Renal Physiology Part 2
Hypokalemia causes (6)
Increased K+ movement into cells (developing alkalosis) Decreased K+ intake Increased K+ loss (diarrhea, diuretics) hyperinsulinemia hyperaldosteronism iIcreased epi (B2 activity) without exercise
What 3 effects does angiotensin II stimulate?
Increased aldosterone Increased proximal reabsorption Increased filtration fraction
What are we relying on to correct our NaCl delivery to the distal tubule?
Increasing our GFR
Calcitonins main target is...?
Inhibition of osteoclastic activity --> net bone deposition
What is used emergently to lower plasma K+?
Insulin
What stimulates movement of K+ into cells? (3)
Insulin Epinephrine Aldosterone
What are three ways to get K_ back into the cell?
Insulin epinephrine (not preferred, has many other effects) aldosterone (not preferred, steroid, takes longer
How do you treat hyperkalemics?
Insulin infusion (with Calcium and glucose) - to protect heart and blood sugar
Efferent constriction has what effect on peritubular capillary pressure?
It decreases it
Describe the rate of blood flow through the renal medulla?
It has a low flow rate, so that we do not wash out the gradient created by the NaCl reabsorption in the thick ascending limb.
Where does angiotensin II come from?
It is formed by the successive actions of the enzyme renin and ACE.
The external sphincter of the bladder is controlled how?
It's skeletal muscle controlled by an alpha motor neuron
Juxtamedullary nephrons are? Cortical nephrons are?
JM nephrons --> salt conserving (long LOH) Cortical nephrons --> salt wasting (short LOH)
Prostaglandins preferentially dilate the _________?
Juxtamedullary afferent arteriole
What 2 things increase K+ secretion?
K+ and aldosterone in the distal tubule and cortical collecting duct
What must be given in conjunction with Amiloride?
K+ because it can deplete the body's stores
What ion will you "run out of" first for your Na+/K+/2 Cl-?
K+ because your K+ concentration outside the cell is low
What is the only kind of diuretic that will work on the principal cell?
K+ sparing
What kind of diuretic is amiloride?
K+ sparing diuretic - these are the only ones that will work on the principal cell.
What kind of diuretic are furosemide and thiazide?
K+ wasting diuretics
What are 3 causes of increased urination frequency?
Large urine volumes Decreased bladder capacity Increased end post-void residual volume from bladder outlet obstruction
Furosemide is a type of?
Lasics - loop diuretic
Where does ADH have its effects?
Late distal tubule and collecting ducts
What is a better buffer? Why?
Phosphate is a better buffer for our plasma pH than bicarbonate, but we can regulate HCO3-. Phosphate we have no control over because they come from food and are not tied to our breathing.
What are the two symptoms of diabetes inspidus?
Polyuria (12L + a day) Compensatory polydipsia
How is water loss controlled?
Predominantly by urine production, stimulated by decreases in osmolarity, or to a lesser degree, hypertension or high blood volume
What do prostaglandins do?
Preferentially dilate the salt-conserving juxtamedullary nephron afferent arteriole
Hypercalcemia causes (2)
Primary hyperparathyroidism Malignancy
What is the job of principal cells, vs intercalated cells?
Principal cells reabsorb Na+ and secrete K+ intercalated cells secrete H+.
Where is 2/3 of ca2+ reabsorbed paracellularly?
Proximal tubule, with some in the thin ascending loop paracellularly
In short, what is the action of aldosterone?
Reabsorption of Na+ and secretion of K+ in the distal tubule and cortical collecting duct. It does this by synthesizing more Na+ leak channels on the apical surface, and more Na+/K+ ATPases on the basolateral surface.
What are the systemic effects of PTH?
Reabsorption of bone Decreased renal calcium excretion (thru vitamin D) increased dietary calcium absorption
What are the 4 inputs for tubuloglomerular feedback?
Sympathetic stimulation Low blood pressure Low plasma Na+ B-adrinergics
ADH has what effect on urea?
ADH also causes the insertion of urea transport channels on to the apical surface, but only in the inner medullary collecting duct tubules.
What receptors use ADH and how?
ADH binds to V2 receptors in the kidney to augment water reabsorption, and binds V1 receptors on blood vessels to cause vasoconstriction
What does ADH do?
ADH in the bloodstream binds the V2 receptor on the basal side, activating cAMP. This synthesizes aquaporins and transfers them to the cell membraen.
ADH is made and released where?
ADH is synthesized in the hypothalamus and released from the posterior pituitary
What is the sodium excreting hormone?
ANP - whose analogue BNP is used to monitor CHF
Acidosis causes _______ at the cellular and kidney level
Acidosis causes hyperkalemia at the cellular and kidney level
What are the 3 effects of PTH?
Acutely and chronically increases Ca2+ reabsorption by: 1. Ca ATPase on basolateral surface 2. Na/Ca exchange on basolateral surface 3. Decreases PO4 reabsorption in the proximal tubule
What is the juxtaglomerular apparatus?
Afferent arteriole Efferent arteriole Distal tubule
What is the effect of alcohol on ADH?
Alcohol inhibits release of ADH
What happens in the presence of excessive ADH? (2)
Almost all water is reabsorbed from the distal tubule and collecting duct Urine production can be lower than 0.5 mL/min and osmolarity as high as 1600 mOsm
What is the anion gap?
An estimation of the anions that are not reported in normal blood chemistry. ex.) Normal plasma Na+ (140) K+ (4) = 144 cations Normal plasma Cl- = 105 HCO3 = 24 =129 anions The anion gap is 15
What is the micturition reflex?
An increase in all tension caused by filling of the bladder initiates a spinal reflex that results in increased activity of the parasympathetic nerves supplying the bladder.
What is the abnormal production of urine?
Anuria < 100 mL/24 hrs Oliguria 100-400 mL/day Polyuria more than 1800 mL day
Where are the tight tight junctions?
Ascending limb of LOH, distal tubule, and collecting duct
How do the intercalated cells regulate H+ excretion?
With some H+/ATPases facing the lumen, some with the H+/ATPase facing the blood. Meaning we can regulate both the pH of our urine and our blood this way, but via different intercalated cells.
2 causes of K+ imbalances
acidosis, or cellular damage
How do we measure how much H+ is in the urine?
Cannot measure the pH because there are many buffers involved within the urine. We must titrate all the way back up to neutrality to learn how much H+ is getting out
What are the two types of inadequate ADH activity?
Central (hypothalamic) Nephrogenic (V2 receptor defect)
What causes siadh?
hypersecretion from pituitary
Increased Na/K ATPase activity in skeletal muscle cells is caused by (3)
insulin B adrinergics (epinephrine) cell swelling
What does aldosterone stimulate?
reabsorption of Na+ and secretion of K+ by increasing the expression of the apical sodium leak channels and expression AND activity of the basolateral Na+/K+ ATPase pumps
What are symptoms of siadh? (5)
water retention, water intoxication causing cells to swell, weight fain, swelling, concentrated urine
How do we treat siadh? (3)
diuretics, hypertonic fluids, v2 receptor blocker
An ACE inhibitor uses what mechanisms to treat hypertensive patients?
-Block vasoconstriction -Block increased cardiovascular response -Block thirst from the hypothalamus -Block Aldosterone release
How does PTH work to increase Ca2_ reabsorption? (3)
1. Ca2+ travels down its concentration gradient via the TRPV5 channel. 2. PTH stimulates the TRPV5 channels to suck in even more Ca2+ from the lumen into the cell, which has the lowest Ca2+ concentration. 3. Some of the Ca2+ that comes in is bound to calbindin, and gets freed by the Ca2+ ATPase pump or the Na+/Ca2+ exchanger (2nd active transport).
What does angiotensin II do? (3)
1. Constricts vascular smooth muscle 2. Stimulates aldosterone release 3. Directly stimulates tubular sodium reabsorption
Difference in central DI vs nephrogenic DI
1. Impaired hypothalamic ADH synthesis/release 2. Low circulating ADH 3. Kidneys still respond to exogenous ADH Nephrogenic: 1. Imapired renal ADH receptors 2. High circulating plasma ADH levels 3. No effect of exogenous ADH
Control of water output (by ADH) comes from what 6 major stimuli?
1. Increased osmolality 2. Decreased arterial pressure 3. Decreased blood volume 4. Trauma 5. Surgery 6. Drugs (opiates and anesthetics)
Control of water intake comes from what 4 stimuli? (thirst)
1. Increased osmolarity of plasma 2. Decreased arterial pressure 3. Decreased blood volume 4. Angiotensin II
What are the 4 actions of ADH?
1. Increases permeability of entire collecting duct to water 2. Increases permeability of medullary collecting duct to urea 3. Decreases vasa recta blood flow 4. Incresaes expression of the Na/K/2Cl transporter in the TAL
What are the 2 actions of ADH?
1. Kidney - aquaporin channel insertion to reabsorb water (V2 receptor) 2- Vascular smooth muscle - contraction (V1 receptor)
What causes renin release from juxtaglomerular cells? (4)
1. Renal sympathetic nerves 2. Hypotension 3. Decrease in plasma sodium 4. B1 adrinergics
What are the 5 steps for micturition? (5)
1. Stretch receptors fire 2. Parasympathetic neurons fire 3. Motor neurons stop firing 4. Smooth muscle contracts (Internal sphincter is passively pulled open) 5. External sphincter relaxes
So if we want to excrete more acid, due to chronic acidosis, how can we achieve this?
1. We can increase/produce glutamine. 2. Glutamine is broken down in the cortex, and NH3 is generated. 3. NH3 which is neutral, can freely cross our cell membranes. 4. The NH3 will capture H+ ions floating around in our urine and soak them up to generate NH4+ to bring up the pH. Does not show up in the titratable acid excretion.
K+ daily intake
100 mmol/day
K+ daily excretion
100 mmol/day (90% urine, 10% feces)
What is a normal value for anion gap?
5-11 (excluding K+)
What is the net movement of urea?
50% of the urea that comes in will stick around in the medulla, while the other 50% gets filtered out at Bowman's capsule.
How much of our total plasma Ca2+ gets filtered?
50-60% (the rest is bound to albumin and other plasma prteins that cannot get across the glomerular capillaries)
What is the viable range for pH?
6.80-7.80
Normal plasma pH?
7.35-7.45, with typical value of 7.40.
Of the 120 mmol/day we lose of our sodium, where is it lost to?
98% is lost to urine 1% poop 1% sweat
Where is most of our K+ normally?
98% is within our cells. Abnormalities in extracellular K+ are most commonly tied to disordered exchange from the cellular and extracellular pools
What is the net effect of ADH? (2)
Increase the osmolarity of the renal medulla Through aquaporins increases the permeability of the entire collecting duct to water
Why is Ca2+ not available to be filtered at the real glomerulus? (2)
Because 99% of the calcium in the body is contained within bone. About half of the calcium in the plasma is bound to albumin and other large proteins.
Why is filtrate osmolarity about equal to interstitial osmolarity from Bowman's capsule to the descending LOH?
Because of "leaky" tight junctions and the paracellular movement of water
Where is the filtrate osmolarity very different from interstitial fluid osmolarity? Why?
Because of relatively "tight" tight junctions and the lack of paracellular movement of water, filtrate osmolarity from the ascending LOH through the CD
Why are thiazide not as strong as furosemide?
Because we are not reabsorbing as much Na+ here in the early distal tubule as we did in the thick ascending limb of LOH
By what point has all of your K+ been reabsorbed?
Before the distal tubule
When do tight junctions stop leaking and become tight?
Beginning at the ascending loop of Henle, the tight junctions become very tight and impede water movement by the paracellular pathway.
What does ANP do?
Binds at the lumen, activates cGMP, and inhibits the Na+ leak channels so that Na+ stays in the lumen to decrease Na+ reabsorption, giving a weak diuretic effect.
How is the bladder lined and controlled?
Bladder lined with smooth muscle Parasympathetic nerves contract the bladder through muscarinic receptor activation and sympathetic nerves (B3 receptor) relax the bladder
PTH seeks to free Ca2+ from?
Bones
How is the H+ dumped into the lumen buffered?
By HPO42- or SO42-
How is distal tubule Ca2+ reabsorption regulated?
By PTH
How does Amiloride work?
By blocking Na+ entry through the apical leak channel. This spares our K+
How do thiazides work?
By blocking the Na+ Cl- symporter and leaving behind particles in the lumen
How does furosemide act?
By blocking the Na+/K+/2 Cl- pump, keeping these ions in the lumen, producing a massive diuretic effect by acting as osmotic particles.
What is the purpose of the positive trans-epithelial potential?
By having the lumen be positive, it will drive the Na+, Ca2+ and Mg2+ through the paracellular pathway. Remember, enough + charges will allow for passage through the very tight junctions that don't allow water.
Where is urine most acidic?
By the distal tubule and collecting duct, where urine can drop to 4.5
By when is all of our K+ reabsorbed?
By the end of the thick ascending limb of LOH
How is water intake primarily controlled?
By thirst, stimulated by increased osmolarity, or to a lesser degree, hypotension or low blood volume.
Volatile acids
CO2+H2O-->H2CO3-->HCO3- + H+
What is a difference between cortical LOH and medullary LOH?
Cortical LOH are shorter and more NaCl wasting
What are the renal responses to respiratory alkalosis? (2)
Decrease tubular H+ secretion Dimnished reabsorption of filtered HCO3- (filtered HCO3- is lost in urine) (makes urine alkaline)
What are the 3 renal responses to metabolic acidosis?
Decreased filtered HCO3- load Increased H+ secretion If chronic, increased NH3 production (making urine acidic)
Decreases in GFR have what effect on Na+ excretion?
Decreases Na+ excretion
What are diseases caused by ADH?
Diabetes insipidus - lack of ADH hormone or action SIADH - oversecretion of ADH
Decreased Na/K ATPase activity in skeletal muscle cells can be caused by (2)
Digitalis (cardiac glycosides) ATP depletion
What 3 thins happen when distal tubula NaCl delivery falls?
Dilate afferent arteriole Release renin Constrict efferent
NSAIDs can exacerbate?
Diminished renal function
What is the first site of endocrine control of electrolytes?
Distal tubule
Where is the macula densa?
Distal tubule
Where does ammonium trapping happen?
Distal tubule and collecting duct, where [H+] is 1000x greater in the lumen.
Where does aldosterone have its action?
Distal tubule and cortical collecting duct principal cells.
What causes excretion of K+ in the urine?
Due to K+ secretion by the distal tubule principalcell
Why does renal medullary interstitial fluid have a high osmolarity?
Due to the accumulation of sodium and chloride from the thick ascending limb of the loop of henle and urea from the inner medullary collecting duct.
When is calcitonin most relevant?
During pregnancy
Almost all of our Na+ regulation is targeted at what store of Na+?
ECF
What factors is the body trying to control?
ECF volume and ECF osmolarity.
What are the ways we can acquire acidosis or alkalosis?
Excessive CO2 accuulation (respiratory acidosis) Diminished HCO3 levels (metabolic acidosis) Diminished CO2 levels (respiratory alkalosis) Elevated HCO3 levels (metabolic alkalosis)
Causes of hyponatremia (5)
Excessive water intake or retention MDMA Advanced renal failure (impaired exccretion) Excessive sodium excretion (thiazides, diuretics) Endocrine impairment (SIADH, hypoadlsoteronism)
Renal net acid excretion includes what? (4)
Free H+ Titratable acids bound to HCO3- Phosphate and sulfate buffers NH4+
Urine flows how?
From the renal pelvis into the bladder through the ureters, propelled by peristalsis
Non-volatile acids (fixed acids)
H+ + SO42- +PO42- (from amino acid metabolism)
what part of the reaction does carbonic anhydrase participate in?
H2Co3<--> H2O & CO2
What happens in our descending LOH?
H2O is reabsorbed NaCl and urea diffuse in paracellularly
Plasma pH is tightly tied to?
HCO3, because the lungs can regulate CO2 eliminiation adn the kidneys can regulate HCO3 excretion
Increased anion gap acidosis
HCO3- decreases adn replaced by other anions so no Cl- shift ex.) renal failure and DKA
Normal anion gap acidosis
HCO3- decreases and replaced by Cl- shift ex.) diarrhea or simple gain of H+
What are the 4 main sodium-conserving mechanisms?
Hemodynamics Angiotensin II Sympathetic nervous system Aldosterone
What is the feedback regulation for aldosterone?
High K+
What is a secondary effect of of aldosterone?
Higher blood volume and/or blood pressure
The normal bladder holds? How often do we urinate?
Holds 300-500 mL Adults void 5-6x a day
What three things stimulate aldosterone release?
Hyperkalemia Angiotensin II (to a lesser extent) ACTH
What are consequences of decreased Na/K ATPase activity (2)
Hyperkalemia and depolarization
When is PTH released?
Hypocalcemia
Hypocalcemia cause
Hypoparathyroidism
The tubular fluid in the thick ascending limb is _________?
Hyposmotic
What is the only reason K+ would have been excreted in the urine?
If aldosterone was released
Where does PTH-dependent Ca2+ reabsorption happen?
In the distal tubule
Where are the major osmoreceptors?
In the hypothalamus
What are the tw H+-ATPase transporters?
In the intercalated cells of the collecting duct One secretes H+ into the lumen of the collecting duct Other secrets hydrogen across the basolateral surface of the cell Their activity is determined by PLASMA PH
Where is the first place ADH sensitive changes are made?
In the late distal tubule, increasing urea and water reabsorption
Where does peristalsis for urination occur?
In the ureters
What are the major and minor stimulus for ADH?
Major: increase in plasma osmolarity Minor: Reduced plasma volume, decreased arterial BP
Aldosterone is a _________ that comes from where?
Mineralocorticoid that comes from the adrenal cortex.
What is net acid excretion?
NAE = NH4+ + TA - HCO3 TA: titratable acid
What diuretic acts on the early distal tubule? And what ions are moving?
Na+, Cl-, thiazides
If urea accounts for half of the particles accumulating in our medulla, what accounts for the other half?
Na/K/2Cl transporter in the thick ascending limb, stimulated by ADH
Where does thiazide have its actions?
NaCl symport in the early distal tubule
What is true, in the absence of ADH?
No water is reabsorbed from the distal tubule and the collecting duct, making urine production as high as 20 mL/minute with osmolarity as low as 70 mOsm
Does the early distal tubule have a transepithelial potential?
No.
Where does ADH have its activity?
On the collecting duct.
Where does ANP have its effects?
On the medullary collecting duct
Where does aldosterone have its actions?
On the principal cells of the distal tubule and collecting duct
When does the Na+/K+/2 Cl- transporter work?
Only when all 4 positions are filled.
How does PTH have its actions on bone?
Osteoblasts have receptors for PTH, which will stimulate osteoclasts to reabsorb bone
What is the effect of PTH on phosphates?
PTH inhibits proximal tubule PO4 reabsorption PTH increases renal PO4 excretion (pee out phosphates)
Hyperkalemia causes?(3)
Reduced urinary K+ excretion (kidney disease) Increased K+ release from cells (metabolic acidosis, tissue damage, exercise) Decreased cellular K+ uptake (digitalis) decreasing Na+/K+ ATPase activity Hypoaldosteronism Insulin deficiency
What does tubuloglomerular feedback do?
Regulates the delivery of NaCl to the macula densa of the distal tubule by altering the balance of afferent and efferent arteriolar constriction
Why does PTH effect our phosphate levels?
Remember, the goal of PTH is to free up Ca2+ for the blood. The less plasma PO4, means more free Ca2+
Respiratory adjustments vs renal/metabolic adjustments to pH
Respiratory adjustments --> occur within minutes Renal/metabolic adjustments --> occur over days
The internal sphincter (bladder neck) is contracted by ?
The SNS activation of a-1 adrinergic nerves.
What happens if distal tubular NaCl delivery falls?
The afferent arteriole dilates, and renin release stimulates angiotension II to constrict the efferent arteriole. These two changes increase glomerular capillary hydrostatic pressure, and the consequent increase in GFR should correct the sodium chloride delivery deficit.
What produces the positive trans-epithelial potential?
The apical K+ leak channel.
What accounts for 20% of renal tubule reabsorption?
The electroneutral Na+/K+/2Cl- transport protein in the thick ascending limb.
What happens to the filtrate if ADH is around? What happens to the filtrate if there is no ADH?
The filtrate will start to look like the ISF surrounding it, meaning the filtrate osmolarity will get all the way around 1400 but the time it is leaving the collecting duct. If there is no ADH, the filtrate will stay around 100 mOsm, despite coming in at about 150 mOsm
What are the body's 2 requirements to produce concentrated urine?
The first is that antidiuretic hormone must cause an increase in water and urea permeability of the late distal tubule and collecting duct. Second is that there must be an osmotic gradient between the tubular filtrate (in the late distal tubule and collecting duct) compared to the renal interstitial fluid
How does ADH have its effects? (2)
The late distal tubule and collecting ducts respond to ADH by inserting aquaporin water channels on to the apical membrane of the epithelial cells, allowing water to move based on the osmotic gradient. ADH also causes the insertion of urea transport channels on to the apical surface, but only in the inner medullary collecting duct tubules.
What is the major effector of ECF osmolarity and volume?
The presence (or lack thereof) of ADH
In chronic acid-base disturbances, what happens?
The unaffected system attempts to restore pH. ex.) Chronic respiratory acidosis --> renal retention of HCO3- can help restore pH back to normal ex.) chronic metabolic acidosis --> hyperventilation can help restore pH back toward normal
Where does ang II have its effects on Na+ reabsorption?
These bind to the proximal tubule cell to activate a Ca2+/calmodulin second messenger system Angiotensin II and NE increase Na+ reabsorption in the proximal tubule by stimulating the Na+/H+ exchanger, to enhance Na retention and permitting volume contraction alkalosis, while also increasing the number of Na+ leak channels
How do NO and ANP have their effects?
They cause the mesangial cels surrounding the capillaries to relax, increasing permeability to Na+
How do NE, epi, and ADH have their effects?
They contract the mesangial cells surrounding our capillaries to make them less permeable to Na+
What diuretic targets the early distal tubule?
Thiazides (less powerful than furosemide)
What is the major "diluting" segment?
Thick ascending limb of LOH
Where does furosemide act?
Thick ascending limb of LOH
What is the site of Ca2+ and 50% of the Mg2+ reabsorption?
Thick ascending limb of Loop of Henle
What does it mean to be a K+ wasting diuretic?
Think about the action of furosemide on the thick ascending limb of the LOH. If we block the action of the Na+/K+/2 Cl- on the cell, all of these will be left in the lumen upstream of the distal tubule. Thus, the K+ leak channels in place in the ascending limb will continue to leak out K+ down the gradient, and we will lose K+ in the urine.
Why would you want to increase the permeability of the medullary collecting duct to urea?
To keep urea within the renal medulla. Urea accounts for half of the particles accumulating in our medulla.
What is the job of the counter current exchanger?
To perfuse the deep medulla without disrupting the concentration gradient
What is the job of the intercalated cells of the distal tubule?
To regulate the pH of our urine by regulating H+ excretion.
What is the osmolarity like in the thick ascending loop of henle?
Tubular fluid osmolarity drops dramatically (as low as 100 mOsm/L).
How does the micturition reflex stop?
Until the tension plateaus, the reflex fatigues, or the internal and external bladder sphincter relax allowing urination
What is treatment for diabetes inspidus?
VP analogue Diuretics
What is the major job of the collecting duct?
Water and urea (in the medullary CD) reabsorption from the filtrate.
7 causes of hypernatremia
Water deprivation (dehydration) Intake of salt without water Impaired thirst mechanism Diarrhea Hypertonic fluids DI Hyperaldosteronism
The net effect of angiotensin II is?
We filter more, but also reabsorb more Na+.
Where are the JG cells?
afferent arteriole
What is the risk with siadh?
dilutional hyponatremia (nausea, vomiting, confusion, seizing, coma, death)
High plasma Ca2+ will cause C cells of the thyroid to release?
calcitonin
The consequence of increased Na/K ATPase activity is (2)
decreased cell osmolarity hypokalemia and hyperpolarization
What is responsible for renal medullary interstitial osmolarity? (3)
due to the selective accumulation of sodium chloride and urea within the medullary interstitium The NaCl accumulation occurs predominantly in thick ascending limb of the loop of Henle. In its renal tubule segment, water cannot pass through the tight junctions, so there is the creation of a high osmolarity in the interstitium, and a low osmolarity in the tubular filtrate. The continuous of loss of sodium chloride into the renal medullary interstitial space is called countercurrent multiplication. maximum of about 1600 mOsm, with around 800 mOsm being due to urea, and most of the remainder due to NaCl
What is the biggest effect on urea concentration due to?
due to water movement rather than to urea movement.
