Renal_1 Flashcards
What is the definition of homeostasis?
What does its maintenance require?
Tendency to maintain relative constancy of physiological variables
Stimulus → Receptor → (afferent pathway) → Integrative Center → (efferent pathway) → effector → response → negative loop onto stimulus
What are the characteristics of homeostasis?
- Steady-state
- Set-point (threshold at which things get activated)
- Negative feedback (sensitive to osmolarity → release hormones)
- Positive freedback (mostly in metabolic pathways)
- Error signal (when deviation from the set point)
- Physiological range
What are the advantages and disadvantages of being multicellular?
Advantage → Division of labour between different cell types can provide selective advantage → increased complexity, better adaptation to the environment
Disadvatange → requires body fluids that have a stable composition and osmolality
- Cells have to be surrounded by an environment that is homeostatically controlled
What are the 3 main functions of the kidney?
- Endocrine function
- Homeostatic function → maintain the ionic and osmotic balance
- Excretory function
What are 2 ways to maintain homeostasis?
- Lowering gradients → less work needed to maintain hemeostasis
- Lowering permeability → minimize dissipation of gradients
What are the main advatages and disadvantages of terrestrial life?
Adv → the concentration in the aire is much higher → 20.9% vs < 1% → allow higher metabolic rate and thermal regulation
Disadv → water loss (dessication)
In mammals, how did kidney evolve to allow homeostasis in very different envrionments?
- Waxy monkey frog → wax on the surface of the frog to reduce loss of water
- Water-holding frog → Enormous urinary bladder used as storage for water
LOOP of henle only in birds and mammals:
3. Kangaroo rat → Loops of Henle in the kidneys are very long to concentrate the urine (to conserve water)
*Beaver live in fresh water → no need so short loops of henle
What variables of homeostasis are regulated by the kidney?
- ECF volume
- ECF osmolality
- Acid-base status
- ECF K+ concentration
- Divalent ion concentration → bone and immune function
- Blood pressure → maintain perfusion to vital organs
- RBC mass
- Skeletal integrity → VitD and Calcium regulation
What is the order of the different parts of the nephron?
- Bowman’s capsule/space
- Proximal convoluted tubule (C)
- Proximal straight tubule (M)
- Descending thin limb of Henle’s loop (M)
- Ascending thin limb of Henle’s loop (M)
- Thick ascending limb of Henle’s loop (M/C ends at the macula densa in cortex)
- Distal convoluted tubule (C)
- Cortical collecing duct (C)
- Medullary collecting duct (M)
*Actually 4 parts: Proximal tubule → Loop of Henle → Distal convoluted tubule → Collecting duct
How do animals deal with aquatic and terrestrial environments?
Many strategies used to maintain ionic and osmotic gradients:
- reducing permeability of epithelial surfaces
- Specialized excretory organs and secretory glands
- Behavioural and other adaptations
*Kidney is the primary regulatory and excretory organ
What compounds are excreted by the kidney as an organ of excretion?
Nitrogenous wastes → DNA and RNA wastes, protein breakdown, uric acids
Dietary end products → antibiotics
Drugs and drug metabolites
Products of metabolism
What compounds/hormones are produced by the kidney?
- Erythropoietin
- 1,25-OH Vitamin D → Calcium regulation and auto-immunity
- Renin → important for generating hormones
What are the cellular components of the Glomerulus?
- Epithelial cells:
- Synthesis of matrix components
- Maintenance of capillary wall permeability by cleaning the filtration barrier
- Found in the inner surface of the bowman’s capsule → podocytes (have foot processes that rap around capillaries to allow filtration sites) - Endothelial cells:
- Synthesis of matrix components (coming from both sides)
- Found in the glomerular capillaries → regulate filtration of plasma - Mesangial cells :
- Contain contractile elements and receptors for angiotensin II (and other factors) that regulate renal hemodynamics
- Contribute to the synthesis of matrix components
- Have capacity for phagocytosis
- Fill the spaces between glomerular capillary loops
What is the composition of the basement membrane of the glomerular barrier?
- Type IV collagen → form a mesh work on which epithelial cells sit, trimeric protein (3 domains) with alpha-helical structures (different from collagen I, II, III)
- Laminin →important for cell attachement, interacts with collagen + cell, concentrated in lamina rara externa and rara interna
- Fibronectin → important for cell attachement
- Heparan sulphate proteoglycan → have negatively charged side chains (sulfate chains) → repel negatively charged proteins from being filtered, important role in filtration selectivity
Concentrated in lamina rara externa and interna (but everywhere in GBM), core protein + glycosaminoglycan
*Also has O- and N-linked carbohydrates
*All synthesized by epithelial, endothelial and mesangial cells
What are the 3 layers of the filtration barrier in the glomerulus?
Plasma
1. Endothelial cells
2. Glomerular basement membrane
3. Epithelial cells (+ podocytes)
Bowman’s capsule
Which elements are likely to be filtrated through the glomerular barrier and which are not likely?
Likely: Na+, K+, Cl-, H2O, Urea, Glucose, Sucrose, Inulin
Not likely: Lactoglobulin, Egg albumin, Hemoglobin (Proteins)
What are the 2 main forces driving filtration?
- Hydrostatic pressure → 45 mmHg (towards the Bowman’s capsule)
*Does not change much between the afferent and efferent arterioles - Colloid osmotic pressure → 30 mm Hg (towards the capillaries)
*Increases to reach the hydrostatic pressure → no net filtration pressure by the end of the glomerular capillaries (even in the 2nd half, not much filtration)
Net filtration force at the start = 15 mm Hg towards the Bowman’s space
What is the equation for the Glomerular filtration rate?
GFR = Kf * Puf = Kf (Pgc - Pt - πgc)
Puf = net ultrafiltration pressure = Pgc - Pt - πgc
Kf = filtering ability of the membrane (ultrafiltration coefficient → include hydraulic permeability, surface area)
Pgc = hydrostatic pressure in the glomerular capillaries
Pt = hydraulic pressure in Bowman’s space
πgc = oncotic pressure in the GC
*no significant Bowman oncotic pressure
What are the advantages and disadvantages of clearance?
Advantages:
- Simple
- Gives overall assessment of renal handling of the solute
- Vitrually the only in vivo method available for use on patients
Disadvantages:
- provides no info on location of transport process / mechanism
- Only provides net transport (no info about reabsorption vs filtration vs excretion or about counter-acting forces)
- Flux could be active or passive (no info)
What is the definition and equation for clearance?
Clearance is the minimum volume of plasma from which the kidney could, in 1 minute, remove all substance X.
Clearance in ml/min = [X]u * V / [x]p
[X]u = concentration of substance X in urine (mg/ml)
V = urine flow rate (ml/min)
[x]p = concentration of X in plasma (mg/ml)
*Indirect, but most practical approach to measure GFR, RPF (renal plasma flow), tubular transport functions
What are the general movements/transports of inulin, glucose, PAH, Potassium along the kidney?
Inulin → Only filtered → measure of GFR (can be compared with other substances to see if reabsorption or secretion occurs)
Glucose → Filtered and reabsorbed
PAH → Filtered and secreted (flow-limited)
Potassium → Filtered, reabsorped and secreted
What percentage of the plasma volume is filtrated at the glomerulus?
What volume do the glomeruli filter appromimately/day?
As blood flows through the glomerular capillary, 20% of plasma volume is filtered due to the pressures
Glomeruli filters approx. 180 liters/day → small fraction of the filtrate is actually excreted in urine (0.6-2.5 L)
What is the filtration fraction (FF)?
FF = GFR/RPF ~ 15%-20%
It is the proprtion between glomerular filtration rate and renal plasma flow rate → not fixed, but may vary depending on the magnitude of GFR, the composition of the blood, condition of the glomerular capillary
Up to what size, do molecules pass freely through the glomerular filtration?
Up to 10,000 Da
Between 10,000 → 60,000 increasing restriction
*Electrical charge of macromolecules also influences restriction
- Negatively charged molecules are repelled by HSP
- Positively charged molecules (such as dextrans) are allowed to pass faster than neutral molecules of the same size
→ No restriction by the endothelial cells
→ Charge restriction by Heparan sulfate proteoglycan + size restriction at the GBM
→ Additional restriction by the epithelial cells at the filtration slit diaphragms
What variables can affect GFR?
- BP
- Kf
- GBF
- Mesangial contraction
- Macula densa flow rate
*All related
What is the tubulo-glomerular feedback?
An intrarenal mechanism that sense correlates of flow through the distal tubule → acts to reduce the filtration rate of the same nephron
System by which the macula densa communicates with the afferent arterioles after sensing changes in the NaCl concentrations
For a substance that is reabsorbed, how can we calculate the amount of substance that was filtrated freely?
GFRPs = UsV + Ts
Ps = plasma concentration of the substance
Us = concentration of substance S in the urine
V = urine flow rate
Ts - amount of substance S reabsrbed by tubules/time
For a substance that is reabsorbed, what equation allows us to calculate the amount of a substance that was reabsorbed by the tubule/unit time?
Ts = (GFRPs) - UsV
Ps = plasma concentration of the substance
Us = concentration of substance S in the urine
V = urine flow rate
Ts = amount of substance S reabsorbed by tubules/time
*minimal amount because absorption and secretion could occur sequentially in different segments
For a substance that is secreted, what equation allows us to calculate the amount of a substance that was secreted from the peritubular compartment/unit time?
Ts = UsV - (GFRPs)
Ps = plasma concentration of the substance
Us = concentration of substance S in the urine
V = urine flow rate
Ts = amount of substance S secreted by tubules/time
For a substance that is secreted, how can we calculate the minimal amount of substance that appears in the final urine?
UsV = (GFRPs) + Ts
Ps = plasma concentration of the substance
Us = concentration of substance S in the urine
V = urine flow rate
Ts = amount of substance S secreted by tubules/time
What is creatinine useful for?
Creatinine is a product of muscle metabolism that is constantly produced and excreted → indicator of renal failure because its steady-state concentration in the plasma varies directly with GFR
*Can replace inulin (clearance ~ GFR because not absorbed nor secreted)
*At steady-state production ~ excretion → if GFR drops, cocnentration increases in the plasma (indication of renal failure, can monitor someone over time)
What do the titration curves for Glucose indicate?
Glucose in only filtrated and reabsorbed:
At low glucose concentration → low filtration, all reabsorbed
When reabsorption plateaus → at TmG (transport maximum for Glucose) → Glucose starts being excreted
From that point on, linear increase in excretion with increase in glucose plasma concentration
*Filtered glucose concentration = linear increase all the way
What do the titration curves of PAH look like?
PAH is filtered and secreted (not reabsorbed)
Filtered load increases linearly
Amount secreted increases a lot at first (until 0.25 mg/ml) then plateaus (depends on what the transporters can do, at low concentration, not saturated, when plateaus, its because they are saturated)
Amount excreted = secreted + filtered
What is the difference between excretion and secretion?
Secretion happens in the kidneys
Excretion is final delivery in the urine
How can we calculate GFR from inulin clearance?
*For inulin, excretion = GFR → Clearance of inulin = GFR
Qf = Pin * GFR
Qf = filtered load
Qe = Uin*V
Qe = amount excreted
QF = QE → Pin * GFR = Uin * V
→ GFR = Uin*V/Pin = ml/min (U and P are mg/ml and neutralize)
What is the formula for clearance?
C = U*V/P = ml/min
Cin = GFR
What happens to creatinine if GFR is acutely lowered by 50% → goes from 120ml/min to 60 ml/min?
- QE (creatinine filtered & excreted) → drops by 1/2 → slowly increase back to its initial value (~mg/hr)
- Constant rate of production, but rate of filtration drops by half → plasma concentration increase *2 (cumulative creatinine balance goes from 0mg → 400mg)
Metabolism continues to produce the same amount of creatinine, but 1/2 of the filtrate stays so plasma concentration will increase
What is PAH used for?
PAH → filtered + avidly secreted by transporters in the proximal tubule → Clearance is flow limited (marker for effective RPF)
20% is filtered (rest of the plasma volume is sent direclty to the efferent arteriole → secretion) + rest is secreted → ~90% excreted
effective RPF = C pah = Vu* ([PAH]u/[PAH]p)
*C = clearance
[PAH]p = arterial-venous PAH concentration difference
A bit of PAH gets into the venous system and is not excreted (~5%) → its clearance is actually about 10% less than the true RPF
What is the difference between RBF and RPF?
Which equation relates them?
RBF = renal blood flow
RPF = renal plasma flow → corrects for the presence of red blood cells
RBF»_space; RPF
RBF = RPF/(1-Hct)
What equation relates Urinary PAH content and renal plasma flow?
Upah * V = Ppah * Cpah
Clearance of PAH ~= RPF
Upah * V = Ppah * RPF
How much blood does the kidney get from the circulation?
20-25% of the total CO passes through the kidney
Only 0.05% of total body weight → uses 7% of total O2 for reabsorption mostly
SLIDE 12, L3
How do the hydrostatic pressure and colloid osmotic pressure change in the different blood vessels of the kidneys? (Karl Ludwig’s model)
Renal artery → afferent arteriole → glomerular capillary → efferent arteriole → peritubular capillary → intrarenal vein → renal vein
Hydrostatic pressure:
- Major drop (100 mm Hg → 40 mm Hg) in the afferent arteriole
- Constant inthe glomerular capillaries
- Drop (40 → 20 mm Hg) in efferent arteriole
- Slowly keeps going down until ~ 10 mm Hg in the renal vein
*Pressure drops in high resistance vessels
Colloid osmotic pressure:
- ~30 mm Hg until glomerular capillary
- Increase by ~10 mm Hg in the G.C.
- Decrease a bit in peritubular capillaries (water reabsorbed)
- Constant for the rest
*Changes in capillaries, when there is exchange
What is the effect of constriction of afferent arterioles on RPF and GFR?
- Decrease in RPF
- Decrease in GFR
What is the effect of constriction of the efferent arterioles on RPF and GFR?
- Increase GFR
- Decrease RPF
What is the effect of dilating the efferent arterioles of GFR and RPF?
- Decrease GFR
- Increase RPF
What is the effect of dilating the afferent arterioles on GFR and RPF?
- Increase GFR
- Increase RPF
Which 3 mechanisms are responsible for regulation of GFR?
What is the autoregulation range?
→ Over a range of arterial blood pressure from 80-180 mm Hg, total resistances of the renal circulation varies in direct proportion to arterial pressure → RBF and GFR are cst (Autoregulation)
→Under 80 mm Hg or over 180 mm Hg, autoregulatory mechanisms are not able of varying resistances/flow changes in proprtion to pressure
*Afferent arteriole has intrinsic ability to sense pressure changes → keep proportional pressure
- Intrinsic myogenic response → increase in tension leads to vasoconstriction to increase resistance
- Local rening angiotensin system (not specific, overall control by angiotensin II)
- Tubuloglomerular feedback (TGF) → involves the macula densa which monitors flow in the tubule (DConv.T)
GFR and RBF increase between 0-80 mm Hg arterial pressue and plateau after that → plateau part = autoregulation rangle (80 - 200 mm Hg)
What are normal values for RBF and GFR?
GFR ~ 120 ml/min
RBF ~ 1200 ml/min
What are some humoral regulator of renal hemodynamics?
Vasodilators:
- Prostaglandins
- NO
- Dopamine
- ANP (through cGMP)
Constrictors:
- Endothelin
- Angiotensin II
- Catocholamines
- ADH (anti-diuretic hormones) → keep H2O
What are the steps of renal blood circulation?
- Enters the kidney in the renal artery through the hilus
- Interlobar arteries (in medullas) → pass outward to the junction of cortex and medulla
- Turn to follow the junction → Arcuate arteries
- Branch to form interlobular arteries (ascend in the cortex)
- Divide into afferent arterioles → carry blood to the glomeruli
- They reassemble to for efferent arteriole → re-divied to form capillaries around the proximal tubule of superficial nephrons
6.5 Efferent blood flow from the glomeruli of juxtamedullary nephrons flows through vasa recta → descend into the mdeulla and follows the loops of Henle
What is the role fo cathcolamines in the proximal tubule?
binds to specific a-adregenic receptors stimulate Na reabsorption
How is blood flow distributed in the kidney between the cortex and the medulla?
100% flows through the cortex (peritubular capillaries)
8% goes down to the medulla → 1% reaches the papillae (inner medullar)
*Renal blood flow DECREASES along the corticomedullary axis
Where in the kidneys is renal circulation better maintained?
A stimulus that decreases renal blood flow leads to a proportionately greater fall in renal blood flow of the cortex than the medulla → Renal circulation is better maintained in the medulla than in the cortex, but less volume of blood goes through the medulla than the cortex
When total flow is decreased (hemorrhagic shock), where is the flow decreased the most?
Decreased in all zones, but mostly the outer zones
When total flow increased (volume expansion or acetylcholine) → increase in all zone, but more increase in the inner zones
Does glomerular capillary pressure always follow arterial blood pressure?
No, glomerular capillary pressure can be changes independently of arterial BP
What is the impact of an increase in sympathetic activity on the renal blood flow?
Increase in sympathetic (a-adrenergic) nerve activity → vasoconstriction and reduced blood flow
Due to extrinsic factors → haemorrhage, trauma, exercise, pain
Normal regulation is due to intrinsic factors such as autoregulation
How does the tubuloglomerular feedback mechanism function?
Intrarenal mechanism that sense flow through the distal tubule → reduces the filtration rate of the same nephron (tubulo-glomerular)
Macula densa cell of distal tubule = sensing site + adjacent to the vascular pole of the glomerulus of the same nephron
Mediated y the juxtaglomerular complex
