Renal Flashcards
Name major kidney functions
- Regulation of systemic blood pressure and extracellular fluid volume
- Excretion of metabolic waste and foreign substances
- Regulation of RBC production
- Regulation of acid-base balance
- Regulation of Vit. D production and Ca2+/Ph balance
- Gluconeogenesis
In which 2 major ways do kidneys regulate systemic blood pressure?
1) Determining blood volume -> controls cardiac output
2) Making hormones that regulate the vascular resistance
SBP = CO x VR
CO = heart rate x stroke volume
Stroke volume = end diastolic volume - end systolic volume
What are uremic retention solutes or uremic toxins
Urea (from proteins)
Uric acid (from nucleic acids)
Creatinine (from muscle creatine)
Urobilin (end product of hemoglobin)
If they are not excreted and plasma levels increase -> uremia
Where is erythropoietin produced during embryological development? and in the adults?
Liver
Kidneys
Stimulus to secrete erythropoietin
Reduction in partial pressure of oxygen in the local environment of the secreting cells.
Conditions that stimulate EPO secretion
Anemia
Blood loss
Arterial hypoxia
Inadequate renal blood flow
Why does anemia of chronic renal disease happens
1) Renal metabolism falls -> lower oxygen consumption -> higher local tissue oxygenation.
2) This “fools” the EPO-secreting cells into diminished EPO secretion.
3) Decrease in bone marrow activity - one important causal factor of the anemia.
T/F - Most gluconeogenesis occurs in the liver, but a substantial fraction occurs in the kidneys, particularly during a prolonged fast
TRUE
What does penetrate the renal hilum
Blood vessels
Nerves
Ureters
Describe the major structural components of the kidney
T/F - Pyramids collectively constitute the medulla
TRUE
What are cortex and medulla constructed off?
Almost entirely of tubules (nephrons and collecting tubules) and blood vessels.
Between the tubules and blood vessels -> interstitium, <10% of renal volume.
What does the renal interstitium contains?
Interstitial fluid
Interstitial cells -> fibroblasts and immune cells -> synthesize a matrix of collagen, proteoglycans, glycoproteins and cytokines.
Some of these cells synthesize EPO.
Lymphatics.
Types of nephrons
85% of nephrons - cortical -> glomeruli located in the outer cortex. Short LOH, only penetrates into the outer renal medulla. Reduced vasa recta.
15% of nephrons -> juxtamedullary -> glomeruli near the corticomedullary border. LOH extents deep into the renal medulla. Large network of vasa recta. Provides blood flow to renal medulla.
Where are the renal corpuscules located
Renal cortex
T/F - The cortex contains renal corpuscles, coiled blood vessels and coiled tubules. The medulla contains straight blood vessels and straight tubules.
TRUE
Draw / describe a nephron
Components of renal corpuscule
Bowman’s capsule - epithelial cells
Renal glomerulus - tuft of capillary loops
Draw / describe the structure of the renal corpuscle
- Bowman’s capsule - epithelium
- Glomerulus -> tuft of capillaries -> afferent arteriole brings blood in, efferent drains blood out.
- Mesangial cells and podocytes -> in close association with the capillary loops of the glomerulus.
- Mesangial cells -> act as phagocytes, remove trapped material from the basement membrane of the capillaries.
- Podocytes -> support structure, important role in glomerular filtration.
- Bowman’s space -> where fluid filters from the glomerular capillaries before flowing into the first portion of the tubule.
T/F - Throughout the whole length, the renal tubule is made up of a single layer of epithelial cells resting on a basement membrane.
TRUE.
How are the epithelial cells linked together in the renal tubules?
Via tight junctions
Name the renal tubular segments
Describe the structure of the nephron and where each part falls in relationship with cortex / medulla structure
Is the urine altered once it enters a calyx?
No
T/F - The border between outer and inner stripe of the outer medula is determined by where all the descending limbs of all nephrons begin (all at the same level)
TRUE
T/F - Thick ascending limbs of LOH do not begin at the same level
FALSE - they do begin at the same level, which marks the inner and outer medulla border.
What marks the end of the thick ascending limb of the LOH and beginning of distal convoluted tubule?
The macula densa
What is different in the epithelial cells of the distal convoluted tubule?
- Up to the DCT, the epithelial cells forming the wall of a nephron in any given segment are homogeneous and distinct for that segment.
- In the DCT -> the epithelium contains 2 types of cells:
- Principal cells -> majority
- Intercalated cells -> intercalated between principal cells.
Role of JGA
Regulates nephron’s blood flow and kidney’s ability to regulate SBP.
Type of cells in the JGA
1) Granular cells -> differentiated smooth muscle cells in the walls of the afferent arterioles. They contain secretory vesicles with renin inside.
2) Extraglomerular mesangial cells - a continuum with the glomerular mesangial cells but outside the Bowman’s capsule (BC).
3) Macula densa cells - detect flow rate and composition of fluid within the nephron at the very end of the thick ascending limb -> control renin secretion.
Basic renal processes
Filtration
Secretion
Reabsorption
Excretion
Filtration
Process by which water and solutes in the blood leave the vascular system through the filtration barrier and enter Bowman’s space.
Composition of glomerular filtrate (within bowman’s capsule)
- Very much like blood plasma
- Contains very little proteins -> large proteins are not filtrated.
- Inorganic ions and LMW organic solutes in same concentration as plasma.
What is the glomerular filtration rate. Normal values in healthy adult young male?
The volume of filtrate formed per unit of time.
125mL/min (180L/day -> all other capillaries of the body, approx. 4L/day).
Average total volume of plasma in humans: 3L -> entire plasma volume is filtered 60 times / day.
Secretion
Process of transporting substances into the tubular lumen from the cytosol of epithelial cells that form the wall of the nephron (either synthesized there, or coming from the blood).
Reabsorption
Process of moving substances from the lumen across the epithelial layer into the surrounding interstitium and then into the blood.
T/F Most of the tubular transport consists on reabsorption rather than secretion
TRUE
T/F - Reabsorption of waste products is partial, so that large fractions of the filtered amounts can be excreted in urine.
TRUE
T/F - Reabsoprtion of most “useful” plasma components is either complete or nearly so, so that very little is excreted in urine
TRUE
Amount filtered per day, amount excreted and % reabsorbed of water, Na, Glucose and urea
What are the main metabolic processes performed by tubular cells?
- They extract nutrients and metabolize them as dictated by the cell’s own nutrient requirements.
- They also do other metabolic transformations directed toward altering the composition of urine/plasma.
- Most important:
- Gluconeogenesis
- Synthesis of ammonium from glutamine
- Production of bicarbonate
What are the main mechanisms to regulate renal processes
- Neuronal signals -> originate in the sympathetic celiac plexus.
- Hormonal signals -> from adrenal gland, pituitary, parathyroid and heart.
- Intrarenal chemical messengers - originate in one part of the kidney and act in another part -> NO, superoxide, eicosanoids… also influence basic renal processes.
How much % of the CO kidneys receive?
About 20% of the resting CO
Where is the blood flow to the kidneys delivered?
To the cortex.
Then 5-10% of that cortical blood flow is directed to the medulla before returning to the systemic circulation.
Describe the renal blood flow
- Blood enters each kidney at the hilum via a renal artery
- After several divisions into smaller arteries blood reaches arcuate arteries that course across the tops of the pyramids between the medulla and cortex.
- From these, interlobular arteries (also called cortical radial arteries) project upward toward the kidney surface.
- These arteries give off numerous arterioles, each of which leads to an individual Bowman’s capsule and the glomerulus within.
- These arteries and glomeruli are found only in the cortex, never in the medulla.
- The arterioles leading to glomeruli are called afferent arterioles and have important functional characteristics discussed later.
- In most organs, capillaries recombine to form the beginnings of the venous system, but the glomerular capillaries instead recombine to form another set of arterioles, the efferent arterioles.
- The vast majority of the efferent arterioles soon subdivide into a second set of capillaries called peritubular capillaries / vasa recta.
- These capillaries are widely distributed throughout the cortex in close proximity to the tubular segments.
- The peritubular capillaries then rejoin to form the veins by which blood ultimately leaves the kidney.
The resistance of any single vessel is a function of
- Blood viscosity
- Vessel length
- Vessel RADIUS -> see formulas, Poiseuille’s law
Why is Poiseuille’s law important?
Because it describes the relationship between radius and resistance -> resistance can be controlled physiologically via small changes in vessel radius, mediated by arteriole smooth muscle.
T/F Most of the times, resistance of afferent and efferent arterioles are about equal and account for most of the total renal vascular resistance
TRUE
Where is hydrostatic pressure higher, in the glomerular capillaries or in the peritubular capillaries?
In the glomerular capillaries.
This difference is crucial for function -> leads to net filtration in glomerulus and reabsorption in peritubular capillaries.
How can changes in resistance of the afferent / efferent arterioles affect GFR?
T/F The sites with higher vascular resistance is where larger blood pressure drops occur
TRUE
Describe structure of the glomerular filtration barrier
1) Endothelial cells of the capillaries, is perforated by many large fenestrae, which occupy about 10% of the endothelial surface area. They are freely permeable to everything in the blood except red blood cells and platelets. 60-80nm.
2) The middle layer, the capillary basement membrane, is a gel-like acellular meshwork of glycoproteins and proteoglycans, with a structure like a kitchen sponge. It has negative charges, repelling negatively charged molecules (like albumin).
3) The third layer consists of epithelial cells (podocytes) that surround the capillaries and rest on the capillary basement membrane. The podocytes have an unusual octopus-like structure. Arms extend from the soma and wrap around several nearby glomerular capillaries. Small “fingers,” called pedicels (or foot processes), extend from each arm and are embedded in the basement membrane. The spaces between the pedicels, called slits, are the passageway through which the glomerular filtrate passes. The pedicels are coated by a thick layer of extracellular material, which partially occludes the slits. 30-40nm.
4) Finally, extremely thin processes called slit diaphragms bridge the slits between the pedicels.
What is the selectivity of the filtration barrier based on?
Molecular size
Electrical charge
Substances with molecular weight less than ________ can move easily through the filtration barrier
7000Da
The filtration barrier excludes molecules bigger than ________
70,000 Da
T/F For any given size, negatively charged macromolecules are filtered to a greater extent, and positively charged macromolecules to a lesser extent, than neutral molecules
FALSE - negative filtered to a LESSER extent, positive to a GREATER extent
T/F The negative charges in the filtration membrane it is a hindrance only to macromolecules, not to mineral anions or LMW organic anions -> chloride and bicarbonate are freely filtered despite their negative charge
TRUE
The glomerular basement membrane is extremely negatively charged due to
Heparin sulfate on the lamina rara interna and externa
Examples of substances that can filtrate through the glomerular filtration barrier
1) Electrolytes: HCO3–, Na+, K+, Cl–, Ca2+, Mg2+, H2O
* Despite the negative charge on some of these electrolytes, they’re very small; hence, they will get freely filtered
2) Non-negatively charged low-molecular weight molecules: glucose, amino acids, lipids, urea, creatinine, vitamins.
What is the main component of the slit diaphragm?
Nephrin
Components of the net filtration pressure
- Glomerular hydrostatic pressure GHP
- Colloid osmotic pressure COP
- Capsular hydrostatic pressure CHP
- Capsular oncotic pressure CoP
These are known as the Starling forces
NFP = (forces that want to push out) - (forces that want to push in)
NFP = (GHP + CoP) - (COP + CHP)
NFP = (55 + 0) - (30 + 15) = 10mmHg
Glomerular hydrostatic pressure
1) Force that pushes plasma out of the glomerular capsule into the bowman’s space
2) Directly dependent on systolic blood pressure
High BP = High GHP
Low BP = Low GHP
3) Average value: 55 mmHg
Colloid osmotic pressure
- Exerted by plasma proteins like albumin
- Keeps water in the blood
- Average value: 30 mmHg
Clinical Correlates:
• Multiple myeloma: increases amount of proteins in blood -> holds on to more water in the blood -> increases COP.
• Hypoproteinemia -> loses substances/proteins -> can’t hold on to water as much -> decreases COP.
Capsular hydrostatic pressure
As fluid is being filtered out, the pressure will push things back into the capillary bed
* By the pressure build-up in the Bowman’s capsule
* Average value: 15 mmHg
Clinical Correlate:
• Renal calculi
o Kidney stone stuck in nephron
o > 5mm in diameter
o Pressure backs up and starts increasing -> increases CHP
• Hydronephrosis
o Due to renal ptosis
o Rapid weight loss
o Increased CHP -> more fluid being pushed back into the glomeruli and not much glomerular filtration.
Capsular osmotic pressure
As long as the filtration membrane is intact, there should be no proteins in the Bowman’s capsule -> average value: 0 mmHg
Glomerular filtration rate
- Plasma volume being filtered out of the glomerulus into the bowman’s capsule every minute
- On average, 125 mL/min
- Per min., 1.2L goes to AA -> 625mL used in filtration process -> only 20% (125mL) is filtered.
GFR = NFP x Kf
T/F The hydrostatic pressure is nearly constant within the glomeruli but the oncotic pressure in the glomerular capillaries does change substantially along the length of the glomeruli
TRUE
Explain why the oncotic pressure in the glomeruli changes
As water is filtered out of the vascular space, it leaves most of the proteins behind, thereby increasing protein concentration and hence, the oncotic pressure of the unfiltered plasma remaining in the glomerular capillaries -> NFP decreases from the beginning to the end of the glomerulus.
An increase in afferent arteriole resistance will increase or decrease glomerular pressure?
Decrease
An increase in efferent arteriolar resistance will increase or decrease glomerular pressure?
Increase
Dilation of the afferent arteriole
Raises glomerular pressure and hence GFR
Dilation of the efferent arteriole
Decreases glomerular pressure and GFR
T/F Kidneys can regulate glomerular pressure and hence GFR, independently of renal blood flow
TRUE
Anything that increases glomerular oncotic pressure tends to ___________ net filtration pressure and hence GFR
Decrease
If renal blood flow is low, what will happen to the oncotic pressure? And in high renal blood flow conditions?
1) In conditions with low renal blood flow -> oncotic pressure at the end of the capillaries is higher than normal -> will lower NFP and hence, GFR
2) With high renal blood flow -> glomerular oncotic pressure will increase less than normal -> higher NFP -> higher GFR
Renal plasma flow and filtration fraction
RPF = the flow of plasma through the glomeruli
Filtration fraction: ratio GFR / RPF, normally about 20% -> about 20% of the plasma entering the kidneys is removed from the blood.
T/F The increase in glomerular oncotic pressure along the glomerular capillaries is directly proportional to the filtration fraction
TRUE - if relatively more of the plasma is filtered, the increase in oncotic pressure is greater
What causes most often changes in the filtration coeficient? (Kf)
Glomerular diseases
Major cause of decreased GFR in aging / renal disease
Is not a change on the Kf within individual glomeruli, rather a decrease in the number of functioning nephrons and this reduces whole kidney Kf
What is filtered load?
The amount of substance filtered per unit of time.
For freely filtered substances, that is the product of GFR x plasma concentration of that substance.
Na+ for example:
Plasma: 140mEq/L = 0.14mEq/mL
Normal GFR = 125mL/min
Na+ filtered load = 0.14 x 125 = 17.5mEq/min.
What is presented to the rest of the nephron to handle!
Why are glomerular capillaries more sensitives to hypertension than capillaries in other parts of the body?
Because vascular pressure in the thin-walled glomerular capillaries is higher than in other capillary beds, and hypertensive damage ensues if pressures are too high.
What is the most important of the factors that tends to change GFR?
Renal artery pressure -> in a healthy kidney is the same as systemic arterial pressure -> variations on SBP has potential effects on GFR.
T/F - Autoregulation prevents large changes in GFR in the face of changes in arterial pressure
TRUE
Via which mechanism can the kidney modify the renal blood flow and urine output?
Intrinsic mechanisms:
* Myogenic mechanism
* Tubuloglomerular feedback
Extrisinc mechanisms:
* Sympathetic NS
* RAAS - Renin - angiotensin - aldosterone - ADH system
Intrinsic myogenic mechanism when blood pressure increases
↑BP → ↑GHP → ↑GFR -> higher glomerular filtration rate (GFR), more urine.
Kidneys modulate the GFR so that it is not too excessive making too much urine, or the blood pressure does not remain too high causing injury on the glomerular capillaries.
Myogenic response -> blood flows through the afferent arteriole (AA) then to the efferent arteriole (EA) -> ↑BP = more blood to the AA -> Na channels in the smooth muscle of the afferent arteriole are sensitive to stretch -> AA vasoconstricts → ↓glomerular blood flow (GBF) → ↓filtered plasma and other substance (↓GFR)
Intrinsic myogenic mechanism when blood pressure decreases
↓BP → ↓GHP → ↓GFR
↓BP = ↓urine = can cause kidney injury -> how does the kidney prevent it?
Mechanism:
↓BP => ↓blood to the AA -> ↓stretch on the AA -> ↓stretch therefore less Na+ enter in the smooth muscle cell → less positive charge → ↓Ca2+ released by the sarcoplasmic reticulum → less contraction => relaxation.
Summary of intrinsic myogenic mechanism
↑BP = ↑GFR
o Counteracted by vasoconstriction of AA → ↓GFR
↓BP = ↓GFR
o Counteracted by vasodilation of AA → ↑GFR
Tubuloglomerular feedback with increased BP
This mechanism is sensitive to NaCl -> NaCl gets reabsorbed in the proximal convoluted tubule (PCT).
1) ↑BP = ↑GFR = ↑NaCl excretion into the kidney tubules
2) When NaCl transporters in the PCT are saturated, NaCl can escape and move to the LH and then to the DCT where macula densa cells are found
o Special NaCl sensors
o Release adenosine when it detects ↑NaCl
3) Adenosine functions to:
o Vasoconstrict AA → ↓GBF → ↓GFR → ↓NaCl being filtered
o Inhibit juxtaglomerular (JG) cells → ↓renin → ↓blood pressure
Tubuloglomerular feedback with decreased BP
↓BP = ↓GFR = ↓NaCl excretion into the kidney tubules
When macula densa cells detect ↓NaCl in DCT, they release PGI2 and nitric oxide (NO)
PGI2 and NO function:
o Vasodilate the AA → ↑GBF → ↑GFR → ↑NaCl filtered
o Stimulates juxtaglomerular (JG) cells → increases renin release → increases blood pressure
Summary of tubuloglomerular feedback
↑BP = ↑GFR = ↑NaCl filtered
o ↑NaCl detected by MD cells → release adenosine → vasoconstricts AA and inhibits JG cells to release renin.
↓BP = ↓GFR = ↓NaCl filtered
o ↓NaCl detected by MD cells → release PGI2 and NO → vasodilates AA and stimulates JG cells to release renin.
Extrinsic mechanism - sympathetic nervous system
1) Stimulus: ↓↓↓SBP → MAP < 65 mmHg
o MAP (mean arterial pressure): measure of perfusion
o When MAP < 65 mmHg, kidney is not perfused; blood flow is redirected to other “more important” organs such as the heart, brain and muscles.
↓BP → ↓GFR → ↓urine output
o ↓blood flow can cause kidney injury
o SNS do its best to increase blood flow
MECHANISM:
1) ↓BP triggers baroreceptors → CN IX and CN X send less signals to the medulla oblongata (vasomotor center)
2) Vasomotor center activates sympathetic nerve fibers in the thoracic part causing release of NE and epinephrine, that will act in different systems:
a) Heart
NE and epi stimulate the β1 receptors in the nodal system and contractile fibers → ↑HR and ↑SV (due to ↑contractility) respectively → ↑CO → ↑BP -> to increase blood flow in the kidneys to avoid injury.
Chronotropic: change in heart rate / Ionotropic: change in contractility
b) Renal afferent and efferent arterioles -> NE and EPI will act on the α1 receptors of the AA and EA → vasoconstriction → ↓GBF → ↓GFR
YES, the goal is to increase the blood flow towards the kidney BUT in sympathetic crisis, the SNS DOES NOT respect the kidneys
c) Systemic vessels -> NE and EPI act on the α1 receptors on the systemic vessels → vasoconstriction of multiple vessels → ↑systemic vascular resistance (SVR) → ↑BP
d) Juxtoglomerular Cells -> NE and EPI stimulate the β1 receptors on the JG cells → ↑renin → activates angiotensin II →→→ ↑BP
Summary of SNS effects when BP is low
Increase HR and SV
Vasoconstriction of the renal afferent and efferent arterioles
Vasoconstriction of the systemic vessels → ↑SVR
Triggers release of renin from the JGA
The effects are the exact opposite when the blood pressure is HIGH.
Extrinsic mechanism - Initiation of RAAS to produce ATII
1) ↓BP → ↓GFR
2) Juxtoglomerular cells are sensitive to changes in blood pressure -> when BP is low, JG cells release renin.
3) Renin cleaves angiotensinogen to produce angiotensin I
4) Angiotensin I move to the capillaries in the lungs and get converted to angiotensin II by angiotensin converting enzyme (ACE).
Extrinsic mechanism - ATII functions - RAAS
1) ADH Release -> stimulates the hypothalamus that trigger release of ADH from the pituitary gland.
ADH (aka vasopressin or antidiuretic hormone) -> acts on the aquaporin in the collecting duct to reabsorb water -> ↑H2O in blood → ↑blood volume → ↑BP
2) ↑Thirst -> makes you thirsty → ↑water intake → ↑blood volume → ↑BP
3) Aldosterone release -> stimulates release of aldosterone from the zona glomerulosa in the adrenal gland. Aldosterone -> acts on the DCT to make them permeable water and Na+ -> ↑Na+ and H2O reabsorption → ↑BV → ↑BP
4) Vasoconstriction of efferent arteriole and ↑GFR
Angiotensin II binds on the receptor on the EA → vasoconstriction of EA -> less blood can escape from the glomerulus, more blood stays in the glomerulus → more blood filtered out → ↑GFR
NOTE: Some books say that it also affects the AA; but the effect is much greater in EA (EA»_space;> AA)
5) Angiotensin II also act on the PCT to cause increased reabsorption of Na+ and H2O -> ↑Na+ and H2O → ↑BV → ↑BP
6) Vasoconstriction of systemic vessels -> acts on systemic vessels → potent vasoconstriction → ↑SVR → ↑BP → ↑GFR
What happens when BP is increased?
In cases of HIGH BP, JG cells do NOT release renin. Therefore the RAAS does not occur.
Atrial natriuretic peptide -> released from the heart in cases of ↑BP and it can block any function of the angiotensin II:
a. Blocks ADH release = no water and Na+ reabsorption = urinate water and Na+ = ↓blood volume.
b. Blocks aldosterone release = no water and Na+ reabsorption = urinate water and Na+ = ↓blood volume
c. Prevents vasoconstriction of EA = ↓GFR
d. Causes vasodilation of blood vessels = ↓SVR = ↓BP
Summary of autoregulatory mechanisms
What is clearance
Removal of metabolic waste products, ingested substances and excess salts and waters via urine, feces, biochemical transformations in the liver and for volatile substances, exhalation.
How can rate of removal be expressed?
2 ways:
Plasma half-life -> time it takes for the concentration of a substance in plasma to be reduced by 50%
Clearance -> measures the volume of plasma from which all of a substance is removed in a given time.
Renal clearance
The substance is removed from the plasma ONLY by the kidneys and is either excreted in urine or catabolized by the renal tubules.
The volume of plasma that needs to pass through the kidneys in a given amount of time in order to excrete a given quantity of a substance in the urine
T/F Assessing the renal clearance of certain substances that are not reabsorbed nor secreted by the nephron is very useful as it is an indicator of renal function
TRUE
T/F The utility on measuring renal clearance is to measure GFR
TRUE
Why is measuring GFR important?
- Because the most commonly used marker of kidney disease (plasma creatinine concentrations) is not sensitive
- Plasma creatinine concentrations do not increase until 75% of the nephrons are non functional.
- Therefore GFR is much more sensitive.
Renal clearance equation
T/F If the clearance of a substance is higher than the GFR, there must have been net secretion
TRUE
T/F If the clearance of a substance is less than the GFR, there must have been net reabsorption
TRUE
What are the 3 approaches to quantify GFR using renal clearance?
1) Clearance of exogenous markers - inulin, radioactive markers, iohexol.
2) Clearance of endogenous markers - creatinine, cystatin C, urea.
3) Imaging of the kidneys -> renal scintigraphy, CT.
Gold standard of measuring GFR
Inulin clearance - one of the few substances that satisfies the requirement of an ideal marker of GFR.
Creatinine clearance
Practical and common
Low cost & convenient
Easier than inulin
Less invasive
Cr clearance is slightly higher than GFR (by 10% to 20%)
Cystatin C
- Produced by all nucleated cells at a constant rate.
- Only eliminated by kidneys.
- All filtered cystatin is removed from the body (no reabsorption)
- Production increases with large doses of corticoids.
- Production affected by thyroid dysfunction and cancer.
Urea clearance
- Less accurate indicator of GFR
- Range of normal plasma urea concentrations varies widely depending on protein intake and changes in tissue catabolism.
- Urea excretion is under partial hormonal regulation.
Urea clearance
- Less accurate indicator of GFR
- Range of normal plasma urea concentrations varies widely depending on protein intake and changes in tissue catabolism.
- Urea excretion is under partial hormonal regulation.
Renal scintigraphy
- Assesses function of each kidney separately
- Inject a radiotracer in blood
- Measure rise and fall of radioactive counts in each kidney separately
What are the differences in endothelium and interstitium between renal cortex and renal medulla?
Renal cortex:
Fenestrated vascular endothelium—noresistance to passive movement of water and small solutes.
Cortical interstitium (between basal membrane and endothelial cells)—similar osmolality and concentration of small solutes to plasma.
Renal medulla:
Only some fenestrated capillaries.
Medullary interstitium is not plasma-like.
How can substances cross the tubular epithelium?
Paracellular
Transcellular
Transcellular vs paracellular transport
Transcellular -> through cells -> in on one side, out at the other side
Paracelluar -> around cells through tight junctions
Mechanisms for substances to cross barriers
- Diffusion - concentration gradient
- Channels - pores that allow specific solutes to pass through
- Transporters - allow passage of otherwise impermeable substances.
- Simporters: 2 substances, same direction
- Antiporter: 2 substances, opposite direction
- Primary active transporters: require ATP, agains electrochemical gradient.
- Receptor mediated endocytosis and transcytosis.
T/F - Blood flow and transport mechanisms are faster in the medulla compared to cortex
FALSE - faster in the renal cortex
What is selectivity
The ability to choose which substance is permitted to move
Its it only the cell membrane that is selective or also the tight junctions?
Both are selective
Family of proteins that are key for the tight junctions
Claudin
How is the permeability / expression of channels/transporters regulated?
1) Gated channels:
- Ligand - gated -> reversible binding of small molecules
- Voltage-gated -> changes in membrane potential
- Mechanical distorsion -> stretch gated.
2) Phosphorylation sites -> it can either open or close the channel
3) Some can be moved back and forth between the surface membrane and intracellular vesicles
4) Transcription and expression of channels regulated
Difference between a channel and a uniporter
A channel is a tiny hole, whereas an uniporter requires that the solute binds to a site that is alternatively available to one side and then the other side of the membrane
How is normally called movement through an uniporter
Facilitated diffusion
T/F Symporters are also called cotransporters and antiporters, exchangers
TRUE
Key symporters (cotransporters) in the kidneys
Na-Glu
Na-K-2Cl
Key antiporters (exchangers) in the kidneys
Na+ / H+
Cl- / HCO3
Primary active transporters
Move one or more solutes agains concentration gradient, using ATP
Na/K ATPase
H-ATPase (H out of the cell)
CA-ATPase (Ca out of the cell)
Multidrug resistance proteins
Which transport mechanism is important in the host defense mechanisms of the kidney and in prevention of UTIs?
Transcytosis
Osmolarity
Volume of particles per liter of solvent (mol/L).
Generally, in the glomerulus, the blood is 300 mOsm/L
Proximal convoluted tubule I - tubular reabsorption (glucose, aa and lactate)
1) Sodium-Potassium ATPase -> 3 Na+ out and 2 K+ ions in.
- Na+ and K+ move against their concentration gradient -> primary active transport -> requires ATP (97% of K in our bodies is inside the cell).
What does it do to the inside of the cell -> decreases Na and increases K.
2) Secondary active transport - passive diffusion of one substance helps facilitate the active transport of another substance (can transport two things at once inside the cell - cotransporter)
a) Sodium-glucose cotransporter -> since there’s low Na inside the cell, it’s moving passively along its concentration gradient. Glucose is high inside the cell -> Na+ helps glucose move against its concentration gradient. When it gets into the cell, there are specific transporters on the basolateral membrane that transports glucose out of the cell and into the bloodstream.
b) Sodium / amino acids Cotransporter -> transports Na+ inside the cell along with amino acids -> high concentration of amino acids inside the cell. Inside the cell, amino acids have specific transporters that facilitate their diffusion out of the tubular cell and into the blood.
c) Sodium-lactate Cotransporter -> passive diffusion of sodium facilitates transport of lactate
Assuming normal physiological conditions, 100% of the glucose, amino acids, and lactate get reabsorbed from the kidney tubules into the blood.
Proximal convoluted tubule - II - tubular reabsorption - bicarbonate.
How does bicarbonate (HCO3–) gets into the cell?
Via CO2 + H2O -> H2CO3 -> H+ + HCO3–
o CO2 -> can be found in our blood and can move into the cell (through the basolateral membrane) and react with water to form carbonic acid.
o Carbonic acid (H2CO3) -> unstable; dissociates into a proton (H+) and bicarbonate (HCO3–)
o What happens to the proton (H+) -> Sodium-hydrogen exchanger -> secondary active transport -> as Na+ moves through the channel to go in the cell, it helps push H+ out -> H+ combines with HCO3– outside of the cell -> H2CO3 is converted by carbonic anhydrase into CO2 and H2O in the lumen of the PCT.
o What happens to the bicarbonate (HCO3–)? -> approximately 90% of HCO3– gets pushed into the blood.
Proximal convoluted tubule - III - tubular reabsorption - bicarbonate reabsorption regulation
Regulation of reabsorption of filtered HCO3-
1) Filtered load -> increases in the filtered load of HC03- result in increased rates of HC03- reabsorption. However, if the plasma HC03- concentration becomes very high (e.g., metabolic alkalosis), the filtered load will exceed the reabsorptive capacity, and HC03- will be excreted in the urine.
2) PCO2
* Increases in PCO2 result in increased rates of HC03- reabsorption because the supply of intracellular H+ for secretion is increased. This mechanism is the basis for the renal compensation for respiratory acidosis.
- Decreases in PCO2 result in decreased rates of HC03- reabsorption because the supply of intracellular H+ for secretion is decreased . This mechanism is the basis for the renal compensation for respiratory alkalosis.
3) ECF volume
ECF volume expansion results in decreased HC03 reabsorption.
ECF volume contraction results in increased HC03- reabsorption (contraction alkalosis).
4) Angiotensin II -> stimulates Na+-H+ exchange and thus increases HC03- reabsorption, contributing to the contraction alkalosis that occurs secondary to ECF volume contraction
Proximal convoluted tubule - IV - tubular reabsorption - water
- Sodium is very critical in the process of OBLIGATORY WATER REABSORPTION -> when water is obliged to follow sodium (solutes) and move back into the blood.
- For example, in the sodium-glucose channel -> when sodium is coming in with the glucose, water feels obliged to follow sodium -> water moves by the process of osmosis, from the kidney tubules into the blood.
- About 65% of sodium is being reabsorbed, hence, 65% of water is also being reabsorbed.
Proximal convoluted tubule - V - tubular reabsorption - paracellular transport
About 50% of Cl– and 55% of K+ are reabsorbed via paracellular transport. Very little Ca2+ and Mg2+ are reabsorbed in this area.
Proximal convoluted tubule - VI - tubular reabsorption - Na/Cl cotransport
Sodium-chloride cotransport -> moves sodium and chloride ions into the cell (in the late proximal tubule) and they are then pushed into the blood.
Proximal convoluted tubule - VII - tubular reabsorption - lipids
Lipid-soluble substances can pass through the phospholipid bilayer, like urea.
Can pass through the membrane and into the blood.
Not all of it gets reabsorbed -> about 50%.
Proximal convoluted tubule - VIII - tubular reabsorption - small proteins (insulin, hemoglobin)
- There are specific protein receptors on the membrane.
- If these small proteins are filtered (normally they are not), they can get caught on these receptors
- Proteins are endocytosed and taken into the cell, then combined inside the cell with lysozymes (hydrolytic enzymes that break down the proteins into their constituent amino acids). The vesicle then fuses with the cell membrane and amino acids are released into the blood
- Receptors are recycled.
Proximal convoluted tubule - IX - sodium-phosphate cotransport
- Cotransporter normally brings both Na+ and HPO42– into the cell.
- There’s a receptor for the PTH on the basolateral membrane of the cells in the PCT.
- PTH binds with the receptor and activates the G-stimulatory protein.
- G-stimulatory protein activates adenylate cyclase, activating protein kinase A.
- pkA phosphorylates the Na/phosphate cotransporter, inhibiting it.
- Phosphates don’t get reabsorbed -> they get excreted.
Proximal convoluted tubule - summary of tubular reabsorption
Proximal convoluted tubule - compensation for metabolic acidosis
Glutamine is a specific type of amino acid -> it can undergo deamination, resulting into 2 ammonium ions (NH4+), and the acidified glutamine will be oxidized into 2 bicarbonate ions.
Normal blood pH is 7.35-7.45 -> in metabolic acidosis blood pH is low ( < 7.35), and the body has to compensate for that.
Bicarbonate resulting from the glutamine metabolism will be taken into the blood to bring the pH back up. In exchange, chloride ion will need to go out of the blood into the cell to maintain electroneutrality.
The ammonium ions also produced from the glutamine metabolism will be pushed out of the cell and into the kidney tubule -> it will dissociate into ammonia (NH3) and H+
- REMEMBER - the other mechanism to reabsorb HCO3 and increase blood pH is via CO2 present in the blood and taken into the cells to be converted into H+ and HCO3 and the H+ secreted in the lumen in exchange for Na.
Proximal convoluted tubule - secretion
In the blood, there are certain things that we either reabsorb too much or we can’t get rid of - organic bases and acids, like certain drugs (penicillin, cephalosporins, methotrexate), and similar with uric acid, bile salts, morphine, those substances have to be secreted.
The process of getting these excreted into the kidney tubules is an active process -> requires ATP.
Loop of Henle - I how many parts does it have?
Two. Ascending limb and descending limb.
Loop of Henle - II - Osmolality values through the LOH
- Inside the glomerulus: ~300 mosm -> is the blood plasma
- In Bowman’s capsule: ~300 mosm -> sotonic with the blood plasma
- When fluid leaves the PCT -> is still at 300 mosm -> it didn’t change because equal amounts of solutes and water were being reabsorbed (due to obligatory water reabsorption).
- Medullary interstitial osmolality gets saltier or more hypertonic as we go down the renal medulla -> 300 mosm -> 500 mosm -> 700 mosm -> 900 mosm -> 1200 mosm
Loop of Henle - III - LOH - how does the medullary interstitium gets more hypertonic?
Na+/K+/2Cl– cotransporter:
- Transports sodium, chloride, and potassium from lumen of filtrate into epithelial cell of ascending limb.
- There are specific channels for each ion in the cell -> Na+ and Cl– will be pushed out (towards the medullary interstitium), increasing osmolality.
- Only some of the K+ will pass to the interstitium, some of the K+ gets pushed back in the lumen. Creates depolarization of the inner side of the membrane of the ascending limb -> causes Mg2+ and Ca2+ to undergo paracellular transport.
IMPORTANT:
* The descending limb of loop of Henle is completely impermeable to solutes and permeable to water.
- Exact opposite of the ascending limb which is only permeable to solutes, but impermeable to water.
Loop of Henle - IV - LOH - what happens due to the salty medullary interstitial space?
Counter-Current Multiplier Mechanism:
- Water will flow out TO the area where the salt is -> from the descending limb to the ascending limb (due to obligatory water reabsorption).
- Via Aquaporin-I -> always open in the descending limb of Loop of Henle
- Since the medullary interstitial space is saltier as we go down, more water will leave as we go down the descending limb -> by the time the loop of Henle takes a turn to go up, its osmolality will be 1200 mosm -> becomes hypertonic as we move down.
- When it goes up, however, the osmolality starts to go down because the ascending limb is losing salt -> by the time it reaches the Distal Convoluted Tubule (DCT) -> the osmolality will be around 120-200 mosm -> hypotonic compared to the plasma.
Loop of Henle - V - LOH - vasa recta
- Peritubular capillary in the medulla, branching from the Efferent Arteriole
- Known as the “Counter-Current Exchanger”
- Plasma Osmolality Gradient in medullary interstitium -> 300 -> 500 -> 700 -> 900 -> 1200
- Blood flow to vasa recta is really slow -> function: prevents rapid removal of sodium chloride
- Does not develop the medullary interstitial gradient or the counter-current multiplier mechanism -> it’s maintaining the gradient; not generating it.
- Vasa recta also delivers oxygen and nutrients.
Loop of Henle - summary
Descending Limb
o H2O permeable
o Solute impermeable
o Aquaporin-I - allows water to move out to the medullary interstitium
Ascending Limb
o H2O impermeable
o Solute permeable
o Na+/K+/2Cl– cotransporter -> pushes these solutes out into the medullary interstitium (salty; high osmolality) -> some K+ gets pushed back in the lumen, creating a depolarization on the inner side of the membrane of the ascending limb -> causes Mg2+ and Ca2+ to undergo paracellular transport.
Counter-Current Multiplier Mechanism
o Maintained by the vasa recta (vasa recta is the counter-current exchanger).
Distal convoluted tubule - I - early DCT - Na and Cl
1) Na-K Pump -> in basolateral membrane, requires ATP -> 3 Na+ ions out and 2 K+ ions in
2) Sodium-chloride symporter -> specialized transporters on the luminal membrane -> sodium and chloride both go into the cell.
* Since Na+ ions are going out via the Na-K pump, it means that DCT has high [Na+] compared to inside the cell (going against concentration gradient) * Only 5-6% of Na+ is being reabsorbed here -> 4-5% is left * Cl– will move in together with Na -> Cl- has a special channels in the basolateral mechanism that pumps it into the blood.
- THIAZIDE * -> diuretic that inhibits sodium-chloride symporter -> it will affect both the salt and water reabsorption -> instead of reabsorbing the 5-6% back, you’ll lose them to the urine together with a bit of the blood volume
Distal convoluted tubule - II - early DCT - calcium reabsorption
- When there are low blood calcium levels -> stimulate parathyroid gland to secrete PTH
- PTH has a receptor on the cell of the distal convoluted tubule -> PTH binds and stimulates the receptor -> G stimulatory protein -> cAMP -> activates protein kinase A
- pkA stimulates calcium modulated channels (very sensitive to PTH levels) via phosphorylation -> causes channels to pull in Ca2+ into the cell -> calcium can be bound to protein called calbindin inside the cell, but it will be a low percentage.
- Even if blood calcium level is low, there’s still less calcium inside the cell compared to blood -> calcium will be moving against its concentration gradient. Two mechanisms to get calcium out
a) Ca2+/Na+ Transporter
• Proteins on the basolateral membrane
• Pumps calcium out and brings sodium in -> secondary active transport as Na goes down concentration gradient.
b) Ca2+/H+ transporter -> uses ATP -> calcium out, H+ in.
Distal convoluted tubule - III - late DCT - aldosterone
- Generally impermeable to water.
- Has specialized cells responsible for responding to aldosterone: principal cells -> responsible for mineral and water balance.
- Aldosterone -> steroid hormone produced in the globular cells of the adrenal gland
- Stimulus for aldosterone secretion: angiotensin-II (wants to increase pressure), hyponatremia and hyperkalemia. Small amounts of CRH can also stimulate its secretion.
- Aldosterone passes through the cell’s lipid bilayer because it’s a steroid hormone -> it will activate specific transcription factors to produces different proteins:
1) ) Na channel -> protein embedded in the luminal membrane -> Na is allowed to go inside the cell due to the effects of the Na+/K+ Transporter (low intracellular Na)
2) Na+/K+ transporter in the basolateral membrane -> active transport, uses ATP. Puts 3 Na+ out of the cell, brings 2 K+ in.
Na+ would want to go from high concentration to low concentration -> Na+ goes inside the cell via the sodium channel
K+ enters the cell -> higher concentration in the cell
3) Potassium channel -> embedded in the luminal membrane -> since there’s high K+ inside the cell, the channel will move it out of the cell where it will eventually be excreted into the urine.
Distal convoluted tubule - IV - late DCT - ADH
- Can act on the principal cells, together with aldosterone
- Presence of ADH will open up the aquaporins-II
- Water will have to follow the salt and go into the cell and into the bloodstream -> increases blood pressure.
Late DCT / Collecting duct - I - intercalated cells
o Maintain acid-base balance -> keep body within homeostatic range.
o Found in the late distal tubule and collecting duct.
o Intercalated A cells: acidic conditions.
o Intercalated B cells: basic conditions.
There are also other cells that could be secreting drugs: toxins, creatinine… and via the intercalated cells we will be secreting H+, HCO3-, ammonium…
Late DCT / Collecting duct - II - Intercalated A cells - acidosis
They respond to ACIDOSIS (metabolic or respiratory)
Scenario: there’s increased CO2 in the blood:
o In an acidosis, there is low pH = many protons.
o Very little bases to counteract the protons.
CO2 + H2O -> H2CO3 -> H+ + HCO3-
o Circulating carbon dioxide -> moves into the intercalate A cell, and combines with water to form carbonic acid (catalyzed by CA)
o Carbonic acid (H2CO3) -> unstable; dissociates into protons and HCO3–
o Protons (H+) -> there is an H+ / K+ ATPase in the luminal membrane -> K+ goes into the cell and H+ goes out, both against concentration gradient.
o Bicarbonate (HCO3–) -> will be pumped out of the cell into the blood via the HCO3–/Cl– transporter in the basolateral membrane.
o The body needs to secrete substances it doesn’t want, like ammonia (NH3) -> it can be excreted out into the urine where it will combine with the protons secreted to produce ammonium (NH4+).
Late DCT / Collecting duct - III - Intercalated B cells - alkalosis
Responds to ALKALOSIS (respiratory or metabolic)
The same pathway as intercalated-A cell, but flipped.
o Get rid of bicarbonate instead of the protons
o Reabsorb proton into the blood instead of bicarbonate
o Increased blood pH -> low H+ and high HCO3-
o CO2 + H2O -> H2CO3 -> H+ + HCO3-
o CO2 -> found in our blood -> moves into the intercalated B cell, and combines with water to form carbonic acid via CA -> carbonic acid -> unstable -> dissociates into protons and HCO3–
o HCO3– goes out of the cell -> pumped out of the cell into the urine via HCO3- / Cl- cotransporter -> Cl- goes into the cell in the luminal membrane via cotransporter and will exit the cell via the chloride channels on the basolateral membrane.
o Protons (H+) -> will be reabsorbed via H+ / K+ ATPase in the basolateral membrane (both ions are moving against their concentration gradients) -> K+ goes into the cell, H+ goes out of the cell into the bloodstream.
Late DCT / Collecting duct - IV - principal cells - ADH
Cells that maintain mineral and water balance
o Hypothalamus has a collection of neurons from the supraoptic nucleus
o Their axons move through from the hypothalamus to the posterior pituitary
o When stimulated, it will release ADH
o ADH will be released whenever the plasma osmolality is changing and can work in the late distal tubule and collecting duct. Second strong stimulus will be low blood volume (will cause the release of ATII -> will stimulate ADH release).
Collecting duct - V - principal cells - ADH
o ADH binds to the vasopressin receptor on the principal cell in the collecting duct of the kidneys -> adenylate cyclase -> activates pkA
o Phosphorylates the proteins on intracellular vesicles -> presynthesized vesicles with proteins and channels (aquaporins)
o Activates aquaporin-II -> vesicles fuses with the cell membrane
o There are aquaporin-III and aquaporin-IV in the basolateral membrane
o Water goes into the cell via aquaporin-II, then passes through aquaporins III & IV and goes into the blood -> increases blood volume, and increases blood pressure
o Also reaches normal plasma osmolality -> isotonic.
Urea recycling and medullary interstitium
o A lot of urea still gets lost in the urine, but some is recycled -> gets reabsorbed in the last part of the collecting duct.
o After all the water has been reabsorbed, urea starts increasing in the tubular lumen
o It then moves out of the collecting duct and into the medullary interstitium via facilitated diffusion (lipid soluble).
o It gets reabsorbed in the ascending limb of Loop of Henle and it also accumulates outside in the medullary interstitium.
Renal processess SUMMARY ALL
Total body water
60%
Distribution of body water and composition
- Intracellular fluid is two-thirds of TBW.
The major cations of ICF are K+ and Mg.
The major anions of ICF are protein and organic phosphates (ATP, ADP and AMP). - Extracellular fluid is one-third of TBW and is composed of interstitial fluid + plasma.
The major cation of ECF is Na+.
The major anions of ECF are Cl- and HC03- .
a. Plasma is 25% (1/4) of the ECF. The major plasma proteins are albumin and globulins.
b. Interstitial fluid is 75% (3/4) of the ECF.
The composition of interstitial fluid is the same as that of plasma except that it has
little protein. Thus, interstitial fluid is an ultrafiltrate of plasma.
- 60-40-20 rule
TBW is 60% of body weight.
ICF is 40% of body weight.
ECF is 20% of body weight.
Osmolarity
a. Osmolarity is concentration of solute particles.
b. Plasma osmolarity is estimated as:
Posm= 2 x Na + Glucose/18 + BUN/2.8 => mOsm/L
Na+ =plasma Na+ concentration (mEq/L)
Glucose = plasma glucose concentration (mg/dL)
BUN= blood urea nitrogen concentration (mg/dL)
c. At steady state, ECF osmolarity and ICF osmolarity are equal.
d. To achieve this equality, water shifts between the ECF and ICF compartments.
e. It is assumed that solutes such as NaCl and mannitol do not cross cell membranes and are confined to ECF.
Shift of water within compartments - adding isotonic fluid
Is also called isosmotic volume expansion.
1) ECF volume increases, but no change occurs in the osmolarity of ECF or ICF. Because osmolarity is unchanged, water does not shift between the ECF and ICF compartments.
2) Plasma protein concentration and hematocrit decrease because the addition of fluid to the ECF dilutes the protein and red blood cells (RBCs). Because ECF osmolarity is unchanged, the RBCs will not shrink or swell.
3) Arterial blood pressure increases because ECF volume increases.
Shift of water within compartments - loss of isotonic fluid
For example, diarrhea. Is also called isosmotic volume contraction.
1) ECF volume decreases, but no change occurs in the osmolarity of ECF or ICF. Because osmolarity is unchanged, water does not shift between the ECF and ICF compartments.
2) Plasma protein concentration and hematocrit increase because the loss of ECF concentrates the protein and RBCs. Because ECF osmolarity is unchanged, the RBCs will not shrink or swell.
3) Arterial blood pressure decreases because ECF volume decreases.
Shift of water within compartments - adding hypotonic fluid
SIADH - gain of water. Also called hypoosmotic volume expansion
1) The osmolarity of ECF decreases because excess water is retained.
2) ECF volume increases because of the water retention. Water shifts into the cells; as a result of this shift, ICF osmolarity decreases until it equals ECF osmolarity, and ICF volume increases.
3) Plasma protein concentration decreases because of the increase in ECF volume. Although hematocrit might also be expected to decrease, it remains unchanged because water shifts into the RBCs, increasing their volume and offsetting the dilut- ing effect of the gain of ECF volume.
Shift of water within compartments - loss of hypotonic fluid
Excessive sweat - also called hypertonic volume contraction
1) The osmolarity of ECF increases because sweat is hyposmotic (relatively more water than salt is lost).
2) ECF volume decreases because of the loss of volume in the sweat. Water shifts out of ICF; as a result of the shift, ICF osmolarity increases until it is equal to ECF osmolarity, and ICF volume decreases.
3) Plasma protein concentration increases because of the decrease in ECF volume. Although hematocrit might also be expected to increase, it remains unchanged because water shifts out of the RBCs, decreasing their volume and offsetting the concentrating effect of the decreased ECF volume.
Shift of water within compartments - adding hypertonic fluid
For example, excessive NaCl intake. Also called hypertonic volume expansion
1) The osmolarity of ECF increases because osmoles (NaCl) have been added to the ECF.
2) Water shifts from ICF to ECF. As a result of this shift, ICF osmolarity increases until it equals that of ECF.
3) As a result of the shift of water out of the cells, ECF volume increases (volume expansion) and ICF volume decreases.
4) Plasma protein concentration and hematocrit decrease because of the increase in ECF volume.
Shift of water within compartments - loss of hypertonic fluid
Adrenocortical insufficiency. Loss of NaCI. Is also called hyposmotic volume contraction.
1) The osmolarity of ECF decreases. As a result of the lack of aldosterone in adrenocortical insufficiency, there is decreased NaCl reabsorption, and the kidneys excrete more NaCl than water.
2) ECF volume decreases. Water shifts into the cells because ECF osmolarity decreases; as a result of this shift, ICF osmolarity decreases until it equals ECF osmolarity, and ICF volume increases.
3) Plasma protein concentration increases because of the decrease in ECF volume. Hematocrit increases because of the decreased ECF volume and because the RBCs swell as a result of water entry.
4) Arterial blood pressure decreases because of the decrease in ECF volume.
Clearance exercise - If the plasma [Na+] is 140 mEq/L, the urine [Na+] is 700 mEq/L, and the urine flow rate is 1 mL/min, what is the clearance of Na+?
T/F - RBF is directly proportional to the pressure difference between the renal artery and the renal vein and is inversely proportional to the resistance of the renal vasculature.
TRUE
T/F - Vasoconstriction of renal arterioles leads to a decrease in RBF
TRUE
Causes of vasoconstriction of renal arterioles
- Produced by activation of the sympathetic nervous system and angiotensin II.
- At low concentrations, angiotensin II preferentially constricts efferent arterioles, thereby “protecting” (increasing) the GFR.
- Angiotensin-converting enzyme inhibitors dilate efferent arterioles and produce a decrease in GFR; these drugs reduce hyperfiltration and the occurrence of diabetic nephropathy in diabetes mellitus.
Causes of vasodilation of renal arterioles
Leads to an increase in RBF.
Is produced by prostaglandins E2 and I2, bradykinin, nitric oxide, and dopamine.
Effects of ANP on renal arterioles
Causes vasodilation of afferent arterioles and, to a lesser extent, vasoconstriction of efferent arterioles.
Overall increases RBF and GFR.
T/F Measurement of renal plasma flow (RPF) can be done with the clearance of PAH
TRUE
Formula RBF
RBF = RPF / (1-Ht)
Note that the denominator in this equation, 1 - hematocrit, is the fraction of blood
volume occupied by plasma.
Effect of changes in Starling forces on GFR, RPF and Filtration Fraction
T/F - Na+-glucose cotransport in the early proximal tubule reabsorbs glucose from tubular
fluid into the blood. There are a limited number of Na+-glucose transporters and they can get saturated.
TRUE
cAt plasma glucose concentrations greater than ______ mg/dL, the carriers are saturated
350mg/dL
Substances with the ________ (highest/lowest) clearances are those that are both filtered across the glomerular capillaries and secreted from the peritubular capillaries into urine (e.g., PAH).
Highest
Substances with the _______ (highest/lowest) clearances are those that either are not filtered (e.g., protein) or are filtered and subsequently reabsorbed into peritubular capillary blood (e.g., Na+, glucose, amino acids, HC03- , CI-).
Lowest
T/F - Substances with clearance equal to GFR are glomerular markers
TRUE- Those that are freely filtered but not secreted nor reabsorbed (inulin).
Explain what happens with weak acids in urine
o weak acids have an HA form and an A- form.
o The HA form, which is uncharged and lipid soluble, can “back-diffuse” from urine to blood.
o The A- form, which is charged and not lipid soluble, cannot back-diffuse.
o At acidic urine pH, the HA form predominates, there is more back-diffusion, and there is decreased excretion of the weak acid.
o At alkaline urine pH, the A- form predominates, there is less back-diffusion, and there is increased excretion of the weak acid. For example, the excretion of salicylic acid (a weak acid) can be increased by alkalinizing the urine.
Explain what happens with weak bases in urine
o Weak bases have a BH+ form and a B form .
o The B form, which is uncharged and lipid soluble, can “back-diffuse” from urine to blood.
o The BH+ form, which is charged and not lipid soluble, cannot back-diffuse.
o At acidic urine pH, the BH+ form predominates, there is less back-diffusion, and there is increased excretion of the weak base. For example, the excretion of morphine (a weak base) can be increased by acidifying the urine.
o At alkaline urine pH, the B form predominates, there is more back-diffusion, and there is decreased excretion of the weak base.
TF/Px ratio - explain and examples
- Tubular fluid (TF) is urine at any point along the nephron.
- Plasma (P) is systemic plasma. It is considered to be constant.
TF/Px ratio compares the concentration of a substance in tubular fluid at any point along the
nephron with the concentration in plasma.
a. If TF/P= 1.0, then either there has been no reabsorption of the substance or reabsorption of the substance has been exactly proportional to the reabsorption of water.
For example, if TF/PN/ = 1.0, the [Na+] in tubular fluid is identical to the [Na+] in plasma.
For any freely filtered substance, TF/P = 1.0 in Bowman space (before any reabsorption or secretion has taken place to modify the tubular fluid).
b. If TF/P < 1.0, then reabsorption of the substance has been greater than the reabsorption of water and the concentration in tubular fluid is less than that in plasma.
For example, if TF/PNa+ = 8.0, then the [Na+] in tubular fluid is 80% of the [Na+] in plasma.
c. If TF/P >1.0, then either reabsorption of the substance has been less than the reabsorption of water or there has been secretion of the substance.
Na+ reabsorbption along the nephron
Explain the glomerulotubular balance in the proximal tubule
o Maintains constant fractional reabsorption (two-thirds, or 67%) of the filtered Na+
and H20.
1) For example, if GFR spontaneously increases, the filtered load of Na+ also increases. Without a change in reabsorption, this increase in GFR would lead to increased Na+ excretion.
2) However, glomerulotubular balance functions such that Na+ reabsorption also will increase, ensuring that a constant fraction is reabsorbed.
3) The mechanism of glomerulotubular balance is based on Starling forces in the peritubular capillaries, which alter the reabsorption of Na+ and H20 in the proximal tubule.
4) The route of isosmotic fluid reabsorption is from the lumen, to the proximal tubule cell, to the lateral intercellular space, and then to the peritubular capillary blood.
5) Starling forces in the peritubular capillary blood govern how much of this isosmotic fluid will be reabsorbed.
6) Fluid reabsorption is increased by increases in oncotic pressure of the peritubular capillary blood and decreased by decreases in oncotic pressure.
7) Increases in GFR and filtration fraction cause the protein concentration and oncotic pressure of peritubular capillary blood to increase. This increase, in turn, produces an increase in fluid reabsorption. Thus, there is matching of filtration and reabsorption, or glomerulotubular balance.
Effects of ECF volume on proximal tubular reabsorption
1) ECF volume contraction increases reabsorption. Volume contraction increases peritubular capillary protein concentration and oncotic pressure, and decreases peritubular capillary hydrostatic pressure. Together, these changes in Starling forces in peritubular capillary blood cause an increase in proximal tubular reabsorption.
2) ECF volume expansion decreases reabsorption. Volume expansion decreases peritubular capillary protein concentration and oncotic pressure and increases hydrostatic pressure Together, these changes in Starling forces in peritubular capillary blood cause a decrease in proximal tubular reabsorption.
Renal regulation of K
o K+ is filtered, reabsorbed, and secreted by the nephron.
o K+ balance is achieved when urinary excretion of r exactly equals intake of K in the diet.
o K+ excretion can vary widely from 1% to 110% of the filtered load, depending on dietary K+ intake, aldosterone levels, and acid-base status.
Summary of K processes across renal neprhon
1) Glomerular capillaries -filtration occurs freely across the glomerular capillaries. Therefore, TF/P of K in Bowman space is 1.0.
2) Proximal tubule reabsorbs 67% of the filtered K+ along with Na+ and H20.
3) Thick ascending limb of the loop of Henle reabsorbs 20% of the filtered K+.
Reabsorption involves the Na+-K+-2cl- cotransporter in the luminal membrane of cells in the thick ascending limb.
4) Distal tubule and collecting duct either reabsorb or secrete K+, depending on dietary K+ intake.
o Reabsorption of K involves an H+ / K+ -ATPase in the luminal membrane of the intercalated A cells. Occurs only on a low-K+ diet (K+ depletion). Under these conditions, K+ excretion can be as low as 1% of the filtered load because the kidney conserves as much K+ as possible. o Secretion of K+ occurs in the principal cells. Is variable and accounts for the wide range of urinary K+ excretion. Depends on factors such as dietary K+, aldosterone levels, acid-base status, and urine flow rate.
Causes of changes in K+ distal secretion
T/F Hyperaldosteronism causes hyperkalemia
FALSE - causes HYPOkalemia
What is the effect of loop and thiazide diuretics on K secretion?
o They increase K+ secretion.
o Loop and thiazide diuretics that increase flow rate through the late distal tubule and collecting ducts cause dilution of the luminal K+ concentration, increasing the driving force for K+ secretion.
o Loop and thiazide diuretics also increase Na+ delivery to the late distal tubule and collecting ducts, which leads to increased Na+ entry across the luminal membrane of principle cells, increased Na+ pumping out of the cells by the Na+-K+ pump, increased intracellular K+ concentration, and increased driving force for K+ secretion.
o Also, as a result of increased K+ secretion, these diuretics cause hypokalemia.
K+ sparing diuretics
o Decrease K+ secretion. If used alone, they cause hyperkalemia.
o Spironolactone is an antagonist of aldosterone; triamterene and amiloride act directly on the principal cells.
o The most important use of the K-sparing diuretics is in combination with thiazide or loop diuretics to offset (reduce) urinary K losses.
T/F - Excess anions (e.g., HC03-) in the lumen cause an increase in K+ secretion by increasing the negativity of the lumen and increasing the driving force for K+ secretion.
TRUE
Regulation of urea excretion
o Urea is reabsorbed and secreted in the nephron by diffusion, either simple or facilitated, depending on the segment of the nephron.
o Fifty percent of the filtered urea is reabsorbed in the proximal tubule by simple diffusion.
o Urea is secreted into the thin descending limb of the loop of Henle by simple diffusion (from the high concentration of urea in the medullary interstitial fluid).
o The distal tubule, cortical collecting ducts, and outer medullary collecting ducts are impermeable to urea; thus, no urea is reabsorbed by these segments.
o ADH stimulates a facilitated diffusion transporter for urea in the inner medullary collecting ducts. In the presence of ADH, urea reabsorption from inner medullary collecting ducts contributes to urea recycling in the inner medulla and to the addition of urea to the corticopapillary osmotic gradient.
o Urea excretion varies with urine flow rate. At high levels of water reabsorption (low urine flow rate), there is greater urea reabsorption and decreased urea excretion. At low levels of water reabsorption (high urine flow rate), there is less urea reabsorption and increased urea excretion.
Regulation of phosphate
o Eighty-five percent of the filtered phosphate is reabsorbed in the proximal tubule by Na+- phosphate cotransport. Because distal segments of the nephron do not reabsorb phosphate, 15% of the filtered load is excreted in urine.
o Parathyroid hormone (PTH) inhibits phosphate reabsorption in the early proximal tubule by activating adenylate cyclase, generating cAMP, and inhibiting Na+-phosphate cotransport. Therefore, PTH causes phosphaturia and increased urinary cAMP.
o Phosphate is a urinary buffer for H+; excretion of H2P04- is called titratable acid.
o Fibroblast growth factor (FGF23), which is secreted by bone, inhibits Na+-phosphate cotransport in the early proximal tubule.
Regulation of Ca2+
o 60% of the plasma Ca2+ is filtered across the glomerular capillaries.
o Together, the proximal tubule and thick ascending limb reabsorb more than 90% of the filtered Ca2+by passive processes that are coupled to Na+ reabsorption.
o Loop diuretics (e.g., furosemide) cause increased urinary Ca2+ excretion. Because Ca2+ reabsorption is driven by the lumen-positive potential difference in the loop of Henle, inhibiting the Na+-zCI–K+ cotransporter reabsorption with a loop diuretic inhibits the lumen-positive potential difference and thereby inhibits Ca2+reabsorption. If volume is replaced, loop diuretics can be used in the treatment of hypercalcemia.
o Together, the distal tubule and collecting duct reabsorb 8% of the filtered Ca2 + by an active process, based on hormonal signals -> PTH increases Ca2+reabsorption by activating adenylate cyclase in the distal tubule.
o Thiazide diuretics increase Ca2+ reabsorption in the early distal tubule and therefore decrease Ca2+excretion. For this reason, thiazides are used in the treatment of idiopathic hypercalciuria.
Regulation of Mg2+
o It is reabsorbed in the proximal tubule, thick ascending limb of the loop of Henle, and distal tubule.
o In the thick ascending limb, Mg2+ and Ca2+compete for reabsorption; therefore, hypercal- cemia causes an increase in Mg2+ excretion (by inhibiting Mg2+ reabsorption).
o Likewise, hypermagnesemia causes an increase in Ca2+ excretion (by inhibiting Ca2+ reabsorption).
What is a concentrated urine?
It is also called hyperosmotic urine, in which urine osmolarity > blood osmolarity.
When do we produce a concentrated urine?
When circulating ADH levels are high (e.g., water deprivation, volume depletion, SIADH)
Explain what is the corticopapillary osmotic gradient
o Is the gradient of osmolarity from the cortex (300 mOsm/L) to the papilla (1200 mOsm/L) and is composed primarily of NaCl and urea.
o Is established by countercurrent multiplication in the loops of Henle and urea recycling in the inner medullary collecting ducts.
o Is maintained by countercurrent exchange in the vasa recta.
Corticopapillary osmotic gradient -> countercurrent multiplier in the LOH
o Depends on NaCI reabsorption in the thick ascending limb and countercurrent flow in the descending and ascending limbs of the loop of Henle.
o Is augmented by ADH, which stimulates NaCl reabsorption in the thick ascending limb. Therefore, the presence of ADH increases the size of the corticopapillary osmotic gradient.
Corticopapillary osmotic gradient -> urea recycling and vasa recta
o Urea recycling from the inner medullary collecting ducts into the medullary interstitial fluid also is augmented byADH (by stimulating the UT1 transporter).
o Vasa recta are the capillaries that supply the loop of Henle. They maintain the corti- copapillary gradient by serving as osmotic exchangers. Vasa recta blood equilibrates osmotically with the interstitial fluid of the medulla and papilla.