Chapter 17

Physiology of the Kidneys

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Kidney Function

Regulate ECF (plasma and interstitial fluid) through formation of urine.

Primary function.

Regulate volume of blood plasma.

BP.

Regulate [waste products] in the blood. Regulate concentration of electrolytes.

Regulate pH. Secrete erythropoietin.

Na+, K+, and HC03- and other ions.

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Structure of the Kidney

Outer cortex:

Contains many capillaries.

Renal pyramids separated by renal columns. Pyramid contains minor calyces which unite to form a major calyx.

Medulla:

Major calyces form renal pelvis. Renal pelvis collects urine. Transports urine to ureters.

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Micturition Reflex

Actions of the internal urethral sphincter and the external urethral sphincter are regulated by reflex control center located in the spinal cord.

Filling of the urinary bladder activates the stretch receptors, that send impulses to the micturition center.

Activates parasympathetic neurons, causing rhythmic contraction of the detrusor muscle and relaxation of the internal urethral sphincter.

Voluntary control over the external urethral sphincter.

When urination occurs, descending motor tracts to the micturition center inhibit somatic motor fibers of the external urethral sphincter.

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Nephron

Functional unit of the kidney. Consists of:

Blood vessels:

Vasa recta. Peritubular capillaries. PCT. LH. DCT. CD.

Urinary tubules:

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Renal Blood Vessels

Afferent arteriole:

Delivers blood into the glomeruli. Capillary network that produces filtrate that enters the urinary tubules. Delivers blood from glomeruli to peritubular capillaries. Deliver blood to vasa recta.

Glomeruli:

Efferent arteriole:

Peritubular capillaries:

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Renal Blood Vessels

(continued)

Insert fig. 17.5

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Nephron Tubules

Glomerular capsule. Proximal convoluted tubule (PCT). Descending and ascending limbs of Loop of Henle (LH). Distal convoluted tubule (DCT). Collecting duct (CD).

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Glomerular Capsule

Bowmans capsule:

Surrounds the glomerulus.

Insert fig. 17.6

Location where glomerular filtration occurs.

Filtrate passes into the urinary space into PCT.

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Proximal Convoluted Tubule

Single layer of cuboidal cells with millions of microvilli.

Increase surface area for reabsorption. Reabsorption. Secretion.

PCT functions:

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Loop of Henle

Fluid passes from PCT to LH. Descending limb:

H20 reabsorption. Active transport of Na+. Impermeable to H20.

Ascending limb:

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Distal Convoluted Tubule

Contains few microvilli. Functions:

Secretion. Reabsorption.

Terminates in CD.

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Type of Nephrons

Cortical nephron:

Originates in outer 2/3 of cortex.

Osmolarity of 300 mOsm/l.

Involved in solute reabsorption.

Insert fig. 17.6

Juxtamedullary nephron:

Originates in inner 1/3 cortex.

Important in the ability to produce a concentrated urine.

Has longer LH.

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Collecting Duct

Receives fluid from the DCT of several nephrons. Passes through renal pyramid into minor calyx. Functions:

Reabsorption.

Secretion.

H20 reabsorption influenced by ADH.

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Glomerular Filtration Membrane

Endothelial capillary pores are large fenestrae. 100-400 times more permeable to plasma, H20, and dissolved solutes than capillaries of skeletal muscles. Pores are small enough to prevent RBCs, platelets, and WBCs from passing through the pores.

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Glomerular Filtration Membrane

(continued)

Filtrate must pass through the basement membrane:

Thin glycoprotein layer. Negatively charged. Foot pedicels form small filtration slits. Passageway through which filtered molecules must pass.

Podocytes:

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Glomerular Filtration Membrane

(continued)

Insert fig. 17.8

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Glomerular Ultrafiltrate

Fluid that enters glomerular capsule is called ultrafiltrate.

Glomerular filtration:

Mechanism of producing ultrafiltrate under hydrostatic pressure of the blood.

Process similar to the formation of tissue fluid by other capillary beds.

Glomerular filtration rate (GFR):

Volume of filtrate produced by both kidneys each minute.

Averages 115 ml/min. in women; 125 ml/min. in men.

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Regulation of GFR

Vasoconstriction or dilation of the afferent arterioles affects the rate of blood flow to the glomerulus.

Affects GFR. Sympathetic nervous system. Autoregulation.

Mechanisms to regulate GFR:

Changes in diameter result from extrinsic and intrinsic mechanisms.

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Sympathetic Regulation of GFR

Stimulates vasoconstriction of afferent arterioles.

Preserves blood volume to muscles and heart. Decreases glomerular capillary hydrostatic pressure. Decreases urine output (UO).

Insert fig. 17.11

Cardiovascular shock:

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Renal Autoregulation of GFR

Ability of kidney to maintain a constant GFR under systemic changes.

Achieved through effects of locally produced chemicals on the afferent arterioles.

When MAP drops to 70 mm Hg, afferent arteriole dilates. When MAP increases, vasoconstrict afferent arterioles. Tubuloglomerular feedback:

Increased flow of filtrate sensed by macula densa cells in thick ascending LH.

Signals afferent arterioles to constrict.

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Reabsorption of Salt and H20

Return of most of the molecules and H20 from the urine filtrate back into the peritubular capillaries.

About 180 L/day of ultrafiltrate produced; however, only 12 L of urine excreted/24 hours.

Urine volume varies according to the needs of the body.

Minimum of 400 ml/day urine necessary to excrete metabolic wastes (obligatory water loss).

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Reabsorption in Proximal Tubule

Insert fig. 17.13

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PCT

Total [solute] is = 300 mOsm/L. Reabsorption of H20 by osmosis, cannot occur without active transport:

[Na+] in glomerular ultrafiltrate is 300 mOm/L.

PCT epithelial cells have lower [Na+].

Due to low permeability of plasma membrane to Na+.

Active transport of Na+ out of the cell by Na+/K+ pumps.

Favors [Na+] gradient:

Na+ diffusion into cell.

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PCT

(continued)

Na+/K+ ATPase pump located in basal and lateral sides of cell membrane, creates gradient for diffusion of Na+ across the apical membrane. Na+/K+ ATPase pump extrudes Na+.

Creates potential difference across the wall of the tubule, with lumen as pole.

Electrical gradient causes Cl- movement towards higher [Na+].

H20 follows by osmosis.

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Salt and Water Reabsorption in Proximal Tubule

Insert fig. 17.14

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Significance of PCT Reabsorption

65% Na+, Cl-, and H20 reabsorbed across the PCT into the vascular system. 90% K+ reabsorbed. Reabsorption occurs constantly regardless of hydration state.

Not subject to hormonal regulation.

Energy expenditure is 6% of calories consumed at rest.

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Countercurrent Multiplier

In order for H20 to be reabsorbed, interstitial fluid must be hypertonic. Osmotic pressure of the interstitial tissue fluid is 4 x that of plasma.

Results partly from the fact that the tubule bends permitting interaction between the descending and ascending limbs.

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Ascending Limb LH

NaCl is actively extruded from the ascending limb into surrounding interstitial fluid. Na+ diffuses into tubular cell with the secondary active transport of K+ and Cl-. Occurs at a ratio of 1 Na+ and 1 K+ to 2 Cl-.

Insert fig. 17.15

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Ascending Limb LH

(continued)

Na+ actively transported across the basolateral membrane by Na+/ K+ ATPase pump. Cl- passively follows Na+ down electrical gradient. K+ passively diffuses back into filtrate. Ascending walls are impermeable to H20.

Insert fig. 17.15

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Descending Limb LH

Deeper regions of medulla reach 1400 mOsm/L. Impermeable to passive diffusion of NaCl. Permeable to H20. Hypertonic interstitial fluid causes H20 movement out of the descending limb via osmosis, and H20 enters capillaries. Fluid volume decreases in tubule, causing higher [Na+] in the ascending limb.

Insert fig. 17.16

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Countercurrent Multiplier System

Multiplies the [interstitial fluid] and [descending limb fluid]. Flow in opposite directions in the ascending and descending limbs. Close proximity of the 2 limbs:

Insert fig. 17.16

Allows interaction.

Positive feedback.

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Vasa Recta

Countercurrent exchange. Recycles NaCl in medulla. Transports H20 from interstitial fluid. Descending limb:

Insert fig. 17.17

Urea transporters. Aquaporin proteins (H20 channels). Fenestrated capillaries.

Ascending limb:

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Vasa Recta

(continued)

Vasa recta maintains hypertonicity by countercurrent exchange. NaCl and urea diffuse into descending limb and diffuse back into medullary tissue fluid. At each level of the medulla, [solute] is higher in the ascending limb than in the interstitial fluid; and higher in the interstitial fluid than in descending vessels. Walls are permeable to H20, NaCl and urea. Colloid osmotic pressure in vasa recta > interstitial fluid.

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Osmolality of Different Regions of the Kidney

Insert fig. 17.19

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Urea

Contributes to total osmolality of interstitial fluid. Ascending limb LH and terminal CD are permeable to urea.

Insert fig. 17.18

Terminal CD has urea transporters.

Urea diffuses out CD and into ascending limb LH.

Recycle urea.

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Collecting Duct

Medullary area impermeable to high [NaCl] that surrounds it.

H20 is drawn out of the CD by osmosis.

The walls of the CD are permeable to H20.

Rate of osmotic movement is determined by the # of aquaporins in the cell membrane.

Permeable to H20 depends upon the presence of ADH.

When ADH binds to its membrane receptors on CD, it acts via cAMP.

Stimulates fusion of vesicles with plasma membrane.

Incorporates water channels into plasma membrane.

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Secretion

Secretion of substances from the peritubular capillaries into interstitial fluid.

Then transported into lumen of tubule, and into the urine.

Allows the kidneys to rapidly eliminate certain potential toxins.

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Proximal Tubule

Secretion

Insert fig. 17.13

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Transport Process Affecting Renal Clearance

Ability of the kidneys to remove molecules from plasma and excrete those molecules in the urine. If a substance is not reabsorbed or secreted, then the amount excreted = amount filtered. Quantity excreted = V x U

Quantity excreted = mg/min. V = rate of urine formation. U = inulin concentration in urine.

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Measurement of GFR

If a substance is neither reabsorbed nor secreted by tubule:

The amount excreted in urine/min. will be equal to the amount filtered out of the glomeruli/min.

Rate at which a substance is filtered by the glomeruli can be calculated: Quantity filtered = GFR x P

P = inulin concentration in plasma.

Amount filtered = amount excreted GFR = V x U P

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Renal Clearance of Inulin

Insert fig. 17.22

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Renal Plasma Clearance

Volume of plasma from which a substance is completely removed in 1 min. by excretion in the urine. Substance is filtered, but not reabsorbed:

All filtered will be excreted.

Substance filtered, but also secreted and excreted will be:

> GFR (GFR = 120 ml/ min.).

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Renal Plasma Clearance

Renal plasma clearance = V x U P

V = urine volume per min. U = concentration of substance in urine P = concentration of substance in plasma

Compare renal handling of various substances in terms of reabsorption or secretion.

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Clearance of Urea

Urea is secreted into blood and filtered into glomerular capsule. Urea clearance is 75 ml/min., compared to clearance of inulin (120 ml/min.).

40-60% of filtered urea is always reabsorbed.

Passive process because of the presence of carriers for facilitative diffusion of urea.

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Measurement of Renal Blood Flow

Not all blood delivered to glomeruli is filtered in the glomerular capsules.

Most of glomerular blood passes to the efferent arterioles. 20% renal plasma flow filtered.

Substances are returned back to blood.

Substances in unfiltered blood must be secreted into tubules to be cleared by active transport (PAH).

PAH can be used to measure renal plasma flow.

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Measurement of Renal Blood Flow

(continued)

Filtration and secretion clear only the molecules dissolved in plasma.

PAH clearance actually measures renal plasma flow.

To convert to total renal blood flow, the amount of blood occupied by erythrocytes must be taken into account.

Averages 625 ml/min.

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Total Renal Blood Flow

45% blood is RBCs 55% plasma Total renal blood flow =

Insert fig. 17.23

PAH clearance 0.55

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Glucose and Amino Acid Reabsorption

Filtered glucose and amino acids are normally reabsorbed by the nephrons.

In PCT occurs by secondary active transport with membrane carriers.

Carrier mediated transport displays:

Saturation. Tm. [Transported molecules] needed to saturate carriers and achieve maximum transport rate.

Renal transport threshold:

Minimum plasma [substance] that results in excretion of that substance in the urine.

Renal plasma threshold for glucose = 180-200 mg/dl.

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Electrolyte Balance

Kidneys regulate Na+, K+, H+, Cl-, HC03-, and PO4-3. Control of plasma Na+ is important in regulation of blood volume and pressure. Control of plasma of K+ important in proper function of cardiac and skeletal muscles.

Match ingestion with urinary excretion.

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Na+ Reabsorption

90% filtered Na+ reabsorbed in PCT. In the absence of aldosterone, 80% of the remaining Na+ is reabsorbed in DCT. Final [Na+] controlled in CD by aldosterone. When aldosterone is secreted in maximal amounts, all Na+ in DCT is reabsorbed.

Insert fig. 17.26

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K+ Secretion

90% filtered K+ is reabsorbed in early part of the nephron. Secretion of K+ occurs in CD.

Amount of K+ secreted depends upon:

Amount of Na+ delivered to the region. Amount of aldosterone secreted.

As Na+ is reabsorbed, lumen of tubule becomes charged.

Potential difference drives secretion of K+ into tubule.

Transport carriers for Na+ separate from transporters for K+.

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K+ Secretion

(continued)

Final [K+] controlled in CD by aldosterone.

When aldosterone is absent, no K+ is excreted in the urine.

Insert fig. 17.24

High [K+] or low [Na+] stimulates the secretion of aldosterone. Only means by which K+ is secreted.

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Juxtaglomerular Apparatus

Region in each nephron where the afferent arteriole comes in contact with the thick ascending limb LH. Granular cells within afferent arteriole secrete renin:

Converts angiotensinogen to angiotensin I. Initiates the renin-angiotensin-aldosterone system. Negative feedback.

Macula densa:

Region where ascending limb is in contact with afferent arteriole. Inhibits renin secretion when blood [Na+] in blood increases.

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Juxtaglomerular Apparatus

(continued)

Insert fig. 17.25

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ANP

Produced by atria due to stretching of walls. Antagonist to aldosterone. Increases Na+ and H20 excretion. Acts as an endogenous diuretic.

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Na+, K+, and H+ Relationship

Na+ reabsorption in CD creates electrical gradient for K+ secretion. Plasma [K+] indirectly affects [H+]. When extracellular [H+] increases, H+ moves into the cell, causing K+ to diffuse into the ECF. In severe acidosis, H+ is secreted at the expense of K+.

Insert fig. 17.27

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Renal Acid-Base Regulation

Kidneys help regulate blood pH by excreting H+ and reabsorbing HC03-. Most of the H+ secretion occurs across the walls of the PCT in exchange for Na+.

Antiport mechanism.

Moves Na+ and H+ in opposite directions.

Normal urine normally is slightly acidic because the kidneys reabsorb almost all HC03- and excrete H+.

Returns blood pH back to normal range.

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Reabsorption of HCO3

Apical membranes of tubule cells are impermeable to HCO3-.

Reabsorption is indirect.

When urine is acidic, HCO3- combines with H+ to form H2C03-, which is catalyzed by ca located in the apical cell membrane of PCT.

HCO3- generated within tubule cell diffuses into peritubular capillary.

As [C02] increases in the filtrate, C02 diffuses into tubule cell and forms H2C03. H2C03 dissociates to HCO3- and H+.

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Acidification of Urine
Insert fig. 17.28

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Urinary Buffers

Nephron cannot produce a urine pH < 4.5. In order to excrete more H+, the acid must be buffered. H+ secreted into the urine tubule and combines with HPO4-2 or NH3. HPO4-2 + H+ H2PO4NH3 + H+ NH4+

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Diuretics

Increase urine volume excreted.

Increase the proportion of glomerular filtrate that is excreted as urine. Inhibit NaCl transport out of the ascending limb of the LH. Inhibit NaCl reabsorption in the 1st segment of the DCT.

Loop diuretics:

Thiazide diuretics:

Ca inhibitors:

Prevent H20 reabsorption in PCT when HC0s- is reabsorbed.

Increase osmotic pressure of filtrate.

Osmotic diuretics:

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Clinical Diuretics Sites of Action

Insert fig. 17.29

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Kidney Diseases

Acute renal failure:

Ability of kidneys to excrete wastes and regulate homeostasis of blood volume, pH, and electrolytes impaired.

Rise in blood [creatinine]. Decrease in renal plasma clearance of creatinine.

Glomerulonephritis:

Inflammation of the glomeruli. Autoimmune disease by which antibodies have been raised against the glomerulus basement membrane.

Leakage of protein into the urine.

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Kidney Diseases

(continued)

Renal insufficiency:

Nephrons are destroyed. Clinical manifestations:

Salt and H20 retention. Uremia. Elevated plasma [H+] and [K+].

Dialysis:

Separates molecules on the basis of the ability to diffuse through selectively permeable membrane.