Midterm 2 (Kidney) Flashcards
What are the functions of the kidney? What are the disorders related to each?
- excretion of substances: endogenous wastes, exogenous toxins, drugs
- uremia - NaCl balance: regulation of ECF volume, plasma volume, blood pressure
- hypertension, edema - Water balance: regulation of osmolality and ECF Na+ concentration
- hyponatremia - K+ balance
- hyperkalemia - Acid-base balance
- acidosis - PO4 and Ca2+ balance; activation of vitamin D
- bone disease - Secretion of erythropoietin
- anemia
What are the principles of kidney physiology?
- Maintain high and constant glomerular filtration rate (150-180 L/day) to excrete toxic substances
- To maintain extraordinarily high filtration rate requires very high renal blood flow; 25% of cardiac output
- Regulate excretion of NaCl and water to achieve balance by regulating their reabsorption, not changing GFR
- Protection of adequate ECF volume, plasma volume, and blood pressure almost always takes precedence over all other regulation
What is the difference between filtration, reabsorption, secretion, and excretion?
Filtration:
Occurs in the glomerulus.
The process by which blood plasma (minus large proteins and cells) is filtered out of the blood into the Bowman’s capsule to form glomerular filtrate.
Reabsorption:
Occurs primarily in the proximal tubule and other parts of the nephron.
Involves the movement of essential substances (water, ions, glucose) from the filtrate back into the bloodstream.
Secretion:
Happens mostly in the distal tubule and collecting ducts.
The process where certain substances (like hydrogen ions, potassium, and toxins) are actively transported from the blood into the filtrate to be eliminated.
Excretion:
Final step where the urine (containing waste products) is expelled from the body via the ureters, bladder, and urethra.
What is the formula for the amount excreted ?
amount excreted = amount filtered - amount reabsorbed + amount secreted
What does filtration depend on?
size and charge
- positive charge filters filtration because of negative charge of the glomerular filtration barrier
most plasma proteins (albumin) are excluded, electrolytes and water are freely filtered
What is the formula for GFR? What is the filtration fraction?
GFR = Kf x {(Pgc -Pbs)-π gc}
Kf: function of permeability and surface area of capillary
Pgc: Glomerular capillary hydrostatic pressure
Pbs: Bowman’s space hydrostatic pressure
π gc: Glomerular capillary oncotic pressure
20%: for every 100 mL of plasma entering via the afferent arterioles, 20 mL is filtered, 80 mL exit via efferent arteriole
How does arteriole constriction and dilation affect the GFR?
afferent arteriole
- constriction: reduces Pgc and GFR
- dilation: raises Pgc and GFR
efferent arteriole
- constriction: raises Pgc and GFR
- dilation: reduces Pgc and GFR
What happens in states of low renal perfusion pressure?
dilation of afferent arteriole , constriction of efferent arteriole maintains GFR
prostaglandins are mediators of afferent arteriole dilation and angiotensin II is major mediator of efferent arteriole constriction
- NSAIDS block prostaglandin synthesis
What are the two mechanisms for afferent constriction in response to increased renal perfusion pressure?
- Myogenic response: increased blood pressure stretches smooth muscle in afferent arteriole, mechanosensitive ion channels are activated, Ca2+ influx causes muscle contraction, afferent arteriole constricts, reducing blood flow to stabilize filtration.
- Tubuloglomerular feedback: increase GFR, increase NaCl to macula densa, increase NaCl entry by Na-K-Cl cotransporter, release of paracrine factors (adenosine) that constrict afferent arteriole
What are the roles of tubuloglomerular feedback?
- maintain constancy of GFR despite changes in blood pressure
- prevent glomerular capillary hypertension and damage
- prevent against ECF and plasma volume depletion and hypotension if tubular function is impaired
- toxic injury to proximal tubule, decrease NaCl reabsorption, increase NaCl in tubular fluid, afferent arteriole constriction, lowers Pgc, lowers GFR
What is renal clearance? What are extreme examples?
the volume of plasma completely cleared of the substance by excretion into the urine per unit time
max: substance is completely cleared from all the plasma that perfuses into the kidney; clearance = renal plasma flow (RPF)
min: substance is not at all removed
How do you calculate renal clearance?
amount removed from the plasma/time = amount excreted in the urine/time
clearance = (V/t)(Ux)/Px
- substance filtered but no reabsorbed or secreted (inulin, creatinine): GFR x plasma concentration = urine flow rate x urine concentration
- GFR(Px) = (V/t)(Ux) - substance secreted and completely removed from plasma (PAH): RPF(Px) = (V/t)(Ux)
What is the difference between GFR and RPF?
GFR: amount filtered by the kidney
RPF: total amount of plasma that passes through the kidney
What can we learn from measuring the clearance?
- GFR by measuring the clearance of a substance filtered but not reabsorbed or secreted
- RPF by measuring the clearance of a substance secreted and completely cleared
- Substance that is filtered and reabsorbed, clearance < GFR
- Substance that is filtered and secreted, clearance > GFR
Substance falls between RPF and 0.
How is creatinine used and cleared?
substance is cleared by GFR and endogenously produced at constant rate (not reabsorbed or secreted)
steady state plasma concentration is inversely proportional to GFR
GFR x plasma creatinine = urine flow rate x urine [creatinine]
urinary excretion rate of creatinine = production rate of creatinine
GFR x plasma [creatinine] = production rate of creatinine = constant
changes in plasma concentration used to estimate changes in GFR
Describe sodium transport along the nephron
filtered Na+ > 25,000 meg/day
Proximal tubule: 65-70% filtered load
Thick ascending limb: 25% filtered load
Distal convoluted tubule: 5% filtered load
Collecting tubule: 1-3% filtered load
Urinary excretion: <1% filtered load
What is the difference between paracellular and transcellular routes?
para: between tight junctions of cells
trans: through the cell
How do the nephron segments differ?
- Mechanism of apical membrane Na+ entry and its regulation
- Targets of action of diuretic drugs
- Permeability to water
- Leakiness of tight junctions and importance of paracellular pathways
- Pathways for Cl- reabsorption
- Addition pathways for K+ transport
Describe transport in the proximal tubule.
- Reabsorption of Na+/glucose cotransporter and Na-H exchange into the cell from lumen
- Na/K pump out of cell into interstitium
- Complete reabsorption of filtered glucose, amino acids, and bicarbonate
- High water permeability
- Highly leaky tight junctions allow substantial reabsorption of Cl, Na, and K down passive gradient from water reabsorption
What affects Na+ reabsorption in the proximal tubule?
- sensitive to inhibition by carbonic anhydrase inhibitors and SGLT2 (sodium glucose transport) inhibitors
- Na-H exchange is stimulated by angiotensin II and renal sympathetic nerves; inhibited by dopamine
- acute elevation of blood pressure inhibits Na+ reabsorption by local paracrine signaling mechanisms (eicosanoids and NO)
Describe transport in the thick ascending limb.
- Na+/2Cl-/K+ cotransport into the cell
- Na/K pump out of the cell into the interstitium
- Low permeability to water, so urine is diluted as solutes get reabsorbed
- Generates high solute concentration in the interstitium to allow for concentration of the urine
Loop diuretics block #1
NaCl reabsorption stimulated by anti-diuretic hormone (ADH) and by angiotensin II
Describe transport in the distal convoluted tubule.
- Na/Cl cotransport
- Na/K pump
- Low water permeability so urine is diluted
thiazide diuretics affect #1
NaCl reabsorption stimulated by angiotensin II and renal sympathetic nerves
inhibited by high plasma K+, stimulated by low plasma K+
Describe transport in the collecting tubule.
- Reabsorption by epithelial Na channel (ENaC)
- Cl- reabsorption is part paracellular
- Site of K secretion = major determinant of K excretion
without ADH, very low water permeability, so urine is dilute
with ADH, high water permeability
Explain K-sparing diuretics.
ENaC is site of “K-sparing” diuretics amiloride
- blocks sodium reabsorption
- promotes diuresis (increase urine production)
ENaC: Na reabsorption and K secretion stimulated by aldosterone
- Aldosterone antagonists like spironolactone are K-sparing
What stimulates K secretion in the collecting tubule?
- high plasma [K+]
- high aldosterone
- high luminal flow rate
- high luminal Na delivery
- diuretics acting upstream (loop, thiazide)
What inhibits K+ secretion in the collecting tubule?
- low plasma [K+]
- low aldosterone
- low luminal flow rate
- low luminal Na delivery
- K-sparing diuretics
What is ADH?
anti-diuretic hormone = vasopressin
- controls water excretion, NOT solute
- need to excrete salts and urea; concentrates the urine
- binds to GPCR, synthesize AQP2 that make the collecting duct highly permeable to water (reabsorption + concentration)
What are the general principles of salt and water balance?
changes in total body NaCl greatly affect ECF, PV, and BP
- change volume, change salt
- change in renin mechanism/sympathetic response sensed by afferent arteriole JGA, baroreceptors (cardiac filling)
Changes in pure H2O affect Na concentration and osmolality of ECF
- change osmolality, use water
- change in ADH, thirst sensed by osmoreceptors
What are the steps that happen after Na+ increases?
- increase ECF volume
- increase plasma volume, increase blood pressure
3 i) central pressure/volume receptors reduce sympathetic activity
3 ii) increase renal perfusion pressure
(a) increase GFR–> increase auto/paracrine factors (dopamine/NO) that reduce Na reabsorption
(b) decrease renin, decrease angiotensin II, decrease aldosterone - decrease tubule Na reabsorption
What are the renin-angiotensin-aldosterone system?
promotes Na retention next to macula densa (distal tubule) – JGA – secrete renin
- stimulated when renal perfusion pressure is reduced
- suppressed when RPP increased
change in pressure is sensed by stretch of afferent arteriole and decreased Na concentration at macula densa
What is the mechanism of the renin-angiotensin-aldosterone system?
- Renin secreted from JGA due to decreased perfusion pressure
- Liver normally releases Angiotensinogen into circulation,
- Angiotensinogen becomes angiotensin I through cleavage by renin
- ACE from the lungs turn it into angiotensin II
Angiotensin II:
- Increases thirst and ADH release from the pituitary
-Stimulates adrenal gland to produce aldosterone
-Vasoconstriction
- Enhances tubuloglomerular feedback (Macula densa senses Na, controls afferent arteriole tone)
OVERALL: work to increase Na reabsorption, increase water retention, and thus increase body water and blood pressure back to normal
Which is more important for determining long-term blood pressure: intrarenal perfusion pressure or central pressure?
intrarenal perfusion pressure: more powerful than sympathetic system
How does the kidney regulate pH balance?
CO2 + H2O <–> H2CO3 <–> H+ + HCO3-
pH = 6.1 + log { [HCO3]/(k*pCO2) } , k = 0.03, pCO2 from alveolar ventilation
Bicarbonate – base load, increases pH
CO2 – acid load, decreases pH
Kidney can excrete net acid or base (NH4+ vs HCO3-) depending on what is needed to bring pH to baseline
- close to 7.40
- Bicarbonate is freely filtered from the blood into the nephron
- Kidney also makes new bicarbonate
- Kidney must reabsorb the bicarbonate filtered in addition to the new bicarbonate needed to match the sulfuric acid from protein intake in the diet
How is bicarbonate reabsorbed and produced by the kidney?
H2O + CO2 –c.a.–> proton + bicarb
- Reabsorption of filtered bicarb: Secreted protons recombine with filtered bicarbonate. Turns to water and CO2. Cells reabsorb CO2. CO2 in the cell reacts with water, bicarb reabsorbed into blood
- Titratable acids: Secreted protons react with biphosphate. Leftover bicarb absorbed.
- Ammonia: Secreted protons react with biphosphate. Leftover bicarb absorbed.
Where is bicarbonate reabsorbed and produced?
- proximal tubule: reabsorption of filtered HCO3-
- sodium proton exchange
- c.a. breaks down CO2+H2O to H+ and HCO3-
- stimulated by acidosis - collecting tubule: secretion of NH4+ and generating new HCO3-
- H+ ATPase creates huge gradient
- stimulated by acidosis
- H+ traps NH4+ in urine
- need NH3
Describe the cortical collecting tubule.
principle cells: Na/K balance (ENaC), secrete K+, ADH increase H2O
alpha-intercalated: secrete H+, reabsorb HCO3- to buffer blood, acidosis
beta-intercalated: increase secretion HCO3- to counteract base, reabsorb Cl-, H+ into blood
What are the dietary sources of acids and bases?
- protein generates acid
- methionine and cysteine –> 2H+ and SO4(2-) - fruits and vegetables generates base
- metabolism of organic anions –> HCO3-
What are the major organs of the GI and their functions?
- stomach: storage/controlled emptying, mixing, digestion, secretion
- small intestine (duodenum, jejunum, illeum): digestion, absorption, secretion, mixing
- large intestine: absorption, secretion, excretion
- liver: produces bile, store nutrients, excretes toxins
- pancreas: secretes digestive enzymes and bicarbonate, digestion
- gallbladder: stores bile
What are the functions of longitudinal and circular smooth muscle layers in the GI?
- surface absorptive cell: nutrient absorption
- goblet cell: secretes mucus
- enteric endocrine cell: secrete hormones
- stem/progenitor cell: regenerate cells
- undifferentiated crypt cell: precursor
What does muscle activity in the GI tract produce?
- mixing
- propulsion produced by peristalsis
- holding of reservoirs (sphincter)
What is the role of the enteric nervous system in the GI and how does it relate to the ANS?
ENS: regulates contractions along GI tract (peristalsis), secretion; operate independently through intrinsic nerves
extrinsic nerves: into CNS; sympathetic innervation slows down digestion
intrinsic nerves: within the gut; sensory, excitatory, and inhibitory neurons; independently control and coordinate digestion
What is peristalsis?
wave-like contraction that moves bolus through digestive tract
Explain gastric filling, mixing, and emptying.
- propulsion: bolus pushed towards closed pylorus
- grinding: antrum churns trapped material
- retropulsion: bolus pushed back into proximal stomach
What are the stimuli, secreted products, and physiological role of major cells in the gastric epithelium?
exocrine (into lumen GI)
1. mucous: mechanical (movement of food), secretes mucous, protects from pepsin, HCl
2. chief: ACh, gastrin; secretes pepsinogen; begins protein digestion
2. parietal: ACh, gastrin, histamine; secretes HCl; activates pepsin, denature proteins, kills microorganisms
endocrine (into blood)
1. ECL: ACh, gastrin; secretes histamine; stimulates parietal cells
2. G cells: ACh, peptides; secretes gastrin; stimulates parietal, chief, and ECL cells
3. D cells: acid; secretes somatostatin; inhibits parietal, chief, and ECL cells
How is gastric acid secretion regulated?
H-K pump (ATPase) responsible for acid secretion; K+ in, H+ out
- ACh, gastrin, histamine stimulate acid secretion from parietal cell
- ACh and gastrin also stimulate ECL cell to secrete histamine
Example of negative and positive feedback in regulation of acid secretion?
- Positive Feedback:
- Gastrin from G cells stimulates acid secretion (HCl), which further promotes gastrin release.
- Amplified acid production to aid digestion. - Negative Feedback:
- Somatostatin release in response to low pH inhibits gastrin and acid secretion.
- Prevention of excessive acidity and protection of gastric mucosa.
How is the gastric surface protected?
- impermeability to H+ of epithelial barrier (tight junctions)
- secretion of mucins that form mucus layer
- secretion of bicarbonate to buffer acid
Name the major components of the protease cascade that allow inactive enzymes to be secreted and activated when in the intestinal lumen.
- zymogens
- trypsinogen
- chymotrypsinogen (protein)
- procarboxypeptidase (protein) - enteropeptidase
- enterokinase on brush border of small intestine activates trypsinogen - Trypsin: cleaves other zymogens
What regulates pancreatic exocrine activity?
- HCO3- secreted to neutralize stomach acid; increases secretin release in duodenum, stimulates duct cells
- proteolytic enzymes ^
CCK released in duodenum, stimulates acinar cells - pancreatic amylase: digests carbs
- pancreatic lipase: digests triglycerides to FA
Fluid balance in the GI tract: intake, secretion, absorption, excretion.
- small intestine absorbs 6.5 L of fluid per day
- H2O, Na+, Cl-, K+
- secretes HCO3- - colon absorbs 1.9 L per day
- H2O, Na+, Cl-
- secretes K+ and bicarb - stomach secretes 2.0 L/day
~2.0 L of fluid intake from food
Anatomy of small and large intestines.
small
- more SA, longer
- folds, villi, crypts, microvilli
- nutrient absorption
- active Na+ transport
- no K+ secretion
large
- less SA, shorter
- folds, no villi, crypts, microvilli
- NO nutrient absorption
- active Na+ transport
- K+ secretion
Three direct modes of intestinal Na absorption and indirect solvent drag.
- nutrient-coupled absorption: glucose/Na; AA/Na
- Na-H exchange
- epithelial Na Channels
all powered by Na/K pump
solvent drag: movement of water across epithelial barrier transports Na+, even against concentration gradient
- osmotic or hydrostatic pressure drives water paracellularly
- jejunum
Describe intestinal chloride absorption.
Cl- follows Na+ into cell
1. passive (Na transport)
2. Cl-HCO3 exchange
3. parallel Na-H and Cl-HCO3 exchange
exception: Cl- secreted to hydrate mucus
What is the CFTR mechanism of cholera?
CFTR: chloride channel in epithelial cells
cholera binds to surface of epithelial cells; modifies G protein; increases cAMP, activates CFTR channels, increase Cl- secretion into lumen, draws water in, diarrhea
treatment: drinking glucose facilitates Na+ absorption
Fundamental basis of nutrient absorption?
Generic Process:
* Initial digestion by
secreted enzymes
etc.
* More digestion by
brush border
enzymes
* Apical membrane
transport
* Basolateral
membrane transport
Lipids: more complex!
proximal small intestine!
How are proteins digested?
- Proteins must be reduced
to tripeptides,
dipeptides, or single
amino acids (luminal hydrolysis); pepsin, trypsin, etc. - brush border hydrolysis: peptidases cleave oligos to AAs
- Many apical AA
transporters, each
specific to AA type - cystolic hydrolysis: peptidases cleave to AAs
- Single AAs transported
across basolateral
membrane
How are carbohydrates digested?
only monosaccharides absorbable
1. Intraluminal hydrolysis to
oligosaccharides by alpha-amylase
(salivary glands, pancreas)
2. Digestion to monosaccharides by brush
border enzymes (lactase)
3. absorption of mono
What is the liver? What are the functions of the liver?
It is one of the largest organs in the body
* The liver biotransforms and degrades substances taken up from blood and either
returns them to the circulation or excretes them into bile.
* The liver stores carbohydrates, lipids, vitamins,
and minerals; it synthesizes carbohydrates,
proteins, and intermediary metabolites.
* glucose –> glycogen for storage
Reproduce the unique circulatory system of the liver,
which receives blood from the arterial and intestinal portal
systems.
- portal vein bring deoxygenated blood from the spleen and intestines
- hepatic artery bring oxygenated blood
- hepatic vein brings deoxygenated blood back to the heart
stores nutrients, eliminates pathogens
Describe the organization of the liver lobules, including the
flow of blood from arterial/portal triad to central vein.
liver lobule: hexagonal shape
portal triad: each lobule contains portal triad at its corners consisting of hepatic artery, portal vein, and bile duct
blood from portal triad flows into sinusoids (specialized capillaries with fenestrated endothelial cells)
blood from the sinusoids flows into central vein at the center of each lobule
central vein –> hepatic vein
What are hepatocytes? How are they organized?
main functional cells of the liver radiating from the central vein
- basolateral: faces sinusoids and involve with nutrient exchange
-apical: faces bile canaliculus that collects bile
Describe the hepatic processing of molecules.
- Hepatocyte imports compounds from blood
through basolateral surface (sinusoid); - Hepatocyte transports material through the
cell; - Hepatocyte may chemically modify or degrade
the compound; - Hepatocyte excretes some molecules through
its apical surface (bile canalicular surface).
How are molecules transported in hepatocytes?
- Na-K-ATPase maintains low intracellular Na+ and high K+;
- Na+ gradient allows for transports to promote
uptake of AA and other molecules;
Describe the role of liver-produced bile salts in the
absorption of lipids in the intestine.
Bile salts synthesized in liver from cholesterol and secreted into bile
- break down large fat globules into smaller micelles, increasing SA for digestive enzymes (emulsification, gastric acid lipase releases FA)
- micelles = bile salts and lipids; enhance solubility; transport to the intestinal epithelial cells
- lipids diffuse across enterocyte membrane and reform triglycerides
- triglycerides are packaged into chylomicrons for transport to body via lymphatics
Describe the recycling of bile salts via the enterohepatic pathway.
largely reabsorbed in the ileum
enter bloodtream and transported back to the liver via the portal vein
re-secretes into bile salts
