Kidney Flashcards
1
Q
Body fluid compartments
A
- Humans are 50-60% water
- Ratio of fat/muscle determines body water as fraction of weight
- Muscle contains most water in body
- More fat/muscle in women compared to men, older compared to younger, chronic illness compared to healthy
- Females have less water content as they get older
2
Q
Where is the water found in
A
Extracellular
- Interstitial space
- Vascular compartments
Intracellular
- Cells
3
Q
Total body fluid
A
- 2/3 is intracellular fluid
- 28L
- 1/3 is extracellular fluid
- 80% interstitial
- 20% plasma
- 14 L
- 42L total
4
Q
Water channels (aquaporins)
A
- Family of integral membrane proteins
- Provide channels for rapid movement of water molecules across all plasma molecules
- Ten aquaporins are known in humans
- RBC contain 2x10^5 copies of AQP-1 per cell
- Plasma membrane of PCT cells contain five different aquaporin types
5
Q
Solutes, Ions, Osmolality
A
- Solutes: Particles dissolve in a water solution (sodium, potassium, glucose)
- Ions(electrolytes): charged solutes (cations are positive and anions are negatives)
- Osmolality: concentration of solutes in water which generates an osmotic force
6
Q
Osmolality
A
- Move from higher water to lower water / less solute to more solute
7
Q
Osmotic pressure
A
- Movement of water across a semi-permeable membrane in response to an osmotic gradient
- Osmotic gradient: difference in the osmolality in the compartments separated by the membrane
- Water moves from the compartment with low osmolality to the compartment with high osmolality
- Osmolality is the same in each fluid compartment
8
Q
Are solute concentrations same in all body fluid compartments
A
- More Na+ outside the cell in plasma and interstitium
- More K+ inside the cell in cellular compartment
- Osmolality is the same in ICF and ECF but dominant positively charged ions differ
9
Q
Na+ - K+ pump
A
- Cells have a high intracellular K+ concentration and a low Na+ concentration
- Na+ - K+ pump is responsible for maintenance of high K+ and low Na+ concentration in the cells
- Brought about by an integral plasma membrane protein: Na+ - K+ ATPase
- Na+ - K+ ATPase pumps 3 Na+ ions from inside cell to outside and brings 2 K+ ions from outside to inside with concomitant hydrolysis of intracellular ATP
- Drugs that inhibit Na+ - K+ pump are ouabain (steroid derivative) and digoxin (steroid glycoside used in treatment of cardiac failure)
- Uses about 30% of cell energy
- Has 2K+ binding site, ouabain binding site, ATP binding site, phosphorylation site, 3Na+ binding site, ATPase
10
Q
Rules
A
- Sodium (with anion) is restricted to the ECF and is main ECF osmole
- Water crosses cell membranes to equalize osmolality in ECF and ICF
11
Q
What happens to ICF and ECF volumes if we drink water
A
- Water absorbed from gut into the ECF, lowers ECF sodium concentration and osmolality
- Water moves from ECF to ICF
- Both ECF and ICF volumes increase
12
Q
Cell size when drinking water
A
- Isotonic -> Hypotonic
- Increase in cell size
13
Q
What happens to ECF and ICF volumes when we eat salt
A
- Increase in ECF sodium content and concentration (sodium stays in ECF)
- Leads to an increase in ECF osmolality
- Water moves from ICF to ECF
- Decrease in ICF volume and increase in ECF volume and cells shrink
- Isotonic -> Hypertonic
14
Q
What determines movement of water between interstitial and plasma compartments
A
- Leaky exchange epithelium allows movement through gaps between cells
15
Q
Plasma volume vs interstitial volume
A
- Water flux determined by starling forces
- Hydrostatic pressure gradient (heart)
- Blood pressure
- Move water from vascular -> interstitial
- Osmotic pressure gradient (protein albumin)
- Capillary permeability to water
16
Q
Albumin
A
- Main protein in plasma (40 g/L in plasma but low in interstitium
- Molecular weight of 68,000
- Capillaries have limited permeability to albumin
- Provides oncotic pressure in plasma > ISF
- Holds water in plasma
17
Q
Fluid movement across capillaries
A
- Fluid flux = permeability x (hydrostatic pressure gradient - oncotic pressure gradient)
- Hydrostatic pressure generated within capillaries by pumping action of heart
18
Q
Capillary Hydrostatic Pressure
A
- Fluid move from plasma to interstitium
19
Q
Capillary Oncotic Pressure
A
- Fluid move from interstitium to plasma
20
Q
Case of day: 45 yo woman runs first marathon, finish in 5 hours. Rehydrated with water. Complained of headache, felt nauseated, vomited then has seizure
A
- Excessive water intake, no solutes
- Water dilute sodium core, lower osmolality. Move from outside to inside cell
- Severe, acute, decrease in sodium (122 mmol/L vs normal concentration of 140 mmol/L)
- Water crosses cell membrane from ECF to ICF
- Brain cells swell, intracranial pressure rises to cause seizure, coma, death
- Women have lower BW and lower muscle mass
- Lower water content, increase in sodium decrease
- Treatment by intravenous infusion of concentrated saline solution to move water out of brain cells
21
Q
Kidney glomerulus
A
- Filters approximately 144 L a day
22
Q
Blood flow
A
- Kidneys located retroperitoneally at level of lower ribs
- Cardiac output: 5L/min
- Comes through aorta and into both kidneys through renal artery - Renal blood flow: 1L/min
- Renal plasma flow: 500mL/min
- Equivalent to one bottle of water
- Glomerular filtration
- 100-120 mL/min
- 150-170 L/day
23
Q
Glomerulus
A
- Filters water into bowman space
- Anatomy: Efferent arteriole, podocyte, proximal convulated tube, glomerular capillary, afferent arteriole, Renal nerve, juxtaglomerular cells, macula densa
24
Q
Ultrafiltration (Starling Forces)
A
- Glomerular Capillary Pressure (PCG): Difference in hydrostatic pressure in capillary space and bowman capsule. Exceed pressure in bowman capsule, fewer movement of water into bowman space
- Tubular Hydrostatic Pressure (PT)
- Oncotic Pressure: serve to keep water in capillary space. Difference in oncotic pressure generated by albumin vs. bowman space
- Ultrafiltration Coefficient (Kf): Area available for filtration to occur
- Plasma flow (QA): Maintain starling force by continuous flow
- PCG - PT: 38-40 mmHg
- Oncotic pressure: 20-25 mmHg
- High hydraulic conductivity (leaky capillary)
25
Glomerular filtration rate
- Two million glomeruli ultrafilter 150-180 L per day
- Approximately 100-125 mL/min
26
Determinants of ultrafiltration across glomerular capillary
- Ultrafiltration coefficient
- Oncotic pressure
- Plasma flow
27
Determinant of GFR
- Renal blood flow (plasma flow)
- Determined by arterial pressure (BP) and renal vascular resistance
28
Autoregulation of renal blood flow and glomerular filtration rate
- Renal blood flow is relatively constant over mean arterial pressures 70 to 150 mmHg
- Main factor: myogenic reflex in afferent arterioles
- If BP falls, afferent arteriole dilates
- If BP rises, afferent arteriole constricts
29
Renal Microcirculation: decrease BP
- Resistance changes in renal arterioles alter renal blood flow and GFR
- Decrease in BP
- Efferent arteriole
- Glomerulus
- Afferent arteriole
- Dilate
- Arterial resistance
- Renal blood flow
- Increase
- Bowman's capsule
- Maintain plasma flow
- GFR
30
Tubulo-glomerular feedback
- Adenosine release -> Vasoconstriction -> VSMC contraction in afferent arteriole -> Increased resistance in afferent arteriole -> Reduced plasma flow -> Reduced GFR
- Regulate GFR by sensing NaCl concentration -> too much causes constriction, too little causes dilation
31
Renal microcirculation: increase BP
- Vasoconstriction of afferent arteriole increases resistance and decreases renal blood flow, capillary blood pressure, and GFR
32
Renal microcirculation: increase resistance of efferent arteriole
- Increased resistance of efferent arteriole decreases renal blood flow but increases capillary blood pressure and GFR
- Angiotensin 2
33
Filtration of small solutes
- Convection is movement of small solutes with bulk flow of water
- Freely filtered: Sodium, potassium, chloride, glucose, bicarbonate, urea, creatine
34
Oncotic pressure low
- When oncotic pressure in bowman low -> restricted to capillary lumen -> albumin cannot freely move
- Called "perm-selectivity": Measures how well a membrane can differentiate between different ions
35
Glomerular Capillary Permselectivity
- Less restricted for positive ions
- More restricted for negative ions
- Size selective
36
Movement of macromolecules
- Determined by molecular weight: <15 kDa freely filtered: plasma = Bowman's space
- Also dependent on charge + > -
- 15 kDa to 60 kDa: progressive restriction to filtration
- Albumin (68 kDa): negligible filtration
- Healthy person excretes less than 10 mg/24h
37
Why measure glomerular filtration rate
- Most commonly used measure of kidney function
- Most kidney diseases affect the glomerulus
- Correlates well with clinical consequences of reduced kidney function
38
How to measure GFR
- Need solute that is freely filtered
- Neither reabsorbed nor secreted by the tubules
- Amount filtered in a unit of time = amount excreted in a unit of time
- Clearance of solute from circulation by kidney is then equal to GFR
39
In research lab: use inulin
- No reabsorption by tubule
- Clearance = GFR
- Inulin has to be given intravenously
- Generally administered in a physiology laboratory
40
In clinical medicine: use creatinine
- Creatinine production from muscle constant from day to day
- Creatinine freely filtered with limited secretion <10%
- Normal concentration: 70-110 micromole/L
- Collect urine for 24 hours, measure urine volume, measure plasma creatinine concentration, measure urine creatinine concentration to derive creatinine clearance
- Creatinine clearance: Urine flow rate (V/min) x Ucreat / Pcreat (GFR)
- Normal value: 90-120 mL/min
- GFR is inversely proportional to Pcreat
- If patient has baseline creatinine of 100 uM and GFR of 100 mL/min, what is GFR when serum creatinine is...
- If creatinine doubles, GFR is halved
- 200 uM : 50 mL/min
- 400 uM : 25 mL/min
41
How to assess perm selectivity
- Measure total protein (<0.15 g/24 h) or albumin (<30mg/24h) in urine
42
Glomerulus filtration
- Kidney glomerulus filters approximately 150-170 L a day
- About 1000 mg of albumin enters Bowman's space
- Kidney excretes 10mg albumin
43
Case of day: 55 yo woman has history of diabetes mellitus, serum creatinine is 160 uM, Found to have 500 mg of protein in 24 hour urine collection
- Abnormal glomerular function
- Diabetes injures glomerulus and impairs perm selectivity so increased amounts of protein and albumin cross glomerular capillary wall
- Ultrafiltration declines (indicated by rise in serum creatinine concentration)
44
Parts of nephron
- Responsible for filtering blood, reabsorbing substances, and waste excretion to form urine
- Bowman's capsule -> proximal tubule -> Descending limb -> Loop of henle -> Ascending limb -> Distal tubule -> Collecting duct -> to bladder
45
What does kidney do
- Filters a large volume of plasma water and solutes at glomerulus : GFR
- Filtered fluid enters tubules
- Tubules reabsorb solute and water, or secrete solutes so body composition and volumes remain normal
46
GFR, water, tubular function
- Normal GFR is >10 mL/min or >150 L/day
- Normal urine volume = 0.5-2L/d
- So >99% of filtered water must be reabsorbed by tubules everyday
47
Urine flow rate
- Cardiact output (5L/min) -> Renal blood flow (1L/min) -> Renal plasma flow (500 mL/min) -> Plasma volume entering afferent arteriole = 100% -> 20% of volume filters -> >19% of fluid reabsorbed -> >99% of plasma entering kidney returns to systemic circulation -> <1% of volume is excreted to external environment.
- Urine flow rate: 1mL/min
48
GFR, sodium, and tubular function
- Normal GFR is >10 mL/min or >150 L/day
- Filter >22,500mmol of sodium per day and excrete only 150 mmol per day
- >99% of filtered sodium must be reabsorbed by tubules every day
49
How do kidney epithelial cells reabsorb sodium
- Cells are polarized
- Different transport proteins present in luminal membrane (apical) and basolateral (blood) membrane
- Na+ - K+ ATPase localized to basolateral membrane
50
Sodium Hydrogen Exchanger (NHE)
- Transport sodium into cell in exchange for H+ ions
51
Sodium Co-transporter (SGLT, NaP)
- SGLT transport glucose and sodium into cell
- NaP transport sodium and phosphate into cell
52
Epithelial sodium channel (ENaC)
- Transports sodium across luminal membrane into cell down concentration gradient
- Plays key role in sodium reabsorbtion and potassium secretion
- Dependent on low Na+ concentration intracellularly
- Transport of sodium from lumen -> cell -> interstitial creates osmolality gradient (water follows gradient), reabsorb salt and water in parallel
53
Model of tubular reabsorption and secretion
- Low IC cell sodium concentration low driven by Na-K ATPase
- Luminal sodim enters cell down large electrochemical gradient (cell interior negative)
- Sodium entering cell exits basolateral membrane through Na-K ATPase
- Localization of transporters lead to directional transport of sodum -> lead to reclammation of sodium, water follows as well
- Reabsorption or secretion of other solutes linked to sodium through luminal membrane transport proteins
54
How do nephron segments differ
- Specific luminal transport proteins
- Leakiness of tubule to water and solutes
- Nature of tight junctions between cells
- Confer differences in solute and water permeability
- Presence of channels such as aquaporins
- Facilitate movement of water across segments
- Presence of hormone receptors: aldosterone, vasopressin, angiotensin 2
- Sodium reabsorption and water reabsorption
55
Proximial tubule
- Site of bulk reabsorption of sodium chloride, water, potassium, bicarbonate
- Most important luminal sodium transport protein is sodium-hydrogen exchanger (NHE3)
- Mechanism for bicarbonate reabsorption
- Site of glucose, phosphate, amino acid, cotransporters: only found on proximal tubule
- Make sure urine doesn't secrete these molecules
- Very leaky: isotonic reabsorption of sodium. Cannot generate large gradients
56
Ascending Limb of Loop of Henle
- Reabsorbs 20-30% of filtered sodium
- Lumenal transport protein: Na-K-2Cl (NKCC2) inhibited by diuretic furosemide
- Very impermeable to water
- Fluid leaving thick ascending limb is always less concentrated than plasma (hypotonic)
- Salt added to medullary interstitium without water concentrates medulla, necessary for urine concentration
57
Distal convoluted tubule
- Reabsorbs 5-10% of filtered sodium, water
- Lumenal sodium transporter is sodium-chloride cotransporter (NCC)
- Inhibited by diuretic group: thiazides
- Thiazides are less potent than furosemide because this segment reabsorbs less sodium than loop
- Important in urinary dilution
58
Collecting duct
- Reabsorbs 1-3% of filtered sodium. Luminal sodium transport protein is epithelial sodium channel (ENaC)
- Aldosterone receptors increases number and open probability of sodium channels to increase sodium reabsorption
- Vasopressin (ADH) receptors increases water reabsorption by increasing aquaporin 2
- Less permeable to chloride lumen. Negative PD facilitates potassium secretion
- Low capacity but capable of generating large concentration gradients. Tight
59
Filtration of glucose
- FIltration of glucose proportional to plasma concentration. Filtration does not saturate
60
Reabsorption of glucose
- Reabsorption of glucose is proportional to plasma concentration until transport maximum reached
- 100-200 mg is approximate normal range of blood glucose
61
Excretion = Filtration - Reabsorption
- Glucose excretion is zero until renal threshold is reached
- Renal threshold is 300 mg
- Transport maximum of glucose around 375 mg/min
62
Transport of glucose
- Na+ - glucose symporter brings glucose into cell against gradient using energy stored in Na+ concentration gradient
- GLUT transporter transfers glucose to ECF facilitated diffusion
- Na+-K+ ATPase pumps Na+ out of cell, keeping ICF Na+ concentration low
- Critical to avoid losing glucose in urine (600 calories/day)
- Urine is normally glucose free
- Two transporters: one proximal, low affinity, high capacity. one distal, high affinity, low capacity
63
Case of day: 15 yo has routine physical by family doctor including a urinalysis. Blood and protein are negative but glucose is moderately positive. Urgent blood glucose is normal
- Renal glycosuria
- Mutation in SGLT2 gene
- Loss of function: no ability to captire glucose in lumen. No sodium-glucose transporter
- Pharmacologic inhibitors of SGLT2 used in trials to treat hyperglycemia of diabetes. Lower blood glucose and reduce weight
64
Sodium
- Sodium is critical for life
- Required for normal blood volume, blood pressure, organ perfusion
- HUman kidneys designed to retain sodium to maintain blood volume
- We eat too much salt in modern times, leading to high blood pressure
65
Normal/recommended sodium intake
- Recommended max: 100 mmol/day and 2300 mg/day
- Recommended: 70 mmol/day and 1600 mg/day
66
How do you lose sodium
- Excessive sweating (Na+ = 35mmol/L)
- Diarrhea (Na+ = 100-120 mmol/L)
- Vomiting (Gastric fluid Na+ = 10 mM)
- Osmotic diuresis : hyperglycemia
- Diuretics: Blood loss and decreased intake
67
Sodium Reabsorption in main nephron segments
- Proximal tubule (70%)
- Loop of henle (20-30%)
- Distal tubule (5-10%)
- Collecting duct (1-3%)
- Filtered Na+ remaining decreases as you go further along the nephron
68
Overall excretion
- Filtered volume: 150L
- Na: 140 mmol/L
- Filtered Na: 21,000 mmoles
- <1% excreted -> 150 mmoles excreted
69
Long trek in desert
- Need to reabsorb more sodium (99.95%)
- Prevents decrease in vascular volume and blood pressure
- <0.5% -> 10 mmoles excreted
70
How do we sense volume in extracellular space
- Arterial baroreceptors in carotid body and aortic arch)
- Afferent arteriole (kidney)
- Atrial stretch receptors (heart)
71
Signals
- If low volume/pressure -> low firing -> increase sympathetic output
- If high volume/pressure -> too much nerve traffic -> provide negative influence (down regulation)
72
SNS activation and renin angiotensin system
- SNS activate RAAS system
- Angiotensinogen cleave to angiotensin 1 via renin, angiotensin 1 cleave to angiotensin 2 via ACE -> increase sodium reabsorption
73
Regulation of renin secretion
- Baroreceptors in arch of aorta (SNS), carotid body (SNS), and afferent arteriole activate RAAS
- Arterial blood pressure (afferent arteriolar stretch, macula densa) : low pressure = increase in renin
- Sympathetic nervous system (baroreceptors) increase SNS activity -> increase renin
- Dietary sodium/low sodium intake = increase renin
74
Angiotensin 2 affects sodium transporter activity
- Proximal Tubule:
- Site of bulk reabsorption of sodium, chloride, water, potassium. bicarbonate (60%)
- Most important lumenal sodium transport protein is sodium-hydrogen exchanger (NHE3)
- Angiotensin 2 increase activity of transport, more Na+ in
- Distal Convoluted Tubule:
- Reabsorbs 5-10% of filtered sodium, water
- Lumenal sodium transporter is sodium chloride co-transporter (NCC)
- Angiotensin 2 increase activity, more Na+ in
75
Angiotensin 2 has hemodynamic effects in renal microcirculation that enhance proximal tubule reabsorption
- Favor of water movement from lumen into peritubular capillary because low hydrostatic pressure caused by efferent vasoconstriction -> increase in oncotic pressure
- Angiotensin 2 increase filtration fraction and increase oncotic pressure in peritubular capillaries
76
Aldosterone effect
- Collecting duct:
- Reabsorbs 1-3% of filtered sodium
- Lumenal sodium transport protein is epithelial sodium channel (ENaC)
- Aldosterone receptors increase number of sodium channels to increase sodium reabsorption
- Aldosterone combines with cytoplasmic receptor -> hormone-receptor complex initiates transcription in nucleus -> translation and protein synthesis makes new protein channels and pumps -> aldosterone inducedd proteins modulate existing channels and pumps -> result is increased Na+ reabsorption and K+ secretion
77
Eating too much sodium or sitting in hot tub
- Push of water -> pushes against interstitial space + transient pressure -> changes starling forces -> drive water from interstitial space to vascular compartment -> increase volume + pressure
- Increase sodium excretion >1.5%, 300 mmoles
- Increase baroreceptor activation and decrease SNS activity to shut down renin angiotensin system
78
Cardiac atria as volume receptors
- Atrial myocytes secrete a hormone in response to atrial stretch
- Secrete atrial natriuretic peptide, kdieny to excrete sodium and water
- Increase vascular volume -> stretch of atrial myocytes -> increase ANP -> Sympathoinhibitory (decrease salt and water appetite), Vasodilation, Aldosterone inhibition (Natriuresis, Diuresis, Renin inhibition)
79
ANP induced action in medullary collecting duct cells
- Inhibits pumps (ENaC, NKA, TRPP
80
How accurately does kidney maintain ECF volume
- When sodium intake increases, sodium excretion does not increase immediately so ECF volume increases
- When sodium intake increases (150 -> 300 mmol/d), it takes several days for sodium excretion to increase to 300 mmol/d ECF volume increases
- After few days, sodium intake = excretion
81
Case of day: 16 yo started having fever, abdominal cramps, and profuse water diarrhea. BP is 90/50, heart rate is 130/min, lethargic, unable to drink, sunken eyes, poor skin turgor
- Severe depletion of sodium due to diarrhea
- Low ECF volume
- Requires immediate intravenous sodium and water replacement
- Isotonic saline (150 mmol/L), will likely need >10% of body weight
- Give soup to drink (contain high sodium + water)
82
Water Balance in Body
Water gain:
- 2.2L/day from food and drink
- 0.3 from metabolism
Water loss:
- 0.9L/day loss from skin/lungs
- 1.5L/day loss from urine
- 0.1L/day loss from feces
83
Water reabsorption in kidney
- Proximal: 70%
- Loop: 15%
- DCT/CD: 15%
- Filtered volume (150 L) <1% excreted -> 1.5L
84
What happens to water excretion in desert
- <0.3% excreted, <0.5L
85
When drinking a lot of water (3L)
- <2% excreted, increase flow rate -> 3.0 L
86
How do we sense ICF volume
- Anterior hypothalamus for water balance
- Pons/medulla control SNS output
- Suprasoptic nucleus(SON) and Paraventricular nucleus(PVN) signal changes in cell volume
87
Hypothalamic osmoreceptors
- Located in anterior hypothalamus OVLT
- Stretch inhibited cation channels
- Osmoreceptor cells shrink
- Channels open
- Cations enter and depolarize cell
- Generate action potential -> lead to increase vasopressin secretion and increase thirst
88
Vasopressin storage and release
- AVP made and packaged in cell body of neuron
- Vesicles transported down cell
- Vesciles containing AVP stored in posterior pituitary
- AVP released into blood
89
Effect of plasma osmolality on vasopressin secretion by posterior pituitary
- As plasma osmolality increase -> secrete more plasma vasopressin
90
Countercurrent multiplication
- Creation of osmotic gradient in loop of henle allowing reabsorption of water from tubular fluid and producing concentrated urine
- Ascending limb impermeable to water -> osmolality high in descending limb to drive water reabsorption -> increase in sodium conc in descending limb, decrease in sodium conc in ascending limb -> increase in conc gradient in descending limb -> as sodium removed and go up to ascending limb, go from osmolality of 300 in descending limb to 100 in ascending limb
91
Collecting duct permeability
- Water permeability of collecting duct dependent on arginine vasopressin
- More water collecting duct reabsorbs -> lower urine flow rate -> greater urine flow rate in absence of AVP
92
Water reabsorption
- Isoosmotic fluid leaving proximal tubule becomes progressively more concentrated in descending limb
- Removal of solute in thick ascending limb creates hyposmotic fluid
- Permeability to water and solutes in distal tubule and collecting duct regulated by hormones
- Final urine osmolarity depends on reabsorption in collecting duct
- Descending limb: only water reabsorbed
- Ascending limb: ions reabsorbed but no water
- Distal tubule: variable reabsorption of water and solutes
- Collecting duct: Variable reabsorption of water and solutes
- 50-1200 mOsM urine excreted
93
Vasopressin
- Vasopressin binds to membrane receptor
- Receptor activates cAMP second messenger system
- Cell inserts AQP2 water pores into apical membrane -> makes luminal membrane more permeable to water
- Water is absorbed by osmosis into the blood
94
Water conservation: vasopressin present
- high AVP, high cAMP
- membrane permeable to water to reduce urine flow -> reabsorb water
95
Water excretion: vasopressin absent
- Reduction in water permeability
96
Making a concentrated urine
- Hypertonic medullary intestitium
- NaCl added from thick ascending limb and urea from MCD
- Countercurrent arrangement of vessels in medulla prevents removal of solutes
- Vasopressin opens water channels in lumen of collecting duct cells
- Water moves from lumen to hypertonic interstitium
- Make concentrated urine with urine osmolality exceed 300 million osmoles
97
Chugging water
- Cells swell -> reduce action potential and AVP -> no water permeability
- Urine osmolality low, flow rate high
98
Excretion of dilute urine (Uosmolality < 300 mosmol/kg)
- Fluid leaving thick ascending limb always dilute
- No ADH: Collecting duct relatively impermeable to water
- NaCl reasbsorbed by DCT, CCD, MCD so urine become progressively more dilute
- Minimum urine osmolality = 50 mosmol/kg
99
Case of day: Healthy 48 yo slip while skating and hit head on ice -> lose consciousness. Over next two week, increase urine volume, increase thirst, passing 10-12L of urine daily, up every night to pee
- Serum sodium normal 140 mmol/L
- Urine volume 7L/d
- Urine osmolality 60 mosmol/L
- Water restricted for 4 hours, no change in urine flow or osmolality
- No secretion of AVP to reduce urine flow
- Given synthetic vasopressin -> rapid increase in urine osmolality and decrease in urine flow
- Central diabetes insipidus: vasopressin deficiency caused by trauma
- Abnormal posterior pituitary on MRI
- Intact thirst to maintain water balance, cannot sleep because no vasopressin
100
Overall Potassium Balance
- Typical diet is 50--100 mmol/d
- 100% absorbed from gut
- >90% excreted in urine
- Small amount in stool
101
Potassium Distribution
- 56 mmoles in ECF (<2%)
- 4200 mmoles in ICF (>98%)
102
Potassium and Resting Membrane Potential
- Leak of potassium out of cells through potassium channels keeps cell interior negatively charges
- Kecf/Kicf is major determinant of cell transmembrane potential gradient (Nernst equation)
- critical for muscle, nerve, cardiac function
103
Adrenergic and insulin mediated regulatory pathways for K+ uptake
- B2-catecholamine receptor activation by adrenaline promotes K uptake -> cAMP -> PKA -> increase activity of Na-K ATPase
- Insulin also promotes K uptake -> PI3-K -> PDPK1 -> aPKC -> increase activity of Na-K ATPase
- Acidosis reduces uptake of K
-
104
Extracellular Potassium Concentration and Cell Membrane Potential
- Hypokalemia: hyperpolarizes excitable tissues
- Hyperkalemia: depolarizes excitable tissues
105
Low ECF Potassium Levels and the RMP
- decrease Kecf
- decrease Kecf/Kicf
- RMP more negative
- Cell hyperpolarized
106
High ECF Potassium Levels and RMP
- increase Kecf
- increase Kecf/Kicf
- RMP more negative
- Cell hypo polarized
107
Clinical Consequences
- Hypokalemia
- Muscle contraction difficult
- Muscle weakness
- Promote cardiac arrhythmias
- Hyperkalemia
- Muscle stiffness and weakness
- Abnormal ECG
- Life threatening cardiac arrhythmias
108
When eating
- High potassium meal can contain 60 mmol of potassium
- Lead to double ECF potassium concentration -> cardiac arrest
- Eating glucose stimulate insulin secretion
- Insulin stimulate muscle cell uptake of potassium to prevent lethal hyperkalemia
109
When exercising
- Exercise causes muscles to release potassium
- Local increase in potassium concentration cause local arterioles to dilate and increase muscle blood glow
- Excess potassium in ECF redistributed into resting tissue by increase adrenaline
110
Thick Ascending Limb of Loop of Henle
- Fluid leaving thick ascending limb has almost no potassium
111
Collecting Duct
- Less permeable to chloride. Lumen negative PD facilitates potassium secretion
- Aldosterone receptors
- Cell responsible for K secretion in initial collecting duct and cortical collecting duct is principal cell
- Intercalated cell is another cell responsible for K secretion in the cortical collecting duct
112
Potassium regulation by aldosterone
- Hyperkalemia stimulates aldosterone secretion
- Hypokalemia inhibits aldosterone secretion
113
Aldosterone action on collecting duct
- Increases the number and open probability of sodium channels
- Increases sodium reabsorption
- Increases lumen negativity
- Increases K secretion
114
How is K balance achieved with changes in effective circulating volume
- Low ECF volume stimulates renin, angiotensin 2, and aldosterone
- Low volume state reduces GFR and reduces flow to CCD
- Increased aldosterone and reduced flow to CCD counteract each other -> normal K secretion
- Expanded ECF volume inhibits renin, angiotensin 2, and aldosterone secretion
- Expanded ECF increases GFR, inhibits proximal reabsorption, increases flow to CCD
- Low aldosterone and increased CCF flow counteract each other
115
Case of Day: 18 yo boy with progressive weakness over few weeks during gym class. Severe muscle weakness and serum potassium level was 1.2 mmol
- Give oral and intravenous potassium
- Have very high urine potassium
- Loss of function mutation in gene coding for sodium chloride transporter in distal convoluted tubule
- Loss of sodium in urine, high aldosterone
- Increased potassium loss in urine
116
H+ comes from diet and metabolism
- Fatty acids
- Proteins contain sulfur containing amino acids cysteine and methionine which are metabolized to sulphuric acid (H2SO4)
- On a usual high protein diet, this generates about 70 mmol of H+ a day
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How do we prevent acidosis
- Buffers: HCO3- in extracellular fluid, Proteins, hemoglobin, phosphates in cells, ammonia in urine
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Buffer systems
- Buffers limit change in H+ concentration when an acid is added to a solution
- Buffers in humans: Bicarbonate(HCO3-), Monohydrogen phosphate (HPO4), Ammonia(NH3)
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Bicarbonate buffer system
- H+ and HCO3- <-> H2CO3 <-> CO2 and H2O
- Increasing H+ decreases H2CO3
- From henderson-hasselbalch equation, decreasing HCO3 and increasing PCO2 decreases pH
- Increasing PCO2 increases H+ and HCO3
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Why is BBS efficient
- Both sides of equilibrium can be independently regulated
- CO2 can be increased or decreased by lungs
- Bicarbonate can be increased or decreased by kidney
- If fall in bicarbonate, lungs can lower CO2 and bring pH towards normal
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Role of kidney in acid-base balance
- Reabsorbs filtered bicarbonate to prevent loss in urine
- Makes new bicarbonate and add it to body fluids in response to decrease in blood pH
- New bicarbonate is generated by excretion of acid in urine in form of ammonium (NH4+) and dihydrogen phosphate (H2PO4)
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Bicarbonate reabsorption
- 3750 mmol/L reabsorbed
- Bicarbonate mainly reabsorbed in proximal tubule (>80%)
- No HCO3 excreted in urine
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How is bicarbonate reabsorbed
- NHE secretes H+
- H+ in filtrate combines with filtered HCO3 to form CO2
- CO2 diffuses into cell
- CO2 combines with water to form H+ and HCO3
- H+ secreted again
- HCO3 reabsorbed with Na+
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Ammonium/ammonia
- Ammonium is weak acid
- Ammonia (NH3) freely diffuses across cell membranes and blood vessels
- Ammonium (NH4+) does not readily cross cell membranes
- Ammonium concentration increases in a more acid environment
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Excretion of ammonia
- NH4 enter lumen of proximal tubule via NHE3
- Sodium entry drives secretion of ammonium
- Move into interstitial space using sodium-hydrogen protein
- Enter collecting duct via Rh proteins
- H+ secretion in CD traps ammonium in lumen of CD
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Ammoniagenesis
- Metabolism of glutamine makes NH4 and bicarbonate
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How does kidney secrete H+ ions
- Bicarbonate reabsorbed in proximal tubule
- New bicarbonate generated by ammoniagenesis
- H+ excreted by CD with ammonia
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Kidney and acid base
- For every H+ secreted, one bicarbonate is added back to blood
- One ammonium in urine equals one new bicarbonate
- Ammonia is much more important urinary buffer than HPO4
- Amount of phosphate limited and cannot be adjusted
- Kidney can increase availability of ammonia by 5-10x
- Variations in acid excretion by kidney depend mainly on changes in ammonium secretion
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Case of day: 45 yo man with end stage kidney disease undergoes dialysis. Fell into comatose and had pH 6.92 (7.40), PCO2 40 (40), and HCO3 8 (25)
- Severe acidosis
- Metabolic acidosis because bicarbonate low
- Failure to hyperventilate in response to metabolic acidosis makes the pH lower
- Cannot regenerate bicarbonate, and respiratory muscle fatigue so cannot lower PCO2
- Need hemodialysis to provide new bicarbonate
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Where does urea come from
- Amino group from protein amino acids removed and converted to urea
- We eat 60-120g of protein every day -> urea 200-800 mmol/day
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Urea generation from ammonia and protein
- Ammonia generated from amino acid breakdown is toxic -> converted to urea in the liver
- Urea is non-toxic and excreted in urine
- Ammonia enters urea cycle as carbamoyl phosphate and secreted as urea
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Ure clearance
- Freely filtered into glomerular bowman space
- If filtration is greater than excretion, there is net reabsorption
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Regulated Urea transport across collecting duct cell
- Vasopressin release cAMP and activate PKA and Epac to stimulate UT-A1 for urea transport -> UT-A3
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Urea excretion
- Readily filtered
- Minimal reasbsorption
- Urea excretion: 200-800 mmol/day
- Directly related to protein intake
- Each urea has 2 nitrogens
- Regulated by ADH
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Erythropoietin
- Excretion of erythropoietin -> stimulates stem cells in bone marrow -> increase RBCs -> Increase oxygen carrying capacity (negative feedback on EPO)
- Hypoxia and low hemoglobin (low oxygen tension at proximal tubule) stimulate Epo secretion
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Erythropoietin summary
- Glycoprotein synthesized by pericytes at border of medulla and cortex where O2 levels are low
- Cells respond to decreasing oxygen availability
- Increase secretion of EPO with anemia or hypoxia
- EPO increases red blood cell production in bone marrow
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Vitamin D metabolism
- 7-dehydrocholesterol -> UV sunlight -> vitamin D3(cholecalciferol) -> Liver (25-hydroxylase) -> Kidney (1a-hydroxylase) -> 1,25 -dihydroxyvitamin D3 (active form of vitamin D)
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Vitamin D
- Increases calcium and phosphorus absorption
- Mobilizes calcium stores
- Maintain serum calcium and phosphorus
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Case of Day: 65 yo man diabetic for 25 years complaining of fatigue and weakness. Swelling of feet and ankles. Poor memory, etc.
Edema and high BP (180/110), pale, involuntary muscle movement, breath smells like urine
- Uremia is syndrome consisting of symptoms due to severe kidney failure. GFR typically <15 mL/min. Most common cause is diabetes.
- Anemia and reduced erythropoietin by damaged kidney reduces oxygen carrying capacity of blood. Uremia (acidosis) reduces muscle mass -> cause fatigue and weakness
- Hypertension and edema caused by impaired sodium excretion by damaged kidney, expanded ECF
- Urea and creatinine levels high due to decreased excretion of urine due to low GFR
- Hyperkalemia: serum potassium high, contributes to muscle dysfunction, risk of heart rhythm problem, due to impaired potassium excretion
- Bicarbonate low due to impaired ammonium excretion by damaged kidney
- Blood calcium high due to failure of kidney to synthesize vitamin D, hypocalcemia -> stimulate PTH secretion -> decalcification of bones
