Chapter 17

Physiology of the Kidneys

17-1

Kidney Function

• Is to regulate plasma & interstitial fluid by formation of urine

• In process of urine formation, kidneys regulate:– Volume of blood plasma, which contributes to BP– Waste products in blood– Concentration of electrolytes

• Including Na+, K+, HC03-, & others

– Plasma pH

17-3

Fig 17.5

17-13

Type of Nephrons

• Cortical nephrons originate in outer 2/3 of cortex

• Juxtamedullary nephrons originate in inner 1/3 cortex– Have long LHs– Important in

producing concentrated urine

Fig 17.617-17

Mechanisms of Urine Formation

• Urine formation and adjustment of blood composition involves three major processes – Glomerular

filtration– Tubular

reabsorption– Secretion

Figure 25.8

Glomerular Filtration

• Glomerular capillaries & Bowman's capsule form a filter for blood – Glomerular Caps are fenestrated--have large pores

between its endothelial cells• 100-400 times more permeable than other Caps• Small enough to keep RBCs, platelets, & WBCs from

passing• Pores are lined with negative charges to keep blood

proteins from filtering

17-19

• To enter tubule filtrate must pass through narrow filtration slits formed between pedicels of podycytes of glomerular capsule

Glomerular Filtration continued

Fig 17.817-20

Filtration• Movement of fluid, derived from blood flowing through the glomerulus,

across filtration membrane• Filtrate: water, small molecules, ions that can pass through

membrane• Pressure difference forces filtrate across filtration membrane• Renal fraction: part of total cardiac output that passes through the

kidneys. Varies from 12-30%; averages 21%• Renal blood flow rate: 1176 mL/min• Renal plasma flow rate: renal blood flow rate X fraction of blood that

is plasma: 650 mL/min• Filtration fraction: part of plasma that is filtered into lumen of

Bowman’s capsules; average 19%• Glomerular filtration rate (GFR): amount of filtrate produced each

minute. 180 L/day• Average urine production/day: 1-2 L. Most of filtrate must be

reabsorbed

Glomerular Ultrafiltrate

• Is fluid that enters glomerular capsule, whose filtration was driven by blood pressure

Fig 17.10

17-23

Filtration• Filtration membrane: filtration barrier. It prevents blood cells and

proteins from entering lumen of Bowman’s capsule, but is many times more permeable than a typical capillary– Fenestrated endothelium, basement membrane and pores formed by

podocytes– Some albumin and small hormonal proteins enter the filtrate, but

these are reabsorbed and metabolized by the cells of the proximal tubule. Very little protein normally found in urine

• Filtration pressure: pressure gradient responsible for filtration; forces fluid from glomerular capillary across membrane into lumen of Bowman’s capsules

• Forces that affect movement of fluid into or out of the lumen of Bowman’s capsule– Glomerular capillary pressure (GCP): blood pressure inside

capillary tends to move fluid out of capillary into Bowman’s capsule– Capsule pressure (CP): pressure of filtrate already in the lumen– Blood colloid osmotic pressure (BCOP): osmotic pressure caused

by proteins in blood. Favors fluid movement into the capillary from the lumen. BCOP greater at end of glomerular capillary than at beginning because of fluid leaving capillary and entering lumen

– Filtration pressure (10 mm Hg) = GCP (50 mm Hg) – CP (10 mm Hg) – BCOP (30 mm Hg)

Filtration Pressure

Filtration• Colloid osmotic pressure in Bowman’s capsule normally close to zero.

During diseases like glomerular nephritis, proteins enter the filtrate and filtrate exerts an osmotic pressure, increasing volume of filtrate

• High glomerular capillary pressure results from – Low resistance to blood flow in afferent arterioles– Low resistance to blood flow in glomerular capillaries– High resistance to blood flow in efferent arterioles: small diameter vessels

• Pressure lower in peritubular capillaries downstream from efferent arterioles

• Filtrate is forced across filtration membrane; fluid moves into peritubular capillaries from interstitial fluid

• Changes in afferent and efferent arteriole diameter alter filtration pressure– Dilation of afferent arterioles/constriction efferent arterioles increases

glomerular capillary pressure, increasing filtration pressure and thus glomerular filtration

Net Filtration Pressure (NFP)

• The pressure responsible for filtrate formation• NFP equals the glomerular hydrostatic

pressure (HPg) minus the oncotic pressure of glomerular blood (OPg) combined with the capsular hydrostatic pressure (HPc)

NFP = HPg – (OPg + HPc)

Glomerular Filtration Rate (GFR)

• Is volume of filtrate produced by both kidneys/min– Averages 115 ml/min in women; 125 ml/min in men– Totals about 180L/day (45 gallons)

• So most filtered water must be reabsorbed or death would ensue from water lost through urination

17-24

• GFR is directly proportional to the NFP• Changes in GFR normally result from changes in glomerular blood pressure

Regulation of Glomerular Filtration

• If the GFR is too high:– Needed substances cannot be reabsorbed

quickly enough and are lost in the urine

• If the GFR is too low:– Everything is reabsorbed, including wastes

that are normally disposed of

Regulation of Glomerular Filtration

• Three mechanisms control the GFR – Renal autoregulation (intrinsic system)– Neural controls– Hormonal mechanism (the renin-

angiotensin system)

Intrinsic Controls

• Under normal conditions, renal autoregulation maintains a nearly constant glomerular filtration rate

• Autoregulation entails two types of control– Myogenic – responds to changes in pressure in

the renal blood vessels– Flow-dependent tubuloglomerular feedback –

senses changes in the juxtaglomerular apparatus

Renal Autoregulation

• Is also maintained by negative feedback between afferent arteriole & volume of filtrate (tubuloglomerular feedback)– Increased flow of filtrate sensed by macula densa (part of

juxtaglomerular apparatus) in thick ascending LH• Signals afferent arterioles to constrict

17-29

Renal Autoregulation

• Allows kidney to maintain a constant GFR over wide range of BPs

• Achieved via effects of locally produced chemicals on afferent arterioles

• When average BP drops to 70 mm Hg afferent arteriole dilates

• When average BP increases, afferent arterioles constrict

17-27

Extrinsic Controls

• When the sympathetic nervous system is at rest:– Renal blood vessels are maximally dilated– Autoregulation mechanisms prevail

Extrinsic Controls

• Under stress:– Norepinephrine is released by the sympathetic

nervous system– Epinephrine is released by the adrenal medulla – Afferent arterioles constrict and filtration is

inhibited

• The sympathetic nervous system also stimulates the renin-angiotensin mechanism

Renin-Angiotensin Mechanism

• Is triggered when the JG cells release renin• Renin acts on angiotensinogen to release

angiotensin I • Angiotensin I is converted to angiotensin II • Angiotensin II:

– Causes mean arterial pressure to rise – Stimulates the adrenal cortex to release

aldosterone

• As a result, both systemic and glomerular hydrostatic pressure rise

Sympathetic Effects

• Sympathetic activity constricts afferent arteriole – Helps maintain

BP & shunts blood to heart & muscles

Fig 17.11

17-26

17-28

Tubular Reabsorption: Overview

• Tubular reabsorption: occurs as filtrate flows through the lumens of proximal tubule, loop of Henle, distal tubule, and collecting ducts

• Results because of – Diffusion– Facilitated diffusion– Active transport– Cotransport– Osmosis

• Substances transported to interstitial fluid and reabsorbed into peritubular capillaries: inorganic salts, organic molecules, 99% of filtrate volume. These substances return to general circulation through venous system

Routes of Water and Solute Reabsorption

Figure 25.11

Nonreabsorbed Substances

• Substances are not reabsorbed if they: – Lack carriers– Are not lipid soluble– Are too large to pass through membrane

pores

• Urea, creatinine, and uric acid are the most important nonreabsorbed substances

Nonreabsorbed Substances

• A transport maximum (Tm):

– Reflects the number of carriers in the renal tubules available

– Exists for nearly every substance that is actively reabsorbed

• When the carriers are saturated, excess of that substance is excreted

Reabsorption of Salt & H20

• In PCT returns most molecules & H20 from filtrate back to peritubular capillaries– About 180 L/day of ultrafiltrate produced; only 1–2 L

of urine excreted/24 hours• Urine volume varies according to needs of body• Minimum of 400 ml/day urine necessary to excrete

metabolic wastes (obligatory water loss)

17-31

Reabsorption of Salt & H20 continued

• Return of filtered molecules is called reabsorption

• Water is never transported– Other molecules

are transported & water follows by osmosis

Fig 17.13

17-32

PCT• Filtrate in PCT is

isosmotic to blood (300 mOsm/L)

• Thus reabsorption of H20 by osmosis cannot occur without active transport (AT)– Is achieved by AT of

Na+ out of filtrate• Loss of + charges

causes Cl- to passively follow Na+

• Water follows salt by osmosis

Fig 17.1417-33

Na+ Entry into Tubule Cells

• Passive entry: Na+-K+ ATPase pump• In the PCT: facilitated diffusion using symport

and antiport carriers• In the ascending loop of Henle: facilitated

diffusion via Na+-K+-2Cl symport system• In the DCT: Na+-Cl– symporter• In collecting tubules: diffusion through

membrane pores

Insert fig. 17.14

Fig 17.15

17-34

Significance of PCT Reabsorption

• ≈65% Na+, Cl-, & H20 is reabsorbed in PCT & returned to bloodstream

• An additional 20% is reabsorbed in descending loop of Henle

• Thus 85% of filtered H20 & salt are reabsorbed early in tubule– This is constant & independent of hydration levels– Energy cost is 6% of calories consumed at rest– The remaining 15% is reabsorbed variably,

depending on level of hydration17-35

• Substances reabsorbed in PCT include:– Sodium, all nutrients, cations, anions, and water– Urea and lipid-soluble solutes– Small proteins

• Loop of Henle reabsorbs:– H2O, Na+, Cl, K+ in the descending limb

– Ca2+, Mg2+, and Na+ in the ascending limb

Absorptive Capabilities of Renal Tubules and Collecting Ducts

• DCT absorbs:– Ca2+, Na+, H+, K+, and water

– HCO3 and Cl

• Collecting duct absorbs:– Water and urea

Absorptive Capabilities of Renal Tubules and Collecting Ducts

Concentration Gradient in Kidney

• In order for H20 to be reabsorbed, interstitial fluid must be hypertonic

• Osmolality of medulla interstitial fluid (1200-1400 m O sm) is 4X that of cortex & plasma (300 m O sm) – This concentration gradient results largely from loop

of Henle which allows interaction between descending & ascending limbs

17-36

Osmotic Gradient in the Renal Medulla

Figure 25.13

Osmolality of Different Regions of the Kidney

Fig 17.20

17-47

Descending Limb LH

• Is permeable to H20

• Is impermeable to salt• Because deep regions

of medulla are 1400 mOsm, H20 diffuses out of filtrate until it equilibrates with interstitial fluid– This H20 is reabsorbed

by capillaries

Fig 17.1717-37

Ascending Limb LH

• Has a thin segment in depths of medulla & thick part toward cortex

• Impermeable to H20; permeable to salt; thick part ATs salt out of filtrate– AT of salt causes

filtrate to become dilute (100 mOsm) by end of LH

Fig 17.1717-38

AT in Ascending Limb LH• Fig 17.16

• NaCl is actively extruded from thick ascending limb into interstitial fluid

• Na+ diffuses into tubular cell with secondary active transport of K+ and Cl-

• Occurs at a ratio of 1 Na+ & 1 K+ to 2 Cl-

Insert fig. 17.15

17-39

• Na+ is AT across basolateral membrane by Na+/ K+ pump

• Cl- passively follows Na+ down electrical gradient

• K+ passively diffuses back into filtrate

AT in Ascending Limb LH continued

Fig 17.1617-40

Regulation of Urine Concentration and Volume

• Osmolality– The number of solute particles dissolved in 1L of

water– Reflects the solution’s ability to cause osmosis

• Body fluids are measured in milliosmols (mOsm)

• The kidneys keep the solute load of body fluids constant at about 300 mOsm

• This is accomplished by the countercurrent mechanism

Countercurrent Multiplier System

• Countercurrent flow & proximity allow descending & ascending limbs of LH to interact in a way that causes osmolality to build in medulla

• Salt pumping in thick ascending part raises osmolality around descending limb, causing more H20 to diffuse out of filtrate– This raises osmolality of filtrate in descending limb which causes more

concentrated filtrate to be delivered to ascending limb.– As this concentrated filtrate is subjected to AT of salts, it causes even

higher osmolality around descending limb (positive feedback)– Process repeats until equilibrium is reached when osmolality of medulla

is 1400 mOsm.

17-41

Loop of Henle: Countercurrent Mechanism

Figure 25.14

Formation of Dilute Urine

• Filtrate is diluted in the ascending loop of Henle

• Dilute urine is created by allowing this filtrate to continue into the renal pelvis

• This will happen as long as antidiuretic hormone (ADH) is not being secreted

Formation of Dilute Urine

• Collecting ducts remain impermeable to water; no further water reabsorption occurs

• Sodium and selected ions can be removed by active and passive mechanisms

• Urine osmolality can be as low as 50 mOsm (one-sixth that of plasma)

Formation of Concentrated Urine

• Antidiuretic hormone (ADH) inhibits diuresis

• This equalizes the osmolality of the filtrate and the interstitial fluid

• In the presence of ADH, 99% of the water in filtrate is reabsorbed

Formation of Concentrated Urine

• ADH-dependent water reabsorption is called facultative water reabsorption

• ADH is the signal to produce concentrated urine

• The kidneys’ ability to respond depends upon the high medullary osmotic gradient

Formation of Dilute and Concentrated Urine

Figure 25.15a, b

Vasa Recta

• Is important component of countercurrent multiplier

• Permeable to salt, H20 (via aquaporins), & urea

• Recirculates salt, trapping some in medulla interstitial fluid

• Reabsorbs H20 coming out of descending limb

• Descending section has urea transporters

• Ascending section has fenestrated capillaries

Fig 17.18

17-42

Effects of Urea

• Urea contributes to high osmolality in medulla– Deep region of

collecting duct is permeable to urea & transports it

Fig 17.19

17-43

17-44

Collecting Duct (CD)

• Plays important role in water conservation• Is impermeable to salt in medulla• Permeability to H20 depends on levels of ADH

17-45

ADH

• Is secreted by post pituitary in response to dehydration

• Stimulates insertion of aquaporins (water channels) into plasma membrane of CD

• When ADH is high, H20 is drawn out of CD by high osmolality of interstitial fluid– & reabsorbed by vasa

recta

Fig 17.21

17-46

Glucose & Amino Acid Reabsorption

• Filtered glucose & amino acids are normally 100% reabsorbed from filtrate– Occurs in PCT by carrier-mediated cotransport with

Na+• Transporter displays saturation if ligand concentration in

filtrate is too high– Level needed to saturate carriers & achieve maximum transport

rate is transport maximum (Tm)

– Glucose & amino acid transporters don't saturate under normal conditions

17-58

Glycosuria

• Is presence of glucose in urine• Occurs when glucose > 180-200mg/100ml plasma

(= renal plasma threshold)– Glucose is normally absent because plasma levels stay

below this value– Hyperglycemia has to exceed renal plasma threshold– Diabetes mellitus occurs when hyperglycemia results in

glycosuria

17-59

Hormonal Effects

17-60

Electrolyte Balance

• Kidneys regulate levels of Na+, K+, H+, HC03-,

Cl-, & PO4-3 by matching excretion to ingestion

• Control of plasma Na+ is important in regulation of blood volume & pressure

• Control of plasma of K+ important in proper function of cardiac & skeletal muscles

17-61

Role of Aldosterone in Na+/K+ Balance

• 90% filtered Na+ & K+ reabsorbed before DCT– Remaining is variably reabsorbed in DCT & cortical

CD according to bodily needs• Regulated by aldosterone (controls K+ secretion & Na+

reabsorption)• In the absence of aldosterone, 80% of remaining Na+ is

reabsorbed in DCT & cortical CD• When aldosterone is high all remaining Na+ is reabsorbed

17-62

K+ Secretion

• Is only way K+ ends up in urine

• Is directed by aldosterone & occurs in DCT & cortical CD– High K+ or Na+

will increase aldosterone & K+ secretion

Fig 17.25

17-63

Juxtaglomerular Apparatus (JGA)

• Is specialized region in each nephron where afferent arteriole comes in contact with thick ascending limb LH

Fig 17.26

17-64

Renin-Angiotensin-Aldosterone System

• Is activated by release of renin from granular cells within afferent arteriole – Renin converts angiotensinogen to angiotensin I

• Which is converted to Angio II by angiotensin-converting enzyme (ACE) in lungs

• Angio II stimulates release of aldosterone

17-65

Regulation of Renin Secretion

• Inadequate intake of NaCl always causes decreased blood volume– Because lower osmolality inhibits ADH, causing

less H2O reabsorption

– Low blood volume & renal blood flow stimulate renin release

• Via direct effects of BP on granular cells & by Symp activity initiated by arterial baroreceptor reflex (see Fig 14.26)

17-66

Fig 17.27

17-67

Macula Densa• Is region of

ascending limb in contact with afferent arteriole

• Cells respond to levels of Na+ in filtrate– Inhibit renin

secretion when Na+ levels are high

– Causing less aldosterone secretion, more Na+ excretion

Fig 17.26

17-68

Renin Release

Figure 25.10

17-69

Atrial Natriuretic Peptide (ANP)

• Is produced by atria due to stretching of walls

• Acts opposite to aldosterone

• Stimulates salt & H20 excretion

• Acts as an endogenous diuretic

17-70

Na+, K+, H+, & HC03-

Relationships

17-71

Na+, K+, & H+ Relationship

• Na+ reabsorption in DCT & CD creates electrical gradient for H+ & K+ secretion

• When extracellular H+ increases, H+ moves into cells causing K+ to diffuse out & vice versa– Hyperkalemia can cause

acidosis

• In severe acidosis, H+ is secreted at expense of K+

Insert fig. 17.27

Fig 17.28

17-72

Renal Acid-Base Regulation

• Kidneys help regulate blood pH by excreting H+ &/or reabsorbing HC03

-

• Most H+ secretion occurs across walls of PCT in exchange for Na+ (Na+/H+ antiporter)

• Normal urine is slightly acidic (pH = 5-7) because kidneys reabsorb almost all HC03

- & excrete H+

17-73

Reabsorption of HCO3- in PCT

• Is indirect because apical membranes of PCT cells are impermeable to HCO3

-

17-74

Reabsorption of HCO3- in PCT continued

• When urine is acidic, HCO3- combines with H+ to form H2C03

(catalyzed by CA on apical membrane of PCT cells)• H2C03 dissociates into C02 + H2O• C02 diffuses into PCT cell & forms H2C03 (catalyzed by CA)• H2C03 splits into HCO3

- & H+ ; HCO3- diffuses into blood

Fig 17.29

17-75

Urinary Buffers

• Nephron cannot produce urine with pH < 4.5• Excretes more H+ by buffering H+s with HPO4

-2 or NH3 before excretion

• Phosphate enters tubule during filtration• Ammonia produced in tubule by deaminating

amino acids • Buffering reactions

– HPO4-2 + H+ H2PO4

-

– NH3 + H+ NH4+ (ammonium ion)

17-76

Physical Characteristics of Urine

• Color and transparency– Clear, pale to deep yellow (due to

urochrome)– Concentrated urine has a deeper yellow

color– Drugs, vitamin supplements, and diet can

change the color of urine– Cloudy urine may indicate infection of the

urinary tract

Physical Characteristics of Urine

• Odor– Fresh urine is slightly aromatic– Standing urine develops an ammonia odor– Some drugs and vegetables (asparagus)

alter the usual odor

Physical Characteristics of Urine

• pH – Slightly acidic (pH 6) with a range of 4.5 to

8.0– Diet can alter pH

• Specific gravity– Ranges from 1.001 to 1.035 – Is dependent on solute concentration

Urethra

Figure 25.18a. b

Micturition (Voiding or Urination)

• The act of emptying the bladder• Distension of bladder walls initiates spinal

reflexes that:– Stimulate contraction of the external urethral

sphincter– Inhibit the detrusor muscle and internal sphincter

(temporarily)

• Voiding reflexes:– Stimulate the detrusor muscle to contract– Inhibit the internal and external sphincters

Micturition (Voiding or Urination)

Kidney Diseases

• In acute renal failure, ability of kidneys to excrete wastes & regulate blood volume, pH, & electrolytes is impaired– Rise in blood creatinine & decrease in renal plasma

clearance of creatinine– Can result from atherosclerosis, inflammation of

tubules, kidney ischemia, or overuse of NSAIDs

17-80

Kidney Diseases continued

• Glomerulonephritis is inflammation of glomeruli– Autoimmune attack against glomerular capillary

basement membranes• Causes leakage of protein into urine resulting in

decreased colloid osmotic pressure & resulting edema

17-81

• In renal insufficiency, nephrons have been destroyed as a result of a disease – Clinical manifestations include salt & H20 retention & uremia

(high plasma urea levels)• Uremia is accompanied by high plasma H+ & K+ which can cause

uremic coma

– Treatment includes hemodialysis• Patient's blood is passed through a dialysis machine which separates

molecules on basis of ability to diffuse through selectively permeable membrane

• Urea & other wastes are removed

Kidney Diseases continued

17-82