Nephron

Question 1

lumen voltages: early PT, late PT, TAL, distal tubule, CD

Answer 1

early PT negative (due to electrogenic Na-glucose/AA); late PT positive (due to Cl- leaving lumen paracellularly > bicarb entering lumen paracellularly b/c Cl more permeable); TAL positive (due to NK2Cl -> 2 cations and 2 anions reabs, but K recycles into lumen via ROMPK therefore net loss of negative charge); DT positive (due to Cl- uptake via NCC and K recycling into lumen via Kv1.1); CD very negative (due to ENAC)

Question 2

tubular fluid concentration of inulin, Cl, Na, bicarb, AA, glucose along PT

Answer 2

inulin concentration steadily rises as water is reabsorbed; Cl- concentration rises initially as water is reabsorbed but then levels off as Cl- is absorbed paracellularly in late PCT (not absorbed proximally b/c bicarb is absorbed); Na concentration rises very little yet steadily along PT as both Na and water are reabsorbed (water a bit more than Na, but not much); bicarb concentration drops early as NaHCO3 reabs in early PT (most reabs by end of PT, but not at all); AA and glucose concentration drop very suddenly, and pretty much all reabs by end of PT

Question 3

Cl reabsorption in PT (3)

Answer 3

Cl is the anion that balances Na reabs in PT; Cl reabs mostly paracellular in early PT driven by neg lumen created by electrogenic Na-glucose/AA reabs (not much reabs here b/c HCO3 being reabs w/ Na); Cl reabs transcellular (enter cell transcellularly by counterexchanging w/ organic anions, leaves cell thru Cl channel and prob K-Cl cotransporters) and paracellular (due to high Cl in tubule b/c all HCO3 reabs in early PT) in late PT

Question 4

Cl reabs in TAL mechs (2)

Answer 4

all transcellular into cell via NK2Cl and out of cell via Cl- channels

Question 5

NaCl reabs in CD (3)

Answer 5

Na reabs via ENaC (none paracellularly); Cl reabs paracellularly due to large lumen neg V (created by ENaC) and transcellularly via Cl-HCO3 antitransport on beta IC cells

Question 6

Na reabs throughout nephron (%)

Answer 6

67% filtered load reabs in PT, 23% load in TAL, 5% in DT, 3% in CD, .5% excreted

Question 7

Na reabs in PT mechs (7)

Answer 7

Na reabs via Na synporter w/ glucose, phosphate, sulfate, or organic acids, Na reabs via Na/H antiporter; Na leaves cell via Na/K pump and Na/HCO3 cotransporter; Na backleaks paracellularly due to lumen neg voltage in early PT; Na reabs paracellularly via solvent drag (backleak predominates over solvent drag); in late PT, Na reabs paracellularly due to lumen pos voltage

Question 8

Na reabs in TAL mechs (3)

Answer 8

Na enter cells via NK2Cl and NaH antiporter, leaves cell via Na/K pump; Na also reabs paracellularly due to lumen positive voltage (created by ROMPK)

Question 9

Mg absorption in nephron (%)

Answer 9

15-25% reabs in PT (exception to most solutes) - doesn’t seem to be mediated by claudin or other proteins ; 60-70% reabs in TAL (paracellular due to positive lumen); 5-10% reabs distally (mostly CCD, with active reabs via TRPM6 in early DCT)

Question 10

Ca abs in PT

Answer 10

50-60% filtered load reabs in late PT when lumen becomes positive; claudin-2 functions as paracellular calcium channel

Question 11

Mg and Ca abs in DT

Answer 11

Mg and Ca active reabs only takes place at DT; active Mg transport is confined to DCT1 and DCT2 (early DCT) via TRPM6, while active Ca transport is confined to DCT2 and CNT (late DCT) via TRPV5 (leaves cell basolaterally via NCX1 and PMCA1b)

Question 12

TRPM6

Answer 12

Mg active reabs via this apical channel in early DCT

Question 13

TRPV5

Answer 13

Ca active reabs via this apical channel in late DCT

Question 14

NCX1

Answer 14

Ca leaves DCT cell via this basolateral channel (along w/ PMCA1b) in late DCT

Question 15

PMCA1b

Answer 15

Ca leaves DCT cell via this basolateral channel (along w/ NCX1) in late DCT

Question 16

HCO3- reabsorption locations (%)

Answer 16

PCT reabsorbs 80% filtered load, TAL reabsorbs 10-15%, rest absorbed in DCT and distal nephron; fractional excretion < .01%

Question 17

K reabsorption throughout kidney (%s)

Answer 17

prox nephron not regulated: 80% in PT, 10% in TAL; collecting duct regulated: in hyperkalemia, 20-180% can be secreted in initial collecting duct (20-40% will be reabsorbed again in CD despite hyperkalemia) -> total 10-150% filtered load excreted, vs. in hypokalemia, 2% will be reabsorbed in initial CD w/ 6% reabs in late CD -> total 2% filtered load excreted

Question 18

K handling in PT (3)

Answer 18

in early prox tubule, reabs paracellularly due to solvent drag and concentration gradient ([K] in tubule incr as water reabs); in late tubule, small positive lumen V drives K reabs paracellularly; there is minimal secretion to lumen through luminal K channels

Question 19

K handling in loop of Henle: thin descending limb, thin ascending limb, TAL

Answer 19

K passively secreted in thin descending limb (driven by high K permeability and high medullary K concentration); K passively reabs in thin ascending limb (this traps K in medullary interstitium -> incr capacity to secr K in distal tubule and CD during hyperkalemia); TAL reabs K both actively (accounts for 50%, via NK2Cl) and passively (accounts for 50%, due to positive lumen), some reabs K is secreted back into lumen through ROMPK while some exits the cell basolaterally

Question 20

reabs and secretion of K in CD - what cells/channels are responsible?

Answer 20

principal cells secr K through aldo-sensitive channels and thru apical K-Cl synporter (driven by concentration gradient maintained by fast urine flow and by neg lumen V est by ENAC Na reabs); alpha IC cells reabs K through HK antiporter channels

Question 21

HCO3- reabsorption mechanism in PCT and TAL

Answer 21

H+ secreted through NaH antiporter (driven by low Na in cell established via basolateral NaK pump) and through H+ ATPase; H+ combines w/ HCO3- to form CO2 + water (reaction sped up by brush border CA); CO2 diffuses across membrane where it is turned back into HCO3 + H+ by intracellular CA; H+ is re-secreted to tubule while HCO3 is transported across basolateral membrane to plasma via Na/HCO3 synporter (full PCT and TAL) as well as Cl-HCO3 antiporter and K-HCO3 symporter in late PT and TAL

Question 22

GT balance

Answer 22

at constant RPF, PT reabs of Na is directly proportional to Na filtration -> this is important so that changes in filtration fraction do not cause changes in Na excretion; this occurs b/c more filtration = more water in tubule = less water in plasma = higher oncotic pressure and lower hydrostatic pressure in efferent = more water reabs = more Na reabs via solvent drag

Question 23

effects on GFR by Ag II, NE/epi, endothelin, prostaglandins, NSAIDs, NO

Answer 23

Ag II constricts efferent, therefore decr RPF but incr GFR (works to maintain GFR in hypovolemia); NE/epi constricts afferent (and also decr Kf), therefore decr RPF and GFR; endothelin decr Kf (mesangial contraction) and constricts both aff and eff -> decr both RPF and GFR; prostaglandins (PGE2 and prostacyclin) dilate afferent -> incr RPF and GFR; NSAIDs block PGE2, so NSAIDs constrict afferent and thus decr RPF and GFR (only important in disease states, b/c PGE2 only imp to maintain GFR in disease states); NO dilates afferent -> incr RPF and GFR;

Question 24

renal effects of Ag II

Answer 24

constricts efferent arteriole -> decr RPF and incr GFR -> incr FF -> incr peritublar cap oncotic P and decr hydrostatic P -> more PT Na reabs; constricts efferent -> decr vasa recta flow -> decr urea washout from medullary interstitium -> more urea, therefore less Na in medullary interstitium -> incr gradient for passive NaCl reabs by thin ascending limb

Question 25

NE effects (3)

Answer 25

constricts afferent -> decr RPF and GFR; stims renin release; stims PCT Na reabs by activating NaH antiporters and Na/K basolateral pumps

Question 26

ADH effects (3)

Answer 26

aquaporins in CD; stims NK2CL in TAL (required for maintaining hypertonicity of medullary interstitium); incr number of ENaC (thus can play a role in restoring euvolemia under v. hypovolemic conditions, even though normally works only to restore isotonicity)

Question 27

natriuretic hormones (4)

Answer 27

ANP, dopamine, prostaglandins, endogenous digitalis-like hormones

Question 28

calculating RPF

Answer 28

RPF - RBF(1-Hct)

Question 29

Kf

Answer 29

in Starling equation; reflects the hydraulic permeability of the membrane and the effective surface area; much larger in glomerulus than in other capillaries; reduced in kidney disease (reduction in surface area) and due to Ag II, AVP, some prostaglandins (trigger mesangial cell contraction and thus alter both permeability and surface area)

Question 30

GFR along cap segment, effects of RPF on GFR

Answer 30

GFR decr along segment b/c cap oncotic P rises along segment; incr in RPF makes oncotic P rise less so makes GFR greater (net ultrafiltration is greater)

Question 31

relationship btwn RPF and GFR

Answer 31

above normal RPF, increasing RPF further doesn’t incr GFR much; however, below normal RPF, decreasing RPF further decr GFR a lot (linear relationship)

Question 32

FF: define, normal value

Answer 32

FF = GFR/RPF; normal = 20%

Question 33

autoregulation

Answer 33

mediated by myogenic response (as afferent arterioles are stretched due to high BP, they constrict to restrict RPF) and by tubuloglomerular feedback)

Question 34

tubuloglomerular feedback

Answer 34

as GFR incr, FF incr, NaCl in distal tubule incr, macula densa detects incr NaCl and sends signal (via cation channels, calcium, ATP, adenosine) to constrict afferent arteriole and return GFR to normal

Question 35

filtered load equation

Answer 35

GFR x Px x Fx (Px is plasma concentration of solute, Fx is filterability of solute = 1 for freely filtered substances)

Question 36

clearance equation

Answer 36

clearance = UxV/Px

Question 37

fractional excretion equation

Answer 37

FE = clearance/GFR = (Ux/Px)/(Ucr/Pcr)

Question 38

using creatinine clearance and urea clearance to estimate GFR

Answer 38

creatinine is secreted (10-20%), so clearance > GFR (altho errors in measuring creatinine are about 10-20% so it usually cancels out) , thus Ccr overestimates GFR (more secreted at decr GFR, so Ccr overestimates GFR even more at low GFR); urea is reabsorbed, so clearance < GFR, thus Curea underestimates GFR

Question 39

NaK pump activity throughout nephron

Answer 39

most in DCT > TAL > PCT > CD > loop

Question 40

V gradient along PT

Answer 40

originally neg b/c Na reabs (i.e. w/ glucose), then pos b/c Cl- diffuses out more than bicarb diffuses in

Question 41

water permeability throughout nephron

Answer 41

highest in PT (esp PST), then thin descending limb, then CD (if ADH active); thus don’t need large concentration difference to produce very high rate of water reabs in PT

Question 42

glucose reabs

Answer 42

SGLT2 is high capacity low affinity apical transporter w/ 1:1 Na:glucose stoichiometry that is responsible for the bulk of the glucose transport in PCT (mutations cause glucosuria); SGLT1 is low capacity high affinity apical transporter w/ 2:1 Na:glucose that is responsible for “mopping up” in PST (mutations have little effect); GLUT sends glucose from cell into interstitial fluid

Question 43

phosphate reabsorption: where, how, what inhibits reabs (4), what increases reabs (3)

Answer 43

80% in PT, mediated by Na-Pi cotransporters; PTH, high Pi intake, FGF-23, and acidosis all inhibit Pi reabsorption; Vit D, phosphate deficiency, and GH all incr Pi reabsorption –> Pi is one of the only solutes where PT reabsorption is regulated

Question 44

protein reabsorption in PT

Answer 44

megalin, cubulin, and amnionless in PT mediate reabs of filtered proteins via receptor-mediated endocytosis (proteins are delivered to lysosome -> degradation -> recycling)

Question 45

urea reabs in PT

Answer 45

via paracellullar pathway in PT (no specific transporters)

Question 46

fluid entering loop: Na, Cl, glucose, AA, protein, K, ammonium

Answer 46

[Na] same as plasma (isotonic reabs in PT b/c leaky epithelium); [Cl-] higher than plasma b/c bicarb reabs > Cl- reabs in PT; no glucose, AA, protein (all reabs in PT); rich in K b/c secreted into PST (minor); rich in NH4 b/c synthesized in PT

Question 47

thin descending vs ascending limb

Answer 47

descending is permeable to water but not salt (water leaves tubule); ascending is permeable to salt but not water (salt leaves tubule)

Question 48

fluid leaving thin ascending limb and entering TAL: NaCl, water, Ca, K, glucose, Pi, Mg, bicarb

Answer 48

75% filtered load NaCl reabs (60% in PT, 15% in thin limbs), 75% water reabs (60% PT, 15% thin limbs), 75% Ca reabs (60% PT, 15% thin limbs), 90% K reabs, 100% gluc reabs, 90% Pi reabs, 20% Mg reabs, 100% bicarb reabs

Question 49

ammonia movement in nephron

Answer 49

ammonia generated in PT, reabsorbed in TAL (instead of K in NK2CL) and deposited into medullary interstitium, this leads to high NH4 concentration in interstitium, NH3 diffuses down its gradient into CD where it combines w/ H+ to form trapped ammonia, ammonia enters cells on NaK pump and then is sent into lumen w/ H+; if H+ secr is impaired, NH4 excr will be impaired and NH4 will be reabs -> liver -> turned into urea, which consumes bicarb (net acid change = 0 bad!)

Question 50

reabs in TAL %: NaCl, water, Ca, gluc, Pi, Mg, bicarb, NH3

Answer 50

25% load of NaCl reabs, no water reabs, 20% Ca reabs, no gluc reabs, no Pi reabs, 70% Mg reabs, no bicarb reabs, 90% NH3 reabs (synth in PT, enters interstitium from TAL, then goes in CD)

Question 51

fluid entering distal tubule: tonicity, K, NH4, bicarb, Ca, Mg, NaCl

Answer 51

hypotonic, very little K and NH4, no bicarb, moderate amt of Ca and Mg, about 10% of filtered NaCl

Question 52

fluid leaving DCT: tonicity, NaCl, K, Ca, Mg, bicarb

Answer 52

hypotonic, less NaCl, little if any K, minimal Ca and Mg, little if any bicarb

Question 53

where is Ca actively reabs?

Answer 53

late DCT via TRPV5 (leaves cell basolaterally via NCX1 and PMCA1b)

Question 54

where is Mg actively reabs?

Answer 54

early DCT via TRPM6