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PHRM 100 – APPP > APPP 04 and 07: Kidney > Flashcards

APPP 04 and 07: Kidney Flashcards

1
Q

What is total body fluid distributed between?

A
  • extracellular fluid – divided into interstitial fluid and blood plasma
  • intracellular fluid
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2
Q

What are some of the functions of the kidney? (3)

A
  • to rid the body of waste materials that are either ingested (drugs, pesticides, food additives) or produced by metabolism (urea from metabolism of proteins, creatinine from muscle metabolism, uric acid from nucleic acid metabolism)
  • regulate blood pressure (renin-angiotensin-aldosterone system), controlling reabsorption of water (ADH/vasopressin), and maintaining intravascular volume
  • control the volume and composition (concentration of various ions) of the body fluids
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3
Q

What is the size of the extracellular compartment largely determined by and why?

A

body’s total content of dissolved sodium

  • Na+ is the predominant ion of the ECF is therefore available in quantities sufficient to influence the osmotic distribution or redistribution of large amounts of water
  • movements of Na+ between the extracellular and intracellular compartments are controlled by transport mechanisms
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4
Q

What do diuretics do?

A

inhibit the tubular reabsorption of Na+ ions

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5
Q

What role do the kidneys play in the body?

A
  • blood filtration and reabsorption – keep levels of electrolytes stable, such as Na+, K+, and phosphate
  • excretion of endogenous and exogenous compounds – prevent buildup of wastes and extra fluid in the body
  • endocrine functions – ie. blood pressure regulation
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6
Q

Where are the kidneys located?

A

lie on the posterior wall of the abdomen

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7
Q

How do they kidneys clear waste?

A

kidneys control the volume/composition of body fluids, therefore it clears waste by excretion into urine and returning essentials back into the blood

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8
Q

How much do the kidneys filter?

A

125 ml/min (180 L/day)

  • but make only 1 ml/min urine
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9
Q

How much of the cardiac output do the kidneys receive?

A

20% of the cardiac output – from a pair of renal arteries arising from the abdominal aorta

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10
Q

What do renal arteries become?

A

afferent arterioles

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11
Q

What is each kidney made up of?

A

about 1 million nephrons (filtering units) that are each capable of forming urine

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12
Q

What are the 2 major components of nephrons?

A
  • glomerulus – glomerular capillaries surrounded by Bowman’s capsule
  • long tubule – proximal tubule, loop of Henle, distal tube, and collecting tubule
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13
Q

What happens in the glomerulus?

A

large amounts of fluid are filtered from the blood

  • glomerular capillaries are supplied with blood by the afferent arteriole while blood leaves via the efferent arteriole
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14
Q

What are the two capillary beds of the renal circulation?

A
  • glomerular – afferent arteriole ends in the capillaries of the glomerulus where high pressure causes filtration
  • peritubular – efferent arteriole ends in the peritubular capillary network where low pressure permits absorption
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15
Q

What happens in the long tubule?

A

filtered fluid is converted into urine

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16
Q

The rate at which different substances are excreted in the urine represent the sum of what 3 renal processes?

A

urinary excretion rate = filtration rate - reabsorption rate + secretion rate

  • glomerular filtration
  • reabsorption of substances from the renal tubules into the blood
  • secretion of substances from the blood into the renal tubules
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17
Q

Describe the one of the ways that urine formation occurs.

A
  • blood enters from afferent arteriole
  • filtration from the glomerular capillaries into Bowman’s capsule of a large amount of fluid (180 L/day virtually free of protein) occurs: glomerular hydrostatic pressure (55 mmHg) - osmotic pressure (30 mmHg) + capsular hydrostatic pressure (15 mmHg) = net outward pressure (10 mmHg)
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18
Q

How do glomerular capillary membranes differ from other capillaries?

A

has 3 (instead of the usual 2) major layers

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19
Q

What are the 3 layers of glomerular capillary membranes?

A
  • endothelium
  • basement membrane
  • epithelial cells
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20
Q

What is the endothelium?

A

perforated by thousands of small holes called fenestrae

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21
Q

What is the basement membrane?

A

main filtration barrier – meshwork of collagen and proteoglycans

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22
Q

What are epithelial cells?

A

podocytes – have long ‘foot-like’ processes that wrap around the capillaries, leaving gaps called slit-pores

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23
Q

What do the 3 layers of glomerular capillary membranes make up?

A

the filtration barrier

  • the primary restriction point for plasma proteins appears to be the basement membrane
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24
Q

What can glomerular filtration rate (GFR) be regulated by?

A

constriction or dilation of afferent artrioles

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25
Q

What is the other way that urine formation occurs?

A

as filtered fluid leaves Bowman’s capsule and passes through tubules, it is modified by reabsorption of water and specific solutes back into the blood (active and passive transport depending on substance and site) or by secretion of other substances from the peritubular capillaries into the tubule

  • 125 ml/min is the amount of fluid which leaves the glomerular capillaries to go into the glomerular space (GFR) but only 1 ml/min is excreted in urine
  • blood exits through the efferent arteriole
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26
Q

Is tubular reabsorption or tubular secretion more important the formation of urine?

A

in general, tubular reabsorption is quantitatively more important than tubular secretion

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27
Q

What is the difference between glomerular filtration and tubular reabsorption?

A
  • glomerular filtration is relatively non-selective – all solute in the plasma are filtered except the plasma proteins
  • tubular reabsorption is highly selective
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28
Q

What are some substances that are reabsorbed from the tubules?

A

some substances like glucose and amino acids are almost completely reabsorbed from tubules so that the urinary excretion rate is essentially zero

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29
Q

What are some substances that are poorly reabsorbed from the tubules?

A

certain waste products like urea and creatinine are poorly reabsorbed from the tubules and excreted in relatively large amounts

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30
Q

What are some substances that are secreted into the tubular fluid for removal?

A
  • K+
  • H+
  • urea
  • some drugs like thiazides
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31
Q

What is essential for precise control of the composition of body fluids?

A

kidneys can regulate the excretion of solutes by controlling the rate at which they reabsorb different substances

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32
Q

Where does urine go once it is formed?

A

propelled down the ureter to the bladder where it is stored, and eventually excreted via the urethra

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33
Q

Renin-Angiotension-Aldosterone System

What is renin?

A

a protease produced and secreted by the juxtaglomerular cells (JGC)

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34
Q

Renin-Angiotension-Aldosterone System

What are juxtaglomerular cells (JGC)?

A

specialized set of smooth muscle cells that line the afferent and efferent arterioles

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35
Q

Renin-Angiotension-Aldosterone System

What are the 3 mechanisms that control JGC release of renin?

A
  • a direct pressure sensing mechanism within the afferent arteriole – decreased blood pressure increases renin release
  • sympathetic innervation of the JGC promotes renin release via beta1-adrenoceptor signaling – stimulation of beta1 receptors increases renin release
  • specialized cells within the distal tubule called macula densa that is especially sensitive to electrolyte concentration (especially NaCl) – decreased luminal NaCl delivery increases JGC renin release
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36
Q

Renin-Angiotension-Aldosterone System

What happens once renin is released?

A
  • plasma renin cleaves the circulating angiotensin (large plasma protein) formed by the liver to the decapeptide angiotensin I (ATI)
  • then ATI is cleaved to the active octapeptide angiotensin II (ATII) by angiotensin converting enzyme (ACE)
37
Q

Renin-Angiotension-Aldosterone System

Where is angiotensin-converting enzyme (ACE) found?

A
  • highly expressed in the pulmonary vascular endothelium
  • also present in endothelial cells lining the coronary arteries and blood vessels in the kidneys
38
Q

Renin-Angiotension-Aldosterone System

What are the two most distinctive functions of angiotensin II (ATII)?

A
  • stimulation of aldosterone secretion from the adrenal cortex (which promotes renal tubular reabsorption of NaCl)
  • arteriolar vasoconstriction
39
Q

Renin-Angiotension-Aldosterone System

What else can angiotensin II (ATII) stimulate?

A

thirst and antidiuretic hormone (ADH/vasopressin) secretion

40
Q

Renin-Angiotension-Aldosterone System

What are some functions of vasopressin/ADH?

A

(these actions increase intravascular volume and blood pressure)

  • can increase peripheral vascular resistance and therefore blood pressure by actin on the V1 receptor
  • can promote absorption of water by stimulating the V2 receptor in the cells of the collecting duct – as a consequence, aquaporin (specifically AQ2) or water channels are translocated to the plasma membrane and water is absorbed into the blood
41
Q

What mechanisms does tubular reabsorption (solutes crossing the renal epithelial cell membrane) include?

A

passive and active mechanisms

  • simple diffusion
  • channel-mediated diffusion
  • carrier-mediated (facilitated) diffusion
  • co-transport
  • counter transport
  • ATP-mediated transport
42
Q

What is simple diffusion?

A

solutes with sufficient lipid solubility may diffuse across the membrane down concentration gradients

43
Q

What is channel-mediated diffusion?

A

diffusion of solute through a pore formed by membrane proteins

44
Q

What is carrier-mediated (facilitated) diffusion?

A

transport of solute by carrier protein down electrochemical gradient

45
Q

What is co-transport?

A

co-transport of solutes in the same direction

  • ie. simultaneously transports both Na+ and another solute Cl- or glucose from the tubular lumen into the renal epithelial cell
46
Q

What is counter transport?

A

counter transport of solutes in the opposite direction

  • ie. transports Na+ in, another solute H+ out of renal epithelial cells
47
Q

What is ATP-mediated transport?

A

transport of solute by carrier protein against an electrochemical gradient with aTP hydrolysis providing the driving force

48
Q

Describe how the Na+-K+ ATPase pump works.

A

ATP-mediated transport that functions throughout most parts of the renal tubule

  • present on the basolateral side of the tubular epithelial cell
  • cell membrane has an extensive Na+-K+ ATPase that hydrolyzes ATP and uses the released energy to transport Na+ ions out of the cell into the interstitium and eventually into the peritubular network
  • at the same time, K+ is transported from the interstitium to the inside of the cell (3 Na+ ions are ejected from the cell, while 2 K+ ions gain entry)
  • maintains low intracellular Na+
  • creates a net negative charge within the cell
  • this favours movement of Na+ across the luminal membrane (either via carrier proteins or Na+ channels) into epithelial cells
  • as Na+ diffuses down its electrochemical gradient, the energy released is used to co-transport (like glucose, amino acids, and chloride) or counter-transport (like H+ ions) other substances
49
Q

Proximal Tubule

How much does the proximal tubule absorb?

A

about 65-70% of the filtered load of Na+ and water, and a slightly lower % of filtered Cl- are reabsorbed by the proximal tubule before it reaches the loop of Henle

50
Q

Proximal Tubule

Describe proximal tubule epithelial cells.

A
  • highly metabolic
  • have large numbers of mitochondria to support potent active transport processes
  • have an extensive brush border (densely packed microvilli to provide an extensive membrane surface area)
51
Q

Proximal Tubule

Why does the concentration of Na+ in tubular fluid remain relatively constant?

A

although the amount of Na+ in the tubular fluid decreases markedly along the proximal tubule, the concentration of Na+ remains relatively constant because water permeability of the proximal tubule is so great that water reabsorption keeps pace with Na+ reabsorption

52
Q

Proximal Tubule

What is located at the apical side of the luminal membrane of the proximal tubule epithelial cell?

A

sodium-hydrogen exchanger (NHE3)

53
Q

Proximal Tubule

Where is carbonic anhydrase (CA) located?

A
  • apical side of the cell membrane (CAIV)
  • cytosol (CAII)
54
Q

Proximal Tubule

What does carbonic anhydrase (CA) do?

A

catalyzes the hydration of CO2 and dehydration of CA (H2O + CO2 ↔ H2CO3 ↔ HCO3- + H+)

  • CAIV catalyzes the cleavage of carbonic acid into water and CO2 (which diffuses into the cytoplasm of the proximal epithelial cells
  • CAII rapidly rehydrates intracellular CO2 to carbonic acid
  • this eventually leads to the formation of HCO3- which is then co-transported with Na+ across the basolateral membrane of the epithelial cell by Na+-HCO3- co-transporter NBC1
  • permeability of the luminal membrane of the proximal tubule to HCO3- is poor, therefore reabsorption of HCO3- by the proximal tubule is dependent on CA activity
55
Q

Proximal Tubule

What does CAIV do?

A

catalyzes the cleavage of carbonic acid into water and CO2 (which diffuses into the cytoplasm of the proximal epithelial cells

56
Q

Proximal Tubule

What does CAII do?

A

rapidly rehydrates intracellular CO2 to carbonic acid

57
Q

Proximal Tubule

Describe the reabsorption of Ca2+ in the proximal convoluted tubule.

A

parallels that of Na+ and water

  • reabsorption is thought to occur mainly by passive diffusion and solvent drag (refers to solutes in the ultrafiltrate that are transported back from the renal tubule by the flow of water rather than specifically by ion pumps or other membrane transport protein
  • passive paracellular pathways account for approximately 80% of Ca2+ reabsorption in this segment of the nephron
58
Q

Proximal Tubule

What do organic acid secretory systems present at this location do?

A

secrete a variety of substances like uric acid and diuretics to the luminal fluid from the blood

  • helps to deliver diuretics to the luminal side of the tubule where most of them are active
59
Q

Proximal Tubule

Is salt transport in the proximal tubule under hormonal control?

A

no

60
Q

Where is the sodium-glucose co-transporter (SGLT) located?

A

proximal tubule is a key location

61
Q

Proximal Tubule

What do SGLTs do?

A

couple glucose with sodium

62
Q

Proximal Tubule

What is SGLT-2 (sodium:glucose co-transport ratio of 1:1)?

A

responsible for reabsorption of 90% of glucose filtered in the glomerulus back into the bloodstream

  • present in S1 and S2 convoluted section of the proximal tubule
63
Q

Proximal Tubule

What is SGLT-1 (sodium:glucose co-transport ratio of 2:1)?

A

responsible for reabsorption of the remaining 10% of filtered glucose

  • present in the S3 or straight segment of the proximal tubule
64
Q

Proximal Tubule

What do SGLTs and GLUTs do?

A

facilitate insulin independent reabsorption of filtered glucose

65
Q

Proximal Tubule

Describe the defence mechanism against hyperglycemia.

A
  • at normal levels, the amount of glucose filtered by the glomerulus increases with glycaemia and is entirely reabsorbed from the proximal tubule by SGLT-2 transporters – NO GLYCOSURIA
  • beyond a given glycaemia (the renal threshold for glucose RTg), this reabsorption mechanism becomes saturated and glucose appears in the urine – GLYCOSURIA
66
Q

Loop of Henle

What are the segments of the loop?

A
  • descending thin segment
  • ascending thin segment
  • thick ascending segment
67
Q

Loop of Henle

Describe the descending limb of the loop.

A
  • freely permeable to water
68
Q

Loop of Henle

Describe the thick ascending limb.

A
  • virtually impermeable to water, which remains in the tubule
  • about 20-25% of the filtered loads of Na+, Cl-, and K+ are reabsorbed
  • Na+-K+ ATPase pump maintains a low intracellular Na+ concentration, which in turn provides a favourable gradient for movement of Na+ from the tubular fluid into the cell
69
Q

Loop of Henle

What mediates the movement of Na+ across the luminal membrane in the thick ascending limb?

A

primarily by 1-sodium, 1-potassium, 2-chloride co-transporter (NKCC2)

  • by taking K+ from the lumen into the epithelial cell, which also gains K+ from the interstitial fluid via Na+-K+ ATPase pump, there is backflow of K+ into the lumen
  • this creates a trans-epithelial voltage along the thick ascending limb that is oriented such that the lumen is positive relative to the interstitial fluid
  • this drive the paracellular reabsorption of luminal divalent cations like Mg2+ and Ca2+
70
Q

Loop of Henle

What is NKCC2?

A

electro neutral co-transporter

71
Q

Distal Tubule

What does the first portion of the distal tubule form?

A

part of the juxtaglomerular complex – where the distal convoluted tubule comes in contact with the afferent arteriole

  • at this junction, distal tubular cells become highly specialized (referred to as macula densa) and respond to changes in Na+
  • typically, activation of the macula densa triggers highly specialized cells lining the afferent arterioles (granular juxtaglomerular cells) to release renin into the bloodstream
72
Q

Distal Tubule

Describe the second portion of the distal tubule.

A
  • has many of the reabsorptive characteristics of the thick segment of the ascending limb of the loop of Henle
  • contains the sodium-chloride co-transporter (NCC)
73
Q

Distal Tubule

What does the distal tubule reabsorb?

A
  • about 4-5% of filtered Na+ in the glomerular filtrate
  • mediates the reabsorption of luminal Ca2+ via ion-specific Ca2+ channels (TRPV5) in the apical membrane, under the control of the parathyroid hormone – reabsorbed Ca2+ can then cross the distal tubule basolateral membrane via specific Na+-Ca2+ exchangers and Ca2+-ATPases (that exchanges internal calcium for external H+)
74
Q

Distal Tubule

How does they kidney help maintain healthy bones?

A

in the presence of decrease extracellular Ca2+ levels, reduced activation of the calcium-sensing receptor (CaSR) in the parathyroid glands results in a rapid release of parathyroid hormone (PTH) secretion – PTH acts on:

  • PTH1 receptor (PTH1R) in the kidneys
  • CYP27B1 in the proximal tubule
  • PTH1 receptor in the bone
75
Q

Distal Tubule

What happens when PTH acts on PTH1R in the kidneys?

A

increases tubular calcium reabsorption by activating TRPV5

76
Q

Distal Tubule

What happens when PTH acts on CYP27B1 in the proximal tubuls?

A

promotes the conversion of inactive vitamin D to active vitamin D (also known as calcitrol)

  • calcitrol acts on the intestine to increase absorption of dietary calcium via vitamin D receptor (VDR)
77
Q

Distal Tubule

What happens when PTH acts on PTH1 receptor in the bone?

A

increases osteoclast (that breaks down bone tissue) activity, resulting in a transfer of calcium from bone tissue to the blood

78
Q

Collecting Duct

What does the collecting duct reabsorb?

A

sodium and water

  • less than 4-5% of the filtered Na+
79
Q

Collecting Duct

What does the collecting duct secrete?

A

potassium

80
Q

Collecting Duct

What is the collecting duct under the control of?

A

aldosterone

  • secreted from the adrenal cortex
  • regulates reabsorption of Na+ and its couples secretion of K+ – increases the synthesis of proteins including the Na+ channel and Na+-K+ ATPase in addition to causing mitochondrial biogenesis
  • reabsorption of Na+ can increase blood volume and blood pressure
81
Q

Collecting Duct

Unlike the other segments that reabsorb Na+ using co-transport/counter-transport systems, what does the collecting duct do?

A

cells of the collecting duct have ion channels for Na+ and K+

  • as there is only one ion (Na+) that is being absorbed (no other accompanying ion is being co-transported or counter-transported), Cl- and HCO3- are left behind, making the lumen negative (as much as -50 mV)
  • this is the driving force that draws K+ out of the cell through the apical membrane K+ channel, resulting in K+ secretion
  • this is also the driving force to move Cl- back into the blood via the paracellular pathway
82
Q

Collecting Duct

What is permeability in this region controlled by?

A

hormonally controlled by the level of ADH/vasopressin, in contrast to the proximal tubule

  • ADH secreted from posterior pituitary increases the permeability of the ducts to water, thereby concentrating the urine
  • ADH stimulates a G-protein coupled receptor in the basolateral membrane (V2 receptors)
  • cAMP produced due to this activation promotes the insertion of pre-formed water channels called aquaporin-2 (AQP2) into the apical membrane
  • passive reabsorption of water is the end result (diabetes insipidius)
83
Q

What is diabetes insipidius?

A

deficiency of ADH results in large volumes of urine being excreted

84
Q

Kidneys and RBCs

What are erythropoietin-producing cells (EPCs)?

A

non-endothelial renal interstitial cells that are also called interstitial fibroblasts

85
Q

Kidneys and RBCs

What are EPCs responsible for?

A

under physiologic, non-stimulated conditions, a small number of renal EPCs are responsible for renal erythropoietin output

  • the size of the EPC pool is regulated in an oxygen-dependent manner and increases under hypoxic conditions
  • expansion of the EPC pool (and increase in erythropoietin) requires hypoxia-inducible factor (HIF-2) signaling, which is activated by hypoxia
  • tubular epithelial cells do not produce erythropoietin (EPO)
86
Q

Kidneys and RBCs

What is erythropoietin?

A

the principal hormonal regulator of erythropoiesis

87
Q

Kidneys and RBCs

What happens following chronic kidney disease?

A

EPCs transdifferentiate into myofibroblasts, which synthesize collagen and lose their ability to produce EPO

88
Q

Kidneys and RBCs

What happens with anemia?

A

decreased oxygen transport causes tissue hypoxia, which through activation of the HIF system stimulates the production of EPO

  • EPO stimulates the proliferation and differentiation of erythroid progenitors (more specific than a stem cell) into reticulocytes (immature RBCs) and prevents their apoptosis (cell death)
  • more reticulocytes enter circulating blood, differentiate into erythrocytes (nucleus is ejected), thus increasing the pool of RBCs
89
Q

Kidneys and RBCs

How does EPO play a role in iron metabolism?

A
  • for iron to be taken up from the intestine, divalent metal transporter 1 (DMT1) is the major iron uptake system of intestinal cells
  • inside these cells, ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion
  • this iron can also use ferroportin to be transferred to transferrins that are iron-binding blood plasma proteins that control the level of free iron in biological fluids
  • hepcidin acts on intestinal cells to decrease the amount of iron absorbed into the body – does so by binding to iron transporter ferroportin, which causes ferroportin to be internalized and degraded
  • as a result, more iron remains within the intestinal cell so that the iron that enters this cell gets bound to ferritin
  • in the condition where EPO is decreased, a reduction in erythropoiesis means that the erythroblast decreases erythroferrone production
  • hepcidin (secreted from the liver) is maintained at higher levels by decreased erythroferrone production
  • an increase in hepcific negatively affects iron absorption and mobilization (and explains the anemia associated with renal disease)

PHRM 100 – APPP (22 decks)

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