Renal physiology

Dr. Ramadan Mohamed Ahmed.

Eslam.anes@yahoo.com

Chief Functions of Renal System

1. Regulation of water & electrolyte balance 2. Regulation of acid & base balance 3. Excretion of waste products of protein metabolism, e.g.,  Urea from protein breakdown  Uric acid from nucleic acid breakdown  Creatinine from muscle creatine breakdown  End products of hemoglobin breakdown 4.Excretion of foreign chemicals, e.g., drugs, food additives, pesticides, etc. 5. Endocrine function: erythropoietin, renin, 1,25-dihydoxy-vitamin D.
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FUNCTIONAL ANATOMY OF KIDNEYS & URINARY TRACT

The kidneys lie high on the posterior abdominal wall below the diaphragm & on either side of the vertebral column. In adults each kidney is the size of a clenched fist & weighs ~150 g. Urine produced by the kidneys is delivered to the urinary bladder by 2 ureters. The bladder continuously accumulates urine and periodically empties its contents via urethra under the control of an external urethral sphincter a process known as micturition.
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FUNCTIONAL ANATOMY: kidney

Each kidney is formed of 2 distinct parts: An outer cortex An inner medulla.

The nephron is the functional unit

of the kidney. Each kidney contains ~ 1 million nephrons.

The nephron is composed of 2 main components: A. The renal corpuscle B. The renal tubule

The Nephron

THE NEPHRON
A. Renal Corpuscle: (Site of filtration of blood)
1. The Glomerulus: - It is present in the cortex. - Each glomerulus is formed of a tuft of capillaries that are invaginated into the Bowmans capsule. - Blood enters the capillaries through the afferent arteriole and leaves through the slightly narrower efferent arteriole. - Glomerular capillaries are unique in that they are interposed between 2 arterioles. This arrangement serves to maintain a high hydrostatic pressure in the capillaries, 6 which is necessary for filtration.

THE NEPHRON
A. Renal Corpuscle:
2. The Bowmans Capsule:
It is the proximal expanded portion of the renal tubule forming a double-walled cup

THE NEPHRON
B. Renal Tubule:
1. Proximal convoluted tubule (PCT) 2. Loop of Henle: It is further subdivided into: Thin descending limb Thin ascending limb Thick ascending limb 3. Distal convoluted tubule (DCT) - Many DCTs open into a collecting duct (CD). CDs pass from the cortex (cortical CD) to the medulla (medullary CD) and finally drain urine into the renal pelvis. - PCT & DCT are present in the cortex, while the descending limb of loop of Henle dips into the medulla, forming a hairpin turn & then 8 returns back to the cortex.

THE NEPHRON
Juxtaglomerular Apparatus:
 Each DCT passes between the afferent & efferent arterioles of its own nephron. At this point there is a patch of cells with crowded nuclei in the wall of the DCT called the macula densa. They sense the concentration of NaCl in this portion of the tubule.  The wall of the afferent arteriole opposite the macula densa contains specialized cells known as the juxtaglomerular cells (JG cells). They secrete renin. Together, the macula densa & JG cells are called the juxtaglomerular apparatus (JGA).
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The JuxtaJuxtaglomerular Apparatus

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THE NEPHRON (cont.)

There are 2 types of nephrons in the kidney:
1. Cortical Nephrons: (80% of nephrons)  Their glomeruli lie in the outer layers of the cortex.  Their tubular system is relatively short.  Their loops of Henle penetrate only for a short distance into the outer portion of renal medulla. 2. Juxtamedullary Nephrons: (20% of nephrons)  Their glomeruli lie at the boundary between cortex & medulla.  They have long loops of Henle, which dip deeply down into the medulla toward the tips of the pyramids. 12  They play a major role in the process of urine concentration.

Types of nephrons
Items

Cortical nephrons

Juxtamedullary nephrons

% Of total Glomeruli Loop of Henle

85 % Out part of cortex Short i.e. dips to the junction between inner and outer medulla. Peritubular capillaries No Vasa Recta Na reabsorption Present Present

15% Inner part of cortex . Long i.e. dips deeply into the medullary pyramids to the inner medulla Vasa recta and peritubular capillaries Urine concentration Absent Absent

Blood supply

Special function JG apparatus

Autoregulation

Juxtamedullary Nephron

Cortical Nephron

The efferent vessels of juxtamedullary glomeruli form long looped vessels, called vasa recta which is important for urine concentration.

So,why is the loop of Henle useful?

The longer the loop, the more concentrated the filtrate and the medullary IF become Importance: the collecting tubule runs through the hyperosmotic medulla more ability to reabsorb H2O

Desert animals have long nephron Loop More H2O is reabsorbed

BLOOD VESSELS in the NEPHRONS

Each kidney receives its blood supply from a renal artery, which arises directly from the abdominal aorta. In the kidney, the renal artery progressively subdivides into smaller branches until they form afferent arterioles, which break up into a tuft of capillaries, the glomerulus. Then the capillaries form the efferent arteriole. The efferent arteriole again subdivides to form peritubular capillaries, which surround the various segments of the renal tubules. N.B. There are 2 sets of capillaries & 2 sets of arterioles!! The efferent arterioles of juxtamedullary nephrons form a special type of peritubular capillaries called vasa recta.  They are straight & long capillaries that form hairpin loops along side the loops of Henle.  They play an important role in the process of urine 17 concentration.

Blood supply of the kidney

Major renal capillaries

Glomerular capillary bed Peritubular capillary bed

1. Receives bl from afferent Receives bl from efferent art. art. Low pressure bed 13 mmHg 2. High presure bed 55 mmHg 3.Represents arterial end of cap. 4. allows fluid filtration. Represents venous end of cap. Allows fluid reabsorption.

Blood Supply of Cortical & Juxtamedullary Nephrons

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RENAL BLOOD FLOW (RBF)

Renal blood flow is about 20% of the cardiac output This is a very large flow relative to the weight of the kidneys (350 g) RBF determines GFR RBF also modifies solute and water reabsorption and delivers nutrients to nephron cells. Renal blood flow is autoregulated between 70 and 170 mm Hg by varying renal vascular resistance (RVR). i.e. the resistances of the interlobular artery, afferent arteriole and efferent arteriole

Factors affecting RBF

1) Autoregulation:
RBF is kept relatively constant between ABP; 70-170 mmHg, It is present in denervated, isolated kidney, this proving that this property is intrinsic property.

2) Sympathetic stimulation:

VC of afferent arteriole of cortical nephrons p decreased cortical blood flow. Less effect on juxtamedullary nephrons p remains well perfused. VC of vasa recta p decrease medullary blood flow p more urine concentration.

Autoregulation of RBF & GFR

Note: Autoregulation is important to prevent large changes in GFR that would greatly affect urinary output.

AUTOREGULATION

RBF (L/min)

1.5 1.0 0.5

AUTOREGULATORY RANGE

40

80

120

160

200

240

BP (mmHg)

EFFECT OF ARTERIAL PRESSURE CHANGES ON GFR, RBF AND URINE OUTPUT RBF or GRF (% of normal)

150 RBF 100 GFR Urine Output

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50

100 150 200 Arterial Pressure (mmHg)

Impact of autoregulation
Autoregulation: GFR=180L/day and tubular reabsorption=178.5L/day Results in 1.5L/day in urine Without autoregulation: Small in BP 100 to 125mm Hg, GFR by 25% (180 to 225L/day) If tubular reabsorption constant, urine flow of 46.5 L/day What would happen to plasma volume?

MEASUREMENT OF RENAL BLOOD FLOW

Renal blood flow (RBF) is determined by measuring first the renal plasma flow (RPF) and then calculating the RBF. We measure RPF using paraaminohippuric acid (PAH). PAH is a substance that is:  freely filtered by the glomeruli, secreted in the tubules, but not reabsorbed. If PAH is given by intravenous (IV) infusion so that its concentration is kept low in plasma (e.g., 2 mg%), it is almost completely removed with a single circulation of plasma in the kidneys. 10% of PAH remain in blood, because 10% of the blood that goes to the kidneys does not reach the nephrons, but supplies other renal 27 tissues.

MEASUREMENT OF RENAL BLOOD FLOW

If we apply Ficks principle, we can calculate RPF:

Amount of PAH = filtered & secreted/min

Amount of PAH excreted in urine/min

Amount of PAH filtered & secreted = P x ERPF Amount of PAH excreted in urine/min. = U x V where, P = conc. of PAH in plasma ERPF = effective RPF (90% of plasma only, i.e., taking into account that 10% bypasses the nephrons). U = conc. of PAH in urine V = volume of urine/min. P x ERPF = U x V UxV ERPF = 28 P

Urine formation

Urine Formation
Glomerular Filtration substances move from blood to glomerular capsule Tubular Reabsorption substances move from renal tubules into blood of peritubular capillaries glucose, water, urea, proteins, creatine amino, lactic, citric, and uric acids phosphate, sulfate, calcium, potassium, and sodium ions Tubular Secretion substances move from blood of peritubular capillaries into renal tubules drugs and ions

Overall fluid movement in the kidneys

Glomerular filtration
It takes place between glomerular capillaries endothelium (characterized by the presence of numerous small pores (fenestrations) and Bowmans Bowman capsule (characterized by the presence of podocytes). podocytes). Podocytes are modified squamous epithelial cells with numerous elongated branches called foot processes which are separated by narrow gaps called filtration slits (slit pores). Fluid and small solutes dissolved in the plasma such as glucose, amino acids, Na, K, Cl, HCO3- , other salts, and urea pass through the Cl, membrane and become part of the filtrate. The glomerular membrane hold back blood cells, platelets and most plasma proteins. The filtrate is about 10% of the plasma. 10% The volume of fluid filtered per unite time is called the glomerular filtration rate (GFR). The GFR is about 180 L/day (=125 ml/min.).

COMPOSITION OF GFR
a- Contents: - water - ions: Na+, K+, Cl- freely filtered substances e.g. glucose, amino acids. - 0.03% albumin (molecular weight 6900). b- Osmolality: 300 mosmol/L, isotonic (same osmolality as plasma). C- Specific gravity: 1010 D- pH: drops to 6 in urine due to acidification by the kidney.

Glomerular Filtration Rate (GFR)

In an average man: 125 ml/minute. In women : 10% less. High renal blood flow (20-25% of cardiac output) needed for high GFR. GFR equals about 180 L/day so plasma volume (3L) filtered about 60 times daily, More than 99% of GFR is normally reabsorbed. Normal volume of urine is about 1.5 litre/day.

Glomerular membrane
Capillary endothelium;
It has small holes (70-90 nm). It does not act as a barrier against plasma protein filtration.

Basement membrane; (BM)

filamentous layer attached to glomerular endothelium & podocytes, carry strongve charges which prevent the filtration of plasma proteins, but filters large amount of H2O and solutes.

Podocytes;
Epithelial cells that line the outer surface of the glomeruli. They have numerous foot processes that attach to the BM, forming filtration slits (25 nm wide).

Filterability of the Membrane

Filterability is a term used to describe membrane selectivity based on the molecular size and charge Pore size would favor plasma protein (albumin) passage, but negative charge on protein is repelled by the (-) charged basement membrane (proteoglycan filaments & podocytes) Loss of this (-) charge causes proteinuria.

Forces affecting filtration

Favoring Filtration
Glomerular hydrostatic pressure 60 mm Hg Bowmans capsule colloid osmotic pressure 0 mm Hg

Opposing Filtration
Glomerular capillary colloid osmotic pressure 32 mm Hg Bowmans capsule hydrostatic pressure 18 mm Hg

Net = +10 mm Hg

FORCES of GFR

Regulation of Filtration
(1) Changes in glomerular hydrostatic pressure.
(1) Diameter of the afferent arterioles. VD of afferent arterioles p ++ Hydrostatic pr. in glomerular capillary p ++ GFR. VC of afferent arterioles e.g ++ sympathetic activity p -Hydrostatic pr. in glomerular capillary (HPGC) p -- GFR. (2) Diameter of the efferent arterioles. Moderate VC p ++ Hydrostatic pr. in glomerular capillary p slight ++ of GFR. (3) Arterial Blood Pressure: Between 70 & 170 mmHg: GFR and RBF are kept relatively constant by autoregulatory mechanisms.

Changes in GFR by constriction or dilation of afferent (AA) or efferent (EA) arterioles

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Regulation of Filtration
(2) Changes in Bowmans Capsule hydrostatic pressure ++ Hydrostatic pr in Bowmans capsule e.g. stone in ureter p -- GFR . (3) Change in glomerular colloidal osmotic pressure Increased Colloidal osmotic pressure in glomerular capillary e.g in dehydration p decreased GFR. Decreased Colloidal osmotic pressure in glomerular capillary e.g in hypoproteinemia p increased GFR. (4) Functioning kidney mass

Measurement of GFR:
(1) Inulin clearance; Inulin has the following characteristics: Freely filtered i.e. plasma conc.= filtrate concentration.
not reabsorbed or secreted by renal tubules i.e. amount filtered per min.= amount excreted in urine/min. Not metabolized. Not stored in the kidney. Does not affect filtration rate & its conc. is easily measured.

(2) Creatinine clearance Freely filtered Not reabsorbed partially secreted by renal tubules. Endogenous so used easily but inaccurate.

Renal Clearance
Definition: Volume of the plasma cleared from the substance per minute.

RC = UV/P
RC = renal clearance rate U = concentration (mg/ml) of the substance in urine V = flow rate of urine formation (ml/min) P = concentration of the same substance in plasma

Inulin clearance

TUBULAR FUNCTION
The glomerular filtrate is formed at a rate of 125 ml/min. or 180 L/day. It passes to the renal tubules. In the tubules, the tubular fluid is subjected to the 2 main tubular functions, reabsorption & secretion. It is finally excreted as urine at a rate of about 1-2 ml/min. or ca. 1.5 L/day.

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Tubular Reabsorption is a Function of the Epithelial Cells Making up the Tubule

Lumen Cells

Plasma

Tubular Reabsorption
A) Active transport; against electrochemical gradient.
(1) Primary active transport Requires energy directly from ATP. Example; Na+ reabsorption in PCT (2) Secondary active transport -It does not require energy direct from ATP. a) Co-transport two substances bind to a specific carrier are cotransported in one direction. b) Counter-transport two substances bind to a specific carrier are transported in two directions.

B) Passive reabsorption; (1) Simple diffusion

Passive reabsorption of chloride & Osmosis of water

(2) Facilitated diffusion

Need carrier.

C) Pinocytosis
It is an active transport mechanism for reabsorption of proteins and peptides in the proximal convoluted tubules.

Proximal Convoluted Tubule

65% of the nephron function occurs in PCT. The PCT has a single layer of cuboidal cells with millions of microvilli.
Increased surface reabsorption. area for

PCT's main function is reabsorption. The PCT is full of mitochondria

Reabsorption in Proximal Tubule 100% Glucose, protein and Amino Acids 60% Sodium, Cl, and H2O. 80% PH, HCO3, K. 60% Ca. 50% of Filtered Urea.

Na reabsorption
 At basolateral side of the tubular epithelial cell there is an extensive Na+-K+ ATPase system (= Na+-K+ pump).  It pumps 3 Na+ actively out of the cell into the interstitium, and at the same time carries 2 K+ into the cell.  But K+ will diffuse immediately back into the interstitium due to: (1) high concentration gradient & (2) high permeability of epithelial cells to K+.  As a result of this there is: - q intracellular Na+ concentration  At luminal membrane there will therefore be passive diffusion of Na+ into the cell along concentration gradient created by the Na+-K+ pump. This diffusion is facilitated by a protein carrier.

Na reabsorption

Water Reabsorption

GLUCOSE: GLUCOSE
At normal blood glucose levels (~100 mg%), glucose is freely filtered at a rate of 125 mg/min. (= plasma conc. X GFR = 100 mg% x 125 ml/min.). The amount filtered is completely reabsorbed from the upper half of PCT by Na+-glucose cotransport (mechanism: see before). There is, however, a limited number of Na+-glucose carriers: a- At a blood glucose level of less than 180 mg%, all the filtered glucose can be reabsorbed because plenty of carriers are available. b- At a blood glucose level of 180 mg%, glucose starts to appear in urine. This level of blood glucose is called the renal threshold for glucose. It corresponds to a renal tubular load of 220 mg/min. c- At a renal tubular load of glucose of 320 mg/min, all the carriers are saturated, i.e., the transport maximum for glucose, TmG, is reached. Any further o in filtered glucose is not reabsorbed & is excreted in urine. 61

Glucose reabsorption
The transporter for glucose on the basolateral membrane has a limited capacity to carry glucose back into the blood. If blood glucose rises above 180 mg/dl, some of the glucose fails to be reabsorbed and remains in the urine glucosuria.

Glucose reabsorption

Tubular maximum for glucose (TmG):

The maximum amount of glucose (in mg ) that can be reabsorbed per min. It equals the sum of TmG of all nephrons. Value; 300 mg/min in , 375 mg/ min in .

Renal Threshold for Glucose

Is approximately 180 mg/dl If plasma glucose is greater than 180 mg/dl: Tm of tubular cells is exceeded glucose appears in urine

GLUCOSE REABSORPTION HAS A TUBULAR MAXIMUM

Glucose Reabsorbed mg/min

Filtered

Excreted

Reabsorbed

Plasma Concentration of Glucose

Glucosuria
presence of glucose in urine 1. Diabetes mellitus blood glucose level > renal threshold. 2. Renal glucosuria It is caused by the defect in the glucose transport mechanism. 3. Phlorhizin A plant glucoside which competes with glucose for the carrier and results in glucosuria (phloridzin diabetes).

Bicarbonate reabsorption

Secretion in Proximal Tubule

Hydrogen secretion for acid/base regulation. Ammonia secretion for acid/base regulation. PAH. Creatinine. Uric acid. Penicillin.

Reabsorption: Loop of Henle

SPECIFIC FUNCTIONS OF DIFFERENT TUBULAR SEGMENTS (cont.) II. Loop of Henle:

The loop of Henle with its 3 segments (that differ structurally & functionally) contributes to creating a gradually increasing hyperosmolality (300 p1200 mosmol/L) in the renal medullary interstitium. A. Thin descending limb: - highly permeable to water. 20% of H2O is reabsorbed here. - only moderately permeable to solutes. Osmolality of tubular fluid o gradually as loop dips deep into the medullary pyramid (reaches 1200 mosmol). B. Thin ascending limb: - impermeable to water - low absorptive power for solutes. C. Thick ascending limb: - impermeable to water - high reabsorptive power for solutes: It actively reabsorbs 25% of filtered Na+, K+, & Cl- (by 1 Na+, 2 Cl-, 1 K+ cotransport) to medullary interstitium. Osmolality of tubular fluid q gradually as it reaches DCT (becomes hypoosmotic). It is called the diluting segment.

SPEC. FUNCTIONS OF DIFF. TUBULAR SEGMENTS

III. Distal Convoluted Tubule (DCT) & Collecting Duct (CD):
A. Late DCT & Cortical CD: (1) Principal Cells: a. They actively reabsorb Na+ in exchange for K+ secretion. This action is increased by aldosterone. b. Antidiuretic hormone (ADH) causes p reabsorption of H2O. In the absence of ADH, the principal cells are impermeable to H2O. (2) E-Intercalated Cells: - These cells secrete H+ .This action is increased by aldosterone.

C. Medullary CD:

In this last portion of the nephron there is final adjustment of volume & concentration of urine.  The permeability of this segment to water, same as that of the late DCT & cortical CD, is variable & depends on the level of circulating ADH (= facultative water reabsorption).  This part is also permeable to urea, that diffuses into the interstitium when its concentration in tubular fluid o due to H2O reabsorption. Thus, urea contributes to the hyperosmolality of medullary interstitium.
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DCT and CD

Medullary Collecting Duct

reabsorbs < 10% of filtered Na+ and water final site for processing of urine functional characteristics: 1. permeability to water is controlled by ADH level - o ADH o water reabsorption 2. permeable to urea - urea is reabsorbed into the medullary interstitium where it help increase the osmolality of the interstitium and therefore help to concentrate urine.

Summary For Tubular Functions

Summary of changes in osmolality of tubular fluid in various parts of the nephron

HORMONAL CONTROL OF TUBULAR FUNCTION

Hormones acting on the kidney

1. Aldosterone:
Stimulus for its secretion: q Blood volume (via renin-angiotentin system). Actions & their site: It stimulates Na+ reabsorption in DCT & cortical CD through: 1) In principal cells: o Na+ reabsorption in exchange with K+. 2) In E-intercalated cells: o Na+ reabsorption in exchange with H+.

2. Angiotensin II: It is the most powerful Na+ retaining hormone.

Stimulus for its secretion: q arterial bl. pressure & blood volume, e.g., hemorrhage (via renin). Actions & their site: 1. It o Na+ reabsorption by several mechanisms: a. By stimulating aldosterone secretion. b. In PCT: - By directly stimulating Na+-K+ ATPase at basolateral border. - By directly stimulating Na+-H+ countertransp. at luminal border. 78 2. It constricts efferent arterioles.

Hormones acting on the kidney

3. Atrial Natriuretic Peptide (ANP): It facilitates NaCl & H2O excretion. Stimulus for its secretion:
o Atrial pressure (released from specific atrial fibers when blood volume is o)

Actions & their site:

1. It o GFR by VD of afferent & VC of efferent arteriole. 2. It q Na+ reabsorption from DCT & cortical CD .

4. ADH:
Stimulus for its secretion: o Plasma osmolarity & q blood volume. Actions & their site: o water reabsorption in late DCT, cortical & medullary CD: by inserting aquaporin water channels into their luminal membranes. 5. Parathormone (PTH): Stimulus for its secretion: q Plasma Ca2+ concentration. Actions & their site: 80 1. o Ca2+ reabsorption from DCT. 2. q Phosphate reabsorption from PCT.

Urea Handling
(1) PCT
About 50% of the filtered urea is passively reabsorbed The wall of PCT is partially permeable to urea but highly permeable to water so water reabsorption from PCT increases urea concentration in tubular lumen. This creates concentration gradient Urea reabsorption.

(2) Thick ascending limb of loop of Henle, DCT and cortical collecting tubules
All are relatively impermeable to urea. H2O reabsorbed in DCT and cortical collecting tubule (in presence of ADH) p increased urea concentration in tubular fluid.

(3) Inner medullary portion of the collecting duct

Urea diffuses into the medullary interstitium to increase its osmolality. Diffusion of urea is facilitated by ADH. 40 - 60% of the tubular load of urea is excreted in urine.

Urea cycle

Urea moves from the medullary interstitium into the thin loop of the Henle and back down into the medullary collecting duct and again to medullary interstitium several times before urea is excreted.

Urea recycling

Handling of Hydrogen
Mechanism of H+ secretion
1. PCT 85% 2. Thick ascending loop of Henle 10% 3. DCT and collecting tubule 5%.

A) In PCT, LH and initial part of DCT: Most of H+ is secreted by secondary active transport. It is Na dependent. Antiport carrier at luminal border bind Na and H. B) In late part of DCT and CD: Hydrogen is secreted by primary active transport By Intercalated cells, hydrogen secretion is stimulated by aldosterone and both hydrogen and potassium compete for secretion.

Subs

Description

Proximal tubule

Loop of Henle

Distal tubule

Collecting duct

glucose

If glucose is not reabsorbed by the kidney, it appears in the urine, in a condition known as glucosuria. This is associated with diabetes mellitus.. Almost completely conserved. Regulation of osmolality. Varies with ADH Uses Na-H antiport, Na-glucose symport, sodium ion channels Usually follows sodium. Active (transcellular) and passive (paracellular) Uses aquaporin. Helps maintain acid-base balance. [8] Uses [[vacuolar H+ATPase]]

reabsorption (almost 100%) via sodiumglucose transport proteins(apical) and GLUT(basolateral). Reabsorption (active) reabsorption (50%) via passive transport reabsorption (65%, isosmotic)

amino acids urea sodium

secretion reabsorption (25%, thick ascending, Na-K2Cl symporter) reabsorption (thin ascending, thick ascending, Na-K-2Cl reabsorption (descending) reabsorption (thick ascending)
[10]

reabsorption (5%, sodiumchloride symporter) reabsorption (sodiumchlorid symp -

reabsorption in medullary ducts reabsorption (5%, principal cells), stimulated by aldosterone reabsorption (with ADH, via vasopressin receptor 2) reabsorption (intercalated cells, secretion (intercalated cells)

chloride

reabsorption

water

reabsorption (80-90%)
[9]

HCO3 H

reabsorption (20%, thick ascending, Na-K2Cl symporter)

reabsorption (thick ascending) via passive transport -

Varies upon dietary needs.

reabsorption (80%)

secretion increased by aldosterone) reabsorption stimulated by PTH

-

calcium phosp Excreted as titratable acid.

reabsorption reabsorption (80%) Inhibited by parathyroid hormone.

URINE CONCENTRATION

PRODUCTION OF CONCENTRATED URINE

Concentrated urine is also called hyperosmotic urine (urine osmolarity > blood osmolarity). The kidney excretes excess solutes, but does not excrete excess amounts of water. The basic requirements for forming a concentrated urine are: 1. a high level of ADH, e.g., in water deprivation or hemorrhage p o permeability of late DCT & CDs to water, allowing these segments to reabsorb a large amount of water. 2. a high osmolarity of the renal medullary interstitial fluid p provides the osmotic gradient necessary for water reabsorption to occur in the presence of high levels of ADH. After passing to the interstitium, water is carried by the vasa recta back into the blood.
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PRODUCTION OF CONCENTRATED URINE

Reabsorption of Water in Presence of ADH:
In PCT, loop of Henle & early DCT: - Same as in formation of dilute urine (see before). - The tubular fluid reaching the late DCT is hyposmotic (100 mOsm/L). Late DCT: - ADH o the water permeability of the principal cells of the late DCT. Water is reabsorbed until the osmolarity of the DCT equals that of surrounding interstitial fluid in renal cortex (300 mOsm/L). CDs: - ADH o the water permeability of principal cells of CDs. - As the tubular fluid flows through the CDs, it passes through regions of increasing hyperosmolarity toward the inner medulla. - Water is reabsorbed from the CDs until the osmolarity of the tubular fluid equals that of the surrounding interstitial fluid. 87 The osmolarity of the final urine reaches 1200 mOsm/L.

II. PRODUCTION OF CONCENTRATED URINE (cont.)

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II. PRODUCTION OF CONCENTRATED URINE (cont.)

89

The Countercurrent System

The countercurrent system is responsible for the creation & maintenance of a gradually increasing hyperosmolarity in the renal medullary interstitium, which is essential for enabling the kidney to concentrate urine in the presence of enough circulating ADH. This osmotic gradient is due to accumulation of solutes (primarily NaCl & urea) in great excess of water in the medullary interstitium. Once the high solute concentration in medulla has been achieved, it is maintained by a balanced outflow of solutes & water in the medulla. This osmotic gradient is 1. established by the loop of Henle, which acts as a countercurrent multiplier. 2. potentiated by the collecting duct, which allows urea recycling to occur. 3. maintained by the vasa recta, which act as countercurrent exchangers. 90

THE COUNTERCURRENT SYSTEM Loop of Henle Acting as Counter Current Multiplier How does the renal medulla become hyperosmotic?
1. Before the osmotic gradient of the medulla is established, the osmolarity is the same throughout the nephron (300 mOsm/L). 2. The active pumping of NaCl out of the thick ascending limb occurs without concomitant movement of water p q in osmolarity of tubular fluid inside ascending limb (200 mOsm/L) & o in osmolarity of medullary interstitial fluid (400 mOsm/L). 3. As fluid passes down the descending limb, it reaches osmotic equilibrium with medullary interstitium due to osmosis of water out of descending limb. [Interstitial osmolarity is maintained at 400 mOsm/L due to continued transport of ions out of thick ascending limb.] Thus, there is a gradual o in tubular fluid osmolarity as it flows towards the hairpin bend. 4. As more fluid enters descending limb from PCT, hyperosmotic fluid previously present in descending limb now flows into thick ascending limb.
91

THE COUNTERCURRENT SYSTEM Loop of Henle Acting as Counter Current Multiplier

5. More NaCl is pumped from thick ascending limb into interstitium, but water remains in tubule. This continues until a 200 mOsm/L osmotic gradient is established. Now osmolarity in medullary interstitium has risen further to 500 mOsm/L. 6. Once again the fluid in descending limb equilibrates with hyperosmotic medullary interstitial fluid, now reaching 500 mOsm/L at the tip. 7. These steps are repeated over & over, adding more & more solute to the medulla in excess of water. This process gradually traps solutes in the medulla, eventually raising the interstitial osmolarity to 1200 mOsm/L. Overall, the progressive transport of NaCl from the tubular fluid into the interstitium results in the establishment of a longitudinal osmotic gradient in the medulla.
Thus, the countercurrent arrangement of the loop of Henle multiplies a relatively small transepithelial osmotic gradient into a large longitudinal 92 gradient.

COUNTERCURRENT MULTIPLIER SYSTEM IN LOOP OF HENLE

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Role of DCT & CDs in Urine Concentration

Tubular fluid flowing from loop of Henle into DCT is dilute. The early DCT further dilutes the fluid, because this segment, like the ascending limb of loop of Henle, actively transports NaCl out of tubule, but is impermeable to water. With high ADH concentrations, late DCT & cortical CD become highly permeable to water p large amounts of water are reabsorbed from the tubule into the cortical interstitium, where it is swept away by the peritubular capillaries. With high ADH levels, there is further water reabsorption from medullary CDs to interstitium. However, the amount of water is relatively small compared with that added to the cortical interstitium. Reabsorbed water is quickly carried away by vasa recta into venous blood. N.B. The fact that large amounts of water are reabsorbed into the cortex, rather than into the medulla, helps to preserve the high medullary interstitial fluid osmolarity. Thus, in the presence of ADH, the fluid at the end of CDs has the same osmolarity as the medullary interstitium (1200 mOsm/L). By reabsorbing as much water as94 possible, the kidneys form a highly concentrated urine while adding water back to ECF & compensating for deficit of body water.

Urea Recycling
In the presence of ADH, urea contibutes 40% to the medullary interstitial osmolarity (= 500 mOsm/L) by passive urea reabsorption from the inner medullary CDs into the interstitium. Mechanism: - Ascending limb of loop of Henle, DCT, cortical CDs & outer medullary CDs are impermeable to urea. - As water is reabsorbed from late DCT, cortical & outer medullary CDs, urea concentration o rapidly. - In inner medullary CDs, further water reabsorption takes place, so that urea concentration rises even more. Thus, urea diffuses out of the tubule into renal interstitium because this segment is highly permeable to urea, and ADH increases this permeability even more. - A moderate share of the urea that moves into medullary interstitium diffuses into thin descending limb of loop of Henle, so that it passes again in tubular fluid. It recirculates several times before it is excreted. Each time around it contributes to a higher concentration of urea in interstitium. Urea recirculation provides an additional mechanism for forming a 95 hyperosmotic medulla.

UREA RECYCLING

96

THE COUNTERCURRENT SYSTEM Vasa Recta as Countercurrent Exchanger

Blood must be provided to renal medulla to supply its metabolic needs, but without a special blood flow system, solutes pumped into the medulla by countercurrent multiplier would rapidly get lost. There are 2 special features in medullary blood flow that contribute to the preservation of the high solute concentrations: 1. The medullary blood flow is low (only 1-2% of total RBF) p sufficient for metabolic needs of tissues, but minimizes solute loss. 2. The vasa recta serve as countercurrent exchangers. Countercurrent Exchange Mechanism: As blood descends into medulla, it becomes more & more concentrated, by gaining salt & losing water. At the tips of vasa recta blood has a concentration of 1200 mOsm/L. As blood ascends back toward cortex, the reverse sequence occurs, and blood leaving vasa recta is only slightly hyperosmotic to normal plasma. During its passage through medulla, blood has removed the excess salt & water that have been added by the transport processes occurring in the deeper regions of the medulla. Thus, the U-shape of vasa recta maintains the concentration of solutes established by countercurrent system. 97

Vasa Recta as Countercurrent Exchanger

98

Diuresis and diuretics

Diuresis is an increase in the rate of urine output. (A) H2O diuresis Increase H2O intake p decrease Osmotic. Pr p decrease ADH p decrease facultative H2O reabsorption i.e. Urine large volume and hypotonic. (B) Osmotic diuresis Unreabsorbable solute in PCTp decrease obligatory H2O reabsorption p decrease Na+ concentration in tubular fluid p decrease osmolarity of medullary interstitium p decrease facultative H2O reabsorption. -Urine: large volume and isotonic or hypertonic. (C) Pressure diuresis Increase in arterial blood pressure leads to: GFR. Inhibition of rennin angiotensin system renin and angiotensin II production. Hydrostatic pressure in peritubular capillaries which increase Na+ & H2O excretion.

(4) Diuretic drugs

(A)Thiazides:
inhibit Na reabsorption in DCT.

(B) Aldosterone inhibitors: (Potassium-sparing diuretics) e.g. alldactone:

inhibit Na-K exchange in DCT and collecting tubules p decrease serum Na and increase serum K+.

(C) Carbonic anhydrase inhibitors e.g. acetazolamide (Diamox).

It inhibits carbonic anhydrase enzyme decrease H secretion decrease Na and HCO3- reabsorption in PCT and increase K secretion in DCT increase Na, HCO3 & K excretion in urine. May lead to acidosis.

(D) Loop diuretics e.g. frusemide (lasix):

inhibit Na-K-2Cl cotransporters in the thick ascending limb of loop of Henle.

The act of Micturition

Micturition Reflex
As bladder fills sensory stretch receptors send signals via pelvic nerves to sacral segments of spinal cord. Parasympathetic stimulation of the bladder smooth muscle via the same pelvic nerves occurs. It is self-regenerative, subsides, then regenerates again until the external sphincter is relaxed and urination can occur.

Innervation
Parasympathetic Pre-glanglionic S2, S3, S4 unite to form Pelvic nerves Post-ganglionic onto detrusor muscle & internal sphincter

Sympathetic Pre-ganglionic L1, L2, L3 Post-ganglionic onto trigone, neck, & internal sphincter Little to do with bladder contraction o--------- o-----------------------------------------Ach NE

Innervation cont
Afferents (sensory nerves) Pelvic nerve: impulses due to bladder fullness; micturition reflex; pain impulses Hypogastric nerve: pain impulses Pudendal nerve: sensory impulses from urethra Somatic Efferent (Pudendal nerve) Impulses originate in S1 and S2; innervate external sphincter Mediate voluntary control of micturition

Anatomy of Micturition

 Internal sphincter - detrusor muscle in the bladder neck whose tone normally keeps the bladder neck and posterior urethra empty of urine and therefore prevents emptying of the bladder until the pressure in the main part of the bladder exceeds a critical level External sphincter - layer of voluntary skeletal muscle which surrounds the urethra as it passes through the urogenital diaphragm - under voluntary control and can conciously prevent urination even when involuntary controls are attempting to empty the bladder

Bladder Filling and Micturition

Bladder Filling: 1. Empty bladder: 0 pressure 2. 30 - 50 mls of urine 5 - 10 cm H2O 3. 50 - 300 ml little pressure change 4. With filling, increased activity of external sphincter (maintains continence, or control of excretory functions) 5. > 300 - 400 ml discomfort; leads to urgency Start of Micturition: 1. As bladder fills, micturition (bladder) contractions begin to appear a. Last from a few seconds to more than a minute b. Pressure peaks (micturition waves) may rise a few cm H2O to more than 100 cm H2O c. Caused by micturition reflex

Micturition Cont
2. Micturition reflex (does not need the
brain) a. Filling stimulates sensory stretch receptors b. Afferent impulses in Pelvic nerve c. Signal reflexively sent back to bladder via efferent parasympathetic fibers in the Pelvic nerve d. Detrusor muscle contracts, then relaxes

2. Micturition reflex - continued

e. As bladder fills, micturition reflex occurs more frequently, with greater contraction of bladder wall (positive feedback loop) f. Micturition powerful enough then another signal is sent through Pudendal nerve to inhibit external sphincter (internal relaxes passively when pressure is 20 - 40 cm H2O) g. Voluntary relaxation of external sphincter allows for urination h. Flow thru urethra stimulates parasympathic system, sustaining bladder contraction

Micturition Reflex
stretch reflex initiated by filling of the bladder with urine which results in bladder wall contraction mediated by sensory stretch receptors in the bladder wall,specially by receptors in the posterior urethra BLADDER Detrusor muscle PELVIC NERVE (Parasympathetic Motor Fibers) Sensory stretch receptor PELVIC NERVE (Sensory Fibers) SPINAL CORD (sacral segments)

Voluntary Control of Micturition

1. Micturition reflex can be inhibited by: a. Pons b. Cerebral cortex 2. Voluntary contraction of external bladder sphincter means emptying can be delayed even if a micturition reflex occurs (can go and stop voluntarily) 3. Voluntary emptying: a. Contraction of abdominal muscles causes pressure in bladder micturition reflex and inhibition of external sphincter b. Voluntary relaxation of external sphincter Problems:

Atonic Bladder - destruction of sensory fibers Traumatic spinal cord injury Overflow incontinence. Automatic Bladder - spinal cord injury above sacral region Micturition reflex is intact but uncontrolled

Micturition Abnormalities
Atonic Bladder - destruction of sensory fibers Traumatic spinal cord injury Overflow incontinence. Automatic Bladder - spinal cord injury above sacral region Micturition reflex is intact but uncontrolled