Renal Flashcards

Question 1

Q

Renal Functions

Overview

Answer

A

Excretion:
- metabolic wastes and compounds excreted in the urine
Homeostasis:
- water and electrolyte balance
- extracellular fluid volume
- plasma osmolarity
RBC production:
- secretes erythropoietin (EPO)
Regulation of vascular resistance:
- Renin secreted by juxtaglomerular apparatus cells
- Initiates RAAS controlling vascular resistance
Regulation of acid-base balance
- Secretes or absorbs acids and bases
Vit D production
- Calcitriol
Gluconeogenesis
- Contributes during prolonged fasting

Question 2

Q

Cortex

Answer

A

Outer part of the kidney which contains:

Bowmen’s capsules
glomeruli
proximal convoluted tubules
cortical portions of loop of Henle
distal convoluted tubules
cortical collecting tubules
tubules and microvasculature intertwined in a random fashion

Question 3

Q

Medulla

Answer

A

Inner part of the kidney composed of pyramids.

Contains:

medullary portions of loop of Henle
medullary collecting tubules
collecting ducts
tubules and blood vessels arranged in parallel

Question 4

Q

Calyces

Answer

A

drain into the renal pelvis
renal pelvis forms the head of the ureter
ureter sends urine to the urinary bladder

Question 5

Q

Nephron Structure

Answer

A

Functional unit of the kidney.

Bowman’s capsule is the start of the nephron
- Blood enters via the afferent arteriole
- Moves into the glomerular capillaries
- Exits via the efferent arteriole
- Filtrate enters Bowman’s space
Proximal tubule
- Proximal convoluted tubule (PCT) ⇒ cortex
- Proximal straight tubule (PST) ⇒ medulla
Loop of Henle:
- Descending thin limb (DTL)
- Ascending thin limb (ATL)
- Thick ascending limb (TAL)
Distal convoluted tubule (DCT)
Connecting tubule
Cortical and medullary collecting ducts
Calyx → renal pelvis → ureter → urinary bladder

Question 6

Q

Peritubular Capillaries

Answer

A

Surrounds the nephron tubule
Provides O₂ and nutrients to tubules.
Carries away fluid and electrolytes reabsorbed by tubules.

Question 7

Q

Superificial Nephrons

Answer

A

Receives ~ 90% of renal blood supply
Major site of fluid and electrolyte reabsorption
Short loops of Henle that do not reach the inner medulla

Question 8

Q

Juxtamedullary Nephrons

Answer

A

Receive ~ 10% renal blood supply
Very long loops of Henle that go deep into inner medulla
Peritubular capillaries forms a long looping vascular network ⇒ vasa recta
Creates osmotic gradients that concentrate urine

Question 9

Q

Filtration

Answer

A

Process by which water and solutes leave the glomerular capillaries and enter Bowman’s space.

Question 10

Q

Secretion

Answer

A

Process where substances are transported from the tubular epithelial cells into the nephron lumen.

Substances can be synthesized in the epithelial cells or obtained from surrounding interstitial space.

Question 11

Q

Reabsorption

Answer

A

Process by which substances in the lumen cross the epithelial barrier into the interstitial space where they can be absorbed by peritubular capillaries.

Question 12

Q

Excretion

Answer

A

The exit of substances from the body via the urine.

Question 13

Q

Reabsorption & Secretion

Overview

Answer

A

Proximal Convoluted Tubule (PCT)
- Isomolar reabsorption of ~ 70% of filtered water and solute
- Major role in reclaiming salt and water needed to maintain ECF.
- Carrier-mediated Na⁺ transport.
Loops of Henle (LoH)
- Carrier-mediated NaCl reabsorption by the water impermeable thick ascending limb.
- Generation of corticomedullary concentration gradient.
Distal Convoluted Tubule (DCT)
- Carrier-mediated reabsorption of NaCl.
- Water impermeable.
- Hormone-modulated Ca⁺⁺ reabsorption.
Connecting Tubule (CNT)
- Both carrier-mediated and ion channel (hormone-regulated) Na⁺ reabsorption.
- Hormone-regulated Ca⁺⁺ reabsorption.
- Arginine vasopressin (AVP)-responsive water permeability.
Collecting Tubules and Collecting Ducts
- Different cell types for Na⁺ reabsorption and H⁺ secretion.
- Hormone regulated ion channel Na⁺ reabsorption.
- Hormone modulated K⁺ secretion.
- Hormone modulated H⁺ secretion.
- Arginine vasopressin (AVP)-responsive water permeability.
- Urea transport.

Question 14

Q

Renal Clearance

Answer

A

The volume of plasma the kidneys completely clear of a substance per unit time.

Question 15

Q

Glomerular Filtration Rate

(GFR)

Answer

A

The rate at which the kidney’s are filtering.

Usually corrected to body surface area of 1.73 m².
Normal:
- 125 ± 15 ml/min for young adult males
- 110 ± 15 ml/min for young adult females
GFR declines after age 45-50
- Typically 30-40% lower by age 80
Used to determine:
- Overall kidney function
- How much a substance is filtered per unit time
- Is a substance reabsorbed or secreted
- What percentage of a filtered substance is reabsorbed
Assesses overall renal glomerular and net renal tubular function

Question 16

Q

Inulin Clearance & GFR

Answer

A

Insulin is the gold standard for measuring GFR.

cleared from the plasma by filtration only
freely filtered by the glomeruli
not reabsorbed or secreted by tubular cells
not created or metabolized by the kidneys

Amount of insulin filtered = amount excreted in the urine.

Clearance of inulin = GFR.

Question 17

Q

Renal

Mass Balance

Answer

A

One entrance ⇒ renal artery.
- 20% of plasma filtered into Bowman’s space
- Remainder enters efferent arteriole ⇒ renal vein
Two exits ⇒ renal vein and ureter.
- Reabsorbed fluids/solutes ⇒ renal vein
- Substances not reabsorbed enters ureter ⇒ urine
- Substances secreted into tubules ⇒ ureter ⇒ urine

What enters the kidney equals what exits:

Amount_filtered + Amount_unfiltered = Amount_urine + Amount_vein

Amount filtered is GFR x plasma concentration:

Amount_filtered = GFR x P_x

Amount excreted is urine flow rate x urine concentration:

Amount_x-_excreted = ⩒ x U_x

Question 18

Q

Para-aminohippuric Acid

(PAH)

Answer

A

Used at low concentrations for determination of renal plasma flow rate (RPF) due to these characteristics:

freely filtered by glomeruli
any PAH not filtered is transported by tubular cells from peritubular capillaries into urine
is not synthesized or metabolized by the kidney

* PAH is not naturally-occuring and must be administered by continuous IV.

Question 19

Q

Renal Plasma Flow Rate

(RPF)

Answer

A

The rate of plama flow through the glomeruli in ml/min.

PAH usually used in RPF determinations.

C_PAH = (U_PAH x ⩒) / P_PAH = RPF

Question 20

Q

Renal Blood Flow

(RBF)

Answer

A

The amount of blood flow through the kidneys in ml/min.

Calculated from the renal plasma flow rate (RPF) using the hematocrit (Hct) of the blood.

Since Hct is the fraction of blood volume made up of RBC, the remainder is plasma.

Question 21

Q

Filtration Fraction

(FF)

Answer

A

How much plasma is filtered through the glomeruli compared to how much is not.

Amount of plasma entering the glomerulus = RPF.

Amount of plasma filtered = GFR.

FF = GFR / RPF

Typical filtration fraction ~ 20%.

Question 22

Q

Applications of Clearance

Answer

A

Comparing clearance of any substance to that of inulin allows determination of overall net action of the renal system on that substance.

Question 23

Q

Creatinine Clearance

Answer

A

The clinical standard for estimating GFR (eGFR) utilizing empirical equations.

Creatinine is the muscle creatine phosphate breakdown end-product.
- Daily creatinine production ∝ muscle mass.
If renal function normal: creatinine_excreted = creatinine_produced so plasma_creatinine fairly constant.
Very small amount of creatinine is secreted into urine so creatinine clearance slightly overestimates GFR.
As serum creatinine doubles, GFR decreases by 50%.

Question 24

Q

Total Body Water

(TBW)

Answer

A

TBW ~ 60% of body weight in lean adult male.

TBW ~ 50% of body weight in lean adult female.

The higher the % body fat, the lower contribution of TBW to body weight.

2/3 of TBW is intracellular fluid (ICF).

1/3 of TBW is extracellular fluid (ECF).

~75% of ECF is interstitial fluid and ~25% is plasma.

Total amount of Na⁺ in the body determines ECF volume.

Kidneys control Na⁺ and water reabsorption independently of each other to maintain optimal volume and solute concentrations.

Question 25

Q

TBW

Ionic Compositions

Answer

A

ECF: High [Na⁺] & low [K⁺]

ICF: Low [Na⁺] & high [K⁺]

Distribution of Na⁺ and K⁺ due to the Na/K-ATPase.

Question 26

Q

Indicator-Dilution Technique

Answer

A

Compound known to evenly distribute through compartment of interest used to determine compartment volumes.

At equilibrium, plasma concentration measured.

Volume determined from:

Volume = amount of indicator / [indicator]

Measured using:

TBW
- heavy water (D₂O)
- antipyrene
ECF
- impermeant ions
  - Na⁺
  - radioactive ³⁵SO₄
- inert sugars
  - mannitol
  - sucrose
  - inulin
ICF
- difference between TBW and ECF

Question 27

Q

ECF

Volume Changes

Answer

A

Volume expansion and volume contraction refers to ECF volume changes.

Normal:

Width = volume

2/3 ICF and 1/3 ECF

Height = solute concentration as osmolatity

Osmolality of both compartments 285 mOsm/kg

When NaCl is added to the ECF, all of the NaCl remains in the ECF.

Question 28

Q

Hypo-osmolar

Volume Expansion

Answer

A

2 L of pure water added to ECF

TBW increased 42 L → 44 L
Osmolality decreased due to dilution
Water moves ECF → ICF to maintain osmotic eq.
2/3 water added ends up in ICF

Question 29

Q

Iso-osmolar

Volume Expansion

Answer

A

2 L of isotonic saline (0.9% NaCl) added to ECF.

TBW increases 42 L → 44 L
Osmolality of ECF unchanged
No net water movement
Only ECF volume increases
No change in osmolaity in either compartment

Question 30

Q

Hyper-osmolar

Volume Expansion

Answer

A

1 L of concentrated NaCl (5% NaCl) added to ECF.

TBW increases 42 L → 43 L
ECF osmolality increases
- Water moves ICF → ECF until osmotic gradient eliminated
ICF volume decreases
ECF volume increases
Osmolality of both compartments increased

Question 31

Q

Iso-Molar Volume Contraction

Answer

A

Commonly seen after viral gastroenteritis
Water lost but kidneys maintain ECF [Na⁺] in normal range
ECF volume falls
No net water movement
All of the volume loss from ECF

Question 32

Q

Hyper-osmolar Volume Contraction

Answer

A

Lost in the desert without water
Assume that only water is lost → TBW decreased
ECF volume decreased → osmolality increases
Water moves from ICF → ECF until equilibrium
Both ECF & ICF volumes decreased
2/3 ICF & 1/3 ECF distribution maintained
Osmolality in both compartents equal or greater than before

Question 33

Q

Hypo-osmolar Volume Contraction

Answer

A

Seen with adrenal insufficiency
- Reduced aldosterone production
- Decreased renal absorption of Na⁺
- Slightly decreased water reabsorption → net water loss → reduced TBW
ECF volume and [Na⁺] decreased
Osmolality ICF > ECF
Water moves ECF → ICF
After equilibrium:
- TBW and ECF volumes reduced
- ICF volume increased
- Osmolality of ECF and ICF lower

Question 34

Q

Volume Expansion & Contraction

Summary Table

Question 35

Q

Glomerular Vascular Structure

Answer

A

Glomerular and peritubular capillaries form an arterial portal system.

Glomerular capillaries sit in Bowman’s capsule.
Peritubular capiilaries warps around tubules.
Cells lining tubules reabsorb solutes/water from filtrate or secrete into them.

Renal artery ⇒ afferent arteriole ⇒ glomerular capillary bed ⇒ efferent arteriole ⇒ peritubular capillary bed ⇒ renal vein.

Question 36

Q

Filtration Barrier

Answer

A

Composed of 3 layers:

Capillary endothelium
- Fenestrated
- Minimally-selective openings 70-100 nm diameter
- Negative surface charge ⇒ inhibits passage of negatively charged solutes
Basement membrane
- Secreted by both endothelium and epithelium
- Type IV collagen
  - Inhibits passage of intermediate to large sized molecules
- Negatively charged extracellular matrix material
  - Restricts passage of negatively charged molecules
Epithelial layer
- Made of podocytes
  - Specialized epithelial cells
  - Foot processes with secondary toe-like pedicles
  - Slit diaphrams between pedicles
- Pedicles & slit diaphragms with negative surface charge
  - Inhibits passage of large negatively charged molecules
- Slit diaphragms connected to contractile elements in podocytes
  - Permits control over epithelial permability

Question 37

Q

Ultrafiltration

Answer

A

Filtered fluid from glomeruli enters nephron for further processing
Glomerulus serves as molecular sieves
- water, electrolytes, and solutes with MW < 5,200 freely filtered
- Variably filtered substances with MW 6,000 to 60,000
 - Permeability related to size, shape, and charge

Question 38

Q

Starling’s Law

&

Glomerular Filtration

Answer

A

Forces that govern fluid movement across glomerular capillary

described by Starling’s Law:

GFR = K_f[(P_GC + π_BS) - (π_GC - P_BS)]

K_f = filtration coefficient

P_GC = hydrostatic pressure of glomerular capillary

P_BS= hydrostatic pressure of Bowman’s space

π_GC= oncotic pressure of glomerular capillary

π_BS= oncotic pressure of Bowman’s space ⇒ 0 since proteins are not passed through the capillary

Question 39

Q

Ultrafiltration Pressure

(P_UF)

Answer

A

Net force for fluid movement (P_UF) at glomerular capillaries approximately + 10 mmHg.

Fluid pushed out of the capillary.

P_BSand π_BS constant under normal conditions
π_GC higher at efferent arteriole than afferent
- Due to ~15-20% volume loss by blood
Capillary hydrostatic pressure (P_GC) is the main driving force for filtration
- P_GCat afferent arteriole higher than other capillary beds
  - At start of renal arterial portal system
- Small pressure drop exists along the capillary
  - P_GC@ afferent arteriole ~ 60 mmHg
  - P_GC@ efferent arteriole ~ 58 mmHg
- Depends on
  - aortic pressure
  - renal arterial pressure
  - afferent and efferent arterial resistance

Question 40

Q

Effects of Arteriolar Changes

Answer

A

Afferent arteriole

Constriction decreases glomerular blood flow
- Dec. P_UF and GFR
Dilation increases glomerular blood flow
- Inc. P_UF and GFR

Efferent arteriole

Constriction decreases glomerular blood flow
- Causes pressure to back up in capillary bed ⇒ inc P_GC
- Inc. P_UF and GFR
Dilation increased glomerular blood flow
- Causes drop in P_GC
- Dec. P_UF and GFR

Question 41

Q

Autoregulation

Glomerular Blood Flow

Answer

A

Ensures that RBF and GFR remains relatively stable over a wide range of MAPs (80-180 mmHg).

Minimalizes the impact of changing arterial pressure on Na⁺ excretion.

1. Myogenic Response

2. Tubuloglomerular feedback (TGF)

Question 42

Q

Myogenic Response

Answer

A

Auto-regulatory Mechanism

Increase in pressure results in vascular contraction to maintain a constant blood flow
Mediated by stretch-activated cation channels
- Opens in response to increased translumenal pressure
- Depolarizes smooth muscle cells
- Elicits contraction
Found only in afferent arterioles

Question 43

Q

Tubuloglomerular Feedback

(TGF)

Answer

A

Auto-regulatory mechanism unique to the kidneys.

Mediated by the macula densa
- Part of the juxtaglomerular apparatus
- In the thick ascending limb at the transition of the LoH to the distal convoluted tubule
Macula densa cells monitor local Na⁺ and Cl^- concentrations
- Increased P_GC ⇒ Increased GFR ⇒ Increased NaCl delivery to macula densa
- Cells release ATP ⇒ adenosine
Adenosine binds to:
- A₁ purine receptors on afferent arterioles
  - Vasoconstriction
  - Reduces blood flow & GFR
- A₂ purine receptors on efferent arterioles
  - Vasodilation
  - Increases outflow
  - Decreases P_UF & GFR

At high flow rates:

Increased NaCl delivery to macula densa ⇒ ATP ⇒ adenosine production ⇒ afferent arteriole constriction & efferent arteriole dilation AND renin release from granular cells inhibited ⇒ decreased P_UF & GFR.

At low flow rates:

Decreased NaCl delivery to macula densa ⇒ no adenosine made ⇒ inhibition of renin release removed ⇒ renin starts RAAS cascade ⇒ increased P_UF & GFR.

Question 44

Q

Nervous System Control

Glomerular Blood Flow

Answer

A

Drop in blood pressure triggers carotid and aortic baroreceptor reflex
SNS activation results in release of norepinephrine
Leads to vasoconstriction
- Efferent arterioles more sensitive to norepi
  - Mild SNS activation preferentially constricts efferent arterioles
    - Results in reduced RBF maintaining GFR
  - Intense SNS activation constricts both affrent and efferent arterioles
    - Reduces GFR
- Severe hemorrhage causes prolonged constriction of renal arterioles
  - Can lead to renal ischemia and failure

Question 45

Q

Hormonal Control

Glomerular Blood Flow

Answer

A

Low MAP pressures triggers renin release from granular cells of JGA
- Renin converts Angiotensinogen ⇒ Angiotensin I
- ⇒ Angiotensin II by ACE in lungs
Ang II is a potent vasoconstrictor
- Stronger effect on efferent arteriole compared to afferent
- Net effect that GFR increases and RBF decreases
Ang II also induces renal production of prostaglandin vasodilators PGE₂ and PGI₂
- PGE₂ and PGI₂preferentially dilates afferent arteriole
- counterbalances constriction of afferent arteriole by Ang II
- Ensures that RBF is not decreased too much

Question 46

Q

Glomerular Blood Flow Regulation

Summary Table

Question 47

Q

Renal Transport Mechanisms

Answer

A

Substances can cross the renal epithelial barrier via two pathways:

Paracellular route
- Movement between cells in the epithelia
- Permeability depends upon tightness of intercellular junctions
- Mostly water with associated solvent drag
Transcelluar route
- Movement across the apical and basolateral membranes of epithelial cells
- Usually requires a channel or transporter in each membrane
- Solute and water transport depends on
  - presence of channel/transport
  - distribution along nephron
  - location in basolateral/apical membrane
- Example aquaporins:
  - Always present in proximal tubule and descending thin limb of LoH
  - Controlled expression by ADH/AVP in collecting ducts

Question 48

Q

Driving Force

for

Renal Transport

Answer

A

Electrochemical Na⁺ gradient
- Set up by the basolateral Na/K-ATPase
  - High [Na⁺] in lumen
  - Low intracelluar [Na⁺]
  - Transmembrane potential ~ 70 mV
- Major driving force for solute and water movement
- Drives movement of Na⁺ into epithelial cells
  - Then pumped into interstitial space & returned to circulation
Transepithelial potential
- Also set up by the Na/K-ATPase
- ~ 3 mV with lumen negative
- Driving force for movement of anions via paracellular pathway
Osmotic gradient
- Na/K-ATPase: 3 Na⁺ out for every 2 K⁺ in from insterstitial space
- Drives water movement across epithelial barrier for water reabsorption
  - Transcellular via aquaporins
  - Paracellular via intercellular junctions
    - Water movement can sweep ions and small organic molecules with it ⇒ solvent drag

Question 49

Q

Tubular Transport Maximum

(T_m)

Answer

A

Transporters exhibit saturation at high solute concentrations
Maximal transport rate ⇒ tubular transport maximum (T_m)
As [solute] reaches T_m, not all solute reabsorbed and some excreted in urine.
- Solutes begin appearing in urine before T_m reached ⇒ splay
  - Represents heterogeneity in transporter distribution and function
- As [solute] increases, urine concentration increases

Question 50

Q

Proximal Convoluted Tubule

Transport Overview

Answer

A

Uses both transcellular and paracellular pathways.

Tight junctions are highly permeable to H₂O, Na⁺, K⁺, Cl^-.

Unable to maintain Na⁺ and K⁺ gradient.

PCT reabsorption is isosmotic.

Reabsorbs:
- Essentially all filtered glucose and amino acids
- Largest fraction (~ 70%) of filtered:
  - Na⁺
  - K⁺
  - Ca²⁺
  - Cl^-
  - HCO₃^-
Secretes:
- Various organic cations and anions
Synthesizes and excretes:
- NH₃/NH₄⁺
  - Role in HCO₃^- generation & acid/base regulation

Question 51

Q

PCT

Na⁺ Reabsorption

Answer

A

70% of the Na⁺ that enters PCT is fully reabsorbed.

Transcellular
- Basolateral
  - Na/K-ATPase
    - sets up Na⁺ gradient
    - sets up transmembrane potential
    - starts process of Na⁺ reabsorption
  - Na⁺/HCO₃^- cotransporter
- Apical
  - Various Na⁺ coupled transporters
    - glucose
    - amino acid
    - phosphate
    - organic acid
  - NHE3 Na⁺/H⁺ exchanger
Paracellular
- Driven by the transepithelial potential (- 3 mV in lumen)
- Cl^- from lumen ⇒ interstitial space
- Some reabsorbed Na⁺ can leak back to lumen

Question 52

Q

PCT

Water Reabsorption

Answer

A

Reabsorption:
- Transcellular
  - Aquaporins always present in PCT
- Paracellular
  - Movement of Na⁺ and other solutes creates a temporary osmotic gradient
  - PCT epithelium very water permeable
  - Drives water movement from lumen across epithelial layer
Water that enters interstitial space is absorbed by peritubular capillaries.
- Capillary oncotic pressure (π_PC) > capillary hydrostatic pressure (P_PC)
- Water moves into the capillary

Question 53

Q

PCT

Bicarbonate Reabsorption

Answer

A

PCT is the main site for bicarb recovery (~80%).

HCO₃^- charged & cannot diffuse across cell
No HCO₃^- transporters on apical membrane
PCT secretes H⁺ into lumen using NHE3 Na⁺/H⁺ exchanger
H⁺ converts HCO₃^- into H₂CO₃
Carbonic anhydrase IV converts H₂CO₃ to CO₂ and H₂O
CO₂ and H₂O easily enters the cell.
Inside, carbonic anhydrase II converts CO₂ back to H⁺ and HCO₃^-.
H⁺ re-enters lumen via NHE3 Na⁺/H⁺ exchanger
HCO₃^{-}moved to interstitial space by Na⁺/HCO₃^- cotransporter.

Question 54

Q

Proximal Tubule

Cl^- Reabsorption

Answer

A

Enters the cell (apical)
- Paracellular
  - Throughout PCT
  - Driven by postive transepithelial potential
- Transcellular
  - Only in the proximal straight tubule (PST)
  - Cl^-/base exchanger (CFEX)
Leaves to interstitial space (basolateral)
- Cl^- channel
- K/Cl co-transporter

As Cl^- is reabsorbed, H₂O crosses to a greater extent.

Luminal [Cl^-] in tubular fluid rises slightly as fluid moves down the PCT.

Question 55

Q

PCT

K⁺ Reabsorption

Answer

A

Mainly through passively movement
- Paracellular
- Solvent drag in response to water movement

Question 56

Q

PCT

Ca²⁺ Reabsorption

Answer

A

~ 70% of filtered free Ca²⁺ reabsorbed in the PCT.

Passive and paracellular.

Question 57

Q

PCT

Phosphate Reabsorption

Answer

A

~ 80% of filtered P_i absorbed in PCT

Rate of transport depends on plasma [P_i] and parathyroid hormone (PTH).

Mechanism:

Apical absorption via 2 different Na⁺-phosphate cotransporters:
- NaP_i IIc
- NaP_i IIa
Basolateral membrane mechanism unknown

Regulation:

Transporters with higher affinity for HPO₄^2- than for H₂PO₄^-
pH of plasma affects reabsorption of P_i
- acidosis reduces reabsorption
High plasma [P_i] causes PTH release
- PTH promotes endocytosis and degradation of apical P_i transporters
  - More P_i excreted
Low plasma [P_i]
- Increased transporter density on apical membrane
- Increased reabsorption of P_i

Question 58

Q

Glomerulotubular (GT) Balance

Regulation of Na⁺ Reabsorption

Answer

A

Hemodynamic changes that alter GFR modulate the rate of Na⁺ (and Cl^-) reabsorption.

At normal GFR:
- Low P_PC and high π_PC ⇒ net fluid uptake into capillaries.
Increased GFR due to dec. AA resistance and inc. EA resistance:
- More fluid filtered
- Peritubular protein content increases ⇒ inc. π_PC
- Hydrostatic pressure in peritubular capiilar decreases ⇒ dec. P_PC
- Net effect is increased driving force for fluid movement from interstitial space ⇒ peritubular capillary
- Enhances absorption of fluid and NaCl

Question 59

Q

Neurohumoral Control

Regulation of Na⁺ Reabsorption

Answer

A

Neurohumoral stimuli:

Affects GFR and RPF
- Via constriction/dilation of afferent and efferent arterioles
Affect specific transporters in the kidney
- Affects Na⁺ reabsorption
Hemodynamic changes have a greater effect than transporter-specific effects

Question 60

Q

Loop of Henle

Structure

Answer

A

Three sections:
1. Descending thin limb (DTL)
2. Ascending thin limb (ATL)
3. Thick ascending limb (TAL)
Thin limb walls:
- Very simple cellular structure
- Designed to move filtered fluid through the renal medulla
Thick ascending limb:
- Specialized for transport
- Numerous ion pumps
- Contains many mitochondria

Question 61

Q

Loop of Henle

Permeability and Function

Answer

A

LoH extracts water and ions which were not reabsorbed in the proximal tubule.

70% of filtered Mg²⁺

25-30% of filtered Ca²⁺

25% of filtered Na⁺

15% of filtered HCO₃^-

~10% of filtered K⁺

~10% of filtered water

Each section has varied permeability and functions.

Descending thin limb (DTL):
- no Na⁺ or Cl^- transport
- very water permeable
Ascending thin limb (ATL):
- passive Cl^- transport
- passive Na⁺ absorption
- water impermeable
Thick ascending limb (TAL):
- active Na⁺, K⁺, and Cl^- transport
- water impermeable

Question 62

Q

Corticomedullary Gradient

Answer

A

Hairpin-like structure of LoH and vasa recta coupled with the permeability properties of the various regions generates the corticomedullary gradient.

Contained within the interstitial space.
Gradient increases in magnitude along the length of the loop.
Papillary tip osmolarity between 600 - 1,200 mOsm/kg depending on need to conserve water loss.
Osmolarity of luminal fluid follows that of the corticomedullary gradient.
Vital role in urine concentration.

Question 63

Q

Descending Thin Limb

(DTL)

Answer

A

Permits water movement into interstitial space by both transcellular and paracellular pathways.
- Contains aquaporins.
Impermeant to ions.
- Na⁺ and Cl^- remain in the lumen.
- Becomes progressively more concentrated as water leaves DTL.

Question 64

Q

Ascending Thin Limb

(ATL)

Answer

A

Impermeant to water
- No aquaporins
Permeable to Cl^-
- Cl^- leaves
- Na⁺ follows via paracellular pathway
As Cl^- and Na⁺leave the lumen, tubular fluid osmolarity returns back to ~ 300 mOsm/kg.

Answer 63

A

Basolateral Na/K-ATPase sets up an Na⁺ gradient.
Na⁺, Cl^-, and K⁺ ⇒ epithelial via apical Na/K/2Cl cotransporter (NKCC2) brings all three ions into epithelia
- Uses Na⁺ gradient as driving force
- Target for loop diuretics like furosemide
  - Leads to increased urine production and loss of K⁺ (hypokalemia)
Na⁺ ⇒ interstitial space via basolateral Na/K-ATPase
Cl^- ⇒ interstitial space via basolateral Cl^- channel
K⁺ can either:
⇒ interstitial space via basolateral K⁺ channel
⇒ lumen via apical ROMK (Renal Outer Medullary K Channel)
- Creates transepithelial potential ~ +7 mV
  - Drives Na⁺and K⁺ reabsorption via paracellular pathway
- Ensures enough luminal [K⁺] to maintain NKCC2 function

Answer 64

A

Ca²⁺and Mg²⁺ reabsorption via paracellular transport
Driven by transepithelial potential
Inhibition of NKCC2 by loop diuretics prevents formation of transepithelial potential
- Promotes hypomagnesemia
- Ca²⁺can be reabsorbed later in DCT, hypocalcemia is not seen

Answer 65

A

Bicarbonate reabsorbed via similar mechanism as PCT.

No luminal carbonic anhydrase.

Reaborption slower.

TAL secretes H⁺ into lumen via Na⁺/H⁺ exchanger (NHE3)
H⁺ converts HCO₃^- into H₂CO₃
Spontaneous conversion of H₂CO₃ to CO₂ and H₂O
CO₂ and H₂O easily enters the cell.
Inside, carbonic anhydrase II converts CO₂ back to H⁺ and HCO₃^-.
H⁺ re-enters lumen via NHE3 Na⁺/H⁺ exchanger
HCO₃^{-}moved to interstitial space by Na⁺/HCO₃^- cotransporter.

Answer 66

A

Utilizes the corticomedullary concentration gradient to reabsorb water and salt as filtrate travels through LoH.

Gradient generated by LoH and maintained by vasa recta.

~ 300 mOsm/kg @ cortical end

Up to 1,200 mOsm/kg @ medullary end

Initial osmolarity of lumen and interstitial space is 300 mOsm/kg.
TAL absorbs Na⁺ via NKCC2 transporter.
Basolateral Na/K-ATPase transfers to interstitium.
200 mOsm/kg osmotic difference between lumen and interstitium generated.
Water leaves highly permeable DTL until equilibrium occurs with higher osmolarity in interstitium (at 400 mOsm/kg).
- ATL and TAL imperable to water and not affected.

Process occurs throughout length of TAL and DTL ⇒ single effect.

Fluid entering DTL from proximal tubule displaces 400 mOsm/kg fluid down and around loop.
Single effect occurs again generating higher osmolarity at the tip.
Process continues repeatedly until osmolarity of tip 700 - 1,200 mOsm/kg based on need to conserve water.

Fluid leaving TAL into DCT more dilute than the fluid entering LoH.

Answer 67

A

Urea comprises ~ half of solutes in deep renal medullary interstitium.
Diffuses poorly due to small polar nature.
Urea transporters faciliate movement across membranes.
- Unilateral vs bilateral
Pool of urea in the deep renal medullary interstitium augments the corticomedullary gradient.
Osmolarity would be 600 instead of 1,200 mOsm/kg without urea.

Answer 68

A

Collecting ducts secretes urea into interstitium of inner medulla via unilateral UT-As.
- Apical UT-A1 requires ADH/AVP to operate
- Basolateral UT constiutive
Urea enters tip of LoH via unilateral UT-Bs.
Urea carried through distal segment and returns to collecting duct.
Urea recycling results in accumulation of urea in interstitium at tip of LoH.
- Contributes to corticomedullary gradient.
Vasa recta contains bilateral UT’s.
- Urea in vasa recta equilibrates with interstitial urea.
- Helps maintain osmotic gradient.
- Some can be returned to systemic circulation.

Answer 69

A

Amount of urea excreted vs recycled depends on the body’s water conservation needed.

Decreased water intake:
- ADH/AVP released from posterior pituitary.
  - ADH ⇒ GPCR ⇒ cAMP ⇒ PKA
- Activates apical UT-A1 of collecting duct
- Urea recycled, excretion rates minimal.
Increased water intake:
- ADH/AVP release suppressed
- UT-A1 in collecting ducts operate at low levels
- Urea excreted in the urine

Answer 70

A

Consists of the:
- Distal convoluted tubule (DCT)
- Connecting tubule (CNT)
- Cortical collecting ducts (CCD)
Most of the Na⁺ and water has been reabsorbed from the filtrate at this point.
- Actual amount absorbed in the distal nephron much lower than PCT or LoH
  - ~ 10% filtered Na⁺
  - ~ 20% filtered water
Regulated by hormones associated with Na⁺ and water homeostasis
- Becomes an important point for modifying water and electrolyte transport in response to changing conditions

Answer 71

A

Impermeant to water even in the presence of ADH/AVP
Absorbs ~ 5% of filtered Na⁺
Movement of salts without water causes tubular fluid in DCT to be hypo-osmolar to interstitium

Answer 72

A

Na⁺ and Cl^- from lumen into cell via apical Na/Cl co-transporter (NCC)
- Site of action for tiazide diuretics such as hydrochlorothiazide
Na⁺ leaves via basolateral Na/K-ATPase
Cl^- leaves via basolateral Cl^- channel

Answer 73

A

Together the DCT and CNT reabsorbs ~ 8% of filtered Ca²⁺.

Ca²⁺ crosses the apical membrane via TRPV5 Ca²⁺ channel.
- Driving force is the electrochemical gradient for Ca²⁺
Ca²⁺ binds to calbindin in the cytosol
- Maintains the low cytosolic [Ca²⁺] required by cells.
Ca²⁺/calbindin complex translocated to the basolateral membrne.
Ca²⁺ crosses basolateral membrane via either:
- Ca²⁺-ATPase
- Na/Ca exchanger

Transport of Ca²⁺ regulated by PTH.

When plasma [Ca²⁺] low, PTH released from parathyroid.
PTH acts via a GPCR through both adenylyl cyclase and phospholipase C.
Leads to an increase in:
- TRPV5 open probability
- Activity of both basolateral Ca²⁺-ATPase and Na/Ca exchanger
PTH effects potentiated by Vit D (calcitriol)
- Vit D increases synthesis of most (if not all) proteins involved in Ca²⁺ transport.

Answer 74

A

CNT has transport systems similar to both DCT & CCD.

Na⁺ and Cl^- enter apical membrane via NCC.
Na⁺ also enters via apical aldosterone-sensitive epithelial Na⁺ channel (ENaC)
Na⁺ leaves via basolateral Na/K-ATPase
Cl^- leaves via basolateral Cl^- channel
Ca²⁺ handled by similar PTH-sensitive pathway seen in DCT
- Apical TRPV5 Ca²⁺ channel
- Basolateral Ca-ATPase and Na/Ca exchanger
CNT is permeable to water in the presence of ADH/AVP.
- Increases the levels of aquaporin 2 (AQP2)

Answer 75

A

Three functionally-distinct cell types in the CCD:

Principal cells
- Absorbs Na⁺ via ENaC
- Secretes K⁺ into lumen
- Absorbs water in the presence of ADH/AVP
𝛼-intercalated cells
- Secretes H⁺
- Generates new HCO₃^-
- Reabsorbs K⁺ when plasma [K⁺] is very low
𝛽-intercalated cells
- Secretes HCO₃^-
- Reabsorbs K⁺ when plasma [K⁺] is very low

Answer 76

A

Basolateral Na/K-ATPase sets up Na⁺ gradient
Na⁺ reabsorbed by apical ENaC
- Utilizes Na⁺ gradient as driving force
- Blocked by amiloride
  - K⁺-sparing diuretic
Na⁺ ⇒ insterstitial space via Na/K-ATPase
Transcellular Na⁺ movement generates a large transepithelial potential of ~ -40 mV in the lumen
- Much greater than other sites of the nephron
Transepithelial potential provides strong driving force for paracellular Cl^- movement lumen ⇒ interstitium.
𝛽-intercalated cells reabsorb Cl^- via apical Cl/HCO₃^- exchanger (Pendrin).
- 𝛼-intercalated cells do not participate in Cl^- transport
Cl^- ⇒ interstitium via Cl^- channel

Answer 77

A

K⁺ is secreted by principal cells.
- K⁺ moves into cell from interstitium by Na/K-ATPase
- Enter lumen via ROMK channel
  - Driving force is K⁺ concentration gradient and negative potential within lumen.
- If Na⁺ reabsorption blocked in TAL by loop diurectics or DCT by thiazide diuretics
  - more Na⁺ appears at principal cells
  - more Na⁺ reabsorbed here
  - lumen more electronegative facilitating K⁺ loss into lumen ⇒ explains hypokalemia associated with both classes of diuretics
𝛼-intercalated cells can reabsorb K⁺ via apical H/K-ATPase by exchange with H⁺
- Normally minimal
- Becomes important when plasma [K⁺] very low

Answer 78

A

Handled in the distal nephron by intercalated cells.

𝛼-intercalated cells are the major contributor.
- H⁺ secreted into lumen via apical H⁺-ATPase and H/K-ATPase
- HCO₃^- ⇒ interstitial space via Cl/HCO₃^- exchanger (Pendrin class)
- Able to synthesize HCO₃^- via carbonic anhydrase

𝛽-intercalated cells
- HCO₃^- secreted into lumen via apical Cl/HCO₃^- exchanger (Pendrin, different than ones found in 𝛼 cells)
- H⁺⇒ interstitial space via basolatral H⁺-ATPase and H/K-ATPase

The opposing ability of 𝛼 and 𝛽 cells to secrete titratable acid important in acid/base balance.

Answer 79

A

Aldosterone regulates Na⁺ recovery by principal cells.

Aldosterone produced by RAAS system in response to:
- Decreased blood pressure
- Decreased renal blood flow
Binds to basolateral mineralocorticoid receptor (MR)
Ligand/receptor complex translocated to nucleus
Expression of genes for a number of proteins upregulated including:
- ENaC
- ROMK
- Na/K-ATPase

Answer 80

A

Water reabsorption by principal cells of CCD regulated by ADH/AVP.

Aquaporin 2 (AQP2) constantly expressed in principal cells
- Sequestered in vesicles in the absence of ADH/AVP
Basolateral membrane always contains AQP3 and AQP4
- However, no transcellular water movement without apical AQP2
ADH/AVP released from posterior pituitary in response to:
- Increase in plasma osmolarity
- Decrease in circulating blood volume
Acts via V₂ vasopressin receptors
Causes AQP2 translocation and insertion into apical membrane
Completes the transcellular pathway for water movement.

Answer 81

A

ECF osmolarity determined by [Na⁺]_ECF

Approximate the ECF osmolarity using ECF solute content and ECF solute volume:

ECF_osmolarity = ECF_{solute content} / ECF_volume

Answer 82

A

Almost all of the ECF solute content is Na⁺ and it’s associated anions (Cl^-, HCO₃^-).

Estimate ECF volume as:

ECF_volume = (2 x ECF_{Na⁺ content}) / ECF_osmolarity

ECF osmolarity is tightly controlled.

ECF volume varies with Na⁺ content.

Alterations in Na⁺ reabsorption and/or excretion used to maintain a more or less constant ECF volume in the face of varying conditions.

Answer 83

A

The volume on the arterial side of the circulation that provides sufficient tissue perfusion for ongoing metabolic and functional needs.

Systems which maintain a constant ECF via alterations in Na⁺ reabsorption/excretion monitor the effective circulating volume rather than ECF itself.

General rule:

Increased effective circulating volume ⇒ ↓Na⁺ reabsorption and ↑Na⁺ excretion.

Decreased effective circulating volume ⇒ ↑Na⁺reabsorption and ↓Na⁺excretion.

Answer 84

A

Blood volume affects vascular pressure.

Baroreceptors used to sense effective circulating volume.

Arterial baroreceptors
- located in carotid sinus and aortic arch
- high-pressure baroreceptors
- mediate the classic cardiovascular baroreceptor reflex
  - Increased BP ⇒ increased firing ⇒ inhibition of SNS gas & activation of PNS break
Cardiopulmonary baroreceptors
- located in atria and pulmonary arteries
- low-pressure baroreceptors
- essentially sense blood volume
Intrarenal baroreceptors
- located in granular cells of the afferent arteriole
- play a role in control of renin release by granular cells

Answer 85

A

Ensures constant filtration by the proximal tubule in the face of changing GFR.

Proximal tubule reabsorbs essentially a constant fraction of the Na⁺ presented to it to ensure that Na⁺ is not inappropriately reabsorbed with changes in GFR.

Controlled via the effects of GFR changes on the Starling forces of the peritubular capillaries which governs fluid reabsorption.

Increased GFR leads to increased reabsorption by the peritubular network ensuring a relatively constant Na⁺ reabsorption rate.

At normal GFR:
- Low P_PC and high π_PC ⇒ net fluid uptake into capillaries.
Increased GFR:
- More fluid filtered
- Peritubular protein content increases ⇒ increased π_PC
- Hydrostatic pressure in peritubular capillary decreases ⇒ dec. P_PC
- Net effect is increased driving force for fluid movement from interstitial space ⇒ peritubular capillary
- Enhances absorption of fluid and NaCl

Answer 86

A

SNS alters renal blood flow and GFR
- Acts via 𝛼₁-adrenergic receptors
- Mediates vasoconstriction of afferent and efferent arterioles
- Na⁺ excretion tends to move in the same direction as GFR
- If GFR falls, tubules absorb proportionally more Na⁺ so Na⁺ excretion falls
- However, due to significant amount of autoregulation, GFR changes are minimal under normal conditions.
SNS upregulates Na⁺ transport systems in the proximal tubule via 𝛼-adrenergic stimulation
- Increased activity of apical NHE3 Na⁺/H⁺ exchanger
- Increased activity of basolateral Na⁺/K⁺-ATPase

Answer 87

A

Important role in the RAAS system:

Consists of:

Macula densa
- epithelial cells in the distal end of the TAL of LoH
- releases ATP in response to increased tubule NaCl delivery
- ATP ⇒ Adenosine ⇒ A₁ purine receptors on afferent arterioles and A2 purine receptors on efferent arterioles
- Results in vasoconstriction of afferent arterioles and vasodilation of efferent arterioles ⇒ reduces RBF and GFR
Granular cells
- located in the afferent arterioles mostly
- Renin production and release
Extraglomerular mesangial cells
- serves as a communication conduit between the macula densa and granular cells

Answer 88

A

Major role in controlling Na⁺ reabsorption/excretion and water balance.

Renin released from granular cells of JGA
- Rate-liming step in the RAAS system
- Site of regulation
Renin cleaves circulating angiotensinogen ⇒ angiotensin I
Angiotensin I processed by ACE in the lungs ⇒ angiotensin II
Ang II is the biologically-active form of angiotensin

Answer 89

A

Sympathetic nervous system
- Renal nerve innervates afferent arterioles
- Activation of 𝛽₁-adrenergic receptors on granular cells leads to renin release
- Provides a level of control driven by changes in systemic vascular pressure
- Mediated by high-pressure baroreceptors
- Drop in systemic BP elicits renin release
- Increase in systemic BP inhibits renin release
Afferent artiole pressure
- Granular cells act as intrarenal baroreceptors
- Pressure drop in the afferent arteriole ⇒ increased renin release
Macula densa
- Senses both tubular flow and tubular NaCl content
- When flow/NaCl content too high ⇒ ATP released
  - Reduces GFR
  - Inhibits renin secretion
- When flow/NaCl content too low ⇒ PGE_2,NO, and other mediators released by extraglomerular mesangial cells
  - Increases GFR
  - Increases renin secretion

Answer 90

A

Ang II has multiple effects that alters the ability of the kidney to absorb both water and Na⁺:

Stimulation of aldosterone production by adrenal cortex
- Aldosterone increases activity of apical ENaC and basolateral Na⁺/K⁺-ATPase in the collecting duct
- Results in increased Na⁺ reabsorption
Increases NHE3 and Na/K-ATPase activity in the proximal tubule
- Results in increased Na⁺ reabsorption
Stimulates thirst and secretion of AVP/ADH
- Both increase water reabsorption
Preferentially vasoconstricts the efferent arterioles
- Increases GFR
- Reduces peritubular hydrostatic pressure
- Increases peritubular oncotic pressure
- Net effect:
  - increased Na⁺ and water reabsorption by the PCT
  - increased fluid movement into the peritubular capillaries
- Reduces blood flow to the vasa recta
  - stabilizes and deepens the corticomedullary gradient
  - enhances passive Na⁺ reabsorption by the ATL

Answer 91

A

Major effect is to maintain water balance.

Increases NKCC2 activity in TAL of LoH.

Increases ENaC activity of principal cells in collecting ducts.

Promotes Na⁺ reuptake.

Answer 92

A

ANP released when blood volumes get too high.

Antagonizes actions of RAAS.

Contribution of ANP to overall Na⁺ and water balance is minimal under normal conditions.

Vasodilates afferent arterioles ⇒ increasing GFR
Inhibits Renin and AVP/ADH release
Net result is increased fluid flow but decreased reabsorption
Leads to diuresis and natriuresis

Answer 93

A

Synthesized in the proximal tubule.

Increases in Na⁺ intake ⇒ increased dopamine production.

Exact mechanism unclear.

Dopamine has several effects:

Dilates afferent arterioles ⇒ increases RBF and GFR
Causes removal of NHE3 and Na/K-ATPase from proximal tubule ⇒ decreases transcellular absorption.
Reduces expression of Ang II receptors ⇒ prevents effects of Ang II specifically upregulation of NHE3 and Na/K-ATPase in the PT

Answer 94

A

[K⁺]_ECF = 3.5 - 4.5 mEq/L

[K⁺]_ICF = ~ 140 mEq/L

Concentration gradient is set up by the Na/K-ATPase.
Responsible for the resting membrane potential of cells.
Small alterations in [K⁺]_ECF can have significant affects on membrane potential and ability to fire action potentials.
Both hypokalemia and hyperkalemia can cause cardiac arrhythmias.
Two processes considered in K⁺ balance:
- Distribution of K⁺ between ECF and ICF
- Total amount of K⁺ in the body

Answer 95

A

Skeletal muscle represents 2/3 of total cell mass and thus 2/3 of total K⁺

Abnormal leakage of K⁺ from muscle can result in dangerously high levels of [K⁺]_ECF

Can occur with crush injury or rhabdomyolysis.

Answer 96

A

[K⁺]_ECF = 3.5 - 4.5 mEq/L and [K⁺]_ICF = ~ 140 mEq/L

Majority of K⁺ is within the ICF.

Movement of small amounts of K⁺ into or out of the ICF can have significant affects.

Two most important factors influencing distribution of K⁺ are activity of Na/K-ATPase and serum [K⁺].

Example: 60 kg female with ~ 20 L of ICF and ~ 10 L of ECF

[K⁺]_ICF @ 140 mEq/L ⇒ 2,800 mEq

[K⁺]_ECF @ 4 mEq/L ⇒ 40 mEq

If 2% of total ICF K⁺ content (56 mEq) moved into the ECF, this would increase [K⁺]_ECF to 9.6 mEq/L ⇒ lethal level

Answer 97

A

Na/K-ATPase pumps K⁺ into the ICF against its concentration gradient.

Na/K-ATPase activity increased by several factors:

Promotes movement of K⁺ into the ICF

Increased plasma [K⁺]
Insulin (+ glucose sometimes used as a treatment for hyperkalemia)
Epinephrine via 𝛽₂ adrenergic stimulation
Thyroid hormone
Aldosterone through principal cells in collecting ducts
Alkalosis

Na/K-ATPase activity impaired by several factors:

Inhibits movement of K⁺ into the ICF

Cardiac glycosides (i.e. digoxin)
Chronic renal failure
Congestive heart failure
Acidosis

Answer 98

A

Several factors increase K⁺ movement out of cells and into the ECF:

Exercise
- K⁺ leaves myocytes during membrane depolarization
- transient event as Na/K-ATPase moves K⁺ back into cells under normal conditions
Increased serum osmolarity
- cells shrink increasing intracellular [K⁺]
- promotes diffusion of K⁺ out of the cell
- can be seen with uncontrolled diabetes
Acidosis
- increased extracellular [H⁺] promotes H⁺ entry into cells
- results in subsequent K⁺ loss
- acts as a virtual H⁺/K⁺ exchanger
  - no such transporter exists
- mechanism may involve the stimulatory effects of acidosis on Na/K-ATPase

Answer 99

A

Movement of K⁺ between ECF/ICF provides moment-to-moment control of plasma [K⁺]

Total body K⁺ content determined by the kidneys

Normal daily intake of K⁺ is 50-150 mEq/day.

K⁺ readily absorbed by the GI system in an unregulated fashion

Equal amount must be excreted to remain in K⁺ balance

90% excreted via the kidneys, 10% excreted via the feces

K⁺ balance maintained by adjusting renal reabsorption and excretion of K

Answer 100

A

Filtered load of Na⁺ is 30-40x greater than K⁺
K⁺ is both absorbed and secreted
- Na⁺ is always reabsorbed
Regulation of K⁺ balance done via regulation of secretion
Renal handing of Na⁺ has a greater effect of handling of K⁺ than K⁺ on Na⁺
- Major point of K⁺ control
K⁺ is freely filtered into Bowman’s space
~ 90% of K⁺ is reabsorbed by the PCT and TAL of LoH
Collecting tubules and collecting ducts can reabsorb and/or secrete K⁺
- ~90% of filtered K⁺ has been absorbed by the time filtrate reaches the distal nephron regardless of intake
- Location of fine-tuning of K⁺ balance to match K⁺ intake

Answer 101

A

PCT reabsorbs ~ 70% of filtered K⁺ mostly via paracellular route.

Driven by two mechanisms:

Transcellular Na+ movement sets up an osmotic gradient
- Drives water movement across PCT via paracellular route
- Creates solvent drag with sweeps K⁺ along with the water
- Greater Na⁺ reabsorption ⇒ greater H₂0 movement ⇒ greater K⁺ movement
Transepithelial potential varies along PCT length becoming slightly positive at the distal end of PCT
- Facilitates K⁺ movement via paracellular route in this region

Answer 102

A

TAL reabsorbs ~ 10% of filtered K⁺ via paracellular and transcellular mechanisms.

Lumen-positive transepithelial potential drives K⁺ movement via paracellular route.
Bulk of K⁺ reabsorption via transcellular route by NKCC2 cotransporter
- Moves Na⁺, K⁺, and Cl^- across the lumen
K⁺ crosses basolateral membrane via:
- K⁺ channel
- K/Cl cotransporter
Luminal ROMK channel recycles some K⁺ back into the lumen
- Moves down its concentration gradient
- Ensures sufficient luminal K⁺ to support NKCC2 function
- If this did not happen, Na⁺ and Cl^- reabsorption would be limited by [K⁺] in the filtrate

Answer 103

A

Electrolyte disorder characterized by reduced reabsorption of Na⁺, K⁺, and Cl^-.

One form caused by a defective ROMK channel.

Answer 104

A

Responsible for secretion of K⁺ in the collecting tubules.

Basolateral Na/K-ATPase moves K⁺ from interstitium into cell and Na⁺ into interstitial space
- Creates driving force for K⁺ movement from cell to lumen
- Creates driving force for Na⁺ movement from lumen into cell
K⁺ moves down its electrochemical gradient from cell ⇒ lumen via apical ROMK channel
- Enhanced by negative transepithelial potential
K⁺ channels present in both apical and basolateral membranes
- More K⁺ channels on apical membrane
- Negative transepithelial potential favors K⁺movement from cell into lumen
- Fraction of K⁺ that does cross basolateral membrane moved back into the cell by Na/K-ATPase
Increased entry of Na⁺ via ENac stimulates Na/K-ATPase
- Increases driving force for K⁺ secretion
- Explains hypokalemia seen with use of loop and thiazide diuretics

Answer 105

A

Responsible for reabsorption of K⁺ in the collecting tubules.

Apical H/K-ATPase pumps K⁺ into cell from lumen and H+ into the lumen
- Important in acid-base regulation
K⁺ moves from cell into interstitium via basolateral K⁺ channels

Answer 106

A

The key regulated step of K⁺ balance is K⁺ secretion by principal cells.

Three transport processes determine the amount of K⁺ secretion:
- K⁺ influx from interstitial space by Na/K-ATPase
- K⁺ efflux into lumen
- K⁺ efflux into insterstitial space (recycling)

Majority of control centered on the activity of K⁺ channels

Two types of K⁺ channels in the apical membrane of principal cells:

ROMK and BK

Each has a different role and regulated by different mechanism.

At low dietary K⁺ ⇒ low K⁺ filtered load
- Both ROMK and BK channels inactive
  - ROMK sequestered in intracellular vesicles
  - BK channels closed
- Low level of K⁺ secretion
At normal K⁺ loads
- ROMK channels moved to apical membrane
- BK channels are still closed
- Moderate level of K⁺ secretion
At high K⁺ loads
- Both ROMK and BK present and active in apical membrane
- High level of K⁺ excretion

Answer 107

A

↑ plasma [K⁺] ⇒ ↑ K⁺ secretion

filtered load of K⁺ proportional to plasma concentration [K⁺]
interstitial space [K⁺] essentially the same as plasma [K⁺]
Na/K-ATPase pumping rate dependent on extracellular [K⁺]
important but not dominant controlling factor

Answer 108

A

↑ Dietary [K⁺] ⇒ ↑ K⁺secretion

renal secretion must match dietary intake
kidney adjusts K⁺ excretion to match intake
mechanism unclear, may involve GI peptide hormones

Answer 109

A

Aldosterone synthesis and secretion also stimulated by increased plasma [K⁺] independent of Ang II mechanism.

Aldosterone:

Stimulates ENaC activity ⇒ increased Na⁺ entry
High Na+ entry stimulates Na/K-ATPase activity ⇒ increased K+ entry
Increased intracellular [K⁺] stimulates ROMK activity
Facilitates K⁺ secretion by ROMK

Spironolactone and eplerenone block the aldosterone receptor ⇒ Reduces K⁺ secretion.

Hypoaldosteronism ⇒ hyperkalemia

Hyperaldosteronism ⇒ hypokalemia

Answer 110

A

Amount of Na⁺ delivery to prinical cells is a major regulator of K⁺ secretion.

High [Na⁺] at the distal nephron increases Na⁺ entry via ENaC
Leads to high Na/K-ATPase activity increasing K⁺entry from interstitium
Elevated intracellular K⁺ facilitates secretion via ROMK
Explains hypokalemia seen with loop and thiazide diuretics
Amiloride or triamterene blocks ENaC ⇒ reduces K⁺ secretion

Answer 111

A

High flow rates ⇒ decreased luminal [K⁺] at principal cells.

Facilitates K+ secretion.

High flow rates ⇒ increased Na⁺ reabsorption.

Facilitates K+ secretion.

Answer 112

A

AVP/ADH has minor effects on K⁺ secretion.

Increases ENaC conductance ⇒ provides larger driving force for K⁺ secretion.
Increases apical K⁺ permeability
However, reduces urine flow ⇒ reduce K⁺ secretion

Most likely the effects of AVP/ADH cancel themselves out.

Answer 113

A

There are two primary acid-base disorders:

Acidosis ⇒ gain H⁺ or lose HCO₃^-

Alkalosis ⇒ lose H⁺ or gain HCO₃^-

There are two ways of developing a primary acid-base disorder:

Respiratory and Metabolic

There are two states of responses:

Compensated and Uncompensated

Answer 114

A

Describes the relationship between plasma pH and [HCO₃^-] at a various P_CO2 values.

P_CO2 Isopleths: shows how pH depends on [HCO₃^-] at a constant P_CO2.

Normal buffer line: shows the total buffering capacity of the system (HCO₃^- and NBB).

Intersection of the two curves represents when both types of buffers are in equilibrium.

We must exist at a point of intersection.

Answer 115

A

Buffer systems
- chemical buffers found in ECF and ICF
- minimalizes changes in pH until compensation can occur
- does not remove the excess acid or base from the body
- works immediately as pH changes
Lungs
- respiratory control centers in the brainstem adjust ventilation rate
- increases or decreases CO₂ transfer to the atmosphere
- changes can take place very quickly
- compensatory response occurs within minutes
Kidneys
- can adjust the amount of H₊ and HCO₃^- secreted and excreted
- involves upregulation of various enzymes and transporters
- full renal compensation may take up to several days

Successful compensation for a primary acid-base distrubance returns the pH close to baseline but normalization may not occur until underlying cause is removed.

Answer 116

A

A weak acid and it’s conjugate base.

Relative concentrations determined by the dissociation constant.

Changes in pH will affect the acid/conjugate base ratio and vice versa.

Explicit relationship given by the Henderson-Hasselbach equation:

pH = pK_eq + log ( [A^-]/[HA] )

Answer 117

A

Two broad categories of buffer systems:

Bicarbonate buffer system (CO₂/HCO₃^-)
- Most important buffer pair in the ECF
Non-bicarbonate buffers in both ECF and ICF
- Blood: proteins, H₂PO₄^-/HPO₄^2-
- Interstitial fluid: H₂PO₄^-/HPO₄^2-
- Intracellular: proteins, H₂PO₄^-/HPO₄^2-, phosphate constituents of organic compoounds (e.g. ATP)

Answer 118

A

Extremely important in acid-base physiology due to:

Abundance of components
- [HCO₃^-]_ECF ~ 24 mM
- metabolism provides unlimited CO₂
Open system
- components can be added or removed from the body at controlled rates
Control by the lungs and kidney

Buffering in the system limited by the amount of available HCO₃^-

Carbonic anhydrase catalyzes formation of carbonic acid.

Using Henry’s Law for [CO₂]_dissolved

Henderson-Hasselbach equation for the system

pH = 6.1 + log [HCO₃^-] / 0.03 P_CO2

pH can be controlled by alternating P_CO2 or [HCO₃^-].

Answer 119

A

CO₂ + H₂0 ⇔ HCO₃^- + H⁺

+

NBB - ⇔ NBBH

Bicarb and plasma NBBs “share” added H⁺.

Pulls reaction to the right.

Renews available bicarb enhancing buffering capacity.

Answer 120

A

Kidneys remove H⁺ if there is excess acid.

Most H⁺ secreted as either:

NH₄⁺

Combined with urinary buffers such as phosphate ⇒ titratable acid

Kidneys remove HCO₃^- if there is excess base.

Answer 121

A

Several portions of the nephron secrete H⁺ into the lumen.

PCT (left panel)
- via NHE3 Na⁺/H⁺ exchanger
- majority of acid secreted
TAL
- also via the NHE3 Na⁺/H⁺ exchanger
𝛼-intercalated cells of the collecting duct (right panel)
- excrete H⁺ via an H/K ATPase or H⁺-ATPase

Answer 122

A

Tubules reabsorb essentially all filtered HCO₃^- mainly in the PCT.

Involves carbonic anhydrase.

H⁺ released by intracellular H₂CO₃ breakdown combines with filtered HCO₃^- and cycles around.

Does not result in H⁺ secretion.

No net creation of HCO₃^- ⇒ only a reclamation process.

Answer 123

A

H⁺ and HCO₃^-produced from CO₂ by carbonic anhydrase.

H⁺ combines with filtered HPO₄^2-⇒ excreted

HCO₃^{-}formed enters blood via basolateral Na/HCO₃^-cotransporter

For every H⁺ excreted as a titratable acid or ammonia, a new HCO₃^-is added to the blood.

Loss of H⁺ in the urine is equivalent to adding new HCO₃^-to the blood.

Loss of HCO₃^-from the body equivalent to adding H⁺ to the blood.

Supply of phosphate and other NBBs limited.

Ammonia excretion used to excrete large amounts of acid.

Answer 124

A

Majority of ammonia synthesized in the proximal tubule from glutamine.

Ammonia can enter urine:

As lipid-soluble NH₃

As NH₄^{+}via NHE3 where NH₄⁺can substitute for H⁺

Answer 125

A

Titratable acid measured ex vivo via titration of urine with NaOH until pH 7.4

Represents the amount of H+ excreted combined with urinary buffers.

Ammonia determined via a seperate method.

Answer 126

A

During stable acid-base balance:

Net acid secretion = net addition of H⁺ by metabolic processes.

Net acid excretion = net HCO₃^- production.

Excretion of HCO₃^- represents a loss of base and must be subtracted.

Net acid excretion (mEq/day) = urinary titratable acid excreted + urinary NH₄⁺ excreted - urinary HCO₃^- excreted.

NAE with normal plasma pH of 7.4 ~ 60-80 mEq/day.

Much higher with acidosis due to increased NH₄⁺ excretion.

Much lower or negative with alkalosis due to increased HCO₃^- excretion.

Answer 127

A

↑ P_CO2 ⇒ ↓ [HCO₃^-]/P_CO2ratio ⇒ ↓ pH

Caused by decreased alveolar ventilation resulting in CO₂ retention.

(airway obstruction, chest trauma, neuromuscular disease affecting breathing, inadequte mechanical ventilation)

Respiratory failure “closes” the bicarbonate buffer system because CO₂ cannot leave.

Reduces effectiveness of bicarbonate as a buffer.

Uncompensated respiratory acidosis with P_CO2 40 mmHg → 80 mmHg results in a pH ~ 7.2 and [HCO₃^-] ~ 28 mM.

Compensation for prolonged respiratory acidosis through increased renal H⁺ secretion and HCO₃^- reabsorption.

Requires 12-24 hours to become evident and ~5 days for max effect.

Answer 128

A

↑ [HCO₃^-]/P_CO2 ratio ⇒ ↑pH

Caused by increased elimination of CO₂due to hyperventilation.

(general respiratory stimuli e.g. anxiety or fever, mechanical or voluntary hyperventilation, peripheral respiratory stimuli e.g. altitude, pneumonia, CHF)

Uncompensated respiratory alkalosis with P_CO2 40 mmHg → 20 mmHg results in pH ~ 7.6 and [HCO₃^-] ~ 20 mM.

Renal compensation via decreased H⁺ secretion with subsequent drop in HCO₃^- synthesis and increased excretion of filtered HCO₃^-.

Brings [HCO₃^-]/P_CO2 ratio back towards normal.

Evident within 1-2 hours and max effect in 24-48 hours.

Answer 129

A

Anion gap = [Na⁺] - ( [Cl^-] + [HCO₃^-] )

Cations must equal anions.

[Cl^-] + [HCO₃^-] ≠ [Na⁺]

Due to unmeasured anions (proteins and organic acids)

Normal anion gap ~ 9-16.

Greater than normal anion gap means an unmeasured anion is elevated.

Answer 130

A

Decreased [HCO₃^-]/P_CO2 ratio due to loss of HCO₃^-or excessive production of H⁺.

Excessive HCO₃^- loss
- Due to GI or renal causes
  - diarrhea ⇒ reduces ability of GI tract to reabsorb HCO₃^-
  - failure to secrete enough H⁺ ⇒ incomplete reabsorption or insufficient generation of HCO₃^-
- Cl^- levels increase as HCO₃^- levels fall
- Anion gap is normal
Increased H⁺ generation
- Excessive production of organic acids such as lactate or ketoacids
  - Starvation or uncontrolled diabetes
- Ingestion of drugs or poisons
  - Ethanol, ethylene glycol, or aspirin
- Cl^- levels do not rise so [Cl^-] + [HCO₃^-] is not constant
- Anion gap is elevated

Uncompensated metabolic acidosis moves down to lower buffer line with pH ~ 7.2 and [HCO₃^-] ~ 16 mM.

Initial respiratory compensation ↓ P_CO2 by ↑ minute ventilation ⇒ ↑ [HCO₃^-]/P_CO2 ratio.

Takes 15-30 minutes, time for ∆ [H⁺] in CSF to affect respiration.

If acidosis persists, renal compensation ↑ H⁺ secretion ⇒ ↑reabsorption/synthesis HCO₃^- ⇒ ↑ [HCO₃^-]/P_CO2 ratio.

Answer 131

A

↑ [HCO₃^-]/P_CO2 ratio ⇒ ↑pH

Due to bicarbonate gain
- administration of bicarb or precursor at rate that exceeds elimination
Due to net H⁺ loss
- vomiting and loss of HCl from GI
- loop diuretics or thiazide diuretics causing ↑ renal H⁺ secretion

Uncompensated metabolic alkalosis moves buffer line up with pH ~ 7.5 and [HCO₃^-] ~ 30 mM.

Respiratory compensation ↑P_CO2 by ↓ ventilation ⇒ ↓ [HCO₃^-]/P_CO2 ratio.

Limited by respiratory drive due to hypoxemia and hypercapnia.

Answer 132

A

Overall goal of compensation to return [HCO₃^-]/P_CO2 ratio back to normal (~20).

Answer 133

A

P_CO2 = {(1.5 x [HCO3-]) + 8} ± 2

Used to predict the degree of respiratory compensation in metabolic acidosis.

Measured P_CO2 within calculated range ⇒ adequate respiratory compensation has taken place.

Measured P_CO2 outside of range ⇒ concomitant respiratory acid-base disorder also present.

P_CO2 > calculated value ⇒ respiratory acidosis.

P_CO2 < calculated value ⇒ respiratory alkalosis.

Rule of thumb:

If there is adequate respiratory compensation, P_CO2 ≈ last 2 digits of pH.

Answer 134

A

P_CO2 = (0.7 x [HCO₃^-]) + 20

Designed to analyze respiratory compensation of metabolic alkalosis.

Infrequently used.

Answer 135

A

Continence ⇒ urine storage.

Bladder acts as a reservoir.

Micturition ⇒ periodic elimination of urine.

Bladder neck, urethra, and urethral sphincter acts as an outlet.

Answer 136

A

Peripheral nervous system regulation of LUT coordinated by

Pontine Micturition Center and Pontine Storage Center

Both located in the rostal pons.

Parasympathetic innervation of LUT via pelvic splanchnic nerves
- originates in the sacral spinal cord
Sympathetic innervation of the LUT via hypogastric nerves
- originates in the thoracolumbar spinal cord
Somatic innervation of the external urethral sphincter via pudendal nerves
- originates in the sacral spinal cord

Answer 137

A

Bladder wall is composed of detrusor smooth muscle
Innermost lining of the bladder is the urothelium
- important protective barrier
- prevents exposure of bladder musculature and CT to urine
Bladder has two functional regions:
- Body (fundus)
  - top 2/3 of bladder
  - storage chamber
  - pump for urine expulsion
  - densely innervated by parasympathetic nerves
  - sparsely innervated by sympathetic nerves
- Base
  - lower 1/3 of bladder
  - functions as a funnel
  - comprised of two subsections:
    - Trigone
      - posterior, lower region
      - bordered by the ureter entrance points (ureterovesical junction) and the urethral orifice
    - Neck
      - funnel-shaped extension of the bladder
      - connects with the urethra
      - wall composed of an outer longitudinal and inner circular layer of smooth muscle
      - richly innervated by sympathetic nerves
      - posseses mainly 𝛼₁ receptors

Answer 138

A

Flap-like valve separates the ureters from the bladder
Anatomical arrangement of the ureters entrance into the bladder
- ureters pass obliquely through bladder wall
- bladder smooth muscle contraction compresses the ureters
- prevents retrograde flow during micturition
- peristaltic contraction of ureters during urine movement creates a pressure wave which opens entrance

Answer 139

A

Abormality often seen in children
Causes:
- congeital abnormality
- short intravesical ureter
  - reflux may resolve with age
- urinary tract infections
  - if ureters become inflamed
  - may lead to pyelonephritis and renal scarring

Answer 140

A

only 3-4 cm long
Smooth muscle throughout entire length
- inner longitudinal
  - important for urethral shortening and funneling during micturation
- outer circular
  - aid in sphincteric mechanism
Mucus-secreting glands throughout

Answer 141

A

Classified into 4 regions:
1. Preprostatic urethra
2. Prostatic urethra
3. Membranous urethra
4. Penile urethra
18-20 cm long
Smooth muscle throughout entire length
- inner longitudinal
  - important for urethral shortening and funneling during micturation
- outer circular
  - aid in sphincteric mechanism
Thickened ring of smooth muscle within the preprostatic urethra ⇒ lissosphincter
Mucus-secreting glands throughout

Answer 142

A

Ring of smooth muscle
Innervation:
- Parasympathetic ⇒ pelvic splanchnic nerves
- Sympathetic ⇒ hypogastric nerves
Sympathetic control most significant

Answer 143

A

Composed of striated muscle
Innervated by the somatic nervous system
- Motor neuron’s originate in Onuf’s nucleus
- Traverse the pudenal nerve
Allows voluntary excretion of urine

Answer 144

A

Parasympathetic Innervation

Stimulates detrusor contraction.

Body mostly innervated by M₂ and M₃ receptors
- M₂ receptors more abundant
- M₃ receptors most significant
M₃ mediates the majority of bladder contraction
- functions via IP₃-gated Ca²⁺ channels
- release of intracellular Ca²⁺ results in activation of MLC kinase ⇒ contraction

Sympathetic Innervation

Inhibits bladder contraction.

Body also has 𝛽2 and 𝛽3 adrenergic receptors
Binding of NE results in detrusor reflaxation
- Via stimulation of adenylyl clycase ⇒ cAMP
Facilitates urine storage

Answer 145

A

Richly innervated by sympathetic nervous system.

Thoracolumbar spine ⇒ hypogastric nerves.

Abundant 𝛼₁ receptors
Binding of NE stimulates contraction of bladder neck
- Via IP₃/DAG pathway

Answer 146

A

Internal Urethral Sphincter

Sympathetic innvervation

Hypogastric nerve ⇒ NE ⇒ 𝛼1 receptors ⇒ IP₃ ⇒ Ca²⁺ ⇒ contraction

External Urethral Sphincter

Somatic Innervation

Pudenal nerve ⇒ Ach at NMJ ⇒ nicotinic receptors ⇒ Ca²⁺ ⇒ contraction

Answer 147

A

LUT afferent axons found in the:

Pelvic splanchnic nerve

Hypogastric nerve

Pudenal nerve

Pelvic splanchnic nerves most important.

Relays information about bladder filling and noxious stimuli.

Answer 148

A

Proper functioning of LUT relies on reciprocal relationship between bladder and urethral activity.

Storage
- bladder body contractility low
  - SNS relaxation
- outlet resistance high
  - SNS contraction of bladder neck and urethra
- somatic contraction of EUS
- little change in intravesical pressure between 100 and 400 mls
Micturition
- bladder body contractility high
  - PNS ⇒ muscarinic receptors ⇒ relaxation
- outlet resistance low
  - inhibition of somatic and sympathetic systems
  - PNS ⇒ NO ⇒ relaxation
- Relies on spino-bulbo-spinal reflexes from rostral pons
- Voluntary control via supra-pontine regions of brain to micturition control center

Answer 149

A

Lack of coordination of bladder and urethral sphincter activity.

Bladder contraction against a closed sphincter
Interferes with bladder emptying
Often seen with spinal cord injury above S4
- descending inhibition of bladder-to-EUS spinal storage reflex interrupted
Bladder may develop hyperreflexia
- frequent, high pressure contractions

Answer 150

A

Primarily involves spinal reflexes.

Pontine Storage Center can modulate them.

Afferent Pathway
- Low level of afferents via pelvic splanchic nerve
- In response to minimal bladder stretch
  - Compliance & passive properties of bladder smooth muscle
Efferent Pathways
- EUS contraction via pudendal nerve
- IUR contraction via SNS
- Inhibition of detrusor muscle contraction via SNS
- PNS to detrusor inactive

Answer 151

A

Increased external urethral sphincter activity in response to an increase in intravesical pressure.

Answer 152

A

When micturition threshold reached, LUT switches from storage phase to voiding phase.

Voiding can be consciously controlled via cortical input to micturition center.

Fluid flow through urethra reflexively causes detrusor contraction and EUS relaxation.

Afferent pathways:
- High levels of vesical afferent activity via pelvic splanchnic nerve
- Due to higher levels of bladder stretch
Efferent pathways:
- Inhibition of EUS
- Inhibition of SNS ⇒ bladder and urethra
- Activation of PNS ⇒ bladder and urethra

Results in relaxation of urethral sphincters & contraction of bladder.

Bladder pressure increases leading to urine flow.

Modulation by cerebral cortex permits voluntary voiding.

Answer 153

A

At 100-150 ml:
- Activation of stretch receptors in bladder wall
- Impulses sent to sacral spinal cord
- Spinobulbospinal reflex stimulated
- First sensation of bladder filling
At 150-300 ml:
- Bladder contracts and IUS relaxes through end of reflex arc
- Cortex senses urge to void & proper location
  - Can allow voluntary EUS relaxation and excretion
At 400 ml:
- Intravesical pressure increases sharply
- Partially due to reflex contractions of detrusor
At 700 ml:
- Pain develops
- Loss of sphincter control

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Renal Flashcards

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