thus, for example, sodium moves“downhill” (passively) into the cell across the luminalmembrane either by diffusion (see Figure 6–23) or byfacilitated diffusion (see Figure 6–24) and then moves“uphill” (actively) out of the cell across the basolateralmembrane via the Na,K-ATPase pumps in this mem-brane. If the movement across either the luminal mem-brane or the basolateral membrane is active, then theentire process will achieve active reabsorption acrossthe overall epithelium.

Figure 6–24 illustrates another important princi-ple that applies to tubular reabsorption: The reab-sorption of many substances is coupled to the reab-sorption of sodium. Note in this figure that substanceX moves uphill into the epithelial cell via a secondaryactive cotransporter as sodium moves downhill into

the cell via this same cotransporter. The high intracel-lular concentration of substance X created by this ac-tive transport then drives “downhill” movement of thesubstance across the basolateral membrane to com-plete the reabsorptive process. This is precisely howglucose, many amino acids, and other organic sub-stances undergo tubular reabsorption. The reabsorp-tion of several inorganic ions is also coupled in a va-riety of ways to the reabsorption of sodium.

Many of the mediated-transport reabsorptive sys-tems in the renal tubule have a limit, termed a trans-port maximum (Tm), to the amounts of material theycan transport per unit time. This is because the bindingsites on the membrane transport proteins become satu-rated. An important example is the secondary active-transport proteins for glucose, located in the proximaltubule and described in the previous paragraph. Asnoted earlier, normal persons do not excrete glucose intheir urine because all filtered glucose is reabsorbed. In-deed, even by eating an extremely carbohydrate-richmeal, normal persons cannot raise their plasma glucoseconcentrations high enough so that the filtered load ofglucose exceeds the renal glucose Tm. In contrast, in peo-ple with diabetes mellitus, a disease in which the hor-monal control of the plasma glucose concentration isdefective (Chapter 18), the plasma glucose concentra-tion can become so high that the filtered load of glu-cose exceeds the ability of the tubules to reabsorb glu-cose—that is, exceeds the glucose Tm—therefore,glucose appears in the urine (glucosuria). In otherwords, the kidneys’ ability to reabsorb glucose is nor-mal in diabetes, but the tubules cannot reabsorb themarkedly increased filtered load.

The pattern described for glucose is also true fora large number of other organic nutrients. For exam-ple, most amino acids and water-soluble vitamins arefiltered in large amounts each day, but almost all thesefiltered molecules are reabsorbed by the proximaltubule. If the plasma concentration becomes highenough, however, reabsorption of the filtered load willnot be as complete, and the substance will appear inlarger amounts in the urine. Thus, persons ingestingvery large quantities of vitamin C manifest progres-sive increases in their plasma concentrations of vita-min C until the filtered load exceeds the tubular reab-sorptive Tm for this substance, and any additionalingested vitamin C is excreted in the urine.

Tubular SecretionTubular secretion moves substances from peritubularcapillaries into the tubular lumen; like glomerular fil-tration, it constitutes a pathway into the tubule. Likereabsorption, secretion can occur by diffusion or bytranscellular mediated transport. The most importantsubstances secreted by the tubules are hydrogen ions






and potassium, but a large number of normally oc-curring organic anions, such as choline and creatinine,are also secreted. So are many foreign chemicals, suchas penicillin. Active secretion of a substance requiresactive transport either from the blood side (the inter-stitial fluid) into the cell (across the basolateral mem-brane) or out of the cell into the lumen (across the lu-minal membrane). Also as in reabsorption, tubularsecretion of certain substances is coupled in one wayor another to the reabsorption of sodium. We’ll de-scribe this later in the context of the secretion of potas-sium and hydrogen ions.

Metabolism by the TubulesWe noted earlier that, during fasting, the cells of therenal tubules synthesize glucose and add it to theblood. They can also synthesize certain substances, no-tably ammonium, which are then secreted into thefluid in the tubular lumen and excreted. Why the cellswould make something just to have it excreted will bemade clear when we discuss the role of ammonium inthe regulation of plasma hydrogen-ion concentration.Also, the cells can catabolize certain organic substances(peptides, for example) taken up from either the tu-bular lumen or peritubular capillaries. Catabolismeliminates these substances from the body as surely asif they had been excreted into the urine.

Regulation of Membrane Channels and TransportersWe emphasized earlier that tubular reabsorptionand/or secretion of many substances is under physio-logical control. For most of these substances, the con-trol is achieved by regulating the activity or concen-trations of the membrane proteins involved in theirtransport—channels and transporters. This regulationis achieved largely by hormones, neurotransmitters,and paracrine/autocrine agents.

Interestingly, the recent explosion of informationconcerning the structures, functions, and regulation ofrenal tubular-cell ion channels and transporters hasmade it possible to explain the underlying defects insome genetic diseases. For example, a genetic muta-tion can lead to an abnormality in the Na/glucosetransporter that mediates active reabsorption of glu-cose in the proximal tubule. This abnormality leads toinadequate glucose reabsorption and loss of glucose inthe urine at normal or even subnormal plasma con-centrations of glucose. Contrast this condition, termedfamilial renal glucosuria, to diabetes mellitus, inwhich the ability to reabsorb glucose is normal, but thefiltered load of glucose is greater than the maximalability of the tubules to reabsorb this sugar.

“Division of Labor” in the TubulesSeveral generalizations concerning tubular functionshould be kept in mind as you proceed through sub-sequent sections of this chapter, which deal with therenal handling of individual substances. As we haveseen, in order to excrete waste products adequately, theGFR must be very large. This, though, means that thefiltered volume of water and the filtered loads of allthe nonwaste low-molecular-weight plasma solutesare also very large. The primary role of the proximaltubule is to reabsorb much of this filtered water andsolutes. This segment has been called a “mass reab-sorber” since for every substance reabsorbed by thetubule, the proximal tubule does most of the reab-sorbing. Similarly, with one major exception (potas-sium) the proximal tubule is quantitatively the majorsite of solute secretion. Henle’s loop also reabsorbs rel-atively large quantities of the major ions and, to a lesserextent, water.

Extensive reabsorption by the proximal tubule andHenle’s loop ensures that the masses of solutes and thevolume of water entering the tubular segments beyondHenle’s loop are relatively small. These segments thendo the fine-tuning for most substances, determiningthe final amounts excreted in the urine by adjustingtheir rates of reabsorption and, in a few cases, secre-tion. It should not be surprising, therefore, that most(but not all) homeostatic controls are exerted on thesemore distal segments.

The Concept of Renal ClearanceA useful way of quantitating renal functions is in termsof clearance. The renal clearance of any substance isthe volume of plasma from which that substance is com-pletely removed (“cleared”) by the kidneys per unittime. Every substance has its own distinct clearancevalue, but the units are always in volume of plasmaper time. The basic clearance formula for any substanceS is

Clearance of S �

Thus, the clearance of a substance really answers thequestion: How much plasma had to be completelycleared of the substance to account for the mass of thesubstance excreted in the urine.

Since the mass of S excreted per unit time is equalto the urine concentration of S multiplied by the urinevolume during that time, the formula for the clearanceof S becomes

CS � �UPS

S

V�

Mass of S excreted per unit time��

Plasma concentration of S






where

CS � clearance of SUS � urine concentration of SV � urine volume per unit timePS � plasma concentration of S

Let us take the particularly important example ofa polysaccharide named inulin (not insulin). This sub-stance is an important research tool in renal physiol-ogy because, as will be described, its clearance is equalto the glomerular filtration rate. It is not found nor-mally in the body, but we will administer it intra-venously to a person at a rate sufficient to maintainplasma concentration constant at 4 mg/L. Urine col-lected over a 1-h period has a volume of 0.1 L and aninulin concentration of 300 mg/L; thus, inulin excre-tion equals 0.1 L/h � 300 mg/L, or 30 mg/h. Howmuch plasma had to be completely cleared of its in-ulin to supply this 30 mg/h? We simply divide 30mg/h by the plasma concentration, 4 mg/L, to obtainthe volume cleared—7.5 L/h. In other words, we arecalculating the inulin clearance (CIn) from the mea-sured urine volume per time (V), urine inulin concen-tration (UIn), and plasma inulin concentration (PIn):

CIn � �UPIn

In

V�

CIn �

CIn � 7.5 L/h

Now for the crucial points. From a variety of ex-periments, it is known that inulin is filterable at the re-nal corpuscle but is not reabsorbed, secreted, or me-tabolized by the tubule. Therefore, the mass of inulinexcreted in our experiment—30 mg/h—must be equalto the mass filtered over that same time period (Fig-ure 16–10). Accordingly, the clearance of inulin mustequal the volume of plasma originally filtered; that is,CIn is equal to GFR.

It is important to realize that the clearance of anysubstance handled by the kidneys in the same way asinulin—filtered, but not reabsorbed, secreted, or me-tabolized—would equal the GFR. Unfortunately, thereare no substances normally present in the plasma thatmeet these criteria. For clinical purposes, the creati-nine clearance (CCr) is commonly used to approximatethe GFR as follows. The waste product creatinine pro-duced by muscle is filtered at the renal corpuscle anddoes not undergo reabsorption. It does undergo a smallamount of secretion, however, so that some plasma iscleared of its creatinine by secretion. Accordingly, theCCr overestimates the GFR but is close enough to behighly useful.

This leads to an important generalization: Whenthe clearance of any substance is greater than the GFR,

300 mg/L � 0.1 L/h��

4 mg/L

as measured by the inulin clearance, that substancemust undergo tubular secretion. Look back now at ourhypothetical substance X (see Figure 16–7): X is fil-tered, and all the X that escapes filtration is secreted;no X is reabsorbed. Accordingly, all the plasma that en-ters the kidney per unit time is cleared of its X, andthe clearance of X is therefore a measure of renalplasma flow. A substance that is handled like X is theorganic anion para-amino-hippurate (PAH), which isused for this purpose (unfortunately, like inulin, itmust be administered intravenously).

A similar logic leads to another important gener-alization: When the clearance of a filterable substanceis less than the GFR, as measured by the inulin clear-ance, that substance must undergo reabsorption.

The remainder of this chapter describes how thekidneys function in the homeostasis of individual sub-stances and how renal function is coordinated withthat of other organs. Before turning to these individ-ual substances, however, we complete the generalstory by describing the mechanisms of eliminatingurine from the body—micturition.

MicturitionUrine flow through the ureters to the bladder is pro-pelled by contractions of the ureter-wall smooth mus-cle. The urine is stored in the bladder and intermit-tently ejected during urination, or micturition.


Concentrationof inulin inplasma = 4 mg/L

Glomerularcapillary

Bowman’sspace

Volume of fluid filtered (GFR)Concentration of inulin in filtrateTotal inulin filtered

= 7.5 L/h

= 4 mg/L= 30 mg/h

No reabsorption of inulinNo secretion of inulin

Total inulin excreted = 30 mg/h

FIGURE 16–10Example of renal handling of inulin, a substance that isfiltered by the renal corpuscles but is neither reabsorbed norsecreted by the tubule. Therefore, the mass of inulinexcreted per unit time is equal to the mass filtered duringthe same time period, and as explained in the text, theclearance of inulin is equal to the glomerular filtration rate.





The bladder is a balloon-like chamber with wallsof smooth muscle collectively termed the detrusormuscle. The contraction of the detrusor musclesqueezes on the urine in the bladder lumen to produceurination. That part of the detrusor muscle at the base(or “neck”) of the bladder where the urethra beginsfunctions as a sphincter called the internal urethralsphincter. Just below the internal urethral sphincter, aring of skeletal muscle surrounds the urethra. This isthe external urethral sphincter, the contraction ofwhich can prevent urination even when the detrusormuscle contracts strongly.

What factors influence these bladder structures(Figure 16–11)? (1) The detrusor muscle is innervatedby parasympathetic neurons, which cause muscularcontraction. Because of the arrangement of the smooth-muscle fibers, when the detrusor muscle is relaxed, theinternal urethral sphincter is closed; when the detru-sor muscle contracts, changes in its shape tend to pullopen the internal urethral sphincter. (2) In addition, theinternal sphincter receives sympathetic innervation,which causes contraction of the sphincter. (3) The ex-ternal urethral sphincter, being skeletal muscle, is in-nervated by somatic motor neurons, which cause con-traction.

As might be predicted from these inputs, while thebladder is filling, there is little parasympathetic inputto the detrusor muscle but strong sympathetic input tothe internal urethral sphincter and strong input by thesomatic motor neurons to the external urethral sphinc-ter. Therefore, the detrusor muscle is relaxed, and thesphincters are closed.

What happens during micturition? As the bladderfills with urine, the pressure within it increases, and

this stimulates stretch receptors in the bladder wall.The afferent fibers from these receptors enter the spinalcord and stimulate the parasympathetic neurons, whichthen cause the detrusor muscle to contract. As notedabove, this contraction facilitates the opening of the in-ternal urethral sphincter. Simultaneously, the afferentinput from the stretch receptors reflexly inhibits thesympathetic neurons to the internal urethral sphincter,which further contributes to its opening. In addition,the afferent input also reflexly inhibits the somatic mo-tor neurons to the external urethral sphincter, causingit to relax. Both sphincters are now open, and the con-traction of the detrusor muscle is able to produce uri-nation.

We have thus far described micturition as a localspinal reflex, but descending pathways from the braincan also profoundly influence this reflex, determiningthe ability to prevent or initiate micturition voluntar-ily. Loss of these descending pathways as a result ofspinal-cord damage eliminates one’s ability to volun-tarily control micturition. Prevention of micturition,learned during childhood, operates in the followingway. As the bladder distends, the input from the blad-der stretch receptors causes, via ascending pathwaysto the brain, a sense of bladder fullness and the urgeto urinate. But in response to this, urination can be vol-untarily prevented by activating descending pathwaysthat stimulate both the sympathetic nerves to the in-ternal urethral sphincter and the somatic motor nervesto the external urethral sphincter.

In contrast, urination can be voluntarily initiatedvia the descending pathways to the appropriate neurons.


MuscleBladder Innervation

Type Duringfilling

Duringmicturition

Detrusor(smooth muscle)

Internal urethralsphincter(smooth muscle)

External urethralsphincter(skeletal muscle)

Parasympathetic(causescontraction)

Sympathetic(causescontraction)

Somatic motor(causescontraction)

Inhibited

Stimulated

Stimulated

Stimulated

Inhibited

Inhibited

FIGURE 16–11Control of the bladder.





Functions and Structure of the Kidneysand Urinary System

I. The kidneys regulate the water and ioniccomposition of the body, excrete waste products,excrete foreign chemicals, produce glucose duringprolonged fasting, and secrete three hormones—renin, 1,25-dihydroxyvitamin D3, and erythropoietin.The first three functions are accomplished bycontinuous processing of the plasma.

II. Each nephron in the kidneys consists of a renalcorpuscle and a tubule.a. Each renal corpuscle comprises a capillary tuft,

termed a glomerulus, and a Bowman’s capsule,into which the tuft protrudes.

b. The tubule extends out from Bowman’s capsuleand is subdivided into many segments, which canbe combined for reference purposes into theproximal tubule, loop of Henle, distal convolutedtubule, and collecting-duct system. At the level ofthe collecting ducts, multiple tubules join andempty into the renal pelvis, from which urineflows through the ureters to the bladder.

c. Each glomerulus is supplied by an afferentarteriole, and an efferent arteriole leaves theglomerulus to branch into peritubular capillaries,which supply the tubule.

Basic Renal ProcessesI. The three basic renal processes are glomerular

filtration, tubular reabsorption, and tubular secretion.In addition, the kidneys synthesize and/or catabolizecertain substances. The excretion of a substance isequal to the amount filtered plus the amountsecreted minus the amount reabsorbed.

II. Urine formation begins with glomerular filtration—approximately 180 L/day—of essentially protein-freeplasma into Bowman’s space.a. Glomerular filtrate contains all plasma substances

other than proteins (and substances bound toproteins) in virtually the same concentrations asin plasma.

b. Glomerular filtration is driven by the hydrostaticpressure in the glomerular capillaries and isopposed by both the hydrostatic pressure inBowman’s space and the osmotic force due to theproteins in the glomerular capillary plasma.

III. As the filtrate moves through the tubules, certainsubstances are reabsorbed either by diffusion ormediated transport.a. Substances to which the tubular epithelium is

permeable are reabsorbed by diffusion becausewater reabsorption creates tubule-interstitiumconcentration gradients for them.

b. Active reabsorption of a substance requires theparticipation of transporters in the luminal orbasolateral membrane.

c. Tubular reabsorption rates are generally very highfor nutrients, ions, and water, but are lower forwaste products.

S E C T I O N A S U M M A R Yd. Many of the mediated-transport systems manifest

transport maximums, so that when the filteredload of a substance exceeds the transportmaximum, large amounts may appear in theurine.

IV. Tubular secretion, like glomerular filtration, is apathway for entrance of a substance into the tubule.

The Concept of Renal ClearanceI. The clearance of any substance can be calculated by

dividing the mass of the substance excreted per unittime by the plasma concentration of the substance.

II. GFR can be measured by means of the inulinclearance and estimated by means of the creatinineclearance.

MicturitionI. In the basic micturition reflex, bladder distention

stimulates stretch receptors that trigger spinalreflexes; these reflexes lead to contraction of thedetrusor muscle, mediated by parasympatheticneurons, and relaxation of both the internal and theexternal urethral sphincters, mediated by inhibitionof the neurons to these muscles.

II. Voluntary control is exerted via descendingpathways to the parasympathetic nerves supplyingthe detrusor muscle, the sympathetic nervessupplying the internal urethral sphincter, and themotor nerves supplying the external urethralsphincter.

renal renal pelvisurea renal cortexuric acid renal medullacreatinine peritubular capillariesgluconeogenesis macula densaureter juxtaglomerular (JG) cellsbladder juxtaglomerular apparatusurethra (JGA)nephron glomerular filtrationrenal corpuscle glomerular filtratetubule tubular reabsorptionglomerulus tubular secretionglomerular capillaries net glomerular filtrationafferent arteriole pressureBowman’s capsule glomerular filtration rateefferent arteriole (GFR)Bowman’s space filtered loadpodocyte luminal membranemesangial cells basolateral membraneproximal tubule transport maximum (Tm)loop of Henle clearancedescending limb inulinascending limb creatinine clearancedistal convoluted tubule micturitioncollecting duct system detrusor musclecortical collecting duct internal urethral sphinctermedullary collecting duct external urethral sphincter

S E C T I O N A K E Y T E R M S






_

1. What are the functions of the kidneys?2. What three hormones do the kidneys secrete?3. Fluid flows in sequence through what structures

from the glomerulus to the bladder? Blood flowsthrough what structures from the renal artery to therenal vein?

4. What are the three basic renal processes that lead tothe formation of urine?

S E C T I O N A R E V I E W Q U E S T I O N S5. How does the composition of the glomerular filtrate

compare with that of plasma?6. Describe the forces that determine the magnitude of

the GFR. What is a normal value of GFR?7. Contrast the mechanisms of reabsorption for glucose

and urea. Which one shows a Tm?8. Diagram the sequence of events leading to

micturition in infants and in adults.


R E G U L A T I O N O F S O D I U M , W A T E R , A N D P O T A S S I U M B A L A N C E

S E C T I O N B

Total-Body Balance of Sodium and WaterTable 16 – 3 summarizes total-body water balance.These are average values, which are subject to consid-erable normal variation. There are two sources of bodywater gain: (1) water produced from the oxidation oforganic nutrients, and (2) water ingested in liquids andso-called solid food (a rare steak is approximately 70percent water). There are four sites from which wateris lost to the external environment: skin, respiratorypassageways, gastrointestinal tract, and urinary tract.Menstrual flow constitutes a fifth potential source ofwater loss in women.

The loss of water by evaporation from the skin andthe lining of respiratory passageways is a continuousprocess. It is called insensible water loss because the

person is unaware of its occurrence. Additional watercan be made available for evaporation from the skinby the production of sweat. Normal gastrointestinalloss of water in feces is generally quite small, but canbe severe in diarrhea. Gastrointestinal loss can also belarge in vomiting.

Table 16–4 is a summary of total-body balance forsodium chloride. The excretion of sodium and chloridevia the skin and gastrointestinal tract is normally quitesmall but may increase markedly during severe sweat-ing, vomiting, or diarrhea. Hemorrhage can also resultin loss of large quantities of both salt and water.

Under normal conditions, as can be seen from Tables 16–3 and 16–4, salt and water losses exactlyequal salt and water gains, and no net change in bodysalt and water occurs. This matching of losses andgains is primarily the result of regulation of urinaryloss, which can be varied over an extremely widerange. For example, urinary water excretion can vary from approximately 0.4 L/day to 25 L/day, TABLE 16–3 Average Daily Water Gain and

Loss in Adults

IntakeIn liquids 1200 mlIn food 1000 mlMetabolically produced 350 ml

Total 2550 ml

OutputInsensible loss (skin and lungs) 900 mlSweat 50 mlIn feces 100 mlUrine 1500 ml

Total 2550 ml

TABLE 16–4 Daily Sodium Chloride Intake andLoss

IntakeFood 10.50 g

OutputSweat 0.25 gFeces 0.25 gUrine 10.00 g

Total 10.50 g





depending upon whether one is lost in the desert orparticipating in a beer-drinking contest. Similarly,some individuals ingest 20 to 25 g of sodium chlorideper day, whereas a person on a low-salt diet may in-gest only 0.05 g; normal kidneys can readily alter theirexcretion of salt over this range to match loss with gain.

We will first present the basic renal processes forsodium and water and then describe the homeostaticreflexes that influence these processes. The renal pro-cessing of chloride is usually coupled directly or indi-rectly to that of sodium, and so we shall have littlemore to say about chloride even though it is the mostabundant anion in the extracellular fluid.

Basic Renal Processes for Sodium and WaterHaving low molecular weights and not being boundto protein, both sodium and water freely filter from theglomerular capillaries into Bowman’s space. They bothundergo considerable reabsorption—normally morethan 99 percent (see Table 16–2)—but no secretion.Most renal energy utilization goes to accomplish thisenormous reabsorptive task. The bulk of sodium andwater reabsorption (about two-thirds) occurs in theproximal tubule, but the major hormonal controls ofreabsorption are exerted on the collecting ducts.

The mechanisms of sodium and water reabsorp-tion can be summarized by two generalizations: (1)Sodium reabsorption is an active process occurring inall tubular segments except the descending limb of theloop of Henle; and (2) water reabsorption is by diffu-sion and is dependent upon sodium reabsorption.

Primary Active Sodium ReabsorptionThe essential feature underlying sodium reabsorptionthroughout the tubule is the primary active transport ofsodium out of the cells and into the interstitial fluid,as illustrated for the cortical collecting duct in Figure16–12. This transport is achieved by Na,K-ATPasepumps in the basolateral membrane of the cells. Theactive transport of sodium out of the cell keeps the in-tracellular concentration of sodium low compared tothe luminal concentration, and so sodium moves“downhill” out of the lumen into the tubular epithe-lial cells. (The fact that the cell interior is negativelycharged relative to the lumen also contributes to theelectrochemical gradient favoring this movement fromlumen to cell.)

The precise mechanism of the downhill sodiummovement across the luminal membrane into the cellvaries from segment to segment of the tubule de-pending upon which channels and/or transport pro-teins are present in their luminal membranes. For

example, as illustrated in Figure 16–12, the luminal en-try step for sodium in the cortical collecting duct is bydiffusion through sodium channels. To take anotherexample, in the proximal tubule the luminal entry stepis either by cotransport with a variety of organic mol-ecules (glucose, for example) or by countertransportwith hydrogen ions (that is, the hydrogen ions movefrom cell to lumen as the sodium moves into the cell).In this manner, in the proximal tubule sodium reab-sorption drives the reabsorption of the cotransportedsubstances and the secretion of hydrogen ions.

While the movement of sodium downhill fromlumen into cell across the luminal membrane varies fromone segment of the tubule to another, the basolateralmembrane step is the same in all sodium-reabsorbingtubular segments—the primary active transport ofsodium out of the cell is via Na,K-ATPase pumps inthis membrane. It is this transport process that lowersintracellular sodium concentration and so makes pos-sible the downhill luminal entry step, whatever itsmechanism.

Coupling of Water Reabsorption to Sodium ReabsorptionHow does active sodium reabsorption lead to passivewater reabsorption? This type of coupling was de-scribed in Chapter 6 (see Figure 6-25) and is summa-rized again in Figure 16–13. (1) Sodium (and other


Cortical collectingduct cells

Tightjunction

Luminalmembrane

Tubularlumen

ADP

K+

Na+

K+

Na+ Na+

Basolateralmembrane

Interstitialfluid

Sodiumchannel

(Diffusion)

ATPPotassiumchannel

K+

FIGURE 16–12Mechanism of sodium reabsorption in the cortical collectingduct. Movement of the reabsorbed sodium from theinterstitial fluid into peritubular capillaries is shown in Figure16–13. The sizes of the letters for Na� and K� denote highand low concentrations of these ions. The fate of thepotassium ions transported by the Na,K-ATPase pumps isdiscussed in the later section dealing with renal potassiumhandling.





solutes whose reabsorption is dependent on sodiumtransport—for example, glucose, amino acids, and bi-carbonate) is transported from the tubular lumen tothe interstitial fluid across the epithelial cells, as de-scribed in the previous section. (2) This removal ofsolute lowers the osmolarity (that is, raises the waterconcentration) of the tubular fluid. It simultaneouslyraises the osmolarity (that is, lowers the water concen-tration) of the interstitial fluid adjacent to the epithe-lial cells. (3) The difference in water concentration be-tween lumen and interstitial fluid causes net diffusionof water from the lumen across the tubular cells’plasma membranes and/or tight junctions into the in-terstitial fluid. (4) From there, water, sodium, andeverything else dissolved in the interstitial fluid movetogether by bulk flow into peritubular capillaries as thefinal step in reabsorption.

Water movement across the tubular epithelium canoccur, however, only if the epithelium is permeable towater. No matter how large its concentration gradient,water cannot cross an epithelium impermeable to it.Water permeability varies from tubular segment to seg-ment and depends largely on the presence of waterchannels, termed aquaporins, in the plasma mem-branes (Chapter 6). The water permeability of the prox-imal tubule is always very high, and so water mole-cules are reabsorbed by this segment almost as rapidlyas sodium ions. As a result, the proximal tubule alwaysreabsorbs sodium and water in the same proportions.

We will describe the water permeability of the nexttubular segments—the loop of Henle and distal con-voluted tubule—later. Now for the really crucial point:The water permeability of the last portions of the

tubules, the cortical and medullary collecting ducts,can be high or low because it is subject to physiologi-cal control, the only tubular segments in which waterpermeability is under such control.

The major determinant of this controlled perme-ability, and hence of water reabsorption in the collect-ing ducts, is a peptide hormone secreted by the poste-rior pituitary and known as vasopressin, or antidiuretichormone, ADH. Vasopressin stimulates the insertioninto the luminal membrane, by exocytosis, of a partic-ular group of aquaporin water channels made by thecollecting-duct cells. Accordingly, in the presence of ahigh plasma concentration of vasopressin, the waterpermeability of the collecting ducts becomes very great.Therefore, water reabsorption is maximal, and the finalurine volume is small—less than 1 percent of the fil-tered water.

Without vasopressin, the water permeability of thecollecting ducts is extremely low, and very little wateris reabsorbed from these sites. Therefore, a large vol-ume of water remains behind in the tubule to be ex-creted in the urine. This increased urine excretion re-sulting from low vasopressin is termed water diuresis(diuresis simply means a large urine flow from anycause). In a subsequent section, we will describe thereflexes that control vasopressin secretion.

The disease diabetes insipidus, which is distinctfrom the other kind of diabetes mentioned earlier inthis chapter (diabetes mellitus or “sugar diabetes”), il-lustrates what happens when the vasopressin systemmalfunctions. Most people with this disease have lostthe ability to produce vasopressin, usually as a resultof damage to the hypothalamus. Thus, the permeabil-ity to water of the collecting ducts is low and un-changing regardless of the state of the body fluids.Therefore a constant water diuresis is present—asmuch as 25 L/day.

Note that in water diuresis, there is an increasedurine flow, but not an increased solute excretion. In allother cases of diuresis, termed osmotic diuresis, theincreased urine flow is the result of a primary increasein solute excretion. For example, failure of normalsodium reabsorption causes both increased sodium ex-cretion and increased water excretion, since, as wehave seen, water reabsorption is absolutely dependenton solute reabsorption. Another example of osmotic di-uresis occurs in people with uncontrolled, marked di-abetes mellitus: In this case, the glucose that escapes re-absorption because of the huge filtered load retainswater in the lumen, causing it to be excreted along withthe glucose. We’ll talk more about the consequences ofthis in Chapter 18.

To summarize, any loss of solute in the urine mustbe accompanied by water loss (osmotic diuresis), butthe reverse is not true; that is, water diuresis is not ac-companied by equivalent solute loss.


1

2

3

Osmolarity

Na+

H2O(Osmosis)

Osmolarity

H2O

Na+

K+

Tubularlumen

Tubularepithelial

cells

Interstitialfluid

Peritubularcapillaries

4Bulkflow

(Downhill)

ADP

ATP

FIGURE 16–13Coupling of water and sodium reabsorption. See text forexplanation of numbers. The reabsorption of solutes otherthan sodium—for example, glucose, amino acids, andbicarbonate—also contributes to the difference in osmolaritybetween lumen and interstitial fluid, but the reabsorption ofall these substances is ultimately dependent on direct orindirect cotransport and countertransport with sodium;therefore, they are not shown in the figure.





Urine Concentration: The CountercurrentMultiplier SystemBefore reading this section you should review, bylooking up in the glossary, several terms presented inChapter 6—hypoosmotic, isoosmotic, and hyperos-motic.

In the section just concluded, we described howthe kidneys produce a small volume of urine when theplasma concentration of vasopressin is high. Underthese conditions, the urine is concentrated (hyperos-motic) relative to plasma. This section describes themechanisms by which this hyperosmolarity is achieved.

The ability of the kidneys to produce hyperosmoticurine is a major determinant of one’s ability to survivewith limited amounts of water. The human kidney can produce a maximal urinary concentration of 1400 mOsmol/L, almost five times the osmolarity ofplasma, which is 290 mOsmol/L (for ease of calcula-tion, we shall round this off to 300 mOsmol/L in fu-ture discussions). The typical daily excretion of urea,sulfate, phosphate, other waste products, and ionsamounts to approximately 600 mOsmol. Therefore, theminimal volume of urine water in which this mass ofsolute can be dissolved equals

� 0.444 L/day

This volume of urine is known as the obligatory wa-ter loss. The loss of this minimal volume of urine (itwould be somewhat lower if no food were available)contributes to dehydration when a person is deprivedof water intake.

Urinary concentration takes place as tubular fluidflows through the medullary collecting ducts. The in-terstitial fluid surrounding these ducts is very hyper-osmotic, and in the presence of vasopressin, water dif-fuses out of the ducts into the interstitial fluid of themedulla and then enters the blood vessels of themedulla to be carried away. The key question is: Howdoes the medullary interstitial fluid become hyperos-motic? The answer is: through the function of Henle’sloop. Recall that Henle’s loop forms a hairpin-like loopbetween the proximal tubule and the distal convolutedtubule (see Figure 16–2). The fluid entering the loopfrom the proximal tubule flows down the descendinglimb, turns the corner, and then flows up the ascend-ing limb. The opposing flows in the two limbs istermed a countercurrent flow, and as described next,the entire loop functions as a countercurrent multi-plier system to create a hyperosmotic medullary in-terstitial fluid.

Because the proximal tubule always reabsorbssodium and water in the same proportions, the fluidentering the descending limb of the loop from theproximal tubule has the same osmolarity as plasma—

600 mOsmol/day��1400 mOsmol/L

300 mOsmol/L. For the moment, let’s skip the de-scending limb since the events in it can only be un-derstood in the context of what the ascending limb isdoing. Along the entire length of the ascending limb,sodium and chloride are reabsorbed into themedullary interstitial fluid. In the upper (thick) por-tion of the ascending limb, this reabsorption isachieved by transporters that actively cotransportsodium and chloride (as well as potassium, which weshall ignore). Such transporters are not present in thelower (thin) portion of the ascending limb, and the re-absorption there is a passive process. For simplicity,however, we shall treat the entire ascending limb as a homogeneous structure that actively reabsorbssodium and chloride.

Very importantly, the ascending limb is relativelyimpermeable to water, so that little water follows thesalt. The net result is that the interstitial fluid of themedulla becomes hyperosmotic compared to the fluidin the ascending limb.


300 200

200300

400

400

Proximal Distal

NaCl

NaCl

Now back to the descending limb. This segment, incontrast to the ascending limb, does not reabsorbsodium chloride and is highly permeable to water.Therefore, there is a net diffusion of water out of thedescending limb into the more concentrated intersti-tial fluid until the osmolarities inside this limb and inthe interstitial fluid are again equal. The interstitial hy-perosmolarity is maintained during this equilibrationbecause the ascending limb continues to pump sodiumchloride to maintain the concentration difference be-tween it and the interstitial fluid.

400 200

200400

400

400

NaCl

NaClH2O

H2O





Thus, because of diffusion of water the osmolari-ties of the descending limb and interstitial fluid be-come equal, and both are higher—by 200 mOsmol/Lin our example—than that of the ascending limb. Thisis the essence of the system: The loop countercurrentmultiplier causes the interstitial fluid of the medullato become concentrated. It is this hyperosmolarity thatwill draw water out of the collecting ducts and con-centrate the urine. However, one more crucialfeature—the “multiplication”—must be considered.

So far we have been analyzing this system asthough the flow through the loop of Henle stoppedwhile the ion pumping and water diffusion were oc-curring. This is not true, so let us see what happenswhen we allow flow in the system: As shown in theloop portion of Figure 16–14, the osmolarity differ-ence—200 mOsmol/L—that exists at each horizontallevel is “multiplied” to a much higher value—1400mOsmol/L—at the bend in the loop. It should be

emphasized that the active sodium chloride transportmechanism in the ascending limb (coupled with lowwater permeability in this segment) is the essentialcomponent of the system. Without it, the countercur-rent flow would have no effect whatever on loop andmedullary interstitial osmolarity, which would simplyremain 300 mOsmol/L throughout.

Now we have our concentrated medullary inter-stitial fluid, but we must still follow the fluid within thetubules from the loop of Henle through the distal con-voluted tubule and into the collecting-duct system, us-ing Figure 16–14 as our guide. As we have seen, thecountercurrent multiplier system concentrates the descending-loop fluid, but then lowers the osmolarityin the ascending loop so that the fluid entering the dis-tal convoluted tubule is actually more dilute (hypoos-motic)—100 mOsmol/L in Figure 16–14—than theplasma. The fluid becomes even more dilute during itspassage through the distal convoluted tubule, sincethis tubular segment, like the ascending loop, activelytransports sodium and chloride out of the tubule butis relatively impermeable to water. This hypoosmoticfluid then enters the cortical collecting duct.

As noted earlier, vasopressin increases tubular per-meability to water in both the cortical and medullarycollecting ducts. In contrast vasopressin does not in-fluence water reabsorption in the parts of the tubuleprior to the collecting ducts, and so, regardless of theplasma concentration of this hormone, the fluid enter-ing the cortical collecting duct is always hypoosmotic.From there on, however, vasopressin is crucial. In thepresence of high levels of vasopressin, water reab-sorption occurs by diffusion from the hypoosmoticfluid in the cortical collecting duct until the fluid in thissegment becomes isoosmotic to plasma in the peri-tubular capillaries of the cortex—that is, until it is onceagain at 300 mOsmol/L.

The isoosmotic tubular fluid then enters and flowsthrough the medullary collecting ducts. In the presenceof high plasma concentrations of vasopressin, waterdiffuses out of the ducts into the medullary interstitialfluid as a result of the high osmolarity set up there bythe loop countercurrent multiplier system. This waterthen enters the medullary capillaries and is carried outof the kidneys by the venous blood. Water reabsorp-tion occurs all along the lengths of the medullary col-lecting ducts so that, in the presence of vasopressin,the fluid at the end of these ducts has essentially thesame osmolarity as the interstitial fluid surroundingthe bend in the loops—that is, at the bottom of themedulla. By this means, the final urine is hyperos-motic. By retaining as much water as possible, the kid-neys minimize the rate at which dehydration occursduring water deprivation.


300

600

Descendinglimb

NaCl

NaCl

100 80

= Active transport

= DiffusionNaCl

NaCl

NaCl

H2O

Corticalcollectingduct

Distal convolutedtubule

NaCl300

600

300 300H2O

H2O

H2O

100

400 Ascendinglimb

NaCl

900 900700H2O

900

H2O

H2ONaCl

NaCl

H2O

H2O

10001200 1200 1200

1400 1400 1400

Medullarycollectingduct

H2O

FIGURE 16–14Generation of an interstitial fluid osmolarity gradient by therenal countercurrent multiplier system and its role in theformation of hyperosmotic urine. The transporter in theascending limb of Henle’s loop is actually a Na,K,2Clcotransporter, but for simplicity we do not include thepotassium since this ion does not contribute to themultiplier effect. Another simplification, as discussed in thetext, is that the entire ascending limb is shown as activelytransporting sodium chloride, whereas this is actually trueonly for the thick (upper) portion of the ascending limb.





In contrast, as we saw earlier, when plasma vaso-pressin concentration is low, both the cortical andmedullary collecting ducts are relatively impermeableto water. As a result, a large volume of hypoosmoticurine is excreted, thereby eliminating an excess of wa-ter in the body.

In describing how the countercurrent gradient iscreated, we have presented only the absolutely essen-tial components, namely the interactions betweensodium, chloride, and water. The story is actually morecomplex and not fully understood, but includes at leastone important role for urea in determining the maxi-mal urine concentration attainable. It also includes aunique function of the medullary circulation, to whichwe now turn.

The Medullary Circulation A major problem withthe countercurrent system as described above is this:Why doesn’t the blood flowing through medullarycapillaries eliminate the countercurrent gradient set upby the loops of Henle? One would think that as plasmahaving the usual osmolarity of 300 mOsm/L enters thehighly concentrated environment of the medulla, therewould be massive net diffusion of sodium and chlo-ride into the capillaries and water out of them, and

thus the interstitial gradient would be “washedaway.” However, the solution to this problem is as fol-lows. The blood vessels in the medulla—termed vasarecta—form hairpin loops that run parallel to theloops of Henle and medullary collecting ducts. Asshown in Figure 16–15, blood enters the top of thevessel loop at an osmolarity of 300 mOsm/L, and asthe blood flows down the loop deeper and deeper intothe medulla, sodium and chloride do indeed diffuseinto, and water out of, the vessel. However, after thebend in the loop is reached, the blood then flows upthe ascending vessel loop, where the process is almostcompletely reversed. Thus, the hairpin-loop structureof the vasa recta minimizes excessive loss of solutefrom the interstitium by diffusion. At the same time,both the salt and water being reabsorbed from theloops of Henle and collecting ducts are carried awayin equivalent amounts by bulk-flow, as determined bythe usual capillary Starling forces, and the steady-statecountercurrent gradient set up by the loops of Henleis maintained.

Renal Sodium RegulationNow we turn to the reflexes that act upon the basic re-nal processes for sodium and, in the next section, wa-ter to regulate their excretion. In normal individuals,urinary sodium excretion is reflexly increased whenthere is a sodium excess in the body and reflexly de-creased when there is a sodium deficit. These reflexesare so precise that total-body sodium normally variesby only a few percent despite a wide range of sodiumintakes and the sporadic occurrence of large losses viathe skin and gastrointestinal tract.

As we have seen, sodium is freely filterable fromthe glomerular capillaries into Bowman’s space and isactively reabsorbed, but not secreted. Therefore:

Sodium excreted � Sodium filtered � Sodium reabsorbed

The body can reflexly adjust sodium excretion bychanging both processes on the right of the equation.Thus, for example, when total-body sodium decreasesfor any reason, sodium excretion is reflexly decreasedbelow normal levels by lowering the GFR and simul-taneously raising sodium reabsorption. Under mostphysiological conditions, however, the reflexly in-duced changes in GFR are relatively small, and sodiumreabsorption is the major controlled process.

Our first problem in understanding the reflexescontrolling sodium reabsorption is to determine whatinputs initiate them; that is, what variables are actu-ally being sensed by receptors? It may come as a sur-prise, but there are no important receptors capable ofdetecting either sodium concentration or the totalamount of sodium in the body. Rather, the reflexes that


300

350

425

575

725

875

1025

1200

1200

1075

925

775

625

475

325

375

450

600

750

900

1050

1200

Descendinglimb of vasa recta

Ascendinglimb of vasa recta

H2OSolutes(mainly Na+

and Cl–)

Interstitial fluid

FIGURE 16–15Function of the vasa recta. All movements of water andsolutes are by diffusion. Not shown is the simultaneouslyoccurring uptake of interstitial fluid by bulk-flow.





regulate urinary sodium excretion are initiated mainlyby various cardiovascular baroreceptors, such as thecarotid sinus.

As described in Chapter 14, baroreceptors respondto pressure changes within the cardiovascular systemand initiate reflexes that rapidly regulate these pres-sures by acting on the heart, arterioles, and veins. Thenew information in this chapter is that regulation of car-diovascular pressures by baroreceptors also simultaneouslyachieves regulation of total-body sodium.

Because sodium is the major extracellular solute(constituting, along with associated anions, approxi-mately 90 percent of these solutes), changes in total-body sodium result in similar changes in extracellularvolume. Since extracellular volume comprises plasmavolume and interstitial volume, plasma volume is alsopositively related to total-body sodium. We saw inChapter 14 that plasma volume is an important deter-minant of, in sequence, the blood pressures in theveins, cardiac chambers, and arteries. Thus, the chainlinking total-body sodium to cardiovascular pressuresis completed: Low total-body sodium leads to lowplasma volume, which leads to low cardiovascularpressures, which, via baroreceptors, initiate reflexesthat influence the renal arterioles and tubules so as tolower GFR and increase sodium reabsorption. Theselatter events decrease sodium excretion, thereby re-taining sodium in the body and preventing further de-creases in plasma volume and cardiovascular pres-sures. Increases in total-body sodium have the reversereflex effects.

To summarize, the amount of sodium in the bodydetermines the extracellular fluid volume, the plasmavolume component of which helps determine cardio-vascular pressures, which initiate the reflexes that con-trol sodium excretion.

Control of GFRFigure 16–16 summarizes the major mechanisms bywhich a lower total-body sodium, as caused by diar-rhea, for example, elicits a decrease in GFR. The maindirect cause of the reduced GFR—a reduced netglomerular filtration pressure—occurs both as a con-sequence of a lowered arterial pressure in the kidneysand, more importantly, as a result of reflexes acting onthe renal arterioles. Note that these reflexes are simplythe basic baroreceptor reflexes described in Chapter 14,where it was pointed out that a decrease in cardio-vascular pressures causes neurally mediated reflexvasoconstriction in many areas of the body. As we shallsee later, the hormones angiotensin II and vasopressinalso participate in this renal vasoconstrictor response.

Conversely, an increased GFR is reflexly elicitedby neuroendocrine inputs when an increased total-body sodium level causes increased plasma volume.

This increased GFR contributes to the increased renalsodium loss that returns extracellular volume to normal.

Control of Sodium ReabsorptionFor long-term regulation of sodium excretion, the con-trol of sodium reabsorption is more important than the control of GFR. The major factor determining therate of tubular sodium reabsorption is the hormone aldosterone.

Aldosterone and the Renin-Angiotensin SystemThe adrenal cortex produces a steroid hormone, al-dosterone, which stimulates sodium reabsorption bythe cortical collecting ducts. An action on this late por-tion of the tubule is just what one would expect for afine-tuning input since most of the filtered sodium hasbeen reabsorbed by the time the filtrate reaches the collecting-duct system. When aldosterone is com-pletely absent, approximately 2 percent of the filteredsodium (equivalent to 35 g of sodium chloride per day)is not reabsorbed but is excreted. In contrast, when theplasma concentration of aldosterone is high, essen-tially all the sodium reaching the cortical collectingducts is reabsorbed. In a normal person, the plasmaconcentration of aldosterone and the amount ofsodium excreted lie somewhere between these ex-tremes.

Aldosterone, like other steroids, acts by inducingthe synthesis of proteins in its target cells; in the caseof the cortical collecting ducts, the proteins participatein sodium transport. Look again at Figure 16–12; al-dosterone induces the synthesis of all the channels andpumps shown in this figure. (By this same mechanism,aldosterone also stimulates sodium absorption fromthe lumens of both the large intestine and the ductscarrying fluid from the sweat glands and salivaryglands. In this manner, less sodium is lost in the fecesand from the surface of the skin in sweat.)

When a person is eating a lot of sodium, aldo-sterone secretion is low, whereas it is high when theperson ingests a low-sodium diet or becomes sodium-depleted for some other reason. What controls the se-cretion of aldosterone under these circumstances? Theanswer is the hormone angiotensin II, which acts di-rectly on the adrenal cortex to stimulate the secretionof aldosterone.

Angiotensin II is a component of the hormonal com-plex termed the renin-angiotensin system, summarizedin Figure 16–17. As stated earlier, renin is an enzyme se-creted by the juxtaglomerular cells of the juxtaglomeru-lar apparatuses in the kidneys. Once in the bloodstream,renin splits a small polypeptide, angiotensin I, from alarge plasma protein, angiotensinogen, which is pro-duced by the liver. Angiotensin I then undergoes furthercleavage to form the active agent of the renin-angiotensin







Activity of renalsympathetic nerves

Na and H2O excreted

Constriction of renal arterioles

Net glomerular filtration pressure

Reflexesmediated byvenous, atrial,and arterialbaroreceptors

Kidneys

Direct effect

Na and H2O lossdue to diarrhea

Begin

Plasma volume

Venous return

Atrial pressure

Ventricular end-diastolic volume

Venous pressure

Stroke volume

Cardiac output

Arterial blood pressure

GFR

FIGURE 16–16Direct and neurally mediated reflex pathways by which the GFR and hence sodium and water excretion are decreased whenplasma volume decreases. The renal nerves also cause contraction of glomerular mesangial cells, resulting in a decreasedsurface area for filtration.





system, angiotensin II. This conversion is mediated byan enzyme known as angiotensin converting enzyme,which is found in very high concentration on the lumi-nal surface of capillary endothelial cells, particularlythose in the lung. Angiotensin II exerts many effects, butthe most important are its stimulation of the secretion ofaldosterone and its constriction of arterioles (describedin Chapter 14). Plasma angiotensin II is high during saltdepletion and low when the individual is sodium re-plete, and it is this change in angiotensin II that bringsabout the changes in aldosterone secretion. Now wemust ask the question: What causes the changes inplasma angiotensin II concentration with changes in saltbalance?

Angiotensinogen and angiotensin converting en-zyme are normally present in high and relatively un-changing concentrations, so the rate-limiting factor inangiotensin II formation is the plasma renin concen-tration. Normally, this concentration depends upon therate of renin secretion by the kidneys. Thus the chainof events in salt depletion is: increased renin secretionn increased plasma renin concentration n increasedplasma angiotensin concentration n increased aldo-sterone secretion n increased plasma aldosterone concentration. Our last task is, therefore, to explain thefirst link in this chain—the mechanisms by whichsodium depletion causes an increase in renin secretion(Figure 16–18).

There are at least three distinct inputs to the jux-taglomerular cells: (1) the renal sympathetic nerves, (2) intrarenal baroreceptors, and (3) the macula densa.We will look at these in turn.

First, the renal sympathetic nerves directly inner-vate the juxtaglomerular cells, and an increase in theactivity of these nerves stimulates renin secretion. Thismakes excellent sense since, as have seen, these nervesare reflexly activated via baroreceptors whenever a re-duction in body sodium (and, hence, plasma volume)lowers cardiovascular pressures (see Figure 16–16).

The other two inputs for controlling reninrelease—intrarenal baroreceptors and the maculadensa—are totally contained within the kidneys andrequire no external neuroendocrine input (althoughthey can be influenced by such input). As noted ear-lier, the juxtaglomerular cells are located in the wallsof the afferent arterioles; they are themselves sensitiveto the pressure within these arterioles, and so functionas intrarenal baroreceptors. When blood pressure inthe kidneys decreases, as occurs when plasma volumeis down, these cells are stretched less and, therefore, se-crete more renin (Figure 16 – 18). Thus, the juxta-glomerular cells respond simultaneously to the com-bined effects of sympathetic input, triggered bybaroreceptors external to the kidneys, and to their ownpressure sensitivity.

The other completely internal input to the juxta-glomerular cells is via the macula densa, which, asnoted earlier, is located near the ends of the ascend-ing loops of Henle (see Figure 16–5). The maculadensa senses the sodium and/or chloride concentra-tion in the tubular fluid flowing past it, a decreased saltconcentration causing increased renin secretion. Forseveral reasons, including a decrease in GFR andhence tubular flow rate, macula densa sodium and


Angiotensinogen

Blood

*Renin

Angiotensin I Angiotensin II Aldosterone

Secretesangiotensinogen

Liver

Secreterenin

Kidneys

Secretes aldosterone

Adrenal cortex

Convertingenzyme

+

FIGURE 16–17Summary of the renin-angiotensin system and the stimulation of aldosterone secretion by angiotensin II. Converting enzyme islocated on the surface of capillary endothelial cells, particularly in the lungs. The plasma concentration of renin (as denoted bythe asterisk) is the rate-limiting factor in the renin-angiotensin system; that is, it is the major determinant of the plasmaconcentration of angiotensin II.





chloride concentrations tend to decrease when a per-son’s arterial pressure is decreased. This input there-fore also signals for increased renin release at the sametime that the sympathetic nerves and intrarenalbaroreceptors are doing so (Figure 16–18).

Obviously, there is considerable redundancy in thecontrol of renin secretion. As illustrated in Figure

16–18, the various mechanisms can all be participat-ing at the same time.

By helping to regulate sodium balance and therebyplasma volume, the renin-angiotensin system con-tributes to the control of arterial blood pressure. How-ever, this is not the only way in which it influences ar-terial pressure. Recall from Chapter 14 that angiotensin


Renin secretion

Renal juxtaglomerular cells

Adrenal cortex

Cortical collecting ducts

Plasma volume

Aldosterone secretion

Sodium reabsorption

Sodium excretion

Plasma angiotensin II

Plasma renin

Activity of renalsympathetic nerves

Direct effectof less stretch

(see Fig. 16-16)

NaCl concentrationin macula densa

Arterialpressure

GFR, which causes flow to macula densa

Plasma aldosterone

FIGURE 16–18Pathways by which decreased plasma volume leads, via the renin-angiotensin system and aldosterone, to increased sodiumreabsorption by the cortical collecting ducts and hence decreased sodium excretion.





II is a potent constrictor of arterioles all over the bodyand that this effect on peripheral resistance increasesarterial pressure.

Other Factors Although aldosterone is the most im-portant controller of sodium reabsorption, many otherfactors also play roles. For example, in addition to theirindirect roles via control of aldosterone secretion, therenal nerves and angiotensin II also act directly on thetubules to stimulate sodium reabsorption.

Another input is the peptide hormone known asatrial natriuretic factor (ANF), which is synthesizedand secreted by cells in the cardiac atria. ANF acts onthe tubules (several tubular segments and mechanismsare involved) to inhibit sodium reabsorption. It can alsoact on the renal blood vessels to increase GFR, whichfurther contributes to increased sodium excretion. Aswould be predicted, the secretion of ANF is increasedwhen there is an excess of sodium in the body, but thestimulus for this increased secretion is not alterationsin sodium concentration. Rather, using the same logic(only in reverse) that applies to the control of renin andaldosterone secretion, ANF secretion increases becauseof the expansion of plasma volume that accompaniesan increase in body sodium. The specific stimulus isincreased atrial distension (Figure 16–19).

Finally, another important input controllingsodium reabsorption is the arterial blood pressure. Wehave previously described how the arterial blood pres-sure constitutes a signal for important reflexes (involv-ing the renin-angiotensin system and aldosterone) thatinfluence sodium reabsorption, but now we are em-phasizing that arterial pressure also acts locally on thetubules themselves. Specifically, an increase in arterialpressure inhibits sodium reabsorption and thereby in-creases sodium excretion; this is termed pressure na-triuresis (“natriuresis” means increased urinarysodium loss). Thus, an increased blood pressure re-duces sodium reabsorption by two mechanisms: It re-duces the activity of the renin-angiotensin-aldosteronesystem, and it also acts locally on the tubules. Con-versely, a decreased blood pressure decreases sodiumexcretion both by stimulating the renin-angiotensin-aldosterone system and acting on the tubules to en-hance sodium reabsorption. Now is a good time to lookback at Figure 14–60, which describes the strongcausal, reciprocal relationship between arterial bloodpressure and blood volume, the result of which is thatblood volume is perhaps the major long-term deter-minant of blood pressure. The direct effect of bloodpressure on sodium excretion is, as shown in Figure 14–60, one of the major links in these relationships.Thus, for example, an important hypothesis is thatmost people who develop hypertension do so becausetheir kidneys, for some reason, do not excrete enoughsodium in response to a normal arterial pressure. Ac-cordingly, at this normal pressure some dietary sodiumis retained, which causes the pressure to rise enough toproduce adequate sodium excretion to balance sodiumintake, albeit at an increased body sodium content.

This completes our survey of the control of sodiumexcretion, which depends upon the control of two re-nal variables—the GFR and sodium reabsorption. Thelatter is controlled by the renin-angiotensin-aldosteronehormone system and by other factors, including atrialnatriuretic factor and arterial blood pressure. The re-flexes that control both GFR and sodium reabsorptionare essentially reflexes that regulate blood pressure,since they are most frequently initiated by changes inarterial or venous pressures.

Renal Water RegulationWater excretion is the difference between the volumeof water filtered (the GFR) and the volume reabsorbed.Accordingly, the baroreceptor-initiated GFR-controllingreflexes described in the previous section tend to havethe same effects on water excretion as on sodium ex-cretion. As is true for sodium, however, the major reg-ulated determinant of water excretion is not GFR butrather the rate of water reabsorption. As we have seen,


Afferent dilation;efferent constriction

Na reabsorption

GFR

Plasma volume

Plasma ANF

Sodium excretion

Distension

ANF secretion

Cardiac atria

Kidneys

Arterioles Tubules

FIGURE 16–19Atrial natriuretic factor (ANF) increases sodium excretion.





this is determined by vasopressin, and so total-bodywater is regulated mainly by reflexes that alter the se-cretion of this hormone.

As described in Chapter 10, vasopressin is pro-duced by a discrete group of hypothalamic neuronswhose axons terminate in the posterior pituitary, fromwhich vasopressin is released into the blood. The mostimportant of the inputs to these neurons are frombaroreceptors and osmoreceptors.

Baroreceptor Control of Vasopressin SecretionWe have seen that a decreased extracellular volume,due say to diarrhea or hemorrhage, reflexly calls forth,via the renin-angiotensin system, an increased aldo-sterone secretion. But the decreased extracellular vol-ume also triggers increased vasopressin secretion. Thisincreased vasopressin increases the water permeabil-ity of the collecting ducts, more water is reabsorbedand less is excreted, and so water is retained in thebody to help stabilize the extracellular volume.

This reflex is initiated by several baroreceptors inthe cardiovascular system (Figure 16–20). The barore-ceptors decrease their rate of firing when cardiovascu-lar pressures decrease, as occurs when blood volumedecreases. Therefore, few impulses are transmitted fromthe baroreceptors via afferent neurons and ascendingpathways to the hypothalamus, and the result is in-creased vasopressin secretion. Conversely, increased car-diovascular pressures cause more firing by the barore-ceptors, resulting in a decrease in vasopressin secretion.

In addition to its effect on water excretion, if theplasma vasopressin concentration becomes very high,it, like angiotensin II, causes widespread arteriolar con-striction. This helps restore arterial blood pressure to-ward normal (Chapter 14).

The baroreceptor reflex for vasopressin, as just de-scribed, has a relatively high threshold—that is, theremust be a sizable reduction in cardiovascular pressuresto trigger it. Therefore, this reflex, compared to the os-moreceptor reflex described next, generally plays alesser role under most physiological circumstances,but it can become very important in pathological statessuch as hemorrhage.

Osmoreceptor Control of Vasopressin SecretionWe have seen how changes in extracellular volume si-multaneously elicit reflex changes in the excretion ofboth sodium and water. This is adaptive since the sit-uations causing extracellular volume alterations arevery often associated with loss or gain of both sodiumand water in approximately proportional amounts. Incontrast, we shall see now that changes in total-bodywater in which no change in total-body sodium occursare compensated for reflexly by altering water excre-tion without altering sodium excretion.

A crucial point in understanding how such reflexesare initiated is that changes in water alone, in contrastto sodium, have relatively little effect on extracellularvolume. The reason is that water, unlike sodium, dis-tributes throughout all the body-fluid compartments,about two-thirds entering the intracellular compartmentrather than simply staying in the extracellular com-partment as sodium does. Therefore, cardiovascularpressures and, hence, baroreceptors are little affectedby pure water gains or losses. In contrast, the majorchange caused by water loss or gain out of proportionto sodium loss or gain is a change in the osmolarity ofthe body fluids. This is a key point because, under con-ditions due predominantly to water gain or loss, the re-ceptors that initiate the reflexes controlling vasopressin


Posterior pituitary

Plasma volume

Venous, atrial,and arterialpressures

H2O excretion

Reflexes mediatedby cardiovascularbaroreceptors

(see Fig. 16-16)

Vasopressin secretion

Plasma vasopressin

Tubular permeabilityto H2O

H2O reabsorption

Collecting ducts

FIGURE 16–20Baroreceptor pathway by which vasopressin secretion isincreased when plasma volume is decreased. The oppositeevents (culminating in a decrease in vasopressin secretion)occur when plasma volume increases.





secretion are osmoreceptors in the hypothalamus, re-ceptors responsive to changes in osmolarity.

As an example, take a person drinking 2 L of sugar-free soft drink, which contains little sodium or othersolute. The excess water lowers the body-fluid osmo-larity (raises the water concentration), which reflexlyinhibits vasopressin secretion via the hypothalamicosmoreceptors (Figure 16–21). As a result, the waterpermeability of the collecting ducts becomes very low,water is not reabsorbed from these segments, and alarge volume of hypoosmotic urine is excreted. In thismanner, the excess water is eliminated.

At the other end of the spectrum, when the os-molarity of the body fluids increases (water concen-tration decreases), say, because of water deprivation,vasopressin secretion is reflexly increased via the os-moreceptors, water reabsorption by the collectingducts is increased, and a very small volume of highlyconcentrated urine is excreted. By retaining relativelymore water than solute, the kidneys help reduce thebody-fluid osmolarity back toward normal.

To summarize, regulation of body-fluid osmolar-ity requires separation of water excretion from sodiumexcretion—that is, requires the kidneys to excrete aurine that, relative to plasma, either contains more wa-ter than sodium and other solutes (water diuresis) orless water than solute (concentrated urine). This ismade possible by two physiological factors: (1) os-moreceptors and (2) vasopressin-dependent dissocia-tion of water reabsorption from sodium reabsorptionin the collecting ducts.

We have now described two afferent pathwayscontrolling the vasopressin-secreting hypothalamiccells, one from baroreceptors and one from osmore-ceptors. To add to the complexity, the hypothalamiccells receive synaptic input from many other brain ar-eas, so that vasopressin secretion, and therefore urinevolume and concentration, can be altered by pain, fear,and a variety of drugs. For example, alcohol is a pow-erful inhibitor of vasopressin release, and this proba-bly accounts for much of the increased urine volumeproduced following ingestion of alcohol, a urine vol-ume well in excess of the volume of beverage con-sumed.

A Summary Example: The Response to SweatingFigure 16–22 shows the factors that control renalsodium and water excretion in response to severesweating. Sweat is a hypoosmotic solution containingmainly water, sodium, and chloride. Therefore, sweat-ing causes both a decrease in extracellular volume andan increase in body-fluid osmolarity (a decrease in wa-ter concentration). The renal retention of water andsodium minimizes the deviations from normal causedby the loss of water and salt in the sweat.

Thirst and Salt AppetiteNow we turn to the other component of any balance—control of intake. Deficits of salt and water must even-tually be compensated for by ingestion of these sub-stances, because the kidneys cannot create new sodiumions or water, they can only minimize their excretionuntil ingestion replaces the losses.


Posterior pituitary

Vasopressin secretion

Plasma vasopressin

Collecting ducts

Tubular permeabilityto H2O

H2O reabsorption

H2O excretion

Firing by hypothalamicosmoreceptors

Body-fluid osmolarity( H2O concentration)

Excess H2O ingested

FIGURE 16–21Osmoreceptor pathway by which vasopressin secretion islowered and water excretion raised when excess water isingested. The opposite events (an increase in vasopressinsecretion) occur when osmolarity increases, as during waterdeprivation.





The subjective feeling of thirst, which leads us toobtain and ingest water, is stimulated both by a lowerextracellular volume and a higher plasma osmolarity(Figure 16–23), the latter being the single most impor-tant stimulus under normal physiological conditions.Note that these are precisely the same two changes that

stimulate vasopressin production, and the osmorecep-tors and baroreceptors that control vasopressin secre-tion are identical to those for thirst. The brain centersthat receive input from these receptors and mediatethirst are located in the hypothalamus, very close tothose areas that produce vasopressin.


Severe sweating

Loss of hypoosmoticsalt solution

Plasma volume

GFR Plasma vasopressinPlasmaaldosterone

Plasma osmolarity H2O concentration)

Sodium excretion H2O excretion

Begin

ReflexesReflexes

(

FIGURE 16–22Pathways by which sodium and water excretion are decreased in response to severe sweating. This figure is an amalgamationof Figures 16–16, 16–18, 16–20, and the reverse of 16–21.

Baroreceptors Osmoreceptors

Dry mouth,throat

Metering ofwater intakeby GI tract

Plasmaosmolarity

Plasmavolume

ThirstAngiotensin II

+

+

+ +

FIGURE 16–23Inputs reflexly controllingthirst. The osmoreceptorinput is the single mostimportant stimulus undermost physiological conditions.Psychosocial factors andconditioned responses are not shown.





Another influencing factor is angiotensin II, whichstimulates thirst by a direct effect on the brain. Thus,the renin-angiotensin system helps regulate not onlysodium balance but water balance as well and consti-tutes one of the pathways by which thirst is stimulatedwhen extracellular volume is decreased.

There are still other pathways controlling thirst.For example, dryness of the mouth and throat causesprofound thirst, which is relieved by merely moisten-ing them. Some kind of “metering” of water intake byother parts of the gastrointestinal tract also occurs; thatis, a thirsty individual given access to water stopsdrinking after replacing the lost water but before mostof the water has been absorbed from the gastrointesti-nal tract and has a chance to eliminate the stimulatoryinputs to the systemic baroreceptors and osmorecep-tors. How this metering occurs remains a mystery, butone function of this feedforward process is to preventoverhydration.

The analog of thirst for sodium, salt appetite, is animportant part of sodium homeostasis in most mam-mals. Salt appetite consists of two components: “he-donistic” appetite and “regulatory” appetite; that is,animals “like” salt and eat it whenever they can, re-gardless of whether they are salt-deficient, and, in ad-dition, their drive to obtain salt is markedly increasedin the presence of bodily salt deficiency. Human be-ings certainly have a strong hedonistic appetite for salt,as manifested by almost universally large intakes ofsalt whenever it is cheap and readily available (for ex-ample, the average American consumes 10–15 g/daydespite the fact that human beings can survive quitenormally on less than 0.5 g/day). However, unlikemost other mammals, humans have relatively littleregulatory salt appetite, at least until a bodily saltdeficit becomes extremely large.

Potassium RegulationPotassium is, as we have seen, the most abundant in-tracellular ion. However, although only 2 percent oftotal-body potassium is in the extracellular fluid, thepotassium concentration in this fluid is extremely im-portant for the function of excitable tissues, notablynerve and muscle. Recall (Chapter 8) that the resting-membrane potentials of these tissues are directly re-lated to the relative intracellular and extracellularpotassium concentrations. Accordingly, either in-creases or decreases in extracellular potassium con-centration can cause abnormal rhythms of the heart(arrhythmias) and abnormalities of skeletal-musclecontraction.

A normal person remains in potassium balance bydaily excreting an amount of potassium in the urineequal to the amount ingested minus the amounts elim-inated in the feces and sweat. Also, like sodium, potas-sium losses via sweat and the gastrointestinal tract are


Potassium

Glomerularcapillary

Bowman’sspace

Proximal tubuleand loop of Henle

Corticalcollecting duct

Excretedin urine

FIGURE 16–24Simplified model of the basic renal processing of potassiumunder most circumstances.


Adrenal cortex

Potassium secretion


Plasma potassium

Plasma aldosterone

Potassium intake

Potassium excretion

FIGURE 16–25Pathways by which an increased potassium intake inducesgreater potassium excretion.

normally quite small, although vomiting or diarrheacan cause large quantities to be lost. The control of uri-nary potassium excretion is the major mechanism bywhich body potassium is regulated.





Renal Regulation of PotassiumPotassium is freely filterable in the renal corpuscle.Normally, the tubules reabsorb most of this filteredpotassium so that very little of the filtered potassiumappears in the urine. However, the cortical collectingducts can secrete potassium, and changes in potassiumexcretion are due mainly to changes in potassium se-cretion by this tubular segment (Figure 16–24).

During potassium depletion, when the homeo-static response is to minimize potassium loss, there isno potassium secretion by the cortical collecting ducts,and only the small amount of filtered potassium thatescapes tubular reabsorption is excreted. In all othersituations, to the small amount of potassium not reab-sorbed is added a variable amount of potassium se-creted by the cortical collecting ducts, an amount nec-essary to maintain total-body potassium balance.

The mechanism of potassium secretion by the cor-tical collecting ducts was illustrated in Figure 16–12.In this tubular segment, the K� pumped into the cellacross the basolateral membrane by Na,K-ATPases dif-fuses into the tubular lumen through K� channels inthe luminal membrane. Thus, the secretion of potas-sium by the cortical collecting duct is associated withthe reabsorption of sodium by this tubular segment.(Potassium secretion does not occur in other sodium-reabsorbing tubular segments because there are fewpotassium channels in the luminal membranes of theircells; rather, in these segments the potassium pumpedinto the cell by Na,K-ATPases simply diffuses backacross the basolateral membrane through potassiumchannels located there.)

What factors influence potassium secretion by thecortical collecting ducts to achieve homeostasis of bod-ily potassium? The single most important factor is asfollows: When a high-potassium diet is ingested (Fig-ure 16–25), plasma potassium concentration increases,though very slightly, and this drives enhanced baso-lateral uptake via the Na,K-ATPase pumps and hencean enhanced potassium secretion. Conversely, a low-potassium diet or a negative potassium balance, for ex-ample, from diarrhea, lowers basolateral potassiumuptake; this reduces potassium secretion and excre-tion, thereby helping to reestablish potassium balance.

A second important factor linking potassium se-cretion to potassium balance is the hormone aldo-sterone (Figure 16–25). Besides stimulating tubularsodium reabsorption by the cortical collecting ducts,aldosterone simultaneously enhances tubular potas-sium secretion by this tubular segment.

The reflex by which an excess or deficit of potas-sium controls aldosterone production (Figure 16–25)is completely different from the reflex described earlier involving the renin-angiotensin system. The aldosterone-secreting cells of the adrenal cortex aresensitive to the potassium concentration of the extracellular fluid bathing them. Thus, an increased in-take of potassium leads to an increased extracellularpotassium concentration, which in turn directly stim-ulates aldosterone production by the adrenal cortex.The resulting increased plasma aldosterone concen-tration increases potassium secretion and thereby elim-inates the excess potassium from the body.

Conversely, a lowered extracellular potassiumconcentration decreases aldosterone production andthereby reduces potassium secretion. Less potassiumthan usual is excreted in the urine, thus helping to re-store the normal extracellular concentration.

The control and major renal tubular effects of al-dosterone are summarized in Figure 16–26. The factthat a single hormone regulates both sodium andpotassium excretion raises the question of potentialconflicts between homeostasis of the two ions. For



Potassiumsecretion

Adrenal cortex

Plasma volume Plasma potassium

Plasma angiotensin II


Plasma aldosterone

Sodiumreabsorption

Potassiumexcretion

Sodiumexcretion

(As in Fig. 16-18)

FIGURE 16–26Summary of the control of aldosterone and its effects onsodium reabsorption and potassium secretion.





example, if a person were sodium-deficient and thereforesecreting large amounts of aldosterone, the potassium-secreting effects of this hormone would tend to causesome potassium loss even though potassium balancewas normal to start with. Usually, such conflicts causeonly minor imbalances because there are a variety ofother counteracting controls of sodium and potassiumexcretion.

Total-Body Balance of Sodium and WaterI. The body gains water via ingestion and internal

production, and it loses water via urine, thegastrointestinal tract, and evaporation from the skinand respiratory tract (as insensible loss and sweat).

II. The body gains sodium and chloride by ingestionand loses them via the skin (in sweat),gastrointestinal tract, and urine.

III. For both water and sodium, the major homeostaticcontrol point for maintaining stable balance is renalexcretion.

Basic Renal Processes for Sodium andWater

I. Sodium is freely filterable at the glomerulus, and itsreabsorption is a primary active process dependentupon Na,K-ATPase pumps in the basolateralmembranes of the tubular epithelium. Sodium is notsecreted.

II. Sodium entry into the cell from the tubular lumen isalways passive. Depending on the tubular segment,it is either through channels or by cotransport orcountertransport with other substances.

III. Sodium reabsorption creates an osmotic differenceacross the tubule, which drives water reabsorption,largely through water channels (aquaporins).

IV. Water reabsorption is independent of the posteriorpituitary hormone vasopressin until the collecting-duct system, where vasopressin increases waterpermeability. A large volume of dilute urine isproduced when plasma vasopressin concentration,and hence water reabsorption by the collecting ducts,is low.

V. A small volume of concentrated urine is producedby the renal countercurrent multiplier system whenplasma vasopressin concentration is high.a. The active transport of sodium chloride by the

ascending loop of Henle causes increasedosmolarity of the interstitial fluid of the medullabut a dilution of the luminal fluid.

b. Vasopressin increases the permeability of thecortical collecting ducts to water, and so water isreabsorbed by this segment until the luminal fluidis isoosmotic to plasma in the cortical peritubularcapillaries.

S E C T I O N B S U M M A R Y

c. The luminal fluid then enters and flows throughthe medullary collecting ducts, and theconcentrated medullary interstitium causes waterto move out of these ducts, made highlypermeable to water by vasopressin. The result isconcentration of the collecting duct fluid and theurine.

d. The hairpin-loop structure of the vasa rectaprevents the countercurrent gradient from beingwashed away.

Renal Sodium RegulationI. Sodium excretion is the difference between the

amount of sodium filtered and the amountreabsorbed.

II. GFR, and hence the filtered load of sodium, iscontrolled by baroreceptor reflexes. Decreasedvascular pressures cause decreased baroreceptorfiring and hence increased sympathetic outflow tothe renal arterioles, resulting in vasoconstriction anddecreased GFR. These changes are generallyrelatively small under most physiological conditions.

III. The major control of tubular sodium reabsorption isthe adrenal cortical hormone aldosterone, whichstimulates sodium reabsorption in the corticalcollecting ducts.

IV. The renin-angiotensin system is one of the two majorcontrollers of aldosterone secretion. Whenextracellular volume decreases, renin secretion isstimulated by three inputs: (1) stimulation of therenal sympathetic nerves to the juxtaglomerular cellsby extrarenal baroreceptor reflexes; (2) pressuredecreases sensed by the juxtaglomerular cells,themselves acting as intrarenal baroreceptors; and (3)a signal generated by low sodium or chlorideconcentration in the lumen of the macula densa.

V. Many other factors influence sodium reabsorption.One of these, atrial natriuretic factor, is secreted bycells in the atria in response to atrial distension; itinhibits sodium reabsorption and it also increasesGFR.

VI. Arterial pressure acts locally on the renal tubules toinfluence sodium reabsorption, an increased pressurecausing decreased reabsorption and hence increasedexcretion.

Renal Water RegulationI. Water excretion is the difference between the amount

of water filtered and the amount reabsorbed.II. GFR regulation via the baroreceptor reflexes plays

some role in regulating water excretion, but themajor control is via vasopressin-mediated control ofwater reabsorption.

III. Vasopressin secretion by the posterior pituitary iscontrolled by cardiovascular baroreceptors and byosmoreceptors in the hypothalamus.






a. Via the baroreceptor reflexes, a low extracellularvolume stimulates vasopressin secretion, and ahigh extracellular volume inhibits it.

b. Via the osmoreceptors, a high body-fluidosmolarity stimulates vasopressin secretion, and alow osmolarity inhibits it.

Thirst and Salt AppetiteI. Thirst is stimulated by a variety of inputs, including

baroreceptors, osmoreceptors, and angiotensin II.II. Salt appetite is not of major regulatory importance in

human beings.

Potassium RegulationI. A person remains in potassium balance by excreting

an amount of potassium in the urine equal to theamount ingested minus the amounts lost in the fecesand sweat.

II. Potassium is freely filterable at the renal corpuscleand undergoes both reabsorption and secretion, thelatter occurring in the cortical collecting ducts andbeing the major controlled variable determiningpotassium excretion.

III. When body potassium is increased, extracellularpotassium concentration increases. This increase actsdirectly on the cortical collecting ducts to increasepotassium secretion and also stimulates aldosteronesecretion, the increased plasma aldosterone then alsostimulating potassium secretion.

insensible water loss aldosteroneaquaporins renin-angiotensin systemvasopressin (antidiuretic renin

hormone, ADH) angiotensin Iwater diuresis angiotensinogendiuresis angiotensin IIosmotic diuresis angiotensin convertinghypoosmotic enzymeisoosmotic intrarenal baroreceptorshyperosmotic atrial natriuretic factorobligatory water loss (ANF)countercurrent multiplier pressure natriuresis

system osmoreceptorsvasa recta salt appetite

S E C T I O N B K E Y T E R M S

1. What are the sources of water gain and loss in thebody? What are the sources of sodium gain and loss?

2. Describe the distribution of water and sodiumbetween intracellular and extracellular fluids.

3. What is the relationship between body sodium andextracellular-fluid volume?

4. What is the mechanism of sodium reabsorption, andhow is the reabsorption of other solutes coupled toit?

5. What is the mechanism of water reabsorption, andhow is it coupled to sodium reabsorption?

6. What is the effect of vasopressin on the renaltubules, and what are the sites affected?

7. Describe the characteristics of the two limbs of theloop of Henle with regard to their transport ofsodium, chloride, and water.

8. Diagram the osmolarities in the two limbs of theloop of Henle, distal convoluted tubule, corticalcollecting duct, cortical interstitium, medullarycollecting duct, and medullary interstitium in thepresence of vasopressin. What happens to thecortical and medullary collecting-duct values in theabsence of vasopressin?

9. What two processes determine how much sodium isexcreted per unit time?

10. Diagram the sequence of events by which a decreasein blood pressure leads to a decreased GFR.

11. List the sequence of events leading from increasedrenin secretion to increased aldosterone secretion.

12. What are the three inputs controlling renin secretion?13. Diagram the sequence of events leading from

decreased cardiovascular pressures or from anincreased plasma osmolarity to an increasedsecretion of vasopressin.

14. What are the stimuli for thirst?15. Which of the basic renal processes apply to

potassium? Which of them is the controlled process,and which tubular segment performs it?

16. Diagram the steps leading from increased plasmapotassium to increased potassium excretion.

17. What are the two major controls of aldosteronesecretion, and what are this hormone’s majoractions?

S E C T I O N B R E V I E W Q U E S T I O N S






_538 PART THREE Coordinated Body Functions

C A L C I U M R E G U L A T I O N

S E C T I O N C

Extracellular calcium concentration normally remainsrelatively constant. Large deviations in either directionwould cause problems. A low plasma calcium con-centration increases the excitability of nerve and mus-cle plasma membranes, so that individuals with lowplasma calcium suffer from hypocalcemic tetany, char-acterized by skeletal-muscle spasms. A high plasmacalcium concentration causes cardiac arrhythmias aswell as depressed neuromuscular excitability. These ef-fects reflect, in part, the ability of extracellular calciumto bind to plasma-membrane proteins that function asion channels, thereby altering membrane potentials.The binding alters the open or closed state of the chan-nels. This effect of calcium on plasma membranes istotally distinct from its role as an intracellular excitation-contraction coupler, as described in Chapter 11.

Effector Sites for CalciumHomeostasisThe sections in this chapter on sodium, water, andpotassium homeostasis were concerned almost en-tirely with the renal handling of these substances. Incontrast, the regulation of calcium depends not onlyon the kidneys but also on bone and the gastroin-testinal tract. The activities of the gastrointestinal tractand kidneys determine the net intake and output ofcalcium for the entire body and, thereby, the overallstate of calcium balance. In contrast, interchanges ofcalcium between extracellular fluid and bone do notalter total-body balance but, rather, the distribution ofcalcium within the body. We will first describe how theeffector sites handle calcium and then discuss howthey are influenced by hormones in the homeostaticcontrol of plasma calcium concentration.

BoneApproximately 90 percent of total-body calcium is con-tained in bone. Therefore, deposition of calcium inbone or its removal very importantly influencesplasma calcium concentration.

Bone has functions, summarized in Table 16–5,other than regulating plasma calcium concentration. Itis important to recognize that its role in maintainingnormal plasma calcium concentration takes prece-dence over the mechanical supportive role, sometimesto the detriment of the latter.

Bone is a special connective tissue made up of sev-eral cell types surrounded by a collagen matrix, calledosteoid, upon which are deposited minerals, particu-larly the crystals of calcium and phosphate known ashydroxyapatite. In some instances, bones have centralmarrow cavities where blood cells are formed (Chap-ter 14). Typically, approximately one-third of a bone,by weight, is osteoid, and two-thirds is mineral (thebone cells contribute negligible weight).

The three types of bone cells (the blood-formingcells of the marrow are not included in this term) areosteoblasts, osteocytes, and osteoclasts (Figure 16–27).Osteoblasts are the bone-forming cells. They secretecollagen to form a surrounding matrix, which then be-comes calcified; just how this mineralization is broughtabout remains controversial. Once surrounded by cal-cified matrix, the osteoblasts are called osteocytes. Theosteocytes have long cytoplasmic processes that extendthroughout the bone and form tight junctions withother osteocytes. Osteoclasts are large multinucleatedcells that break down (resorb) previously formed boneby secreting hydrogen ions, which dissolve the crys-tals, and hydrolytic enzymes, which digest the osteoid.

The growth of bones during childhood will be dis-cussed in Chapter 18. What is important here is thatthroughout life, bone is being constantly “remodeled”by the osteoblasts and osteoclasts working together.Osteoclasts resorb old bone, and then osteoblastsmove into the area and lay down new matrix, whichbecomes calcified. This process is dependent, in part,on the stresses imposed on the bones by gravity andmuscle tension, both of which stimulate osteoblasticactivity. It is also influenced by many hormones, assummarized in Table 16–6, and a bewildering variety

1. Supports the body and imposed loads against gravity.

2. Provides the rigidity that permits locomotion.

3. Affords protection to the internal organs. The rib cage,vertebrae, and skull perform this function.

4. Serves as a reservoir for calcium, inorganic phosphate,and other mineral elements.

5. Produces blood cells in the bone marrow.

TABLE 16–5 Functions of Bone





of autocrine/paracrine growth factors produced lo-cally in the bone. Of the hormones listed, onlyparathyroid hormone and 1,25-dihydroxyvitamin D3

are controlled primarily by reflexes that regulateplasma calcium concentration. Nonetheless, changesin the other listed hormones have important influenceson bone mass and plasma calcium concentration.

KidneysAbout 60 percent of plasma calcium is filterable at therenal corpuscle (the rest is bound to plasma protein),and most of this filtered calcium is reabsorbed. Thereis no tubular secretion of calcium. Accordingly, the uri-nary excretion of calcium is the difference between theamount filtered and the amount reabsorbed. Like thatof sodium, the control of calcium excretion is exertedmainly on reabsorption; that is, reabsorption is reflexlydecreased when plasma calcium concentration goes upfor whatever reason, and reflexly increased whenplasma calcium goes down.

In addition, as we shall see, the renal handling ofphosphate plays a role in the regulation of extracellu-lar calcium. Phosphate, too, is handled by a combina-tion of filtration and reabsorption, the latter being hor-monally controlled.

Gastrointestinal TractThe absorption of sodium, water, and potassium fromthe gastrointestinal tract normally approximates 100percent. There is some homeostatic control of theseprocesses, but it is relatively unimportant and so weignored it. In contrast, a considerable amount of in-gested calcium is not absorbed from the intestine andsimply leaves the body along with the feces. Moreover,the active transport system that achieves calcium ab-sorption is under important hormonal control. Ac-cordingly, there can be large regulated increases or de-creases in the amount of calcium absorbed. Indeed,hormonal control of this absorptive process is the ma-jor means for homeostatically regulating total-bodycalcium balance, more important than the control ofrenal calcium excretion.

Hormonal ControlsThe two major hormones that homeostatically regulateplasma calcium concentration are parathyroid hor-mone and 1,25-dihydroxyvitamin D3. A third hor-mone, calcitonin, plays a more limited role.


Osteoclast Osteoblasts

Osteocyte Calcified matrix

FIGURE 16–27Cross section through a small portion of bone. The light tanarea is mineralized osteoid. The osteocytes have longprocesses that extend through small canals and connectwith each other and to osteoblasts via tight junctions.Adapted from Goodman.

*The effects of all hormones except 1,25-dihydroxyvitamin D3 are ultimatelydue to a hormone-induced alteration of the balance between the activities ofthe osteoblasts and osteoclasts. This altered balance is not always the resultof a direct action of the hormone on these cells, however, but may resultindirectly from some other action of the hormone. For example, largeamounts of cortisol depress intestinal absorption of calcium, which in turncauses reduced plasma calcium, increased parathyroid hormone secretion,and stimulation of osteoclasts by parathyroid hormone. Also, in addition tohormones, many paracrine agents produced by the bone cells and bone-marrow connective-tissue cells influence bone formation and resorption.

TABLE 16–6 Reference Summary of MajorHormonal Influences on BoneMass*

Hormones that favor bone formation and increasedbone mass

InsulinGrowth hormoneInsulin-like growth factor I (IGF-I)EstrogenTestosterone1,25-dihydroxyvitamin D3 (influences only

mineralization, not matrix)Calcitonin

Hormones that favor increased bone resorption anddecreased bone mass

Parathyroid hormoneCortisolThyroid hormones (T4 and T3)






Parathyroid glands

Parathyroid hormone secretion

Begin

Restoration of plasma calcium toward normal

Kidneys Bone

Intestine

Plasma parathyroid hormone

Plasma1,25–(OH)2D3

Resorption

Urinary excretionof phosphate

Plasma calcium

Urinary excretion of calcium

Plasma phosphate

Calcium reabsorption

1,25–(OH)2D3formation

Calcium absorption

Release of calciuminto plasma

Phosphatereabsorption

FIGURE 16–28Reflexes by which a reduction in plasma calcium concentration is restored toward normal via the actions of parathyroidhormone. See Figure 16–29 for a more complete description of 1,25-(OH)2D3.

Parathyroid HormoneAll three of the effector sites described previously—bone, kidneys, and gastrointestinal tract—are subject, directly or indirectly, to control by a protein hormonecalled parathyroid hormone, produced by theparathyroid glands. These glands are in the neck, em-bedded in the surface of the thyroid gland, but are distinct from it. Parathyroid hormone production iscontrolled by the extracellular calcium concentration acting directly on the secretory cells (via a plasma-membrane calcium receptor). Decreased plasma cal-cium concentration stimulates parathyroid hormone

secretion, and an increased plasma calcium concentra-tion does just the opposite.

Parathyroid hormone exerts multiple actions thatincrease extracellular calcium concentration, thus compensating for the decreased concentration thatoriginally stimulated secretion of this hormone (Figure 16–28).

1. It directly increases the resorption of bone byosteoclasts, which results in the movement ofcalcium (and phosphate) from bone intoextracellular fluid.






2. It directly stimulates the formation of 1,25-dihydroxyvitamin D3, (discussed below), andthis latter hormone then increases intestinalabsorption of calcium. Thus, the effect ofparathyroid hormone on the intestinal tract is anindirect one.

3. It directly increases renal tubular calciumreabsorption, thus decreasing urinary calciumexcretion.

In addition, parathyroid hormone directly reducesthe tubular reabsorption of phosphate, thus raising itsurinary excretion. This keeps plasma phosphate fromincreasing at a time when parathyroid hormone is si-multaneously causing increased release of both cal-cium and phosphate from bone.

1,25-Dihydroxyvitamin D3

The term vitamin D denotes a group of closely relatedcompounds. One of these, called vitamin D3 is formedby the action of ultraviolet radiation (from sunlight, usu-ally) on a cholesterol derivative (7-dehydrocholesterol)in skin. Another form of vitamin D very similar to vi-tamin D3 is ingested in food, specifically from plants.(Both forms can be found in vitamin pills and foodsenriched with vitamin D.)

Because of clothing and decreased outdoor living,people are often dependent upon dietary vitamin D,and for this reason it was originally classified as a vi-tamin. However, regardless of source, vitamin D3 andits similar ingested form are metabolized by additionof hydroxyl groups, first in the liver and then in cer-tain kidney tubular cells (Figure 16–29). The end re-sult of these changes is 1,25-dihydroxyvitamin D3 (ab-breviated 1,25-(OH)2D3, also called calcitriol), theactive form of vitamin D. It should be clear from thisdescription that since 1,25-(OH)2D3 is made in thebody, it is not, itself, a vitamin: instead, it fulfills thecriteria for a hormone.

The major action of 1,25-(OH)2D3 is to stimulateabsorption of calcium by the intestine. Thus, the ma-jor event in vitamin D deficiency is decreased intes-tinal calcium absorption, resulting in decreased plasmacalcium.

The blood concentration of 1,25-(OH)2D3 is subjectto physiological control. The major control point is thesecond hydroxylation step, the one that occurs in thekidneys. The enzyme catalyzing this step is stimulatedby parathyroid hormone. Thus, as we have seen, a lowplasma calcium concentration stimulates the secretionof parathyroid hormone, which in turn enhances theproduction of 1,25-(OH)2D3, and both hormones con-tribute to restoration of the plasma calcium towardnormal.

CalcitoninCalcitonin is a peptide hormone secreted by cells(termed parafollicular cells) that are within the thy-roid gland but are distinct from the thyroid follicles.

GI tract

Vitamin D3

25–OH D3

Enzyme

25–OH D3

Enzyme Parathyroidhormone

Plasma 1,25–(OH)2D3

Absorptionof calcium

Kidneys

7-Dehydrocholesterol

Dietaryvitamin D

Sunlight

Vitamin D3

Plasma vitamin D3

1,25–(OH)2D3

Begin

Skin

+

Liver

FIGURE 16–29Metabolism of vitamin D to the active form, 1,25-(OH)2D3.The kidney enzyme that mediates the final step is activatedby parathyroid hormone.





Calcitonin decreases plasma calcium concentration,mainly by inhibiting osteoclasts, thereby reducingbone resorption. Its secretion is stimulated by an in-creased plasma calcium concentration, just the oppo-site of the stimulus for parathyroid hormone secre-tion. Unlike parathyroid hormone and 1,25-(OH)2D3,however, calcitonin plays little role in the normal day-to-day regulation of plasma calcium regulation, but isinvolved primarily in protecting the skeleton from ex-cessive resorption during periods of “calcium stress”such as growth, pregnancy, and lactation.

Metabolic Bone DiseasesVarious diseases reflect abnormalities in the metabo-lism of bone. Rickets (in children) and osteomalacia(in adults) are conditions in which mineralization ofbone matrix is deficient, causing the bones to be softand easily fractured. In addition, a child suffering fromrickets typically is severely bowlegged due to the ef-fect of weight-bearing on the developing leg bones. Amajor cause of rickets and osteomalacia is deficiencyof 1,25-(OH)2D3.

In contrast to these diseases, in osteoporosis bothmatrix and minerals are lost as a result of an imbal-ance between bone resorption and bone formation. Theresulting decrease in bone mass and strength leads toan increased incidence of fractures. Osteoporosis canoccur in people who are immobilized (disuse osteo-porosis), in people who have an excessive plasma con-centration of a hormone that favors bone resorption,and in people who have a deficient plasma concentra-tion of a hormone that favors bone formation (Table 16–6). It is most commonly seen, however, with aging.Everyone loses bone as he or she ages, but osteoporo-sis is much more common in elderly women than menfor several reasons: Women have a smaller bone massto begin with, and the loss that occurs with aging oc-curs more rapidly, particularly after menopause re-moves the bone-promoting influence of estrogen.

Prevention is the focus of attention for osteoporo-sis. Estrogen treatment in postmenopausal women isvery effective in reducing the rate of bone loss. A reg-ular weight-bearing exercise program (brisk walkingand stair-climbing, for example) is also helpful. Adequate dietary calcium (1000 mg/day beforemenopause and 1200–1500 mg/day after menopause)throughout life is important to build up and maintainbone mass. Several agents also provide effective ther-apy once osteoporosis is established. Most prominentis a group of drugs, called bisphosphonates, that in-terfere with the resorption of bone by osteoclasts.Other therapeutic agents include the hormones calci-tonin, 1,25-(OH)2D3, and estrogen, as well as sodiumfluoride, which stimulates osteoblasts to form bone.

Effector Sites for Calcium HomeostasisI. The effector sites for the regulation of plasma

calcium concentration are bone, the gastrointestinaltract, and the kidneys.

II. Approximately 99 percent of total-body calcium iscontained in bone as minerals on a collagen matrix.Bone is constantly remodeled as a result of theinteraction of osteoblasts and osteoclasts, a processthat determines bone mass and provides a means forraising or lowering plasma calcium concentration.

III. Calcium is actively absorbed by the gastrointestinaltract, and this process is under hormonal control.

IV. The amount of calcium excreted in the urine is thedifference between the amount filtered and theamount reabsorbed, the latter process being underhormonal control.

Hormonal ControlsI. Parathyroid hormone increases plasma calcium

concentration by influencing all the effector sites.a. It stimulates tubular reabsorption of calcium,

bone resorption with release of calcium, andformation of the hormone 1,25-dihydroxyvitaminD3, which stimulates calcium absorption by theintestine.

b. It also inhibits the tubular reabsorption ofphosphate.

II. Vitamin D3 is formed in the skin or ingested andthen undergoes hydroxylations in the liver andkidneys, in the latter stimulated by parathyroidhormone, to the active form, 1,25-dihydroxyvitaminD3.

osteoid vitamin Dosteoblast vitamin D3

osteocyte 1,25-dihydroxyvitamin D3

osteoclast [1,25-(OH)2D3]parathyroid hormone calcitonin

1. List the functions of bone.2. Describe bone remodeling.3. Describe the handling of calcium by the kidneys and

gastrointestinal tract.4. What controls the secretion of parathyroid hormone,

and what are this hormone’s four major effects?5. Describe the formation and action of 1,25-(OH)2D3.

How does parathyroid hormone influence theproduction of this hormone?

S E C T I O N C R E V I E W Q U E S T I O N S

S E C T I O N C K E Y T E R M S

S E C T I O N C S U M M A R Y






_Metabolic reactions are highly sensitive to the hydrogen-ion concentration of the fluid in which they occur. Thissensitivity is due to the influence on enzyme functionexerted by hydrogen ions, which change the shapes ofproteins. Accordingly, the hydrogen-ion concentrationof the extracellular fluid is closely regulated. (At thispoint the reader might want to review the section onhydrogen ions, acidity, and pH in Chapter 2.)

This regulation can be viewed in the same way asthe balance of any other ion—that is, as the matchingof gains and losses. When loss exceeds gain, the arte-rial plasma hydrogen-ion concentration goes down(pH goes above 7.4), and this is termed an alkalosis.When gain exceeds loss, the arterial plasma hydrogen-ion concentration goes up (pH goes below 7.4), andthis is termed an acidosis.

Sources of Hydrogen-Ion Gain or LossTable 16–7 summarizes the major routes for gains andlosses of hydrogen ion. First, as described in Chapter15, a huge quantity of CO2—about 20,000 mmol—isgenerated daily as the result of oxidative metabolism,and these CO2 molecules participate in the generationof hydrogen ions during passage of blood through pe-ripheral tissues via the reactions:

carbonic anhydrase

CO2 � H2O 3:::::::4 H2CO3 34 HCO3� � H�

(16-1)

This source does not normally constitute a net gain ofhydrogen ions, however, since all the hydrogen ionsgenerated via these reactions are reincorporated intowater when the reactions are reversed during passageof blood through the lungs (Chapter 15). Net retentionof CO2 does occur, however, in hypoventilation orrespiratory disease and causes a net gain of hydrogenions. Conversely, net loss of CO2 occurs in hyper-ventilation, and this causes net elimination of hydro-gen ions.

The body also produces acids, both organic and in-organic, from sources other than CO2. These are col-lectively termed nonvolatile acids. They include phos-phoric acid and sulfuric acid, generated mainly by thecatabolism of proteins, as well as lactic acid and sev-eral other organic acids. Dissociation of all these acidsyields anions and hydrogen ions. But simultaneously

the metabolism of a variety of organic anions utilizeshydrogen ions and produces bicarbonate. Thus, me-tabolism of “nonvolatile” solutes both generates andutilizes hydrogen ions. In the United States, where thediet is high in protein, the generation of nonvolatileacids predominates in most people and there is an av-erage net production of 40 to 80 mmol of hydrogenions per day.

A third potential source of net body gain or loss ofhydrogen ion is gastrointestinal secretions leaving thebody. Vomitus contains a high concentration of hy-drogen ions and so constitutes a source of net loss. Incontrast, the other gastrointestinal secretions are alka-line; they contain very little hydrogen ion, but theirconcentration of bicarbonate is higher than exists inplasma. Loss of these fluids, as in diarrhea, constitutesin essence a body gain of hydrogen ions. This is an ex-tremely important point: Given the mass action rela-tionship shown in Equation 16-1, when a bicarbonateion is lost from the body it is the same as if the bodyhad gained a hydrogen ion. The reason is that loss ofthe bicarbonate causes the reactions shown in Equa-tion 16-1 to be driven to the right, thereby generatinga hydrogen ion within the body. Similarly, when thebody gains a bicarbonate ion, it is the same as if thebody had lost a hydrogen ion, as the reactions of Equa-tion 16-1 are driven to the left.


H Y D R O G E N - I O N R E G U L A T I O N

S E C T I O N D

TABLE 16–7 Sources of Hydrogen-Ion Gain or Loss

Gain

1. Generation of hydrogen ions from CO2

2. Production of nonvolatile acids from the metabolism ofprotein and other organic molecules

3. Gain of hydrogen ions due to loss of bicarbonate indiarrhea or other nongastric GI fluids

4. Gain of hydrogen ions due to loss of bicarbonate in theurine

Loss

1. Utilization of hydrogen ions in the metabolism of variousorganic anions

2. Loss of hydrogen ions in vomitus

3. Loss of hydrogen ions in the urine

4. Hyperventilation





Finally, the kidneys constitute the fourth source ofnet hydrogen-ion gain or loss; that is, the kidneys can ei-ther remove hydrogen ions from the plasma or add them.

Buffering of Hydrogen Ions in the BodyAny substance that can reversibly bind hydrogen ions is called a buffer. Between their generation in the bodyand their elimination, most hydrogen ions are bufferedby extracellular and intracellular buffers. The normal extracellular-fluid pH of 7.4 corresponds to a hydrogen-ion concentration of only 0.00004 mmol/L (40 nano-mols/L). Without buffering, the daily turnover of the 40to 80 mmol of H� produced from nonvolatile acids gen-erated in the body from metabolism would cause hugechanges in body-fluid hydrogen-ion concentration.

The general form of buffering reactions is:

Buffer� � H� 34 HBuffer (16-2)

HBuffer is a weak acid in that it can dissociate toBuffer� plus H� or it can exist as the undissociatedmolecule (HBuffer). When H� concentration increasesfor whatever reason, the reaction is forced to the right,and more H� is bound by Buffer� to form HBuffer.For example, when H� concentration is increased be-cause of increased production of lactic acid, some ofthe hydrogen ions combine with the body’s buffers,so the hydrogen-ion concentration does not increaseas much as it otherwise would have. Conversely, whenH� concentration decreases because of the loss of hy-drogen ions or the addition of alkali, Equation 16-2proceeds to the left and H� is released from HBuffer.In this manner, the body buffers stabilize H� concen-tration against changes in either direction.

The major extracellular buffer is the CO2/HCO3�

system summarized in Equation 16-1. This system alsoplays some role in buffering within cells, but the ma-jor intracellular buffers are phosphates and proteins.One intracellular protein buffer is hemoglobin, as de-scribed in Chapter 15.

You must recognize that buffering does not elimi-nate hydrogen ions from the body or add them to thebody; it only keeps them “locked-up” until balance canbe restored. How balance is achieved is the subject ofthe rest of our description of hydrogen-ion regulation.

Integration of HomeostaticControlsThe kidneys are ultimately responsible for balancinghydrogen-ion gains and losses so as to maintain a rel-atively constant plasma hydrogen-ion concentration.

Thus, the kidneys normally excrete the excess hydro-gen ions from nonvolatile acids generated in the bodyfrom metabolism—that is, all acids other than carbonicacid. Moreover, if there is an additional net gain of hy-drogen ions due to abnormally increased productionof these nonvolatile acids, or to hypoventilation orrespiratory malfunction, or to loss of alkaline gas-trointestinal secretions, the kidneys increase their elim-ination of hydrogen ions from the body so as to restorebalance. Alternatively, if there is a net loss of hydro-gen ions from the body due to increased metabolic uti-lization of hydrogen ions (as in a vegetarian diet), hy-perventilation, or vomiting, the kidneys replenishthese hydrogen ions.

Although the kidneys are the ultimate hydrogen-ion balancers, the respiratory system also plays a veryimportant homeostatic role. We have pointed out thathypoventilation, respiratory malfunction, and hyper-ventilation can cause a hydrogen-ion imbalance; nowwe emphasize that when a hydrogen-ion imbalance isdue to a nonrespiratory cause, then ventilation is re-flexly altered so as to help compensate for the imbalance.We described this phenomenon in Chapter 15 (see Fig-ure 15-34): An elevated arterial hydrogen-ion concen-tration stimulates ventilation, and this reflex hyper-ventilation causes reduced arterial PCO2

, and hence, bymass action, reduced hydrogen-ion concentration. Al-ternatively, a decreased plasma hydrogen-ion concen-tration inhibits ventilation, thereby raising arterialPCO2

and increasing the hydrogen-ion concentration.Thus, the respiratory system and kidneys work to-

gether. The respiratory response to altered plasma hydrogen-ion concentration is very rapid (minutes)and keeps this concentration from changing too muchuntil the more slowly responding kidneys (hours todays) can actually eliminate the imbalance. Of course,if the respiratory system is the actual cause of the hy-drogen-ion imbalance, then the kidneys are the solehomeostatic responder. By the same token, malfunc-tioning kidneys can create a hydrogen-ion imbalanceby eliminating too little or too much hydrogen ionfrom the body, and then the respiratory response is theonly one operating.

Renal MechanismsIn the previous section we wrote of the kidneys elim-inating hydrogen ions from the body or replenishingthem. The kidneys perform this task by altering plasmabicarbonate concentration. The key to understandinghow altering plasma bicarbonate concentration elimi-nates or replenishes hydrogen ions was stated earlier:The excretion of a bicarbonate in the urine increasesthe plasma hydrogen-ion concentration just as if a hy-drogen ion had been added to the plasma. Similarly,






the addition of a bicarbonate to the plasma lowers theplasma hydrogen-ion concentration just as if a hydro-gen ion had been removed from the plasma.

Thus, when there is a lowering of plasma hydrogen-ion concentration (alkalosis) for whatever reason, thekidneys’ homeostatic response is to excrete large quan-tities of bicarbonate. This raises plasma hydrogen-ionconcentration back toward normal. In contrast, in re-sponse to a rise in plasma hydrogen-ion concentration(acidosis), the kidneys do not excrete bicarbonate inthe urine, but instead kidney tubular cells produce new bicarbonate and add it to the plasma. This lowersthe plasma hydrogen-ion concentration back towardnormal.

Let us now look at the basic mechanisms by whichbicarbonate excretion or addition of new bicarbonateto the plasma is achieved.

Bicarbonate HandlingBicarbonate is completely filterable at the renal cor-puscles and undergoes marked tubular reabsorptionin various tubular segments (the proximal tubule, as-cending loop of Henle, and cortical collecting ducts).Bicarbonate can also be secreted (in the collectingducts). Therefore:

HCO3� excretion �

HCO3� filtered � HCO3

� secreted � HCO3� reabsorbed

For simplicity, we will ignore the secretion of bicar-bonate (because it is always quantitatively much lessthan tubular reabsorption) and treat bicarbonate ex-cretion as the difference between filtration and reab-sorption.

Bicarbonate reabsorption is an active process, butit is not accomplished in the conventional manner ofsimply having an active pump for bicarbonate ions atthe luminal or basolateral membrane of the tubularcells. Instead, bicarbonate reabsorption is absolutelydependent upon the tubular secretion of hydrogenions, which combine in the lumen with filtered bicar-bonates.

Figure 16–30 illustrates the sequence of events.Start this figure inside the cell with the combination ofCO2 and H2O to form H2CO3, a reaction catalyzed bythe enzyme carbonic anhydrase. The H2CO3 immedi-ately dissociates to yield H� and bicarbonate (HCO3

�).The HCO3

� moves down its concentration gradientacross the basolateral membrane into interstitial fluidand then into the blood. Simultaneously the H� is se-creted into the lumen; depending on the tubular seg-ment, this secretion is achieved by some combinationof primary H-ATPase pumps, primary H,K-ATPasepumps, and Na/H countertransporters.

But the secreted H� is not excreted. Instead, it com-bines in the lumen with a filtered HCO3

� and generates

CO2 and H2O (both of which can diffuse into the celland be used for another cycle of hydrogen-ion genera-tion). The overall result is that the bicarbonate filteredfrom the plasma at the renal corpuscle has disappeared,but its place in the plasma has been taken by the bi-carbonate that was produced inside the cell, and so nonet change in plasma bicarbonate concentration has oc-curred. It may seem inaccurate to refer to this processas bicarbonate “reabsorption,” since the bicarbonatethat appears in the peritubular plasma is not the samebicarbonate ion that was filtered. Yet the overall resultis, in effect, the same as if the filtered bicarbonate hadbeen more conventionally reabsorbed like a sodium orpotassium ion.

Except in response to alkalosis (discussed below),the kidneys normally reabsorb all filtered bicarbonate,thereby preventing the loss of bicarbonate in the urine.

Addition of New Bicarbonate to the PlasmaIt is essential to realize in Figure 16–30 that as long asthere are still significant amounts of filtered bicarbon-ate ions in the lumen, almost all secreted hydrogen ionswill combine with them. But what happens to any se-creted hydrogen ions once almost all the bicarbonatehas been reabsorbed and is no longer available in thelumen to combine with the hydrogen ions?


Tubularlumen

Tubular epithelialcells

Interstitialfluid

H2CO3

H2O + CO2

Carbonic

H+ HCO3– HCO3

–

anhydrase

HCO3– + H+

HCO3– (filtered)

H2CO3

H2O + CO2

Begin

FIGURE 16–30Reabsorption of bicarbonate. Start this figure inside the cell, with the combination of CO2 and H2O to form H2CO3.As shown in this figure, active H-ATPase pumps are involvedin the movement of H� out of the cell across the luminalmembrane; in several tubular segments, this transport step is also mediated by Na/H countertransporters and/orH,K-ATPase pumps.





The answer, illustrated in Figure 16–31, is that theextra secreted hydrogen ions combine in the lumenwith a filtered nonbicarbonate buffer, usually HPO4

2�.(Other filtered buffers can also participate, but HPO4

2�

is the most important.) The hydrogen ion is then ex-creted in the urine as part of an H2PO4

� ion. Now forthe critical point: Note in Figure 16–31 that, underthese conditions, the bicarbonate generated within thetubular cell by the carbonic anhydrase reaction and en-tering the plasma constitutes a net gain of bicarbonateby the plasma, not merely a replacement for a filteredbicarbonate. Thus, when a secreted hydrogen ion combines in the lumen with a buffer other than bicar-bonate, the overall effect is not merely one of bicar-bonate conservation, as in Figure 16–30, but rather ofaddition to the plasma of a new bicarbonate. This raises the bicarbonate concentration of the plasma andalkalinizes it.

To repeat, significant numbers of hydrogen ionscombine with filtered nonbicarbonate buffers likeHPO4

2� only after the filtered bicarbonate has virtually

all been reabsorbed. The main reason is that there issuch a large load of filtered bicarbonate buffers—25times more than the load of filtered nonbicarbonatebuffers—competing for the secreted hydrogen ions.

There is a second mechanism by which the tubulescontribute new bicarbonate to the plasma, one that in-volves not hydrogen-ion secretion but rather the renalproduction and secretion of ammonium (NH4

�) (Fig-ure 16–32). Tubular cells, mainly those of the proximaltubule, take up glutamine from both the glomerularfiltrate and peritubular plasma and, by a series of steps,metabolize it. In the process, both NH4

� and bicar-bonate are formed inside the cells. The NH4

� is ac-tively secreted (via Na�/NH4

� countertransport) intothe lumen and excreted, while the bicarbonate movesinto the peritubular capillaries and constitutes newplasma bicarbonate.

A comparison of Figures 16–31 and 16–32 demon-strates that the overall result—renal contribution ofnew bicarbonate to the plasma—is the same regard-less of whether it is achieved by: (1) H� secretion andexcretion on nonbicarbonate buffers such as phosphate(Figure 16–31); or (2) by glutamine metabolism withNH4

� excretion (Figure 16–32). It is convenient, there-fore, to view the latter case as representing H� excre-tion “bound” to NH3, just as the former case consti-tutes H� excretion bound to nonbicarbonate buffers.Thus, the amount of H� excreted in the urine in these


Tubularlumen


Interstitialfluid

H2CO3

H2O + CO2

Carbonic anhydraseH2PO4

–

HPO42– (filtered)

H+ HCO3– HCO3

–HPO42– + H+

Excreted

Begin

FIGURE 16–31Renal contribution of new HCO3

� to the plasma as achievedby tubular secretion of H�. The process of intracellular H�

and HCO3� generation, with H� movement into the lumen

and HCO3� into the plasma, is identical to that shown in

Figure 16–30. Once in the lumen, however, the H�

combines with filtered phosphate (HPO42�) rather than

filtered HCO3� and is excreted. As described in the legend

for Figure 16–30, the transport of hydrogen ions into thelumen is accomplished not only by H-ATPase pumps but, inseveral tubular segments, by Na/H countertransportersand/or H,K-ATPase pumps as well.

Tubularlumen


Interstitialfluid

Glutamine

NH4+

(filtered)Glutamine

HCO3– HCO3

–NH4+

Na+

Na+

Na+

Excreted

Glutamine

Begin Begin

FIGURE 16–32Renal contribution of new HCO3

� to the plasma as achievedby renal metabolism of glutamine and excretion ofammonium (NH4

�). Compare this figure to Figure 16–31.This process occurs mainly in the proximal tubule.





two forms is a measure of the amount of new bicar-bonate added to the plasma by the kidneys. Indeed,“urinary H� excretion” and “renal contribution of newbicarbonate to the plasma” are really two sides of thesame coin and are synonymous phrases.

The kidneys normally contribute enough new bi-carbonate to the blood (excrete enough hydrogen ions)to compensate for the hydrogen ions from nonvolatileacids generated in the body.

One last point needs to be emphasized: The lastparagraphs summarize the two forms in which H� isexcreted in the urine, but to be completely accuratethere is also a third form—as free H�. However, theamount of free H� is always so small that it can be ig-nored. For example, even the most acid of urines (4.4is the lowest pH achievable by the tubules) containsless than 0.1 mmol of free H�, compared to severalhundred mmols of H� bound up in nonbicarbonatebuffers and NH4

�. This emphasizes how importantthese two sources are in achieving the excretion of H�.

Renal Responses to Acidosis and AlkalosisWe can now apply this material to the renal responsesto the presence of an acidosis or alkalosis. These aresummarized in Table 16–8.

Clearly, these homeostatic responses require thatthe rates of hydrogen-ion secretion, glutamine metab-olism, and ammonium excretion be subject to physio-logical control by changes in blood hydrogen-ion con-centration. The specific pathways and mechanismsthat bring about these rate changes are very complex,however, and are not presented here.

Classification of Acidosis andAlkalosisTo repeat, acidosis refers to any situation in which thehydrogen-ion concentration of arterial plasma is ele-vated; alkalosis denotes a reduction. All such situa-tions fit into two distinct categories (Table 16–9): (1)respiratory acidosis or alkalosis; (2) metabolic acido-sis or alkalosis.

As its name implies, respiratory acidosis resultsfrom altered respiration. Respiratory acidosis occurswhen the respiratory system fails to eliminate carbondioxide as fast as it is produced. Respiratory alkalosisoccurs when the respiratory system eliminates carbondioxide faster than it is produced. As described earlier,the imbalance of arterial hydrogen-ion concentrationsin such cases is completely explainable in terms ofmass action. Thus, the hallmark of a respiratory aci-dosis is an elevation in both arterial PCO2

and hydrogen-ion concentration; that of respiratory alkalosis is a re-duction in both.

Metabolic acidosis or alkalosis includes all situa-tions other than those in which the primary problemis respiratory. Some common causes of metabolic aci-dosis are excessive production of lactic acid (during se-vere exercise or hypoxia) or of ketone bodies (in un-controlled diabetes mellitus or fasting, as described inChapter 18). Metabolic acidosis can also result from ex-cessive loss of bicarbonate, as in diarrhea. A frequentcause of metabolic alkalosis is persistent vomiting,with its associated loss of hydrogen ions as HCl fromthe stomach.

What is the arterial PCO2in metabolic acidosis or

alkalosis? Since, by definition, metabolic acidosis andalkalosis must be due to something other than excessretention or loss of carbon dioxide, you might have pre-dicted that arterial PCO2

would be unchanged, but suchis not the case. As emphasized earlier in this chapter,the elevated hydrogen-ion concentration associatedwith metabolic acidosis reflexly stimulates ventilationand lowers arterial PCO2

. By mass action, this helps re-store the hydrogen-ion concentration toward normal.Conversely, a person with metabolic alkalosis will re-flexly have ventilation inhibited. The result is a rise inarterial PCO2

and, by mass action, an associated restora-tion of hydrogen-ion concentration toward normal.


TABLE 16–8 Renal Responses to Acidosis and Alkalosis

Responses to Acidosis

1. Sufficient hydrogen ions are secreted to reabsorb all thefiltered bicarbonate.

2. Still more hydrogen ions are secreted, and this contributesnew bicarbonate to the plasma as these hydrogen ionsare excreted bound to nonbicarbonate urinary bufferssuch as HPO4

2�.

3. Tubular glutamine metabolism and ammonium excretionare enhanced, which also contributes new bicarbonate tothe plasma.

Net result: More new bicarbonate ions than usual areadded to the blood, and plasma bicarbonate isincreased, thereby compensating for theacidosis. The urine is highly acidic (lowestattainable pH � 4.4).

Responses to Alkalosis

1. Rate of hydrogen-ion secretion is inadequate to reabsorball the filtered bicarbonate, so that significant amounts ofbicarbonate are excreted in the urine, and there is little orno excretion of hydrogen ions on nonbicarbonate urinarybuffers.

2. Tubular glutamine metabolism and ammonium excretionare decreased so that little or no new bicarbonate iscontributed to the plasma from this source.

Net result: Plasma bicarbonate concentration is decreased,thereby compensating for the alkalosis. Theurine is alkaline (pH � 7.4).





To reiterate, the plasma PCO2changes in metabolic

acidosis and alkalosis are not the cause of the acidosisor alkalosis but are the result of compensatory reflexresponses to nonrespiratory abnormalities. Thus, inmetabolic, as opposed to respiratory conditions, the ar-terial plasma PCO2 and hydrogen-ion concentration goin opposite directions, as summarized in Table 16–9.

Sources of Hydrogen-Ion Gain or LossI. Total-body balance of hydrogen ions is the result of

both metabolic production of these ions and of netgains or losses via the respiratory system,gastrointestinal tract, and urine (Table 16–7).

II. A stable balance is achieved by regulation of urinarylosses.

Buffering of Hydrogen Ions in the BodyI. Buffering is a means of minimizing changes in

hydrogen-ion concentration by combining these ionsreversibly with anions such as bicarbonate andintracellular proteins.

II. The major extracellular buffering system is theCO2/HCO3

� system, and the major intracellularbuffers are proteins and phosphates.

Integration of Homeostatic ControlsI. The kidneys and the respiratory system are the

homeostatic regulators of plasma hydrogen-ionconcentration.

II. The kidneys are the organs that achieve bodyhydrogen-ion balance.

III. A decrease in arterial plasma hydrogen-ionconcentration causes reflex hypoventilation, whichraises arterial PCO2

and, hence, raises plasmahydrogen-ion concentration toward normal. Anincrease in plasma hydrogen-ion concentrationcauses reflex hyperventilation, which lowers arterialPCO2

and, hence, lowers hydrogen-ion concentrationtoward normal.

Renal MechanismsI. The kidneys maintain a stable plasma hydrogen-ion

concentration by regulating plasma bicarbonate

S E C T I O N D S U M M A R Y

concentration. They can either excrete bicarbonate orcontribute new bicarbonate to the blood.

II. Bicarbonate is reabsorbed when hydrogen ions,generated in the tubular cells by a process catalyzedby carbonic anhydrase, are secreted into the lumenand combine with filtered bicarbonate. The secretedhydrogen ions are not excreted in this situation.

III. In contrast, when the secreted hydrogen ionscombine in the lumen with filtered phosphate orother nonbicarbonate buffer, they are excreted, andthe kidneys have contributed new bicarbonate to theblood.

IV. The kidneys also contribute new bicarbonate to theblood when they produce and excrete ammonium.

Classification of Acidosis and AlkalosisI. Acid-base disorders are categorized as respiratory or

metabolic.a. Respiratory acidosis is due to retention of carbon

dioxide, and respiratory alkalosis to excessiveelimination of carbon dioxide.

b. All other causes of acidosis or alkalosis aretermed metabolic and reflect gain or loss,respectively, of hydrogen ions from a source otherthan carbon dioxide.

nonvolatile acids buffer

1. What are the sources of gain and loss of hydrogenions in the body?

2. List the body’s major buffer systems.3. Describe the role of the respiratory system in the

regulation of hydrogen-ion concentration.4. How does the tubular secretion of hydrogen ions

occur, and how does it achieve bicarbonatereabsorption?

5. How does hydrogen-ion secretion contribute to therenal addition of new bicarbonate to the blood?What determines whether a secreted hydrogen ionwill achieve these events or will instead causebicarbonate reabsorption?

S E C T I O N D R E V I E W Q U E S T I O N S

S E C T I O N D K E Y T E R M S


TABLE 16-9 Changes in the Arterial Concentrations of Hydrogen Ion, Bicarbonate, and Carbon Dioxide in Acid-Base Disorders

Primary Disorder H� HCO3� CO2 Cause of HCO3

� Change Cause of CO2 Change

Respiratory acidosis h h hRenal compensation Primary abnormality

Respiratory alkalosis g g g

Metabolic acidosis h g gPrimary abnormality Reflex ventilatory compensation

Metabolic alkalosis g h h





_6. How does the metabolism of glutamine by the

tubular cells contribute new bicarbonate to the bloodand ammonium to the urine?

7. What two quantities make up “hydrogen-ionexcretion?” Why can this term be equated with“contribution of new bicarbonate to the plasma?”

8. How do the kidneys respond to the presence of anacidosis or alkalosis?

9. Classify the four types of acid-base disordersaccording to plasma hydrogen-ion concentration,bicarbonate concentration, and PCO2

.


D I U R E T I C S A N D K I D N E Y D I S E A S E

S E C T I O N E

DiureticsDrugs used clinically to increase the volume of urine ex-creted are known as diuretics. Such agents act on thetubules to inhibit the reabsorption of sodium, alongwith chloride and/or bicarbonate, resulting in increasedexcretion of these ions. Since water reabsorption is de-pendent upon sodium reabsorption, water reabsorptionis also reduced, resulting in increased water excretion.

A large variety of clinically useful diuretics areavailable and are classified according to the specificmechanisms by which they inhibit sodium reabsorp-tion. For example, one type, called loop diuretics, actson the ascending limb of the loop of Henle to inhibitthe transport protein that mediates the first step insodium reabsorption in this segment—cotransport ofsodium and chloride (and potassium) into the cellacross the luminal membrane.

Except for one category of diuretics, called potassium-sparing diuretics, all diuretics not only in-crease sodium excretion but also cause increasedpotassium excretion, an unwanted side effect. By sev-eral mechanisms, the potassium-sparing diuretics in-hibit sodium reabsorption in the cortical collectingduct, and they simultaneously inhibit potassium se-cretion there. This explains why they do not cause in-creased potassium excretion.

Diuretics are among the most commonly usedmedications. For one thing, they are used to treat dis-eases characterized by renal retention of salt and wa-ter. As emphasized earlier in this chapter, in normalpersons the regulation of blood pressure simultane-ously produces stability of total-body sodium massand extracellular volume because there is a close cor-relation between these variables. In contrast, in severaltypes of disease, this correlation is broken and the re-flexes that maintain blood pressure can cause renal re-tention of sodium. Sodium excretion may fall virtuallyto zero despite continued sodium ingestion, leading toabnormal expansion of the extracellular fluid and for-mation of edema. Diuretics are used to prevent or re-verse this renal retention of sodium and water.

The most common example of this phenomenon iscongestive heart failure (Chapter 14). A person with afailing heart manifests (1) a decreased GFR and (2) in-creased aldosterone secretion, both of which, alongwith other important factors, contribute to the virtualabsence of sodium from the urine. The net result is ex-tracellular volume expansion and formation of edema.The sodium-retaining responses are triggered by thelower cardiac output (a result of cardiac failure) andthe decrease in arterial blood pressure that results di-rectly from this decrease in cardiac output.

Another disease in which diuretics are frequentlyemployed is hypertension (Chapter 14). The decreasein body sodium and water resulting from the diuretic-induced excretion of these substances brings about ar-teriolar dilation and a lowering of the blood pressure;why decreased body sodium causes arteriolar dilationis not known.

Kidney DiseaseThe term “kidney disease” is no more specific than “cartrouble,” since many diseases affect the kidneys. Bac-teria, allergies, congenital defects, kidney stones, tu-mors, and toxic chemicals are some possible sources ofkidney damage. Obstruction of the urethra or a uretermay cause injury as the result of a buildup of pressureand may predispose the kidneys to bacterial infection.

One frequent sign of kidney disease is the ap-pearance of protein in the urine. In normal kidneys,there is a very tiny amount of protein in the glomeru-lar filtrate because the corpuscular membranes are notcompletely impermeable to proteins, particularly thosewith lower molecular weights. However, the cells ofthe proximal tubule completely remove this filteredprotein from the tubular lumen, and no protein ap-pears in the final urine. In contrast, diseased renal cor-puscles may become much more permeable to protein,and diseased proximal tubules may lose their abilityto remove filtered protein from the tubular lumen. Theresult is that protein will appear in the urine.





Although many diseases of the kidney are self-limited and produce no permanent damage, othersprogress if untreated. The symptoms of profound re-nal malfunction are relatively independent of the dam-aging agent and are collectively known as uremia, lit-erally, “urine in the blood.”

The severity of uremia depends upon how well theimpaired kidneys are able to preserve the constancy ofthe internal environment. Assuming that the personcontinues to ingest a normal diet containing the usualquantities of nutrients and electrolytes, what problemsarise? The key fact to keep in mind is that the kidneydestruction markedly reduces the number of func-tioning nephrons. Accordingly, the many substances,particularly potentially toxic waste products, that gainentry to the tubule by filtration build up in the blood.In addition, the excretion of potassium is impaired be-cause there are too few nephrons capable of normal tu-bular secretion of this ion. The person may also developacidosis because the reduced number of nephrons failto add enough new bicarbonate to the blood to com-pensate for the daily metabolic production of non-volatile acids.

The remarkable fact is how large the safety factoris in renal function. In general, the kidneys are still ableto perform their regulatory function quite well as longas 10 percent of the nephrons are functioning. This isbecause these remaining nephrons undergo alterationsin function—filtration, reabsorption, and secretion—so as to compensate for the missing nephrons. For ex-ample, each remaining nephron increases its rate ofpotassium secretion so that the total amount of potas-sium excreted by the kidneys can be maintained at nor-mal levels. The limits of regulation are restricted, how-ever. To use potassium as our example again, ifsomeone with severe renal disease were to go on a diethigh in potassium, the remaining nephrons might notbe able to secrete enough potassium to prevent potas-sium retention.

Other problems arise in uremia because of abnor-mal secretion of the hormones produced by the kid-neys. Thus, decreased secretion of erythropoietin re-sults in anemia (Chapter 14). Decreased ability to form1,25-(OH)2D3 results in deficient absorption of calciumfrom the gastrointestinal tract, with a resulting de-crease in plasma calcium and inadequate bone calcifi-cation. Both of these hormones are now available foradministration to patients with uremia.

The problem with renin, the third of the renal hor-mones, is rarely too little secretion but rather too muchsecretion by the juxtaglomerular cells of the damagedkidneys. The result is increased plasma angiotensin IIconcentration and the development of renal hyper-tension.

Hemodialysis, Peritoneal Dialysis, andTransplantationAs described above, failing kidneys reach a point whenthey can no longer excrete water and ions at rates thatmaintain body balances of these substances, nor canthey excrete waste products as fast as they are pro-duced. Dietary alterations can minimize these prob-lems, for example, by lowering potassium intake andthereby reducing the amount of potassium to be ex-creted, but such alterations cannot eliminate the prob-lems. The techniques used to perform the kidneys’ ex-cretory functions are hemodialysis and peritonealdialysis. The general term “dialysis” means to sepa-rate substances using a membrane.

The artificial kidney is an apparatus that utilizes aprocess termed hemodialysis to remove excess sub-stances from the blood. During hemodialysis, blood ispumped from one of the patient’s arteries through tub-ing that is surrounded by special dialysis fluid. The tub-ing then conducts the blood back into the patient byway of a vein. The tubing is generally made of cello-phane that is highly permeable to most solutes but rel-atively impermeable to protein and completely imper-meable to blood cells—characteristics quite similar tothose of capillaries. The dialysis fluid is a salt solutionwith ionic concentrations similar to or lower than thosein normal plasma, and it contains no creatinine, urea,or other substances to be completely removed from theplasma. As blood flows through the tubing, the con-centrations of nonprotein plasma solutes tend to reachdiffusion equilibrium with those of the solutes in thebath fluid. For example, if the plasma potassium con-centration of the patient is above normal, potassiumdiffuses out of the blood across the cellophane tubingand into the dialysis fluid. Similarly, waste productsand excesses of other substances also diffuse into thedialysis fluid and thus are eliminated from the body.

Patients with acute reversible renal failure may re-quire hemodialysis for only days or weeks. Patientswith chronic irreversible renal failure require treatmentfor the rest of their lives, however, unless they receivea renal transplant. Such patients undergo hemodialy-sis several times a week, often at home.

Another way of removing excess substances fromthe blood is peritoneal dialysis, which uses the liningof the patient’s own abdominal cavity (peritoneum) asa dialysis membrane. Fluid is injected, via a needle in-serted through the abdominal wall, into this cavity andallowed to remain there for hours, during whichsolutes diffuse into the fluid from the person’s blood.The dialysis fluid is then removed by reinserting theneedle and is replaced with new fluid. This procedurecan be performed several times daily by a patient whois simultaneously doing normal activities.






The treatment of choice for most patients with per-manent renal failure is kidney transplantation. Rejec-tion of the transplanted kidney by the recipient’s bodyis a potential problem with transplants, but greatstrides have been made in reducing the frequency ofrejection (Chapter 20). Many people who might bene-fit from a transplant, however, do not receive one.Presently, the major source of kidneys for transplant-ing is recently deceased persons, and improved pub-lic understanding should lead to many more individ-uals giving permission in advance to have theirkidneys and other organs used following their death.

Diuretics and Kidney DiseaseI. Diuretics inhibit reabsorption of sodium and water,

thereby enhancing the excretion of these substances.Different diuretics act on different nephronsegments.

II. Many of the symptoms of uremia—general renalmalfunction—are due to retention of substancesbecause of reduced GFR and, in the case ofpotassium and hydrogen ion, reduced secretion.Other symptoms are due to inadequate secretion oferythropoietin and 1,25-dihydroxyvitamin D3, andtoo much secretion of renin.

III. Either hemodialysis or peritoneal dialysis can beused chronically to eliminate water, ions, and wasteproducts retained during uremia.

glucosuria respiratory alkalosisfamilial renal glycosuria metabolic acidosisdiabetes insipidus metabolic alkalosisarrhythmias diureticshypocalcemic tetany potassium-sparing diureticsrickets edemaosteomalacia congestive heart failureosteoporosis uremiabisphosphonates renal hypertensionalkalosis hemodialysisacidosis peritoneal dialysisrespiratory acidosis

C H A P T E R 1 6 C L I N I C A L T E R M S

S E C T I O N E S U M M A R Y

(Answers are in Appendix A.)1. Substance T is present in the urine. Does this prove

that it is filterable at the glomerulus?2. Substance V is not normally present in the urine.

Does this prove that it is neither filtered norsecreted?

3. The concentration of glucose in plasma is 100mg/100 ml, and the GFR is 125 ml/min. How muchglucose is filtered per minute?

4. A person is found to be excreting abnormally largeamounts of a particular amino acid. Just from thetheoretical description of Tm-limited reabsorptivemechanisms in the text, list several possible causes.

5. The concentration of urea in urine is always muchhigher than the concentration in plasma. Does thismean that urea is secreted?

6. If a drug that blocks the reabsorption of sodium istaken, what will happen to the reabsorption of water,urea, chloride, glucose, and amino acids and to thesecretion of hydrogen ions?

7. Compare the changes in GFR and renin secretionoccurring in response to a moderate hemorrhage intwo individuals—one taking a drug that blocks thesympathetic nerves to the kidneys and the other nottaking such a drug.

8. If a person is taking a drug that completely inhibitsangiotensin converting enzyme, what will happen toaldosterone secretion when the person goes on alow-sodium diet?

9. In the steady state, is the amount of sodium chlorideexcreted daily in the urine by a normal personingesting 12 g of sodium chloride per day: (a) 12g/day or (b) less than 12 g/day? Explain.

10. A young woman who has suffered a head injuryseems to have recovered but is thirsty all the time.What do you think might be the cause?

11. A patient has a tumor in the adrenal cortex thatcontinuously secretes large amounts of aldosterone.What effects does this have on the total amount ofsodium and potassium in her body?

12. A person is taking a drug that inhibits the tubularsecretion of hydrogen ions. What effect does thisdrug have on the body’s balance of sodium, water,and hydrogen ion?

C H A P T E R 1 6 T H O U G H T Q U E S T I O N S


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