Rao: Physiology Flashcards
1
Q
What is total body water (TBW), and its distribution in tissue?
A
- About 60% of body weight; 42L in 70kg adult
- %TBW and %tissue:
1. Muscle: 43, 76
2. Skeleton: 16, 22
3. Organs: 6, 75
4. Adipose: 10, 10
2
Q
What is the relationship between TBW and fat content? Why is this important epi-wise?
A
- Inverse
- TBW lower in women, decreases with age, and decreases with increasing obesity (all due to fat content)
3
Q
Describe the body fluid balance (intake vs. output).
A
- Intake:
1. Oxidation of carbs: 300 mL/day
2. Drink + food: 2200 mL/day - Output:
1. Urine: remaining fluid excreted by kidney (0.5 to 20 L/day w/excessive water drinking)
2. Perspiration (skin & lung): 700 mL/day (up to 5L/day w/burn)
3. Sweat: 100 mL/d (1-2 L/hr w/exercise)
4. Feces: 100 mL/d (excessive w/severe diarrhea)
4
Q
What are the basic functions of the kidney?
A
- Regulation of water and inorganic ion balance
- Removal of metabolic waste products from the blood and their excretion in urine
- Removal of foreign chemicals from blood and their excretion in urine
5
Q
What hormones are secreted by the kidney?
A
- EPO: RBC production
- 1,25-dihydroxyvitamin D3: Ca, phosphate balance
- Renin-angiotensin II production: sodium balance
- Gluconeogenesis: during fasting
6
Q
Describe the ionic composition of the different body fluids (plasma, interstitial, ECF).
A
- Ionic composition of plasma and interstitium similar due to high permeability of capillary wall (20% BW: 1/4 or 3L plasma, 3/4 or 12L interstitium)
1. Na the major cation, Cl the major anion (and bicarbonate)
2. Protein (-) and impermeable (concentrated in plasma), so Na 2% greater in plasma and Cl and bicarbonate lower (Gibbs Donnan effect) - IC (RBCs, other cells): major cation K (and Mg), and major anion phosphates, proteins, and bicarbonate (40% BW, and about the same in all tissue types)
1. No Ca
7
Q
Are humans open or closed systems?
A
- Open: lung, kidney, GI, skin all in contact with the external environment
- All have barrier function to prevent diffusion of molecules into the external environment
8
Q
What is the composition of blood volume?
A
- 8% of BW: 5L (ECF + ICF)
- 60% plasma (ECF) and 40% RBC (hematocrit; ICF)
- Influenced by age, sex, etc.
9
Q
What is the cell membrane permeable to?
A
Water, chloride, urea, and some lipophilic molecules
10
Q
How are the ionic compositions of ICF and ECF different?
A
11
Q
What is the dilution principle? What are the criteria for probe selection for body fluid measurements?
A
- Volume = quantity injected/concentration
- Criteria:
1. Non-toxic at concentration employed
2. Neither synthesized (underestimate volume) nor metabolized (overestimate)
3. Disperses evenly in the fluid
4. Disperses only in the compartment of interest
5. Do not influence fluid compartment volume
12
Q
What probe do we use to measure plasma volume? What is the equation for blood volume?
A
- (131)I-albumin: Evans blue dye (avidly binds plasma protein) -> need probe disbursed only in plasma that can’t penetrate capillary wall or diffuse through PM
- IV injection in small vol (Q) -> withdraw blood and prepare plasma -> measure concentration of probe in plasma (Q/V) -> PV = Q/(Q/V)
- Blood volume = PV/(1-hematocrit)
13
Q
How do we measure EC fluid volume?
A
- Probe: Inulin, thiosulfate, Na -> needs to be able to diffuse across interstitial fluid, but not across PM
- IV injection in small vol (Q) -> withdraw blood and prepare plasma -> measure concentration (Q/V) -> ECFV = Q/(Q/V)
- Interstitial volume = EC volume - plasma volume
14
Q
How do you correct for loss of probe during equilibrium? Provide an example.
A
- Cx due to loss of marker in urine: although some inulin may be lost in urine, you can correct for it
- Example: 1g inulin injected in 70 Kg pt. 60 min later 100 mg of inulin had been excreted in urine and the plasma conc of inulin was 0.06 mg/ml (60 mg/L)
1. ECF = Q/(Q/V) = (1000-100mg)/(0.06mg/mL) = 15000mL or 15L
15
Q
How do we measure TBW?
A
- Probe: 2H2O, 3H2O, antipyrene (lipid soluble)
- IV injection in small vol (Q) -> withdraw blood and prepare plasma -> measure concentration of probe in plasma (Q/V)
1. TBW = Q/(Q/V)
2. ICF = TBW - ECF
16
Q
What factors determine fluid movements between compartments?
A
-
Between plasma and ISF: filtration
1. Starling forces: hydrostatic, oncotic pressure (colloidal osmotic pressure)
2. Net plasma osmolarity -
B/t ECF and ICF: osmosis (main driving force for mvmt of fluid b/t EC and IC is osmotic pressure)
1. Na: impermeable, so conc change in 1 compartment would exert osmotic P and mvmt
2. Urea: permeable, so change in conc will not induce plasma oncotic pressure (H2O same)
3. Water: permeable
4. Glycerol: slowly permeable, so will initially generate osmotic pressure, but will slow down
17
Q
What is osmosis?
A
- Net diffusion of water from region of high conc to to one of low conc
- Water diffuses from compartment with low solute conc (i.e., Na) to the one with high
18
Q
What are osmoles, osmolarity, and osmolality?
A
-
Osmole: 1 mol glu in L solution = 1 osmole
1. 1 mol NaCl in L sol = 2 osmoles (b/c ionizes in water to 2 particles)
2. 1 mol Na(2)SO(4) in L sol = 3 osmoles - Osmolarity: 1 osmole glu per L of solution
- Osmolality: 1 osmole glu per kg of water (measured using osmometer)
- NOTE: clinical difference b/t osmolarity and osmolality negligible
19
Q
What is osmotic pressure? How is it related to osmolarity?
A
- Osmotic pressure: amount of pressure required to prevent osmosis (i.e., net diffusion of water across membrane)
- Osmotic pressure of solution proportional to conc of osmotically active particles in that solution -> 1 mOsmole of gradient = 19.3 mm Hg
1. Depends on # of particles, not size: 1 particle albumin (70,000 daltons) & 1 particle glu (180 daltons) have same osmotic pressure
2. Osmolarity of blood fluid in different compartments (ECF, ICF) SAME (295 mOsmol/L) -> water is freely permeable through barriers
a. ECF - Na and Cl; ICF - K and others
20
Q
How do hypertonic, isotonic, and hypotonic solutions affect RBC’s if the solute is impermeable?
A
- Hypertonic: shrinking of RBC due to loss of water
- Isotonic: fluids in all compartments have the SAME osmolarity
- Hypotonic: water moves from outside to inside, and RBC swells
21
Q
What will happen to an RBC put in solution with low P(Na) and high urea? What about a solution with normal P(Na) and high urea?
A
- Urea is freely and rapidly permeable, so swelling in the iso-osmotic example with urea replacing Na
- No change in volume in second example because urea is highly permeable and will equilibrate
22
Q
What will happen if you put RBC in solution with low P(Na) and high glycerol?
A
23
Q
How does dehydration affect compartment volume and osmolarity?
A
- Loss of water from ECF
- Increase in solutes
- Increase in ECF osmolarity
- Draws water out of ICF
- Decrease in volume of all compartments
- Osmolarity increased in all compartments
- Potential causes: water deprivation, severe diarrhea, comatose pt, trapped in earthquake rubble
24
Q
How do you estimate plasma osmolarity?
A
- Plasma osmolarity = (plasma Na x 2) + glu + urea
25
Q
How do you estimate fluid infusion for tx of dehydration? What do you give?
A
-
Estimation:
1. Know or predict pt’s original body weight and calculate TBW and total mOsmoles of solutes
2. Calculate pt’s TBW using new osmolarity and normal total mOsmoles
3. Calculate difference in TBW to estimate fluid vol necessary to achieve correct osmolarity - IV fluid infusion for severe dehydration: isotonic glucose OR hypotonic saline with glucose
1. Note: some fluid excretion during infusion; do not infuse all at once, but rather titrate the pt
26
Q
What is an osmolarity gap? Why is it important?
A
- When the measured plasma osmolality > estimated plasma osmolarity
1. There is a missing osmotic particle; very clinically useful to know that there is something there (alcohol, methanol, ethyl glycol, etc.)
2. >10 abnormal
27
Q
What happens to the compartment volumes and osmolarities when you infuse isotonic salt solution?
A
- Causes: saline infusion in the clinic
-
Theoretical assessment: increase in ECF volume without change in osmolarity
1. No change in osmolarity or volume of ICF
28
Q
What happens to the compartment volumes and osmolarities when you gain water?
A
- Causes: drinking large amount of water, infusion of fluid for nutritive purposes (glucose solution)
-
Theoretical assessment:
1. Increase in volume of ECF
2. Decrease in ECF osmolarity
3. Flux of water into ICF
4. Increase in volume of all compartments
5. Osmolarity decreased in all compartments
29
Q
What happens to the compartment volumes and osmolarities when you gain salt?
A
- Causes: excessive salt consumption, hypernatremia
-
Theoretical assessment:
1. Increase in ECF osmolarity
2. Draws water from ICF
3. Increase in volume of ECF
4. Decrease in volume of ICF
5. Osmolarity increased in all compartments
30
Q
What happens to the compartment volumes and osmolarities when you lose NaCl?
A
- Causes: hyponatremia (drinking water after profuse sweating)
-
Theoretical assessment:
1. Decrease in ECF osmolarity
2. Flux of water into ICF
3. Decrease in volume of ECF
4. Increase in volume of ICF
5. Osmolarity decreased in all compartments
31
Q
What happens to the compartment volumes and osmolarities when you infuse isotonic urea?
A
-
Theoretical assessment:
1. Urea is freely and rapidly permeable through all cell membranes
2. Increase in volume of all compartments
3. Isotonic osmolarity of all compartments
32
Q
What is the equation of mass flow?
A
Mass flow = concentration (amt/mL) x vol flow (mL/min)
*Always check the UNITS
33
Q
What is mass balance for the whole body?
A
-
Homeostasis: body maintains constant total content of all substances, incl. water, solutes, and solid material stores
1. Ingestion of solute not produced by body, i.e., NaCl: rate of output = rate of intake
2. Metabolism of ingested solutes, e.g., glucose: rate of output = rate of intake + rate of production - metabolism
3. Solutes produced only by metabolism, e.g., urea: rate of output = rate of production - At steady state, plasma concentration constant
34
Q
How does mass balance work in the kidney? Use urea and water as examples.
A
- Rate of input = rate of output (via renal vein, urine, and/or lymphatics) -> 1 in, 3 out
-
Urea example: If arterial BUN is 25 mg/dL, and plasma flow into the kidney is 6.9 dL/min, then urea input into the kidney is = 25 x 6.9 = 172.5 mg/min
1. If urinary output is 20 mg/min, then 152.5 mg/min urea output via vein and lymphatics - Water example: input to kidney about the same as plasma flow (690 mL/min); if urinary outflow 1 mL/min, then 689 mL/min output via vein and lymphatics
35
Q
What are the equations for the filtration and excretion rates in the nephron?
A
- Filtration: GFR x plasma concentration (Px)
- Excretion: UF x urine concentration (Ux)
- Overall:
Filtration + Secretion = Excretion + Reabsorption
36
Q
How is GFR used clinically?
A
- Clinical indicator of extent and progression of renal disease
- Loss of glomeruli due to sclerosis and destruction (would proportionally reduce the GFR)
37
Q
What exogenous substance can we use to measure kidney function (GFR)?
A
- Inulin (polymer of fructose): not metabolized, and excreted only by the kidney (not secreted or reabsorbed by tubules)
- P(in) = rate of infusion (mg/min) / rate of excretion (mL/min)
- Because rate of filtration = rate of excretion, GFR x P(in) = UF x U(in), so GFR = (UF x U(in))/P(in)) = clearance (urinary clearance = GFR for inulin)
- If part of kidney is damaged, plasma concentration of inulin will be significantly high (and output will be X% reduced)
38
Q
What is clearance?
A
- Volume of plasma completely cleared of the substance by the kidneys per unit time
- CL = (UF x Ux)/Px
1. Reabsorption: CL < GFR
2. Secretion: CL > GFR - NOTE: no substance is completely cleared of plasma in one cycle; useful concept to quantify excretory capacity of kidneys. Inulin clearance = GFR b/c no reabsorption or secretion. If it were secreted, clearance would be greater than GFR.
39
Q
What is the extraction ratio? How does this relate to RPF?
A
- Percentage of substance removed from the plasma
-
Ex. ratio X = (Ax - Vx)/Ax
1. Effect of reabsorption: low extraction ratio
2. Effect of secretion: high extraction ratio - If substance X is completely cleared form plasma, Cx = total renal plasma flow (RPF)
1. PAH has extraction ratio around 1, so the CL of PAH is about = effective renal plasma flow
40
Q
What do we use as an endogenous indicator of GFR?
A
-
Creatinine: by-product of skeletal muscle metabolism produced at about 2g/day (do not need to infuse pts)
1. Relatively constant plasma concentration
2. Freely filtered, not reabsorbed, and only slightly secreted; C(cr) = 140 > C(in) = 125 - Plasma creatinine is an index of GFR (clinically important)
- Potential errors: slight tubular secretion, overestimation in assay method (cancel e/o out)
41
Q
What happens if the GFR decreases by half?
A
- Once the GFR is reduced to 30 mL/min, the effect is much greater
- P(cr) = input/output
1. Input = 1800 mg/d
2. Output = creatinine clearance (= GFR)
3. GFR = 1.8 g/d divided by 1 mg/dL = 180 L/d
4. P(cr) = (1800)/180 =10; P(cr) = 1800/90 =20 mg/L
42
Q
How many nephrons are in the kidney?
A
- Nearly 1 million (functional unit of the kidney)
- 15% juxtamedullary
- 85% superficial
43
Q
What is the sequence of vasculature in the kidney?
A
- Renal artery -> segmental aa -> interlobar aa -> arcuate aa -> radial or interlobular aa -> afferent arteriole -> glomerular capillaries -> efferent arteriole -> peritubular capillary bed -> renal vein
- <0.5% of body mass, but receives >20% of total cardiac output
44
Q
How are the pressure profiles of the renal vasculature unique?
A
- Arteriovenous pressure drops in 2 steps, maintaining high hydrostatic pressure in glomerular capillary
- Vasa recta surrounds the Loop of Henle
- Arterioles are the two segments of the renal vasculature that are highly regulated (due to their ability to change pressures)
- Oncotic pressure begins to INC at the glomerular capillary (plasma leaves, so the protein is more concentrated). Maintained in efferent arteriole, then drops again upon entering the peritubular capillary
- Green box: this difference is very important to induce glomerular filtration. The space between the lines is the net filtration pressure
- Hydrostatic pressure: 95 -> 60 -> pretty much maintained in glomerular capillary -> 25, dropping again in the peritubular capillary and veins.
45
Q
What are the 3 processes in urine formation? Provide some examples.
A
- Processes: 1) glomerular filtration, 2) tubular reabsorption, 3) tubular secretion
- No endogenous substance that is not reabsorbed or secreted. Inulin is not reabsorbed or secreted, but is exogenous (this is why it is used to measure ECF)
- Freely filtered, partly reabsorbed, no secretion: urea
- Freely filtered, completely reabsorbed: glucose, AA
- Freely filtered, no reabsorption, secreted: creatinine
46
Q
What is the wisdom of filtering large amounts of body fluids and solutes and reabsorbing most of them back to the body?
A
- Allows kidney to rapidly remove waste products from the body that depend primarily on glomerular filtration for excretion
- Allows all body fluids to be filtered and processed several times each day
47
Q
What is the typical composition of glomerular filtrate?
A
- Similar to plasma, but without large proteins (<1% albumin and globulin; rarely hemoglobin)
- Low level of some molecules bound to proteins, i.e., Ca and fatty acids (free Ca can also be filtered)
- 4-5% more anions and 4-5% fewer cations due to Gibbs Donnan effect (under physiologic pH, most proteins negatively charged, but can’t penetrate the barrier, so this must be balanced by more movement of negatively charged ions across the barrier)
48
Q
What is normal GFR? What is the filtration fraction?
A
- 130 mL/min (180 L/d; decreases w/age, renal disease)
- GFR/RPF (normally = 130/670 = 19.4%)
1. Proportion of renal plasma filtered into Bowman space; if FF increased, GFR increased
49
Q
What barriers are there to glomerular filtration?
A
- Capillary endo: leakier than capillaries in other organs
- Basement membrane: meshwork of collagen and PG fibrils; clear barrier (unclear what barrier is provided by this -> may have some negative charges that repel negatively charged molecules)
- Epithelium (podocyte monolayer): extend foot processes, forming slit pores (much tighter barrier than the endothelium)
50
Q
What factors determine the filterability of solutes?
A
- Size selectivity (glomerular pores about 8 nm or 80 angstroms; albumin about 6 nm or 60 angstroms, so clearly (-) charge is a factor)
- Charge selectivity
51
Q
What does proteinuria mean?
A
-
Barrier failure:
1. Visible barrier breakdown (large pore): filters albumin and cells (nephritic syndrome)
2. Invisible barrier breakdown: loss of charge selectivity (filters albumin -> nephrotic syndrome) - Abnormal circulating protein (mid-size protein): breakdown of tissue, production of abnormal proteins (tumor cells)
52
Q
What are the determinants of the glomerular filtration rate?
A
- GFR = Kf x net filtration pressure
-
Kf = filtration coefficient = hydraulic conductivity x SA of the glomerular capillary (normally 0.08-1)
1. Hydraulic conductivity has to do with the integrity of the barrier (i.e., rough vs. smooth)
2. Diabetes mellitus: reduced Kf; INC thickness of BM and damaged capillaries -
Net filtration pressure: normally about +9 = favoring - opposing factors
1. Favoring filtration: glomerular hydrostatic pressure, Bowman’s space oncotic pressure
2. Opposing filtration: glomerular oncotic pressure, Bowman’s space hydrostatic pressure
53
Q
How is net filtration pressure regulated via glomerular hydrostatic pressure changes?
A
- Via changes in glomerular hydrostatic pressure (Pg)
1. Equal resistance (Rt) in afferent and efferent arterioles = constant Pg and GFR
2. Rt high in afferent or low in efferent -> DEC Pg and GFR
3. Rt low in afferent or high in efferent -> high Pg and INC GFR (may be normalized by increased glomerular oncotic pressure) - Clinical correlation: HTN, arterial stenosis
54
Q
What is the impact of arteriole Rt changes on GFR and RPF? Answer is a table.
A
- Note that efferent and afferent changes have the same effect on RPF, but vary in their effect on GFR
55
Q
How is net filtration pressure regulated via changes in Bowman’s hydrostatic pressure?
A
- P(bs) = resistance of nephron and rate of urine flow
- Obstruction in lower urinary tract, e.g., kidney stone, tumor, hypertrophic prostate in elderly men
- INC P(bs) = net filtration pressure = DEC GFR
- Frequent emptying of the bladder can DEC P(bs), INC net filtration pressure, and INC GFR
- Clinical correlation: lower urinary tract obstruction
56
Q
How do changes in capillary oncotic pressure affect net filtration pressure?
A
- Caused by a change in protein concentration in the glomerular capillary blood
- Reduced RPF (with GFR corrected by autoregulation)
- Low capillary flow -> INC FF -> INC capillary oncotic pressure -> DEC net filtration pressure -> DEC GFR
- When you restrict the renal plasma flow, you reduce the net filtration pressure
- Clinical correlation: diabetes, medications
57
Q
Why is auto-regulation of GFR important?
A
- Maintenance of constant GFR occurs in the face of changes in MAP, venous pressure, obstructions
- Independent of systemic influences: occurs in isolated kidney
- Normal: GFR 180, NFP 9, reabsorption 178.5, urine 1.5
- W/o auto-reg and 20% INC in arterial pressure: GFR INC by 50%, NFP up to 21, and urine up to 90 L/day, depleting blood volume
58
Q
What is the major mechanism of GFR auto-regulation?
A
- INC systemic BP -> INC renal afferent vascular resistance -> DEC RBF -> corrected GFR
- Intrinsic adjustment of vascular resistance that counter-balances any extrinsic factor that would change flow by other than direct influence on renal vascular resistance itself
- AFFERENT ARTERIOLAR RESISTANCE
59
Q
What are the two major theories for changing vascular tone in renal auto-regulation of GFR?
A
- Myogenic mechanism: direct stimulation of arteriolar smooth muscle (questionable)
-
Tubuloglomerular feedback mechanism: specialized cells in the macula densa and juxtaglomerular apparatus
1. Mesangial cells can also contract
2. Rapid changes in GFR sensed by changes in NaCl concentration in tubular fluid -> changes resistance in the afferent arteriole (at the level of the single nephron)
a. Higher NaCl at MD: INC afferent arteriole Rt = DEC GFR
b. Lower NaCl at MD: DEC afferent arteriole Rt = INC GFR
60
Q
What are the three systems of regulation of the changing vascular tone in the renal glomerulus?
A
- Baroreceptor mechanism: INC pressure in afferent arteriole inhibits renin release from JG cells (red arrows); decreased pressure promotes renin release (green arrows)
- SYM nerve mechanism: beta-1 adrenergic NN stimulate renin release (green arrows)
- Macula densa mechanism: INC NaCl in distal nephron inhibits renin release (red arrows); decreased load promotes renin release
61
Q
What is the molecular mechanism of GFR auto-regulation?
A
- INC GFR -> INC chloride in distal tubule -> NK2Cl transporter in MD cells -> release of ATP or arachidonate metabolites (Ca) -> smooth muscle contraction
- It is the GFR and TUBULAR CHLORIDE
62
Q
What is the RAS system?
A
- Renin-angiotensin system: systemic regulation mech not locally controlled in the nephron (NOT auto-reg)
- DEC GFR -> DEC chloride in distal tubule -> renin secretion from JG cells -> INC angiotensin 1 from alpha-2 globulin -> INC angiotensin 2 -> INC arteriolar resistance -> DEC GFR
63
Q
How is the SNS involved in the nuerohormonal regulation of GFR?
A
- Renal blood vessels, incl. afferent and efferent arterioles richly innervated by SYM NN fibers
- SYM activation -> constriction of afferent and efferent arterioles -> DEC RPF and Pg -> DEC GFR
- Stimulates renin secretion and INC Na reabsorption
- Not important under normal conditions (auto-reg dominates)
- Important under severe ECFV loss (over-rides auto-reg)
- Decreases Kf by stimulating mesangial cells
64
Q
What 3 molecules are critical in the nervous and hormonal regulation of GFR?
A
- Adrenaline: constriction of arterioles (preferentially afferent) -> DEC GFR
- Endothelin-1 (from damaged endo cells): constriction of arterioles (afferent and efferent) -> DEC GFR
- NO and prostaglandins: decreased vascular Rt -> INC GFR
- NOTE: usually constriction of the afferent is much more effective in changing the GFR
65
Q
What are the major clinically relevant concepts from the renal blood flow/glomerular filtration lecture?
A
- Renal vasculature distinct from o/capillary beds w/2 capilalry beds, 2 resistance segments of vessels, 2-step arterio-venous pressure drops, high filtration pressure and high blood flow
- Glomerular filtration is ultrafiltration of blood involving 3 barriers; proteinuria a direct result of barrier defect
- GFR is determined by Kf and net filtration pressure involving: hydraulic conductivity, glomerular surface area, capillary hydrostatic pressure, capillary oncotic pressure and Bowman’s space hydrostatic pressure
- GFR under physiologic condition controlled by auto-reg by myogenic and tubulo-glomerular mechanisms
- Systemic regulation of GFR via RAS, SYM stimulation and hormones like adrenaline, endothelin and PG’s
66
Q
How much reabsorption happens in the proximal tubule? How?
A
- 2/3rd of glomerular filtrate reabsorbed here -> scanning EM shows epi cells with microvilli to increase the SA for rapid reabsorption
- This reabsorption is iso-osmotic
- Primary role of the prox tubule is to reabsorb most of the filtered water and solutes -> this is essential in order to maintain the ECFV for CV function
67
Q
How much plasma is filtered through renal glomeruli each day?
A
- Entire plasma filtered through 60x each day; entire body fluid 5x daily
- Allows the kidney to excrete metabolic waste products (can be toxic) as fast as they are produced in the body
68
Q
How do we know that 2/3rds of the glomerular ultra-filtrate is reabsorbed in the prox tubule?
A
Mass flow balance in the prox tubule
GFR - reabsorb + secretion = rate of flow into LOH
GFR x P(in) = TF(in) x V(L)
Volume = (GFR x Pin)/tubular fluid inulin conc
Based on image on front: V(L) = (130x1)/3 = 43 mL/min
43/130 = 1/3, so 1/3rd passes through to LOH, and the other 2/3rds are reabsorbed
REMEMBER: this is iso-osmotic
69
Q
What are the major solutes that contribute to isotonic reabsorption in the prox tubule?
A
- Sodium
- Chloride
- Bicarbonate
- Clearly, the inulin concentration ratio will go up as you get further from the glomerulus
70
Q
Describe Na reabsorption in the prox tubule.
A
- Occurs through length of nephron by active transport and accounts for majority of kidney O2 consumption (about 65% reabsorbed in prox tubule)
- Luminal membrane Na+ channels: 1) Na-H exchanger, 2) Na-glucose co-transporter, 3) Na-AA co-transporter, 4) Na+-phosphate co-transporter
-
Na+K+-ATPase ion pump -> pumps: 3 Na+ out to interstitial fluid, 2 K+ into cell, spending 1 ATP
1. Exclusively in the basolateral membrane - Tight junctions (claudin 2): charge, size selectivity (K, Cl, Na). No gradient, so driving force unknown; has to be something else going on we haven’t discovered
- Driving force for Na+ reabsorption: 1) decrease in intracellular [Na+], 2) increase in membrane potential (via Na/K pump making inside of cell more negative)
- Solute mvmt potential energy in downhill mvmt of Na
- Most Na transported by trans-cellular pathway
71
Q
How are Cl and bicarbonate reabsorption linked to Na reabsorption?
A
- Na+ reabsorption accompanied by equivalent amts of anions to maintain electroneutrality
- Rapid Na+ absorption creates lumen (-) potential fluid of -5 mV: driving force for HCO3 and Cl- reabsorption
- Leaky epi of proximal tubule favors anion transport via paracellular space. Others: anion exchangers
- Cl- absorption low in early proximal tubule; HCO3 is absorbed more rapidly due to active transport system
1. More Cl transport in late part of proximal tubule (leaky for small molecules only)
72
Q
Describe the bicarbonate absorption specific for the proximal tubule.
A
- HCO3 reabsorption preferred over Cl -> coupled to active secretion of H+ in PT (similar in DT and CD)
- In PT, H+ secretion via apical membrane Na+-H+ exchanger
- HCO3- pumped out to ISF by a HCO3-/Na+ co-trans
- HCO3- reacts with H+ to form carbonic acid (carbonic anhydrase; CO2 diffuse in to the cell
- Active transport mechanism, not just neutralization
- About 95% of bicarbonate reabsorption in PT (calculation on slide)
73
Q
How does water reabsorption happen in the PT?
A
- Massive solute reabsorption -> slight decrease in osmolality of tubular luminal fluid and increase in interstitial fluid -> osmotic gradient drives water reabsorption facilitated by the leaky epi with high hydraulic conductivity (high Kf value)
- Follows the NaCl, HCO3 reabsorption; controlled by osmotic gradient and aquaporins
- Aquaporins: AQP-1 (luminal mem), AQP-4/5 (baso-lateral mem), AQP-2 (DT)
- Accounts for maintenance of iso-osmotic filtrate reabsorption
74
Q
How do the capillaries uptake fluid from the interstitial fluid?
A
-
Forces involved: starling forces across peritubular capillary endo drives rapid uptake of fluid from interstitial compartment
1. Positive interstitial fluid pressure (favors uptake)
2. Low hydrostatic pressure in peritubular capillary (reduces opposition)
3. High oncotic pressure in peritubular capillary (favors uptake) - “Peritubular factors”
75
Q
Reabsorption from PT is iso-osmotic, but it is also selective. What does that mean?
A
- Selective: all solutes NOT absorbed to same extent
- Dashed line: Na, K, H2O reabsorption (iso-osmotic)
- AA’s, glucose almost completely reabsorbed in PT
- Inulin conc INC b/c not reabsorbed (same with PAH, but higher ratio b/c also secreted)
- Cl: slight increase in conc due to HCO3 absorption
- Bicarbonate: high reabsorption
- If you blocked glucose transporters, glucose curve would look like inulin because inulin is an example of something that is not reabsorbed or secreted
76
Q
Describe glucose reabsorption. What does this graph show?
A
- Na-glu co-trans in apical mem (SGLT1 and SGLT2); coupled to Na+ electrochemical potential gradient
- Completely reabsorbed up to threshold (200-220 mg/dL); transport maximum (Tm = 370-390 mg/dL), but decreased in chronic renal failure
- SGLT2 very specific for kidney
- Threshold level really only seen in pts with diabetes
- 100% of glucose filtered through glomerular barrier
- GRAPH: Blue line = urine; red line = reabsorbed. You will see glucose in urine at any level above threshold (i.e., b4 the transport maximum). Transport maximum - all the nephrons are saturated (whereas maybe 20% or other arbitrary number are at threshold level)
77
Q
What causes glucosuria?
A
- Causes thirst and nocturia: due to osmotic diuresis
-
Causes: pregnancy (lactose, galactose secretion)
1. Diabetes mellitus
2. Familial renal glucosuria: mut in SGLT1 (int and kidney) and SGLT2 (kidney)
78
Q
Describe the reabsorption of AA’s.
A
- Coupled to Na+ electrochemical potential gradient
- Na-amino acid co-transporter in apical mem (neutral, acidic, and basic amino acid transporter)
- Almost completely reabsorbed - 0.5-2% excreted
79
Q
Describe the reabsorption of organic acids.
A
- Reabsorption of Krebs cycle intermediates is coupled to Na+ electrochemical potential gradient
- Low concentration, but may exceed reabsorption capacity in diabetic ketoacidosis
80
Q
Describe the reabsorption of proteins and peptides.
A
- Low filtration of large proteins, and greater filtration of peptides
- Transporters reabsorb peptides
- Protein excretion high in hemoglobinemia, multiple sclerosis, and myoglobinemia
81
Q
Describe phosphate reabsorption.
A
- Coupled to Na+ electrochemical potential gradient
- Low threshold, so partially excreted continuously in urine
- Threshold poised at plasma concentration: change in plasma concentration = change in urinary excretion
- Transport maximum (Tm): regulated by hormones (e.g. PTH, decrease Tm -> if you do parathyroidectomy, there is increased reabsorption)
82
Q
What 3 molecules are reabsorbed via passive transport?
A
-
Chloride: passively reabsorbed via 1) conc gradient made by H2O reabsorption, and 2) electrochemical potential gradient created by Na+ reabsorption
1. While 66% of fluid reabsorbed in PT, only 60% Cl- reabsorbed due to active transport of HCO3 - Potassium: passive transport along conc gradient through permeant epithelium (claudins; tight junctions)
-
Urea: metabolic by-product; no active transport
1. Passive transport, but slow; 50% reabsorbed
2. INC in UF = INC urea clearance
83
Q
What is Mannitol?
A
- Freely filtered substances not reabsorbed can INC osmolarity, cause diuresis (excessive water excretion)
- Clinical significance: reduction of intracranial, intra-ocular pressure, promote excretion of toxins, edema
-
Mannitol: osmotherapy, cerebral edema
1. Monosaccharide not produced or metabolized in the body (182 daltons)
2. Water soluble: easy to infuse
3. Freely filtered, poorly reabsorbed, no transport - HOW: 30 mmol/L continuous infusion (in clinic) -> plasma osmolarity INC to 320 mOsm/L -> filtered in glomerular filtrate: 3.9 mOsm/min (67.8 mMol/L) -> reduces water reabsorption and increases excretion
84
Q
What secretory processes happen in the PT?
A
- Organic acids and bases, creatinine, PAH, drugs
- Mostly active transport mechanisms
- Na co-transporters and other transporters
85
Q
What are the determinants of the ECFV?
A
- ECFV determines plasma volume, circulatory filling pressure, and cardiac output
-
Determined by:
1. Total body Na+ content -> ECFV = amount of ECF Na+/P(Na); at constant P(Na), ECFV = amount of ECF Na+ (P(Na) = plasma Na)
a. Sodium content and ECFV relationship is why aldosterone is so important
2. ECFV independent of P(Na): P(Na) kept constant via AVP-mediated water excretion in the kidney, so change in P(Na) only occurs when gain or loss of Na+ exceeds thirst mechanism and kidney’s ability to correct the situation
86
Q
What is the consequence of Na retention?
A
- 150 mEq/d -> retention of 1L of water to maintain isotonicity -> increase in body weight by 1 kg (2.2 lbs)
- Significance: change in body weight over a short period of time is an indicator of Na+ balance
- Renal failure (on dialysis): required to monitor BW on a daily basis to calculate how much dialysis may be required
87
Q
Describe the daily intake and output of sodium. What things might cause imbalances in this?
A
- Dietary intake: 8-15 g/d; 150-250 mEq or mmol/d
- Iatrogenic: 150 mmol/L of saline (caused by a clinician, i.e., via medications, etc.)
-
Imbalances: diarrhea, excessive sweating, diuretics
1. If you consume more salt, Na excretion will be higher; if you consume less, it will be lower
88
Q
Where is renal Na+ reabsorbed?
A
- Glomerulus GFR: 180 L/day x 139 mEq/L = 25,000 mEq/day (95-99.99% reabsorbed; 150-250 mEq/day excreted)
- Proximal tubule: Isotonic reabsorption (~64% reabsorbed; ~16,000 mEq/day)
- Loop of Henle: reabsorption, in ascending limb (~28% reabsorbed; ~7,000 mEq/day)
- Distal tubule and collecting ducts: ~7% reabsorbed; 1750-1850 mEq/day
89
Q
What are the signs of ECFV deficit?
A
-
Hypovolemia (diarrhea, vomiting, severe burn, excessive sweating)
1. Hypotension: systolic and diastolic (only when PV is significantly reduced)
2. Orthostatic hypotension
3. Increased pulse
4. Low body temperature
90
Q
What are the signs of ECFV expansion?
A
-
Hypervolemia (chronic renal failure, heart failure due to excessive salt and water retention)
1. Moderate to severe increase: edema, swelling of lower extremities (has to exceed 2L for there to be edema)
2. More severe increase: pulmonary edema (hearing auscultation of lungs, CXR)
3. Heart sounds (presence of S3 gallop, due to progressive increase in venous congestion)
4. Distension of large veins (neck): INC ECFV -> INC central venous pressure -> INC distention
91
Q
When do you get edema with normal or low ECFV?
A
- Hypoalbuminemia (liver disease, nephrotic syndrome)
-
Starling forces determine distribution for fluid b/t ISF and plasma
1. DEC plasma albumin -> DEC plasma colloid pressure -> flux of fluid into ISF -> edema (but reduced PV) - Burn patients: INC endothelial permeability -> flux of albumin and fluid into ISF -> edema
92
Q
What does this graph show?
A
- Change in plasma osmolarity quickly fixed by change in water content of urine (rapid response)
- Increased flow leads to excretion of more solutes in this case
- Water intake (1 L) → diuresis → H2O balance restored (1-2 hours)
1. Thirst and ADH or AVP mechanisms respond quickly
93
Q
What does this graph tell you about the body’s response to changes in Na+ intake?
A
- Isotonic saline intake (1L) -> diuresis/natriuresis -> balance restored (2-4 days)
1. Blue area is amt of salt retained in the body; retaining more fluid will increase body weight - Daily Na+ intake determines ECFV: INC salt intake = INC ECFV, DEC salt intake = DEC ECFV
- HTN pts are recommended to cut salt intake (high salt intake = high ECFV = high BP, and vice versa)
- Some pts respond to reduced Na intake, but others may retain more salt in the body b/c hypersensitive, or “naturally” INC reabsorption (DEC salt intake + give diuretic)
94
Q
What are the receptors of ECFV?
A
- Stretch receptors/baroreceptors localized in large veins, atria, arteries
- Neutral stretch receptors: lg veins, respond to mech stretch due to venous distention; signals to pituitary gland to regulate (INH) AVP/ADH -> regulates renal Na+ excretion (regulates NK2C channel in thick ascending limb of LOH)
- Atrial stretch receptors: atria, respond to distention; send central signal via PARA fibers in vagus N -> variety of centers assoc w/AVP secretion, SYM firing to kidneys and CV centers; also secrete ANP, regulating renal Na+ secretion
- Arterial baroreceptors: arteries, respond to increase in arterial BP or pulse pressure; signals to pituitary gland to control arginine vasopressin secretion (tells kidneys to retain H2O) and regulate Na+ secretion
95
Q
What are the 5 key things that regulate Na+ excretion by the kidney?
A
- Changes in GFR (INC = Na+ excretion; DEC = Na+ retention)
- Aldosterone: INC Na+ reabsorption in DT and CD
- Natriuretic hormone: DEC Na+ reabsorption
- Renin-angiotensin system: DEC ECFV -> INC Na+ reabsorption
- Others: SYM NN, prostaglandins, etc.
96
Q
How do changes in GFR regulate Na+ excretion?
A
- Changes in GFR = proportional changes in filtered load of Na+, and therefore, changes in Na+ excretion
- Small changes in GFR undetectable, but can result in marked change in Na+ excretion and proportional increase in loop of Henle load of Na+
- 10% ↑ GFR → 25,000 to 27,500 mEq/day -> 9,900 mEq/day (instead of 9000 mEq/day) delivered to LOH -> larger amounts passed on to DT and CD
- Pressure natriuresis: 50% ↑ in systolic BP → 3-5 fold ↑ in urine flow and urinary Na+ excretion (auto-reg is likely to reduce GFR change, but does not appear to prevent it completely (INC SBP = INC GFR)
97
Q
What is the role of arterial pressure in regulation of Na+ excretion?
A
- Pressure natriuresis
- Acute effect in isolated kidney: 2-3 fold INC in Na+ output by 30-50 mm Hg change in arterial pressure; independent of SYM and hormonal regulations
-
Chronic effect in intact system: very effective; pressure natriuresis is synergized with reduced formation of renin, angiotensin II and aldosterone
1. Even in isolation of all of the important regulatory factors, output will increase with increasing arterial pressure
98
Q
How is aldosterone involved in the regulation of Na+?
A
- Mineralocorticosteroid secreted by adrenal cortex
- Stimulus: release stimulated by plasma K+ and angiotensin; inhibited by plasma Na+
- Actions: 1) acts exclusively on DCT and CD, 2) INC Na+ reabsorption
-
Mechanism: cell permeable; binds to cytoplasmic and nuclear receptors; gene expression
1. INC # of open Na+ channels in apical membrane of DCT and CD; increase in Na+Cl- cotransporter -> increased Na+ reabsorption
2. INC syn of Na/K ATPase -> increase Na+ reabsorption and K+ secretion
3. INC syn of Krebs cycle enzymes -> increased ATP synthesis - Relatively slow effect on Na+ reabsorption by DT and CD, so not likely to play role in rapid regulation of Na+ excretion (bolus administration of isotonic saline and hemorrhage)
99
Q
How is natriuretic peptide (ANP) involved in Na+ regulation?
A
- Source: produced in cells in cardiac atria, synthesized and secreted to circulation
- Secretion: increased when P(Na) increased, but direct stimulant is atrial distention
- Target: several tubular segments, renal blood vessels
- Actions: 1) tubule - inhibits reabsorption, 2) renal vessel - INC GFR, INC Na+ excretion, 3) adrenal cortex - inhibits aldosterone secretion
100
Q
How is renin-angiotensin involved in Na+ regulation?
A
- DEC systemic BP or DEC tissue perfusion (DEC ECFV -> INC SYM firing; DEC renal arterial BP)
- JG cells secrete renin -> alpha-2 globulin -> angio-tensin 1 -> ACE to angiotensin II
- Adrenal cortex -> aldosterone
- Both Ang II and aldosterone stimulate Na+ reabsorption (via proximal Na:H exchanger and Na+ channels in DT and CD) -> expansion of ECFV (feeding back to JG cells)
- NOTE: b/c Na:H exchanger tied to bicarbonate reabsorption, Ang II = INC blood vol, pressure, & pH
101
Q
What additional factors affect renal Na+ reabsorption?
A
- SYM NN: occurs under relatively non-physiologic conditions -> DEC GFR, INC prox Na+ reabsorption
- Prostaglandins, bradykinin, dopamine: produced in kidney; diuresis and natriuresis
-
Ouabain-like factor: can inhibit Na/K ATPase -> goal to reduce TBW and Na
1. Produced in atrium; diuresis, natriuresis
102
Q
How does volume depletion affect Na+ reabsorption?
A
103
Q
How does volume expansion affect Na+ regulation?
A
104
Q
What does ouabain do to sodium excretion?
A
Increases it
105
Q
By what type of mechanism is bicarbonate absorbed in the proximal tubule?
A
Active transport
106
Q
Does AVP respond more strongly to volume changes or osmolality changes?
A
Volume
107
Q
Why is there concentration of luminal fluid in the thin descending limb of the LOH?
A
Impermeability to NaCl and high expression of aquaporins
108
Q
Why is furosemide most effective (more than thiazides and amiloride?
A
It inhibits NK2C channels in thick ascending limb of LOH
109
Q
What is an important driving force for K secretion in the DCT?
A
Lumen negative potential
110
Q
How are protons secreted in the DT?
A
Active transport mechanism using proton-activated ATPase
111
Q
What are the primary functions of the LOH and DT?
A
- LOH: counter-current multiplication, active transport of NaCl (25%)
- DT: regulated reabsorption of NaCl (5%)
112
Q
What are some of the important characteristics of urine content?
A
- Tubular fluid is converted into urine
1. Osmolarity: 0.2-4.0 fold of plasma
2. Na+: 0-2% of filtered load
3. K+, Ca2+, Mg2+: finely regulated
4. PO4 and H+: maintain pH of urine at 4.5-8.0 - Specialized and tightly regulated transport characteristics
113
Q
Describe the structure, interstitial envo, and of the thin descending loop of Henle.
A
-
Structure: starts as distal end of straight proximal tubule (length varies), runs from cortex to outer medulla, thin epi cells w/few mitochondria
1. Very few mito means not generating a lot of energy, so probably very little active transport - Interstitial environment: hyperosmotic to plasma, INC progressively b/t cortex and medulla, reaches max of 1200 mOsm (600 mOsm urea, 600 NaCl)
- Function: 1) concentrates tubular fluid, 2) no active transepi transport, 3) highly permeable to H2O (mvmt due to osmotic gradient only -> aquaporins), 4) min permeability to NaCl, urea, 5) driving force is osmotic gradient: osmolarity INC from 280 to 1200 mOsm
114
Q
What are the transport properties of the thin ascending limb?
A
- Structure is similar to thin descending limb
- Transport properties are dramatically different:
1. VERY water impermeable (no aquaporins), impermeable to urea -> only way to make things iso-osmolar is for NaCl to move
2. Permeable to NaCl -> strong NaCl reabsorb (20-25% of filtered load; >2/3rd received vol)
3. Driving force is osmotic gradient - Tubular fluid to ISF urea gradient: 50 mOsm to 600
- Due to NaCl diffusion and impermeability to tubular fluid osmolarity drops
115
Q
What are the structure, transport properties, and transporters in the thick ascending limb?
A
- Structure: b/t medulla and cortex, thick epi cells with many mitochondria (i.e., more active transport)
- Transport properties: 1) impermeable to water, 2) strong NaCl reabsorption (active transport)
-
Transporters:
1) Na+K+2Cl- transporter: binding site for Na+, K+, Cl -> down electrochem gradient (electro-neutral); not seen in any o/part of the nephron (target for diuretics: loop)
2) Na+K+-ATPase: Na+ out, K+ in w/use of ATP; creates electrochem gradient (more negative, less Na inside)
3) Other channels: basolateral Cl- channel (electrogenic), basolateral K+-Cl- cotransporter (electroneutral), apical K+ channel
116
Q
How are the NK2C channels regulated?
A
- Diuretic agents (furosemide, bumetanide) w/high affinity for Cl- site in NK2C -> block NaCl reabsorb -> INC NaCl load delivered to distal nephron -> interfere with urine concentration -> diuresis (INC H2O loss in urine)
- Can block about 25% of Na reabsorption; most efficient diuretics (b/c of extent of Na reabsorption -> higher here than in distal tubule)
- ADH/AVP stimulates NaCl reabsorption (in ascending LOH), opposing diuresis
117
Q
What are the structure and water permeability of the DCT and CD?
A
- DCT: runs from thick ascending limb, and 6-8 join together to form collecting duct (in cortex)
- CD: start in cortex and run down to medulla, where they join together to form duct of Bellini
- Distinct cell types in DCT and CD, but similar func
-
Variable permeability to water depending on conditions in the body (i.e., drinking lots of water, or not drinking enough water)
1. This is regulated via ADH (vasopressin), which determines the # of aquaporin 2’s available
118
Q
Describe the tubular fluid processing and water permeability of the DCT and CD.
A
-
Tubular fluid processing:
1. Receives ~10% of filtered load of water; <10% filtered load of NaCl and KCl; and 50% urea
2. Na+ actively reabsorbed, K+ secreted, but Na+ reabsorption > K+ secretion, so Cl- is reabsorbed - Net result: dilution of tubular fluid (if impermeable to water)
-
Water permeability
1. Water drinking: impermeable to water -> diuresis
2. Water deprivation: high permeability -> hyperosmotic urine (ADH)
119
Q
What are the two transport mechanisms for Na in the DCT and CD?
A
-
Electrically conductive Na+ channels (ENAC):
1. Na+ entry down electrochemical gradient
2. Gradient created by Na+-K+ ATPase
3. Present both in DCT and CD -
Na+-Cl- co-transporter:
1. Present only in DCT; different from NK2C
2. Electroneutral transport
120
Q
What are the Na+ diuretics?
A
- Amiloride, triamterene: block ENAC channels in the collecting duct
- Thiazide diuretics: inhibit Na+-Cl- cotransporters in the DCT
- Loop diuretics: 10-fold more efficient; block NK2Cl channels in the ascending LOH
121
Q
Why is there a lumen-negative transepi voltage in the DCT and CD important?
A
- Lumen more negative due to electrically conductive Na+ transport
- Membrane depolarized (similar to action potential)
- More in CD than in DCT
- Driving force for K+ excretion
122
Q
What are the driving forces and regulatory factors in K+ secretion in the DCT and CD?
A
- Specific K+ channel
-
Driving forces:
1. High intracellular K+
2. Lumen-negative voltage -
Regulatory factors:
1. Fluid flow: increased by diuretics = INC K+ secretion
a. If you increase fluid flow, you will have less time for reabsorption of any solutes
2. Delivery of Na+ to the distal tubule -> change in lumen-negative transepi voltage (i.e., less Na+ absorbed pre-DCT = INC K+ loss = loop diuretic)
123
Q
What are the effects of diuretics on K+ secretion?
A
- Loop diuretics: INC flow and Na+ output (> mem depolarization) into distal tubule, INC K+ secretion
- Thiazides: block electro-neutral Na+ transport w/o affecting mem depolarization (possibly slight INC due to INC flow to ENAC and > Na transport via these channels, facilitating K+ secretion)
- Amilorides: prevent mem depolarization -> likely decreases K+ secretion (may cause hyperkalemia)
- If you increase fluid flow, you INC K+ secretion, and have less time for reabsorption of any solutes
124
Q
Describe the regulation of ion transport by aldosterone.
A
- Mineralocorticosteroid secreted by adrenal cortex that acts exclusively on DCT and CD
- Actions: INC Na+ reabsorption and K+ secretion
- Mechanism: cell permeable; binds to cytoplasmic and nuclear receptors; gene expression
-
Changes in the cell (slow process):
1. INC open Na+ channel in apical mem of DCT and CD
2. INC transepithelial voltage
3. INC Na+Cl- cotransporter
4. INC synthesis of N/K ATPase, Kreb’s cycle enzymes, ATP synthesis
5. INC basolateral surface area
6. INC activity of apical membrane K+ channel
125
Q
What pathogenesis is associated with aldosterone?
A
-
Addision’s: complete absence of aldosterone
1. INC urinary excretion of NaCl: reaches max of 500 mEq/L (2% of filtered load), which means 6-8% reabsorbed -> Na+ reabsorb, K+ secretion do not entirely depend on aldosterone -
Conn’s: aldosterone-secreting tumor
1. INC Na+ reabsorption and K+ secretion
2. Excretes <0.2% filtered load of Na+
3. Hypokalemia, hypernatremia, HTN (due to INC fluid volume) - Liddle’s: pseudo-hyperaldosteronism
- 0.1-2% Na excretion –> aldosterone-dependent
126
Q
What are the factors regulating aldosterone secretion?
A
127
Q
What cell types secrete protons in the DCT and CD?By what kind of mechanism?
A
- Final acidification of urine in DCT and CD: H+ secreted and bicarbonate reabsorbed (important part of acid-base balance)
- Cell types: 1) principal cells (Na+ reabsorption and K+ secretion), 2) Intercalated cells (proton secretion; some secrete bicarbonate -> beta)
- Similar to H+ secretion in prox tubule -> active trans
1. Luminal pH 4.5 vs 7.4 in the cyto; 800x greater H+ conc in tubular fluid -> different from prox tubule b/c not dependent on Na gradient - Epithelium is impermeant to diffusion (different from proximal tubule); tight junctions do not allow mvmt
128
Q
What transporter is used for H+ in the collecting duct? Describe it.
A
- Proton activated ATPase: ATP hydrolysis drives transport of H+ from cell to lumen through apical channel -> present in both DCT and CD (different from NHE in proximal tubule)
- INC in intracellular HCO3- drives its diffusion to interstitial fluid via HCO3–Cl- exchanger (different from HCO3- in proximal tubule)
- Under high acidosis condition, cells express a new H+ transporter -> H+K+-ATPase or Proton pump (electroneutral transport)
- Very effective in regulating the acid-base balance
129
Q
When do you have bicarb secretion in the DCT and CD? How?
A
- Under alkalosis condition -> H+-ATPase and HCO3–Cl- exchange channels switch directionality (on opposite membranes)
- Activation of 2 types of intercalated cells (different ones activated based on alkalosis vs. acidosis):
1. α-cells: H+ channel in luminal membrane
2. β-cells: bicarbonate channel in luminal mem
130
Q
What is body-water balance?
A
- One of most important kidney functions: regulates body fluid osmolarity and therefore maintenance of constant body water content
- Kidney response is centrally regulated via the hypothalamus and pituitary -> AVP/ADH, thirst center
- There is uniform distribution of water between different compartments
131
Q
What is plasma osmolarity? How do you calculate it?
A
- Plasma osmolarity: indicator of body water
- 2 x Na + (glu/18) + (urea/2.8)
1. Normal: (2x137)+(100/18)+(15/2.8) = 285 mOsm
132
Q
How does increased osmolarity affect AVP release?
A
- Hypothalamus supraoptic and paraventricular nuclei osmoreceptors (cell shrinkage) sense increased osmolarity and axon from supraoptic nucleus signals nerve endings in posterior pituitary to release AVP via increased IC Ca causing fusion of AVP vesicles
1. AVP leaves, acts on collecting duct epi cells
2. INC water reabsorption - INC Na+ osmolarity (not urea) also triggers hypo-thalamus lateral preoptic osmoreceptors (thirst center) to change behavior, and encourage drinking more water
133
Q
What is AVP/ADH? What does it do?
A
- Under physiologic concentration, it INC water permeability in collecting ducts and vasoconstriction
- Nonapeptide: 9 AA’s, 1100 Daltons
- AVP to V1/V2 receptors -> adenylate cyclase + ATP -> cAMP -> PKA phosphorylates aquaporin 2 vesicles, stimulating them to insert into mem -> rapid process (can happen within 10 minutes)
- High turnover of AVP because you only wanted it when it is needed (degraded in prox tubule/liver)
- If no aquaporins, no water permeability
134
Q
What does this illustrate about AVP?
A
- High plasma osmolarity (on the left) = high AVP = concentrated urine and water reabsorption
- Low plasma osmolarity (right) = low AVP = dilute urine
135
Q
What does this graph show you?
A
- Measurements of plasma AVP via radioimmuno assay
- AVP and thirst only help in the window shown: 265-300 mOsm/kg (about)
- Normal: 0.5 pM
1. 270 mOsm: <0.05 pM
2. Above 280: up to 18 pM - AVP increases with increasing plasma osmolality
136
Q
What happens when you have hyperosmotic plasma?
A
- Activation of osmoreceptors in supraoptic nucleus of hypothalamus -> INC firing of NN fibers w/endings in posterior pituitary, releasing AVP -> INC water permeability of the distal nephron -> excretion of hyperosmotic urine
- Activation of osmoreceptors in hypothalamus in thirst center -> augmentation of behavioral thirst drive -> increased water ingestion
- Both of the above lead to a: decrease of plasma osmolarity toward normal
137
Q
What is the effect of volume on AVP levels?
A
- INC in ECFV (increase in venous filling in thorax) produces water diuresis
- Under severe conditions (diarrhea, vomiting), DEC in volume increases AVP secretion
- Plasma AVP level can reach as high as 50 pg/ml (25% ↓ in ECF)
- Higher threshold than for osmotic change (requires 10-15% decrease in ECFV)
- Can override normal response to plasma osmolarity, e.g., hyponatremia due to GI fluid losses
138
Q
What happens inside the patient experiencing hyponatremia due to GI loss? How do you treat this?
A
- Pt: severe diarrhea and vomiting, cannot eat solid food, but consumes a lot of fluid
- Steps: volume depleted, so strong volume signal for AVP release -> concentration of urine and dilution of plasma -> conserves water (INC ECFV) -> reduced osmolarity and hyponatremia
- Hyponatremia: lethargy, hyporeflexia, mental confusion (severe hyponatremia = 50% mortality)
- Tx: infusion of isotonic saline (avoiding quick change is essential)
139
Q
What are some hyponatremic conditions with no change in ECFV?
A
- Heart failure: loss of pressure stimulates secretion of hypovolemic hormones
- Liver failure: reduce PV and stimulate hypovolemic hormone secretion (hypoproteinemia in the blood bc liver can’t maintain same protein output -> water diffuses into interstitium)
- Differential diagnosis is necessary
140
Q
What are the causes, symptoms of decreased ability to concentrate urine?
A
- Causes: age, renal failure, infection, hypertrophy of prostate, etc.
- Symptom: nocturia (frequent urination at night)
141
Q
What is osmolar clearance?
A
- C(osm) = (UF x U(osm)) / P(osm)
- Normal C(osm) = 2 +/- 0.5 mL/min -> means the amount of the osmole present in 2mL of plasma is excreted out per minute
- Represents the rate at which solute is removed from plasma and excreted in urine
- Same equation as that for GFR with inulin (because not secreted or reabsorbed)
- Units always in mL/min
142
Q
What is free water clearance?
A
- Ability to concentrate urine depends on difference b/t osmolar clearance and clearance of H2O
- C(H2O) = UF x (1 - Uosm/Posm) = UF - Cosm
- If urine is iso-osmolar, free water clearance will be 0
1. If Uosm > Posm: negative CH2O → concentrate urine → ↓plasma osmolarity
2. If Uosm < Posm: positive CH2O → dilute urine → ↑plasma osmolarity
143
Q
Using the information provided, calculate the venous plasma osmolarity and free water clearance. What do these #’s mean?
A
- Flow: 690 - 12 = 678 mL/min
- Osmols: 186.3 - 0.6 = 185.7 mOsm/min
- Venous plasma osmolarity = 185.7/0.678 = 274 mOsm/kg
- C(H2O) = 12 mL/min x (1 - (50/270)) = 9.78 mL/min
- Free water clearance is (+), meaning urine is dilute b/c body is trying to increase osmolarity of hypo-osmolar plasma
144
Q
Using the information provided, calculate the venous plasma osmolarity and free water clearance. What do these #’s mean?
A
- Flow: 690 - 0.5 = 689.5 mL/min
- Osmols: 207 - 0.6 = 206.4 mOsm/min
- Venous plasma osmolarity = 206.4/0.6895 = 206.4 mOsm/kg
- C(H2O) = 0.5 mL/min x (1 - (1200/300)) = -1.5 mL/min
- Free water clearance is (-), meaning urine is concentrated b/c body trying to decrease osmolarity of hyper-osmolar plasma
- 1200 is highest mOsm/kg we can reach in urine
- Human kidney more efficient at clearing water than conservation
145
Q
How does water get from the thin descending limb to the vasa recta?
A
- Renal medullary interstitium osmolarity is high
- Osmosis of water into interstitium
- Water then carried to blood by vasa recta
146
Q
What does this show you?
A
Countercurrent multiplication mechanism
147
Q
Describe the permeability of the thin descending, thin ascending, thick ascending, distal tubule, and cortical and medullary collecting ducts (note: the answer is a table).
A
- NK2C channels in thick ascending limb
- ENAC and NaCl channels in distal tubule on
148
Q
What 5 features of the kidney are responsible for the development of medullary hyperosmolarity?
A
1. Special anatomical arrangement of LOH, vasa recta and peritubular capillaries -> loop like arrangement of LOH and vasa recta
2. Active transport of Na+, co-transport of K+, Cl- out of thick ascending limb into medullary ISF -> capable of creating 200 mOsm gradient b/t tubule and ISF
3. Active transport of Na+ out of collecting duct to ISF
4. Passive diffusion of urea from inner medullary CD into medullary ISF
5. Diffusion of only small amounts of water from medullary tubules into medullary interstitium
149
Q
What are the 6 steps involved in causing hyperosmotic medullary interstitium?
A
- Step 1: 300 mOsm even distribution
- Step 2: Active Na+ transport from thick ascending limb: 200 mOsm gradient
- Step 3: Water transport in descending limb
- Step 4: Add’l flow of fluid from prox tubule to LOH, pushing higher osmolar fluid to lumen of ascending limb
- Step 5: Active transport of Na+ -> new gradient
- Step 6: Water transport in descending limb
- Urea from medullary CD also contributes to all of this (40%). If you disrupt this, you can’t maintain gradient
150
Q
What is the role of urea in maintaining the hyperosmolarity of the medullary IS?
A
- Urea contributes 40% of osmolarity in medullary ISF
- Differential permeability to urea in different tubule segments is key player in its role in hyperosmolarity of medullary ISF
151
Q
How does medullary blood flow maintain the IS hyperosmolarity?
A
- Medullary capillaries do not wash out the hyperosmolar fluid in the medulla
- Two special features contribute to preservation of medullary interstitial hyperosmolarity
a. Medullary blood flow is low (only 1-2% of renal flow; 50 mL/min)
b. Vasa recta serves as countercurrent exchanges
152
Q
Why might the kidney not be able to concentrate or dilute urine?
A
-
Causes:
1. Defect in production or regulation of AVP secretion
2. Inability of collecting ducts to respond to AVP
3. Failure to form medullary osmolarity gradient
153
Q
What is diabetes insipidus?
A
- Entirely different from Diabetes mellitus; high rates of production of dilute urine
1. Central DI: pituitary gland fails to release AVP; rare congenital -> pts dehydrated very quickly
2. Nephrogenic DI: CD’s dont respond to AVP
a. V2 receptor mutation, aquaporin-2 mut, some drugs (lithium, tetracycline, etc)
154
Q
What is polydipsia?
A
- Psychiatric condition characterized by obsession of water drinking
- Complications: hyponatremia (water intoxication); coma and death
155
Q
How might a person lose medullary hyperosmolarity?
A
- Diuretics: furosemide, ethacrylic acid inhibits Na+ transport
- Excessive delivery of fluid into LOH
- Decreased urea production -> decreased filtered load of urea
- Age and renal failure -> reduced # of functional nephrons
156
Q
What tests can you use to distinguish b/t DI, polydipsia, and osmotic diuresis? Answer is a table.
A
WD = water deprivation test. Must stop WD if BW falls >5% or lasma osmolarity >300 mOsml/kg
- Primary polydipsia plasma osmolarity with ADH box incorrect -> should be high (NOT normal)
