PHYSIOLOGY – LECTURE

RENAL PHYSIOLOGY I
Trans no.1 | Shifting No.3 | Dr. Fernando P. Solidum | February 16, 2021

OUTLINE → For many electrolytes, the kidneys are the principal route for
excretion from the body
I. Functions of the Kidneys X. Renal Blood Flow
→ Example: high sodium intake → accumulation of sodium →
II. Structure of the Human A. Autoregulation
raised ECF → hormonal changes and compensatory
Kidneys B. Relationship
mechanisms → sodium excretion
III. Ultrastructure of between RBF
the Nephron and GFR → 67% of solutes and H2O are reabsorbed in the proximal tubule
A. Different Segments of C. Relationship (especially NaCl)
the Nephron between • Regulates acid-base balance
B. Different Types of Resistance → Normal pH is maintained by buffers within the body fluids and
Nephrons and RBF/GFR by the coordinate action of the lungs, liver, and kidneys
C. Vasa Recta D. Sympathetic → Example: Increased H+ in plasma → kidney excretes excess
D. Ultrastructure of Control of H+ ions → maintain normal plasma pH
Renal Corpuscle RBF and → In high pH, the role of the kidney is to conserve the H+ ions
IV. Filtration Barrier GFR • Excretes metabolic products and foreign substances
V. Mesangium E. Hormonal → Urea – from metabolism of amino acids
VI. Ultrastructure of Control of → Creatinine – from muscle creatinine
Juxtaglomerular RBF and → Uric acid – from nucleic acids
Apparatus GFR → Bilirubin – from end products of hemoglobin breakdown
VII. Mass-Balance XI. Transepithelial → Metabolites of various hormones
Relationship of the Kidney Solute and Water → Toxins and other foreign substances that are either produced
VIII. Assessment of Transport by the body or ingested:
Renal Function A. Proximal Tubule ▪ Pesticides
A. Renal Clearance B. Loop of Henle ▪ Drugs
B. Glomerular C. Thick Ascending ▪ Food additives
Filtration Rate Limb • Produces and secretes hormones
C. Filtration Fraction D. Distal → Renin
IX. Glomerular Filtration Tubules ▪ Enzyme that activates the RAA system (blood pressure
A. Determinants and regulation and Na+ & K+ balance)
of Ultrafiltrate Collecting → Calcitriol
Composition Ducts ▪ Metabolite of vitamin D3
B. Dynamics of XII. Review Questions ▪ Necessary for normal absorption of Ca++ by the GIT and
Ultrafiltration XIII. References for its deposition in bone
I. FUNCTIONS OF THE KIDNEY ▪ Renal disease → impaired ability to produce calcitriol →
decreased calcitriol level → decreased Ca++ absorption by
• Regulation of body fluid osmolality and volumes the intestine → bone formation abnormalities (long-term
→ Essential for maintenance of normal cell volume in all tissues consequence)
of the body → Erythropoietin
→ Maintenance of body fluid volume is necessary for normal ▪ Stimulates RBC formation by the bone marrow
function of the cardiovascular system ▪ CKD → decreased EPO production → decreased
→ Regulation of body fluid osmolality erythrocyte production → anemia
▪ Kidneys regulate movement of ions to ensure concentration ▪ In patients with chronic kidney disease: low hgb and
of solutes is normal hematocrit concentration because the kidney is already
▪ Can respond to dehydration and overhydration impaired
▪ Kidneys are able to detect high blood pressure • Regulates arterial pressure
− Ex: increase BP → increase perfusion pressure → → Long-term regulation: excretion of variable amounts of Na and
increase GFR → increase urine output H2O
− Kidneys regulate the amount of blood entering the → Short-term regulation: secretion of hormones and vasoactive
nephrons → urine output regulated factors or substances (ex. Renin) that lead to the formation of
vasoactive products (ex. Angiotensin II)
FYI: • Glucose synthesis
Osmolarity vs Osmolality → Kidneys synthesize glucose from amino acids and other
• Interchangeable, differs only in unit of measurement precursors during prolonged fasting (gluconeogenesis)
• Osmolarity (mOsm/L of water)
→ total no. of dissolved particles in a solution independent II. STRUCTURE OF THE HUMAN KIDNEY
of mass, charge, or chemical composition
→ Normal fluid osmolarity: 280-300 mOsm/L • Kidneys – paired organs that lie on the retroperitoneal space
• Osmolality (mOsm/kg of water) → There is up to 1.2 million nephrons per kidney
→ total no. of dissolved particles per kg of water • Hilum – an indented region at the medial side of the kidney
through which pass the renal artery and vein, lymphatics, nerve
• Regulation of electrolyte balance supply, and ureter, which carries the final urine from the kidney
→ For maintenance of homeostasis, excretion of water and to the bladder
electrolytes must precisely match intake • Two important regions:
▪ Intake > excretion: positive balance → Medulla
▪ Intake < excretion: negative balance ▪ Innermost layer, where majority of absorption occurs
→ Includes Na+, K+, Cl−, bicarbonate (HCO3-), hydrogen (H+), ▪ Divided into conical masses called renal pyramids
Ca++, and Pi

PHYS – LEC Trans no. 2 | Ang, Canlas, Corsino, Ferido, Genilla, Landicho, Mendoza, M., Mendoza, S., Moreno, Sarmiento, Soriano, Suelto, Sugon, Tegrado | TH: Babol 1 of 16
 ▪ Base of each pyramid originates at the border between the → Presence of the brush border which increases the surface
cortex and medulla and the apex terminates in a papilla, area
which lies within a minor calyx → Handled in an isosmotic manner (equal proportion of solute
→ Cortex and water)
▪ Outermost later, where the glomerulus resides • Loop of Henle
→ Minor calyces – collect urine from each papilla; expand into → Thin Descending Limb (Concentrating Segment)
two or three open-ended pouches called the major calyces ▪ Single cell of membrane that separates the tubular fluid
→ Major calyces – feed into the pelvis from the medullary interstitium
→ Pelvis – upper expanded region of the ureter, which carries ▪ Water permeable in the presence of a concentration
urine from the pelvis to the urinary bladder gradient between the tubular fluid and the medullary
• Contractile elements from the calyces, pelvis, and ureter propel interstitium, water will tend to move away from the tubular
urine toward the bladder and emptied via micturition fluid into the medullary interstitium and into the circulation
• Flow of filtered fluid: ▪ Prevents solutes from being reabsorbed from the tubular
→ Pyramids → papillae → minor calyces → major calyces → fluid
pelvis ▪ As water moves away from the tubular fluid, the solutes are
trapped by NaCl, making the tubular fluid hyperosmolar
→ Thin Ascending Limb [2023D Trans]
▪ Water impermeable, permeable to solutes
− Unlike next segment, there is less Na/K ATPase
▪ Entire segment remains in the medullary space and drains
to thick ascending limb which will be the one to enter the
cortical space
→ Thick Ascending Limb (Diluting Segment)
▪ Water impermeable
▪ Almost all of solutes are reabsorbed by several transporters
and channels; can even cross the tight junctions between
the cells of the thick ascending limb
▪ When almost all of the solutes are reabsorbed into the
medullary interstitium the tubular fluid becomes
Figure 1. General organization of the kidneys and the urinary system [Hall, 2016]
hypoosmotic (very dilute)
FYI: • Distal tubule
• Ultrafiltrate – fluid in the Bowman’s space → Divided into two parts: first and second half
• Tubular fluid – fluid in the nephron → First half is impermeable to water
• Urine – fluid after entering the calyx; will eventually leave the → Second half and collecting duct system
collecting duct system; cannot be modified ▪ Permeability depends on the presence of ADH
− Normally water impermeable, fluid would be lost to the
III. ULTRASTRUCTURE OF THE NEPHRON urine
− Presence of ADH would insert aquaporins in the apical
A. DIFFERENT SEGMENTS OF THE NEPHRON membrane of the cells of the collecting duct system that
allows water to use it as a channel to move to one
• Nephron
compartment to another (tubular fluid to the medullary
→ Functional unit of the kidneys
interstitium)
→ Parts:
− Movement also depends on the existing concentration
▪ 1 renal corpuscle
gradient
▪ Proximal tubule
▪ Loop of Henle Table 1. Histological features of each renal tubule segment [Koeppen & Stanton, 2018; 2023D
▪ Distal tubule Trans]

▪ Collecting Duct System

Figure 2. Ultrastructure of the nephron

• Nephron Segments and their Cellular architecture:

• Proximal Tubule
→ Handles 67% of solutes and water as the glomerulus filters the
tubular fluid into the proximal tubule

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Table 2. Osmolarity of the Tubular Fluid in the Renal Tubule Segments [Koeppen & Stanton, 2018; 2023D
C. VASA RECTA
Trans]
• Forms capillary networks deep into the inner medulla that
surround the collecting ducts and the ascending limbs of Henle
• Slow blood flow allows effective exchange of solutes and water
in the tubular fluid, medullary interstitium and capillary network
• Conveys oxygen to nephron segments
• Supplies nutrients to nephron segments
• Acts a pathway for reabsorbed water and solutes to the
circulatory system
• Concentrates and dilutes the urine
• Responsible for maintaining the production of small amounts of
urine during state of dehydration

*Effect on osmolarity depends on the permeability as determined by

the effect of hormones or variation in permeability along the
segment.

B. DIFFERENT TYPES OF NEPHRONS

Figure 4. Ultrastructure of the renal corpuscle.

• Blood flows from the afferent arteriole (AA) into the glomerulus
and enter the efferent arteriole (EA) and go to the peritubular
capillaries and supply the different nephron segments (such as
the PT)
• Glomerulus
→ Specialized network of capillaries that originate from the fusion
of the AA and EA
→ Compromised of several layers that acts as a sieve for filtering
the solutes that would become part of the ultrafiltrate
→ Ultrafiltrate is the fluid that accumulates in the Bowman’s
space after filtration of the glomerulus
→ Layers (Filtration barrier):
Figure 3. Types of nephrons found in the kidney ▪ Capillary endothelium
• Cortical Nephrons ▪ Basement membrane
→ Nephrons found in the cortex ▪ Podocytes
• The JM nephron D. ULTRASTRUCTURE OF THE RENAL CORPUSCLE
→ The loop of Henle is deeper and extends deep into the medulla
→ The efferent arteriole forms a series of vascular loops called • Made up of the afferent arteriole, efferent arteriole, and the
“Vasa Recta” glomerulus [Solidum, 2021]
▪ Vasa recta is the extension of the efferent arteriole → Imagine that the afferent and efferent arteriole is just onse
Table 3. Cortical and Juxtamedullary nephrons [Koeppen & Stanton, 2018; 2023D Trans] single vessel and in the middle, they have a curling which
becomes the glomerulus
→ Blood flow: afferent arteriole → glomerulus → efferent
arteriole
• Blood from the efferent arteriole will enter the peritubular
capillaries and supply the nephron segments specifically the
proximal tubule
Glomerulus___________________________________________
• Network of capillaries supplied by the afferent and efferent
arterioles.
• Has high hydrostatic pressure: 60mmHg
• Has 3 filtration layers which is important in acting like a sieve
→ Capillary endothelium
→ Basement membrane
→ Podocytes
▪ Acts as the visceral layer of the Bowman’s capsule.

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 Macula Densa of the Thick Ascending Limb → Has gaps called filtration slits.
• Connection with the angle between the AA and EA • Filtration slits
• Cells in this area would tend to stain darker microscopically → Has negatively charged membrane glycoprotein called
• Very sensitive in detecting the concentration of NaCl in the podocalyxin
tubular fluid
→ Podocalyxin maintains the opening of the filtration slits.
• The macula densa, AA, extraglomerular mesangial cells are
responsible for activating the juxtamedullary apparatus
Bowman’s Capsule____________________________________
• Encloses the glomerular capillaries.
• Has 2 layers.
→ Visceral layer
▪ Foot processes of the podocytes
→ Parietal layer
▪ Becomes the lumen of the proximal tubule at the urinary
pole.
▪ Urinary pole – is where the proximal tubule joins the
Bowman’s capsule.
• The ultrafiltrate flows from the Bowman’s capsule into the
proximal tubule.
• Has a hydrostatic pressure of 10mmHg.
Bowman’s Space______________________________________
• The space between the visceral and the parietal layer Figure 5. Filtration Barrier.
→ Separates the Bowman’s capsule and the glomerulus.
→ Becomes the lumen of the proximal tubule at the urinary pole NTK:
• Contains the ultrafiltrate. Glomerulonephritis
→ Osmolarity is equal to 300mOsm. • Patients are edematous.
• The filtration barrier is being attacked → inflammatory
IV. FILTRATION BARRIER response → inflammation → swelling of basal membrane →
• Filtration membrane increased diameter of filtration slits → filtration barriers lose
→ Site of filtration its negative charge → impaired filtration barrier → albumin
→ Composed of capillary endothelium, basement membrane, can pass through the barrier → decrease plasma oncotic
and the foot processed of podocytes. pressure → increase plasma hydrostatic pressure → water
▪ All are negatively charged goes to insterstitium → edema.
• Urinalysis: presence of glucose, proteins, blood
Capillary Endothelium__________________________________
• Patients are given with albumin to increase plasma oncotic
• Fenestrated
pressure.
• Permeable to:
→ Water
V. MESANGIUM
→ Dissolve solutes
• Another group of cells that you will find in the glomerulus
→ Plasma proteins
• Responsible for the scaffolding to make the glomerulus round
• Not permeable to RBCs • Yung pagkabilog ng glomerulus is being held together by your
• Has negatively charged glycoproteins on the surface. mesangial cells [Solidum, 2021]
→ Repels negatively charge ions. • Provides structural support
▪ Example is albumin. • Secretes the extracellular matrix
→ Very small negatively charged ions can pass through. • Can also exhibit phagocytic activity
▪ Pushed by the glomerular capillary hydrostatic pressure. • Can secrete prostaglandins and other cytokines
• Capable of regulating GFR via glomerular capillaries or altering
• Synthesize vasoactive substances.
the capillary surface area
→ Endothelin – vasoconstrictor • Holds the glomerulus together
→ Nitric oxide (NO) – vasodilator
Extraglomerular Mesangial
Basement Membrane___________________________________ • Also called Lacis cells or goormaghtigh cells
• Situated between the endothelial cells and the processes of the • Mesangial cells outside the glomerulus (between the afferent
podocytes. and efferent arterioles)
• Negatively charged. • Exhibits phagocytic activity
→ Effective molecular size: 20-40 angstroms
→ Not permeable to plasma proteins
• Regulates glomerular oncotic pressure.
Foot Processes of Podocytes____________________________
• Specialized epithelial cells attached to the basement membrane
by foot processes.
• Has endocytic properties.
• Foot processes
→ Long, finger-like projections that encircles the outer surface
of capillaries.
→ Interdigitates, covering the gaps in the basement membrane.

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 → Macula densa of the thick ascending limb senses the
increased NaCl concentration in the tubuluar fluid
▪ Sensed by the 1Na-1K-2Cl symporter and Na-H exchanger
▪ These 2 important sensors of the macula densa increases
the reabsorption of sodium chloride
▪ Kasi mataas ang concentration at very sensitive yung
sensors, so kinukuha nila yung sodium chloride
→ As NaCl enters the cell of the macula densa, it stimulates the
release of 2 important substances
▪ Adenosine
▪ ATP
▪ Lumalabas itong dalawang substances na to from the
macula densa
▪ Released via the extraglomerular mesangial cells
▪ When they are released, they can act on the smooth
muscles of the afferent arteriole
− Facilitates the entry of calcium ions into the smooth
muscle
Figure 6. Electron micrograph of the measangium, the area between the − When calcium ions enter the smooth muscle, calcium
glomerular capillaries containing mesangial cells. C, glomerular capillaries; will bind to calmodulin to form the calcium-calmodulin
cGBM, capillary glomerular basement membrane surrounded by foot processes complex → contraction will occur
of podocytes (PO) and endothelial cells; M, mesangial cell that gives rise to
several processes, some marked by stars; mGBM, mesangial glomerular
→ Summary
basement membrane surrounded by foot processes of podocytes and mesangial ▪ ↑ blood flow in afferent arteriole → ↑ glomerular capillary
cells; US, urinary space. Note the extensive extracellular matrix surrounded by hydrostatic pressure → ↑ filtration → ↑ NaCl in tubular fluid
mesangial cells (triangles) [Koepen & Stanton, 2017] → sensed by macula densa of thick ascending limb →
NTK: macula densa absorbs NaCl → stimulates release of ATP
From Koeppen & Stanton (2018) and adenosine → promotion of entry of calcium ions into
• Important component of the renal corposcule the smooth muscle → muscle contraction
• Messangium consists of mesangial cells and mesangial → JG apparatus in response to a very high perfusion pressure, it
matrix is actually trying to contract the walls of the afferent arteriole
to prevent the further increase in blood flow
• Messangial cells
→ If JG apparatus is not functioning, imagine the blood flow in
→ Possess many properties of smooth muscles
afferent arteriole will be very and will not be regulated
→ Can contract and are adjacent to glomerular capillaries →
▪ GFR will continuously rise
can influence GFR
▪ As GFR rises, the volume of urine also increases
▪ Loss of fluid and plasma volume will eventually decrease
VI. ULTRASTRUCTURE OF THE JUXTAGLOMERULAR → Imagine this occurs in just 1 single nephron, you have 1.2 M
APPARATUS nephrons in 1 kidney, and 2.4 M for the two kidneys
▪ Imagine of all those nephrons were excreting fluid
• Components
▪ Plasma volume will significantly decrease
→ Macula densa of the thick ascending limb
→ Extraglomerular mesangial cells
NTK:
→ Renin-producing granular cells of the afferent arteriole From Koeppen & Stanton (2018)
• These 3 important structures compromise the juxtaglomerular • Cells of the macula densa represent a morphologically distinct
apparatus region of the thick ascending limb
• Note: • This region passes through the angle formed by the afferent
→ Some books keep on saying it is the distal tubule and efferent arterioles of the same nephron
→ They found out that it is not part of the distal tubule but the • Cells of the macula densa contact the extraglomerular
thick ascending limb because of the presence of the 1Na-1K- mesangial cells and the granular cells of the afferent arterioles
2 Cl symporter which detects sodium chloride concentration in • Granular cells of the afferent arterioles contain smooth muscle
the distal fluid myofilaments and manufacture, store, and release renin
• For example, blood flow to the afferent arteriole is high • Renin is involved in proteolytic generation of angiotensin II
→ Increased perfusion pressure allows more blood to enter the and ultimately in secretion of aldosterone
arteriole • The JG apparatus is one component of the TG feedback
→ As more blood enters the afferent arteriole, it will go to the mechanism
glomerulus
→ In the glomerulus, when blood flow increases, this increases BRAIN BREAK (15 MINS.)
the glomerular hydrostatic capillary pressure
▪ This is applicable in any type of capillary network in the
body
▪ Kapag tumaas ang blood flow, ang hydrostatic pressure
talaga ay tumataas
→ When glomerular hydrostatic capillary pressure increases, this
now promotes glomerular filtration
→ When glomerular filtration increases, it also increases the
filtration of a lot of solutes and water, specifically NaCl
▪ Habang tumataas ang GFR, NaCl filtration also increases
→ This eventually leads to increase in NaCl concentration in the
tubular fluid
▪ So imagine yung tuwing dadaan yung tubular fluid Figure . Welcome back 1-bHie!
tumataas yung kanyang concentration ng sodium chloride
so it eventually reaches the thick ascending limb

PHYS - LEC Trans no. 1 | Renal Physiology I 5 of 16

 VII. MASS BALANCE RELATIONSHIP FOR THE KIDNEY ▪ Inulin
− A polymer of fructose which is used to measure GFR.
− Freely filtered across the glomerulus into the Bowman's
capsule
− Not produced in the body and is not secreted by the
tubules = 100% be excreted by the kidneys.
− Perfect substance to assess renal function but it is not
used in the clinics

→ Creatinine clearance
▪ Creatinine
− Used to measure GFR clinically and provides a
reasonably accurate measure.
− By product of muscle creatinine metabolism
− GFR = urine concentration of creatinine x urine flow/
Plasma creatinine
− Concerns in the use of creatine:
o Can be secreted by the renal tubules leading to an
Figure 7. Fick Principle (mass balance) estimation of GFR.
• Based on Fick's principle o Assumes that all individuals have the same
• The amount of substance that enters the afferent arteriole that is production of creatinine and same serum
neither synthesized nor metabolized = amount that is excreted in concentration.
the urine + amount that goes back to the renal venous blood o Slight increase would correspond to a decrease in
• The amount of substance X that enters the kidney in the renal renal function from 100% of normal (1.0 to 1.5
artery is equal to the amount that leaves the kidney to the mg/DL).
systemic circulation and urine via the renal vein and urethra,
respectively.
• INPUT = OUTPUT

VIII. ASSESSMENT OF RENAL FUNCTION

A. RENAL CLEARANCE
• Renal clearance
→ Rate at which a substance is excreted into the urine.
→ Urinary excretion rate of X (Ux x V) is proportional to the
plasma concentration of X (Pax)
→ A theoretical measurement of Glomerular Filtration Rate
(GFR) and Renal Blood Flow (RBF)
→ The virtual volume of blood plasma from which that substance
is completely removed (cleared) per unit time.
• Clearance
→ Is the volume in which all substance is excreted in the urine
→ Only considers the rate at which the substance is excreted into
the urine
→ Also determines if a substance is reabsorbed or secreted
• “For any substance that is neither synthesized nor metabolized,
the amount that enters the kidneys is equal to the amount that
leaves the kidneys in the renal venous blood.”

B. GLOMERULAR FILTRATION
• Normal Values
→ 90-140 mL/min in males Figure 8. Relationship between GFR and creatinine

→ 80-125 mL/min in females

• Relationship between GFR and creatinine = Indirect
• Glomerular filtration rate
relationship
→ Sum of filtration rates and all functional nephrons (index of
• As GFR increases, creatine concentration decreases because
kidney functions)
creatine is being excreted.
→ The rate at which plasma is filtered by the kidney glomeruli
• As GFR decreases, creatine concentration increases because
→ Fall in GFR: progression of kidney disease
creatine is being retained.
→ Inulin clearance

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 C. FILTRATION FRACTION
• Portion of plasma that is being filtered.
• Filtration fraction = GFR/RPF
• 15 – 20 % = filtered
• 80 – 85 % = do not undergo filtration and continue to pass from
glomerulus → efferent arterioles → peritubular capillaries →
systemic circulation
• Increasing glomerular hydrostatic pressure = Increased filtration
fraction
• High renal blood flow = Decreased filtration fraction
• Filtration fraction changes depending on the diameter of both
afferent and efferent arteriole.

Figure 10. Effect of loss of negative charge of filtration barrier (I.e.,

glomerulonephritis) on filterability of molecules. [Solidum PPT, 2021]

• Cationic molecules are readily filtered than anionic molecules.

IX. GLOMERULAR FILTRATION
B. DYNAMICS OF ULTRAFILTRATION
• 90 to 140 ml/min in males while 80 to 125 ml/min in females.
Forces Affecting Filtration
A. DETERMINANTS OF ULTRAFILTRATE COMPOSITION • Glomerular Capillary Hydrostatic Pressure
Glomerular Filtration Barrier → Only force that favors filtration
• Determines the composition of plasma ultrafiltrate • Hydrostatic Pressure in Bowman’s Space
• Negatively charged; hence positively charged molecules is → Opposes glomerular capillary hydrostatic pressure
more likely to pass through the barrier → May increase in the case of obstruction along nephron
• Larger molecules are less likely to pass through the barrier hence segments, causing backflow of fluid towards Bowman’s space
not filtered → If it increases, there will be no filtration (decrease in GFR)
• Components: • Glomerular Capillary Oncotic Pressure
→ Capillary Endothelium → Increase in oncotic pressure, solutes are greater than the fluid
→ Basement Membrane component then it tends to hold on to the water
→ Filtration Slits → Prevents filtration
• Consequences: → Happens in cases with a decrease in blood flow or
→ 20Å or less filtered easily vasoconstriction in the afferent arteriole
→ 42Å or more not filtered
→ Glomerulus filters ~20% of plasma; causes a decrease in
→ 20Å-42Å filtered to varying degrees (depending on net
glomerular capillary hydrostatic pressure in the efferent
electrical charge)
arteriole
▪ Leads to an increase in oncotic pressure
▪ Plays a role in NaCl absorption in the proximal tubule

Figure 9. Varying dextran solutions. For a patient with massive blood loss,
polyanionic dextran is recommended because it is less likely to be filtered and
excreted out of the body because of negative charge [Solidum PPT, 2021]

• Dextran is used to restore the plasma volume of the patient

(massive bleeding or hypotensive).
Figure 11. Summary of forces affecting filtration in the kidney. [Solidum PPT, 2021]

X. RENAL BLOOD FLOW

• 1.25 L/min.
• 25% of cardiac output
→ 25% of the blood enters the kidneys

PHYS - LEC Trans no. 1 | Renal Physiology I 7 of 16

• Directly proportional to the pressure difference between the → Kidney’s ability to autoregulate has a wide range
renal artery and renal vein [Constanzo, 2015] → Even if the blood pressure outside of the organ has increase
• Inversely proportional to the resistance of the renal vasculature (e.g., hypertensive person), this does not significantly affect
[Constanzo, 2015] the blood flow in the kidney because of its ability to
• Additional flow of blood is to supply enough plasma for the high autoregulate between 90 and 180 mm Hg of pressure
rates of glomerular filtration that are necessary for precise • Relatively constant maintenance of renal blood flow and
regulation of body fluid volumes and solute concentrations glomerular filtration rate is achieved by changes in the vascular
• Mechanisms that regulate RBF are closely linked to the control resistance specifically the afferent arterioles
of GFR and the excretory functions of the kidneys [Hall, 2016] • Main goal is to maintain GFR relatively constant over an
• RBF is determined by the pressure gradient across the renal arterial pressure range between 80 and 170 mm Hg and to allow
vasculature or the difference between renal artery and renal precise control of renal excretion of water and solutes [Hall, 2016]
vein hydrostatic pressures • In certain conditions when the blood flow and blood pressure is
Functions significantly low (<90 mm Hg), autoregulation in the kidney
becomes impaired
1. Determinants of GFR (indirect) → Patient who lost a significant amount of blood: Urine output is
• Greater the blood flow, GFR indirectly increases still adequate, blood pressure did not drop and kidney is not
• The more blood that enters, the more blood is being filtered by affected
the nephrons
→ Massive bleeding (about 50% of the blood volume): significant
2. Modifies rate of solute and water reabsorption by the drop in BP, urine output is decreased
proximal tubule • Application: In hypertension, kidney will prevent high pressure
• The greater the amount of blood that is filtered by the glomerulus, of blood to enter the afferent arteriole by constricting the blood
the greater the amount of fluid that will enter the proximal tubule vessels to limit amount of blood into the glomerulus
• The greater the amount of NaCl that enters the proximal tubule → Urine volume may be still be normal in hypertensive patients
(tubular fluid), the greater amount is being absorbed by the
proximal tubule
• 67% of whatever volume that is introduced in the PT can be
absorbed by the PT
• Increased salt and water reabsorption
• In the same manner, when blood flow decreases, GFR
decreases
• This also decreases the amount of tubular fluid entering the PT
an the rate of absorption of solutes and water also decreases
3. Oxygen, nutrients, and hormonal delivery to nephrons
4. Returns CO2 and reabsorbed fluid to general circulation
5. Substrate delivery to the urine

𝑟𝑒𝑛𝑎𝑙 𝑣𝑒𝑛𝑜𝑢𝑠 𝑝𝑟𝑒𝑠𝑠𝑢𝑟𝑒

𝑅𝐵𝐹 = 𝑎𝑜𝑟𝑡𝑖𝑐 𝑝𝑟𝑒𝑠𝑠𝑢𝑟𝑒 −
𝑟𝑒𝑛𝑎𝑙 𝑣𝑎𝑠𝑐𝑢𝑙𝑎𝑟 𝑟𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒

Determinants of Renal Vascular Resistance

• If arterial pressure changes, a proportional change occurs in
renal vascular resistance to maintain a constant RBF [Constanzo, 2015]
• Afferent arteriole
→ Vasodilation is caused by ANP [Constanzo, 2015]
• Efferent arteriole
Figure 12. Relationship between arterial blood pressure and RBF and between
→ Vasoconstriction [Constanzo, 2015] arterial blood pressure and GFR [Koeppen & Stanton, 2018]
▪ To a lesser extent, caused by ANP
▪ Can also be caused by angiotensin II at low Mechanisms of Autoregulation
concentrations • Myogenic Autoregulation
→ Vasodilation [Constanzo, 2015] → Inherent property of blood vessels not only in the kidneys,
▪ Can be caused by angiotensin-converting enzyme but in general circulation of the body [Solidum, 2021]
(ACE) inhibitors → Pressure-sensitive mechanism that is related to an intrinsic
• Interlobular artery property of vascular smooth muscle (i.e. the tendency to
→ Vessel that is responsible for delivering the blood into the contract when stretched)
renal parenchyma → ↑ arterial pressure → stretching of renal afferent arteriole
→ Resistance of these vessels are regulated by the SNS, (stretches entrance for calcium ions) →smooth muscle
hormones, and local renal control mechanisms depolarization → contraction of smooth muscle → ↑ arteriolar
vascular resistance
A. AUTOREGULATION
→ Rise in vascular resistance offsets increase in pressure →
• Kidney can perform autoregulation RBF (and consequently, GFR) remains constant
→ Renal blood flow remains constant between 90 and 180 mm • Tubuloglomerular Feedback
Hg

PHYS - LEC Trans no. 1 | Renal Physiology I 8 of 16

 → [NaCl]-dependent mechanism which involves a feedback B. RELATIONSHIP BETWEEN RESISTANCE AND RBF/GRF
loop in which a change in GFR leads to alteration in the
concentration of NaCl in tubular fluid.
→ Sensed by the macula densa of the juxtaglomerular
apparatus → converted into signals that affect afferent
arteriolar resistance and thus, GFR
→ ↑ GFR (due to high PGC) → ↑ NaCl in tubular fluid in the
loop of Henle → ↑ NaCl entering the macula densa → ↑ ATP
& adenosine formation and release by the macula densa →
vasoconstriction of afferent arteriole → ↑ afferent arteriole
resistance → normalization of RBF and GFR
▪ When GFR and NaCl in the tubule fluid decrease, less
NaCl enters the macula densa, and both ATP and
adenosine production and release decline.
▪ The fall in ATP and adenosine results in afferent
arteriolar vasodilation, which returns GFR to normal.
→ NO (nitric oxide), a vasodilator produced by the macula
densa, attenuates tubuloglomerular feedback, whereas
angiotensin II enhances tubuloglomerular feedback.
▪ Hence, the macula densa may release both
vasoconstrictors and vasodilators that oppose each Figure 14. Summary of the relationship between selective changes in the
other’s action at the level of the afferent arteriole. (TLDR: resistance of either the afferent arteriole or efferent arteriole and RBF and GFR.
Both from macula densa: Adenosine (VC), and NO (VD)) • Constriction of either the afferent or efferent arteriole → increases
resistance → decreases flow
• Dilation of either the afferent or afferent arteriole → increases flow

Figure 15. Normal diameter of afferent and efferent arterioles.

Changes in RBF and GFR

• Constriction of Afferent Arteriole
→ ↓ diameter of AA → ↓ amount of blood entering the kidney → ↓
PGC (glomerular capillary hydrostatic pressure) → ↓ GFR
→ ↓ amount of blood entering the kidney → ↓ RBF
→ This set-up/arrangement will cause the juxtaglomerular
apparatus to send out a vasodilator to the afferent arteriole
→ decreases resistance of AA → increases flow

Figure 13. Tubuloglomerular feedback [Koeppen & Stanton, 2018]

Three Effector Substances for the Tubuloglomerular

Feedback
• The macula densa may release both vasoconstrictors and Figure 16. Constriction of afferent arteriole.
vasodilators that oppose each other’s action at the level of the
afferent arteriole. • Constriction of Efferent Arteriole
• Adenosine – a vasoconstrictor → ↓ diameter of EA → ↑ resistance in EA → pressure build ups
→ A messenger signal sent by the glomerular mesangial cells to inside the glomerulus → ↑ PGC → ↑ GFR, but with ↓ RBF (as
the afferent arteriole less blood will flow in the efferent arteriole)
• Angiotensin II – a vasoconstrictor
→ Enhances tubuloglomerular feedback
• Nitric oxide – a vasodilator
→ Attenuates tubuloglomerular feedback
Three Points Regarding Autoregulation [Koeppen & Stanton, 2018]
1. Autoregulation is absent when arterial pressure is less than 90 Figure 17. Constriction of Efferent arteriole.
mmHg.
2. Autoregulation is not perfect RBF and GFR do change slightly as
arterial blood pressure varies. • Dilation of Efferent Arteriole
3. Despite autoregulation, RBF and GFR can be changed by several → ↑ diameter of EA → ↓ resistance in EA → ↓ PGC → ↓GFR → faster
hormones and by alterations in sympathetic nerve activity that RBF.
change in response to alterations in the extracellular fluid volumes. ▪ However, we need to have a very slow blood flow into the
glomerular capillary to produce/utilize the 20% filtration
fraction.

PHYS - LEC Trans no. 1 | Renal Physiology I 9 of 16

 ▪ If EA are dilated:
− Filtration fraction will be reduced.
− ↑ Pressure difference between AA and E
− Wide pressure difference → faster blood flow into the
glomerulus (higher velocity) → ↓PGC → ↓GFR → faster
RBF
− [Doc Solidum, 2021]
o Blood just passes through the glomerulus and no
longer participates in the filtration due to already
low hydrostatic pressure.
o Increased velocity favors the forward flow of blood
more than its length of stay in the glomerulus
▪ Hence, PGC will also be reduced due to very fast blood flow;
however, RBF will increase.
▪ Blood flow at vasa recta will decrease → osmolarity of the
medullary interstitium will also decrease (because the
blood flow will just wash out the solutes)

Figure 18. Dilation of efferent arteriole.

• Dilation of Afferent Arteriole Figure 20. Effect of Sympathetic activation in hemorrhage.

→ ↑ diameter of AA → ↑ amount of blood flow into the glomerulus → Presented with a massively bleeding patient, the kidney’s
→ ↑ PGC → ↑ GFR (high arterial pressure is directed into role is to conserve water and restore blood volume via ↓ RBF
the glomerulus) and GFR
→ ↑ amount of blood reaching the efferent arteriole → ↑ RBF → Review the cardio-renal relationship: ↓ cardiac output (CO)
→ ↓ pressure entering the arch of aorta → ↓ baroreceptor
firing → nucleus tractus solitarius senses decrease in firing
rate and activates VMC → ↑ sympathetic outflow → ↑
constriction of arterioles → ↓ RBF and GFR
▪ Vasoconstriction of afferent arterioles → distortion of the
smooth muscle cells of the afferent arteriole → release of
renin from the granular cells of the afferent arteriole →
activation of the RAAS system → consequent release of
plasma and renal angiotensin II → angiotensin II triggers
Figure 19. Dilation of afferent arteriole. release of aldosterone from the adrenal cortex →
aldosterone enhances tubular sodium and water
reabsorption → ↓ renal excretion of sodium and water →
C. SYMPATHETIC CONTROL OF RBF AND GFR
blood volume and blood pressure restored
• Afferent and efferent arterioles are innervated by sympathetic
neurons D. HORMONAL CONTROL OF RBF AND GFR
→ When extracellular fluid volume (ECFV) is normal, VASOCONSTRICTORS
sympathetic tone is minimal Hormone Effects
• ↓ ECFV → release of norepinephrine and dopamine by Angiotensin II • Constricts both afferent & efferent arterioles
sympathetic nerves + circulating epinephrine secreted by → Efferent is more sensitive due to more
adrenal medulla receptors being present
→ Norepinephrine and epinephrine cause vasoconstriction by • Decreases both RBF and GFR
binding to α1-adrenoreceptors, located mainly in afferent • Angiotensin converting enzyme (ACE)
arterioles converts angiotensin I to angiotensin II
→ Activation of α1-adrenoreceptors → ↓RBF and ↓GFR → ACE degrades and inactivates Bradykinin
→ Dehydration and strong stimuli (e.g. fear, pain) also activate → Increases Angiotensin II levels and
sympathetic nerves which reduces RBF and GFR decreases Bradykinin levels
Mechanism of how different signals in the CVS and ANS
regulate RBF and GFR Endothelin • Potent vasoconstrictor secreted by
• What causes sympathetic activation in the kidneys? endothelial cells of the renal vessels,
→ Effect of sympathetic activation in hemorrhage mesangial cells, and distal tubular cells
→ Secreted in response to angiotensin II,
bradykinin, epinephrine, and endothelial
shear stress.
• Profound vasoconstriction of afferent and
efferent arterioles; decreases GFR and
RBF.
• Elevated in a number of glomerular disease
states (e.g. renal disease associated with
DM) but does not necessarily influence
GFR and RBF in resting subjects

PHYS - LEC Trans no. 1 | Renal Physiology I 10 of

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Adenosine • Vasoconstriction of afferent arteriole, Bradykinin • Kininogen is cleaved by kallikrein forming
reducing RBF and GFR. bradykinin
• Important in tubuloglomerular feedback • A by-product of Kininogen breakdown
regulation • Induces release of NO and prostaglandins
→ vasodilation → ↑ RBF & GFR
Adenosine • Released from cells into interstitial fluid
Triphosphate • Can have bidirectional effects on both RBF
Atrial • Released by the specialized cells found in
• and GFR (dual effect)
Natriuretic the right atrium when there is increased
• May play a role in tubuloglomerular Peptide venous return due to high blood volume
feedback (ANP) • Causes vasodilation of afferent arteriole and
• In some conditions may constrict the
vasoconstriction of efferent arteriole.
afferent arteriole, reducing RBF and GFR.
→ More blood is entering glomerulus, but less
→ In other conditions may stimulate NO
volume of blood is going to efferent arteriole.
production and increase RBF & GFR
→ There is an increased pressure inside
glomerulus, leading to an increased PGC,
VASODILATORS thereby increasing GFR.
Hormone Effects → Hence, ANP increases urine output.
Nitric oxide • Endothelium-derived relaxing factor • Modest increase in GFR / No change in
(NO)
• Important vasodilator under basal RBF
conditions
• Counteracts the vasoconstriction produced Histamine • Decreases resistance of afferent and
by angiotensin II and catecholamines. efferent arterioles → ↑RBF but no effect
on GFR
• Dilates afferent and efferent arterioles
• Decreases total peripheral resistance Glucocorticoi • ↑ GFR and RBF
• Inhibition increases BP ds
• ↑ blood flow → ↑ shear forces acting on Dopamine • ↑RBF and inhibits renin secretion
endothelium of arterioles → ↑ NO • Produced in the proximal tubule
production
• Release of NO from endothelium is also
mediated by other hormones such as
acetylcholine, histamine, bradykinin, & ATP
• ↑ NO production → dilation of afferent &
efferent arterioles → ↓ total peripheral
resistance

Prostaglandi • No effect on RBF or GFR in healthy

ns individuals
• In pathologic states, it increases RBF
without affecting GFR
• Dampens the vasocontrictor effects of
sympathetic stimulation and Angiotensin II
• Vasoconstriction of afferent arteriole,
reducing RBF and GFR.
• Produced locally within the kidneys
→ Synthesis is stimulated by ECFV and stress Figure 21. Summary of several factors influencing vasodilation and
(e.g., surgery & anesthesia), angiotensin II, and vasoconstriction. For Vasodilation, NO serves as the second messenger. For
sympathetic nerves Vasoconstriction, Endothelin, Angiotensin II, as well as SNS cathecolamines are
involved.
• Important in maintaining RBF and GFR as
individuals age BRAIN BREAK (15 MINS.)
• Increases RBF without changing GFR in
pathophysiological conditions such as
hemorrhage and reduced ECFV
• Dampens the vasoconstrictor effects of both
sympathetic activation & angiotensin II to
increase RBF
→ Prevents severe and potentially harmful
vasoconstriction & renal ischemia
• Synthesis of prostaglandins is stimulated by
↓ ECFV and stress (e.g., surgery and
anesthesia).
• Nonsteroidal anti-inflammatory drugs
(NSAIDs) potentially inhibit prostaglandin
synthesis → blocks prostaglandin production
→ ↓ RBF & ↑ renal ischemia
Figure . you can do it b-bHie.
• Must not be administered in cases of renal
ischemia and hemorrhagic shock

PHYS - LEC Trans no. 1 | Renal Physiology I 11 of

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 XI. TRANSEPITHELIAL SOLUTE AND WATER TRANSPORT

• Transport of fluids and solutes happens in to two important

pathways
→ Transcellular Pathway
▪ Movement of water and solutes across the cell with the use
of specific channels and transporters
→ Paracellular Pathway
▪ Movement of water and solutes via the tight junctions.
• Na+/K+ ATPase
→ Establishes the electrochemical (concentration) gradient in
between the three compartments
▪ Tubular fluid
▪ Cells of the nephron segments
▪ Interstitium (cortical, medullary or plasma)
→ Pumps 3Na+ ions out of the cell in exchange of 2K+ ions that
goes inside of the cell. (PISO = Potassium In, Sodium Out)
▪ As the Na+ goes out of the cell, the intracellular Na+ Figure 22. Mechanism of Na+/H+ antiporter located in the apical membrane, as
well as the transport of NaHCO3 to the interstitium with the use of Na+/HCO3-
concentration decreases. symporter located in the basolateral membrane. CA: carbonic anhydrase.
▪ The decrease in the intracellular Na+ is the one that creates
the concentration gradient that drives the Na+ ions to go → Na+/Glucose symporter (SGLT2)
inside the cell from the tubular fluid. ▪ Glucose couples the entry of Na+ through this transporter.
− Na+ concentration in the tubular fluid is greater than the ▪ Allows Na+ gradient buildup inside the cell
Na+ concentration in the cytoplasm. ▪ Glucose exits the cell passively and reabsorbed through
− This makes the transepithelial transport mechanisms the presence of GLUT2 transporter located in the
work. basolateral membrane.
▪ This also establishes the negatively-charged intracellular
fluid.
• NaCl and water reabsorption represent the major function of
the nephrons.

A. PROXIMAL TUBULE
• Reabsorbs 67% of the filtered water, Na+, K+, Cl-, HCO3-, all
the glucose and amino acids
→ Done in an isosmotic fashion
▪ Moves equal proportion of solutes and water
→ Osmolarity of the tubular fluid DOES NOT change.
→ It is the volume of the fluid and solutes that change.
→ High reabsorption rate is due to the presence of brush
borders in the apical membrane of the cells.
→ 2/3 moves across the membrane through transcellular
pathway.
→ 1/3 moves across the membrane through paracellular
pathway. Figure 23. Mechanism of Na+/glucose symporter located in the apical
• Na+/K+ ATPase in the basolateral membrane acts as the key membrane. GLUT2 transporter in the basolateral membrane is also shown.
element in the reabsorption of the solutes.
→ Other Na+ reabsorption mechanisms and transporters
NOTE:
▪ Na+ enters the proximal tubule cells via several symporter
• Transport from apical to basolateral = REABSORPTION mechanisms including:
• Transport from basolateral to apical = SECRETION − Na+/amino acid
− Na+/Pi
First Half of the Proximal Tubule
− Na+/lactate
• Na+ is reabsorbed with bicarbonate (HCO3), and a number of • Basolateral Membrane
other solutes (e.g., glucose, amino acids, Pi, lactate)
→ Na+/K+ ATPase
• Reabsorbs significantly more Na+ than the second half. ▪ Any Na+ that enters the cell across the apical membrane
• Apical Membrane leaves the cell and enters the blood via this transporter.
→ Na+/H+ Antiporters (NHE3) → Na+/HCO3- symporter (NBC1)
▪ Couples entry of Na+ with extrusion of H+ from the cell ▪ Transports sodium with bicarbonate towards the
▪ H+ ion comes from the condensation of CO2 and H2O interstitium and reabsorbed in the blood
through the use of carbonic anhydrase to produce → Glucose transporter (GLUT2)
carbonic acid. ▪ Transports reabsorbed glucose from the tubular fluid
▪ Carbonic acid will be dissociated into H+ and HCO3-. towards the circulation
− H+ will be excreted into the tubular fluid. ▪ Inactivation of GLUT2 results in glucosuria and decreased
− HCO3- will be reabsorbed into the interstitium glucose reabsorption
o This is done with the reabsorption of sodium using
Na+/HCO3- symporter (NBC1) located in the Second Half of the Proximal Tubule
basolateral membrane • Na+ is reabsorbed with chloride (Cl-).
• 67% of NaCl is reabsorbed via transcellular (2/3 of the total NaCl
reabsorption) and paracellular (1/3) routes.
• Paracellular route

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 → The low chloride reabsorption in the first half of the proximal
tubule gives rise to an increased chloride concentration in • As you increase the distance in the proximal tubule (from the
the second half of the proximal tubule. Bowman’s space before it becomes the descending thin limb),
→ This creates the concentration gradient that allows diffusion almost all of the solutes are reabsorbed except for the NaCl.
of chloride ions across the tight junctions. • The HCO3-, glucose, amino acids and lactate are absorbed
▪ From tubular lumen into the lateral intercellular space. almost 100% in the first half of the proximal tubule.
→ Due to the movement of negatively charged Cl- ions to the • Na+ and Cl- are still continuously reabsorbed in the second half
intercellular space, this leaves the tubular fluid positively of the proximal tubule.
charged with respect to the blood. • So, more water than chloride is absorbed in the first half of the
→ This positive transepithelial voltage in the lumen of the proximal tubule.
proximal tubule causes diffusion of positively charged Na + out → This explains the increased chloride concentration in the
of the tubular fluid into the blood through entering the tight second half of the proximal tubule.
junctions.
• Transcellular Route Water Reabsorption in the Proximal Tubule
→ Apical Membrane • Reabsorbs 67% of the filtered water.
▪ Na+ enters the cell through the parallel operation of Na+/H+ • Transtubular osmotic gradient
antiporter (NHE3) and one or more Cl—base antiporter → Driving force for water reabsorption
(e.g., CFEX). → Established by solute (e.g., NaCl, Na-glucose) reabsorption in
− Example of bases: formate, oxalate, bicarbonate the proximal tubule
▪ The secreted hydrogen and base combine in the tubular → Reabsorption of sodium along with organic solutes, HCO3-,
fluid and forms H-base complex and reenter the cell and Cl- from the tubular fluid reduces the osmolality of the
through diffusion. tubular fluid
− The H-base dissociates and will be used in the next → The osmolality of the lateral intercellular space increases
sodium and chloride transport. due to the reabsorption of the solutes.
→ Basolateral membrane ▪ The increase in osmolality exceeds the tubular fluid
▪ Na+/K+ ATPase osmolality.
▪ K+/Cl- symporter (KCC) and Cl- channel → There is also an increase in hydrostatic pressure of the
− Transports chloride with K+ from the cell to the blood tubular fluid.
→ These mechanisms drive the passive reabsorption of fluid
via osmosis in the first half of proximal tubule.
→ The movement of water via osmosis across the:
▪ Aquaporin water channels (AQP2) in the apical and
basolateral membranes.
▪ Tight junctions between the cells. (Paracellular pathway)
• Solvent drag
→ Na+ and other solute reabsorption influences the reabsorption
of water.
→ Movement of solutes by the flow of water rather than through
pumps or channels [2023D Trans]
▪ As the Na+ and other solutes are reabsorbed, water is being
dragged into the lateral intercellular space.
→ Accumulation of fluid and solutes in the lateral intercellular
space → ↑ Hydrostatic pressure → Forces fluid and solutes
into the capillaries → Solutes, especially K + and Ca+ are
reabsorbed into the capillaries via the solvent drag as a
consequence of the osmotic water flow.
Figure 24. Sodium transport processes in the second half of the proximal tubule. → ↑ Na+ reabsorption may lead to ↑ HCO3- reabsorption which
may result into metabolic alkalosis.
Solute Concentration In The Tubular Fluid

Figure 26. Routes of reabsorption of water and solute across the proximal
Figure 25. Concentration of solutes in tubule fluid as a function of length along tubule.
the proximal tubule. TF: concentration of substance in tubular fluid; P:
concentration of substance in plasma
PHYS - LEC Trans no. 1 | Renal Physiology I 13 of
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 Protein Reabsorption in the Proximal Tubule • 50% of the reabsorption
• The concentration of proteins in the glomerular ultrafiltrate is only • Apical Membrane
~40 mg/L. → 1Na+/1K+/2Cl- Symporter (NKCC2)
• ~100% of the protein in the tubular fluid is reabsorbed. ▪ Responsible for the take up of solutes from the tubular
→ Therefore, the urine is essentially protein free. fluid
• Proteins are brought in the circulation in the form of amino acids ▪ Couples movement of 1Na+ with 1K+ and 2Cl-
• Filtered proteins are reabsorbed in the proximal tubule by ▪ Using the energy released by the downhill movement of
endocytosis. Na+ and Cl-, drives the uphill movement of K+ into the
• Protein reabsorption → Partial enzyme degradation of protein in cell
the surface of proximal tubule cells → Endocytosis of the → K+ channels (ROMK and Maxi-K)
degraded proteins → Further intracellular breakdown of proteins ▪ Allow the K+ transported into the cell via the
into amino acids → Amino acids leave the cell via the basolateral 1Na+/1K+/2Cl- symporter to be recycled back into the
membrane → Capillary circulation tubular fluid
• Proteinuria − K+ in the tubular fluid is relatively low, K+ recycling is
→ Presence of protein in the urine required for continued operation of the 1Na+/1K+/2Cl-
→ Maybe due to the disruption of the glomerular filtration barrier symporter.
→ Or due to increase in filtered proteins (increased proteins in → Na+/H+ antiporter (NHE3)
the plasma) ▪ Mediates Na+ reabsorption as well as H+ secretion
▪ Uptake of Na+ in exchange for H+
Organic Anion and Cation Secretion Across the Proximal ▪ The production of H+ inside the cell generates HCO3-
Tubule through the action of carbonic anhydrase
• Plays a key role in regulating the plasma levels of: • Basolateral Membrane
→ Xenobiotics (e.g., variety of antibiotics, diuretics, anti- → Na+/K+-ATPase pump
inflammatory drugs, statins) ▪ Maintains a low intracellular Na+, which provides a
→ Toxic compounds (either exogenous or endogenous) favorable chemical gradient for the movement of Na+
• Organic Anion Secretion from the tubular fluid into the cell
→ Utilizes PAH in exchange for organic anion reabsorption. → Cl-/HCO3- antiporter
→ Para-aminohippuric Acid (PAH) ▪ Exit of HCO3- (produced from the carbonic acid) from the
▪ Reduces the secretion of penicillin by the proximal tubule. cell towards the interstitium in exchange for Cl -
▪ Infusion of PAH into individuals receiving penicillin reduces → K+ and Cl- channels and K+/Cl- symporter
penicillin excretion, thus prolonging its effect. ▪ Pathway of K+ and Cl- out of the cell
▪ Used in WWII when penicillin has a short supply. 2. Paracellular Pathway
• Organic Cation Secretion • 50% of the reabsorption
→ Organic cation is secreted across the apical membrane in • Tubular fluid is positively charged relative to blood.
exchange for hydrogen ion. → Increased NaCl transport by the thick ascending limb
▪ Uses multidrug and toxin transporters (MATE1 and increases the magnitude of the positive voltage in the
MATE2-K) lumen.
B. LOOP OF HENLE → This voltage is an important driving force for the
reabsorption of Na+, K+, Mg2+, and Ca2+ across the
• Reabsorbs ~25% of the filtered NaCl paracellular pathway.
• Reabsorbs ~15% of the filtered water
• NaCl reabsorption
→ Occurs in both the thin and thick ascending limb
→ Does not occur in the descending thin limb
• Water reabsorption
→ Occurs only in the descending thin limb
• Responsible for the pumping of solutes into the medullary
interstitium to maintain the countercurrent multiplication system
→ Due to the action of the Na+/K+-ATPase pump
• Acts as the counter current multiplier
→ It multiplies the osmolarity of the medullary interstitium.

Descending Thin Limb

• Part of the loop of Henle where the water reabsorption takes
place, exclusively
→ Mediated by the AQP1 water channels.
• NO NaCl reabsorption takes place.
Thin Ascending Limb
• Reabsorbs NaCl by a passive mechanism.
• Reabsorption of water, but not NaCl, in the descending thin limb
increases NaCl concentration in the tubule fluid entering the
ascending thin limb.
→ Creates the concentration gradient between the tubule fluid
and the medullary interstitial fluid.
Thick Ascending Limb
• Diluting segment
→ Impermeable to water, permeable to solutes.
• Movement of solutes transcellularly and paracellularly. Figure 27. Transport mechanism in the thick ascending limb of the loop of Henle.
1. Transcellular Pathway

PHYS - LEC Trans no. 1 | Renal Physiology I 14 of

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 C. DISTAL TUBULE AND COLLECTING DUCT ▪ ↑ Activity of Na+/K+-ATPase pump → K+ accumulates inside
the cell → ↑ K+ concentration gradient between the principal
• Reabsorbs ~8% of the filtered NaCl [Koppen & Stanton, 2018] cells and the tubular fluid
→ But with the lecture of Dr. Solidum, NaCl reabsorption is → Apical membrane is much more permeable to K+ than the
approximately 7%. basolateral membrane
• Reabsorbs variable (~8-17%) amount of water. → Aldosterone enhances the expression of the ENaC.
▪ Allows more Na+ to be reabsorbed from the tubular fluid
Early Distal Tubule
• ɑ Intercalated Cells
• Reabsorbs Na+, Cl-, and Ca2+
→ Secrete H+
• Impermeable to water
→ Reabsorb both HCO3- and K+
• Part of the diluting segment
▪ Important in regulating acid-base balance and K+ balance
→ Continues the dilution of the tubular fluid from the thick
→ H+,K+-ATPase (HKA)
ascending limb
▪ Reabsorbs K+ in exchange of H+; found in the apical
• Apical Membrane
membrane
→ Na+/Cl- symporter (NCC) • β Intercalated Cells
▪ Mediates the entry of NaCl into the cell
→ Secrete HCO3-
• Basolateral Membrane
→ Reabsorb both H+ and Cl-
→ Na+/K+-ATPase pump
→ Cl-/HCO3- antiporter (Pendrin)
▪ Pathway of reabsorbed Na+ out of the cell
▪ Facilitates Cl- entry into the cell; found in the apical
→ K+/Cl- symporter membrane
▪ Pathway reabsorbed Cl- out of the cell
→ Cl- channels
▪ Facilitate Cl- exit from the cell into the interstitium; found in
the basolateral membrane
• Water Reabsorption
→ Mediated by ADH-regulated AQP2 water channels located in
the plasma membrane and AQP3 and AQP4 located in the
basolateral membrane of the principal cells
→ Presence of ADHwater is reabsorbed
→ Absence of AVP, late distal tubule and collecting ducts
reabsorb little amount of water

Figure 28. Transport mechanism for NaCl reabsorption in the early segment of
the distal tubule.
Late Distal Tubule and Collecting Duct
• Composed of three cell types:
→ Principal Cells
→ Two types of intercalated cells (ɑ and β)
• Principal Cells
→ Reabsorb NaCl and water
→ Secrete K+
→ Epithelial Na+-selective channels (ENaC)
▪ Found in the apical membrane
▪ Reabsorbs the Na+ from the tubular fluid
▪ The negative voltage inside the cell drives the Na + entry.
→ Na+/K+-ATPase
▪ Found in the basolateral membrane.
▪ Activity of this pump control the Na + reabsorption and K+
secretion.
→ Na+ entry → Generates negative luminal voltage → Provides
the driving force for paracellular reabsorption of Cl-.
→ 2 Steps of K+ secretion into the tubular fluid
1. Uptake of K+ across the basolateral membrane mediated
by the Na+/K+-ATPase
2. K+ leaves the cell via passive diffusion through apical cell
membrane K+ channels (ROMK and BK)
− Electrochemical gradient K+ across the apical
membrane promotes the secretion of K+ from the cell
into the tubular fluid. [Recall: K+ has a higher intracellular
concentration than extracellular]
→ Aldosterone enhances K+ secretion by increasing the activity
of the Na+/K+-ATPase pump. Figure 29. Transport pathways in the principal cells, ɑ-intercalated cells, and β-
intercalated cells of the late segment of the distal tubule and collecting duct.

PHYS - LEC Trans no. 1 | Renal Physiology I 15 of

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Table 4. NaCl Transport along the Nephron [Koppen & Stanton, 2018] 2. Increasing the filtration fraction may lead to a _________ in
Segment % Filtered Mechanism of Major hydrostatic pressure in the efferent arteriole.
NaCl Na+ Entry Regulatory a. Increase
Reabsorbed Across the Hormone b. Decrease
Apical
Membrane 3. Which of the following will most likely restore blood volume
Proximal 67 • Na+/H+ • Angiotensin II of a hypotensive patient?
tubule antiporter • Norepinephrine a. Neutral dextran
• Na+ symporter • Epinephrine b. Plain NSS
with amino • Dopamine c. Polyanionic dextran
acids and d. Polycationic dextran
organic solutes
• Paracellular 4. Vasoconstriction of the afferent arteriole will lead to which
Loop of 25 • 1Na+/1K+/2Cl- • Aldosterone of the following consequences?
Henle symporter • Angiotensin II a. Increased plasma oncotic pressure
Distal ~5 • NaCl • Aldosterone b. Increased GFR
tubule symporter • Angiotensin II c. Increased filter fraction
Late ~3 • ENaC Na+ • Aldosterone d. Increased glomerular capillary hydrostatic pressure
distal channels • ANP, BNP
tubule • Urodilatin 5. This is the enzyme that can be released when the JG
and • Uroguanylin apparatus is activated.
Collecting • Guanylin a. Renin
duct • Angiotensin II b. Aldosterone
c. Na/K ATPase
Table 5. Water Transport along the Nephron [Koppen & Stanton, 2018] d. Angiotensin I
Segment % Filtrate Mechanism of Hormones
Reabsorbed Water that Answer: 1. B 2. B 3. C 4. A 5. A
Reabsorption Regulate
Water XI. REFERENCES
Permeability 2023D Trans
Proximal 67 • Passive • None Constanzo, L. S. (2015). Physiology. (6th ed.). Philadelphia (PA): Lippincott
tubule Williams & Wilkins
Dr. Solidum’s PPT Presentation
Loop of 15 • Descending thin • None Hall, J.E. (2016). Guyton and Hall Textbook of Medical Physiology. 13th ed.
Henle limb only; Philadelphia: Elsevier, Inc.
passive Koeppen, B.M. & Stanton, B.A. (2018). Berne and Levy Physiology. 7th ed.
Distal tubule 0 • No water • None Philadelphia: Elsevier, Inc
reabsorption
Late distal ~8 to 17 • Passive • AVP
tubule and • ANP, BNP
Collecting
duct

CONGRATS ON FINISHING THIS TRANS!

Figure . solutes only allowed.

XII. REVIEW QUESTIONS

1. An increase in the NaCl concentration in the tubular fluid

activates this type of autoregulatory response.
a. Baroreceptor reflex
b. Tubuloglomerular feedback
c. RAAS activation
d. Myogenic mechanism

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