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

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Fig 17.5

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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 17.6

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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

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Glomerular Filtration continued

To enter tubule filtrate must pass through narrow filtration slits formed between pedicels of podycytes of glomerular capsule
Fig 17.8
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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 Bowmans 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
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Filtration
Filtration membrane: filtration barrier. It prevents blood cells and proteins from entering lumen of Bowmans 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 Bowmans capsules Forces that affect movement of fluid into or out of the lumen of Bowmans capsule Glomerular capillary pressure (GCP): blood pressure inside capillary tends to move fluid out of capillary into Bowmans 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 Bowmans 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
GFR

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

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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 reninangiotensin 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

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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

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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

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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 12 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)

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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
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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 17.14
17-33

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

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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 hydration
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Absorptive Capabilities of Renal Tubules and Collecting Ducts

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

Concentration Gradient in Kidney

In order for H20 to be reabsorbed, interstitial fluid must be hypertonic Osmolality of medulla interstitial fluid (12001400 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

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Osmotic Gradient in the Renal Medulla

Figure 25.13

Osmolality of Different Regions of the Kidney

Fig 17.20

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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 17.17
17-37

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 17.17
17-38

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

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AT in Ascending Limb LH continued

Na+ is AT across basolateral membrane by Na+/ K+ pump Cl- passively follows Na+ down electrical gradient K+ passively diffuses back into filtrate
Fig 17.16
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Regulation of Urine Concentration and Volume

Osmolality
The number of solute particles dissolved in 1L of water Reflects the solutions 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.

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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

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Effects of Urea
Urea contributes to high osmolality in medulla
Deep region of collecting duct is permeable to urea & transports it

Fig 17.19
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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

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ADH
Fig 17.21 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
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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

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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

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Hormonal Effects

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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

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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

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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
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Juxtaglomerular Apparatus (JGA)

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

Fig 17.26

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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

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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)

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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
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Fig 17.26

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

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Na+, K+, H+, & HC03Relationships

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

Insert fig. 17.27

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

Fig 17.28

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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)

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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

Kidney Diseases continued

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

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