Renal/Urinary Flashcards
Why are IVPs not helpful in animals with ureteral obstructions?
poor filling of obstructed kidney
risk of nephrotoxicity
Name 4 anti-spasmodics and their MOA
- Prazosin: alpha1 nonselective adrenergic antagonist
- Tamsulosin: alpha1a antag
- Verapamil: CCB
- Papverine: PDE inhibitor
At what stage of AKI does irreversible damage occur?
maintenance
What are 4 methods to measure GFR?
Iohexol clearance
Endogenous creatinine clearance
Scintigraphy
Inulin clearance
5 infectious causes of AKI?
RMSF Borrelia burgdorferi Babesia Leishmania Leptospirosis
2 scoring systems for AKI?
RIFLE (risk injury failure end stage kidney disease) & AKIN (acute kidney injury network)
T/F: the RIFLE score has been shown to perform better than the AKIN scoring system for AKI
False- there has been similar performance
T/F: a relative increase in plasma creatinine of >150% or 0.3 mg/dl increase from baseline is associated with increased in-hospital mortality with AKI?
TRUE!!
Name some causes of hemodynamic AKI
decreases in renal perfusion or excessive vasoconstriction; can be rapidly reversible if inciting cause is eliminated
Name and describe the 4 phases of AKI
- Initiation- first stages of renal injury; interventions at this phase may prevent progression to more severe injury; biochemical values may be normal
- Extension- cellular injury progresses to cell death; biochemical and clinical manifestations become evident
- Maintenance- cell death and regeneration occur simultaneously; removal of inciting cause will not reverse damage but may allow balance to shift in favor of parenchymal regeneration
- Recovery- improvement in GFR and tubular fxn; may last weeks to months
Name and describe the 4 stages of VAKIN staging scheme
Stage 0- increase 300% or absolute creat value >4
List 4 common laboratory abnormalities in CKD
- Increased BUN
- Increased creatinine
- Hyperphosphatemia
- Hypercalcemia
- Increased CK
- Hypokalemia
- Metabolic acidosis
Name three reasons a patient with CKD might be anemic
- Decreased RBC life span
- Decreased EPO production
- Blood loss from uremic ulcers
What is “glomerulotubular imbalance?”
This is a phenomenon in which patients with CKD present with azotemia and concentrated urine (USG > 1.030). The pathophysiology has not been determined.
List 4 breeds that have congenital renal dysplasia
Lhasa apso, Shih tzu, Standard poodle, Wheaten terrier, Chow, Alaskan malamute, Miniature schnauzer, Dutch kooiker
List 5 breeds that have familial primary glomerulopathies
Samoyed, English cocker, English springer, Bull terrier, Dalmatian, Doberman, Mastiff, Newfoundland, Rottweiler, Pembroke welsh corgi, Beagle, Wheaten terrier
List 3 breeds that have congenital polycystic kidney disease
Bull terrier, Cairn terrier, Westie
List 3 breeds that have familial amyloidosis
Shar pei, English foxhound, Beagle
List 3 breeds of cats that have congenital/familial renal disease
Persian - polycystic kidney disease
Abysinnian - amyloidosis
Siamese - amyloidosis
What variables are associated with decompensation or mortality for cats with CKD?
Plasma creatinine concentration Urine protein-to-creatinine ratio Urine albumin-to-creatinine ratio Leukocytosis Hyperphosphatemia
What variable in canine CKD has been found to be negatively associated with mortality?
Body condition score
Approximately what percentage of cats with CKD will have normal sized kidneys? small kidneys? large kidneys?
Normal 40%
Small 33%
Large 27%
WHat is the hallmark renal palpation of AKI?
large, painful kidneys
T/F- the urine pH of dogs with AKI is usually alkalotic?
false- usually acidotic unless current UTI
What type of crystals in large #s are supportive of ethylene glycol intoxication?
calcium oxalate
How does uremia and various infectious diseases (such as Lepto) affect coagulation?
cause a thrombocytopathy, prolonging BMBT despite normal coagulation profile
Does ethylene glycol usually cause a hypo or hypercalcemia? why?
hypocalcemia secondary to severe hyperphosphatemia and chelation of calcium by oxalate
what is the hallmark AUS finding in renal lymphoma?
diffusely thickened cortex and perirenal hypoechoic halo
what is the hallmark AUS finding with ethylene glycol intoxication
renal cortices and medulla (lesser extent) are hyperechoic secondary to oxalate crystal deposition increasing the echogenicity
why is GFR usually not helpful in detection of AKI?
because the degree of impairment in GFR is almost always detectable by surrogate markers such as plasma creatinine
What titer is suggestive of Leptospirosa in AKI, with supported clinical signs and absence of recent vaccination
1:800
Titers for Lepto in AKI may be negative for how many days of illness?
7-10 days
Write the equation for anion gap
(Na+K)- (HCO3 + Cl)
Normal value is 12-26
Value is 5 meq/L higher in cats vs dogs
Fluid overload is typically described as what % increase in body weight?
10%
T/F: diuretics have been found to improve outcome in established AKI?
False- no evidence to support this; there have been trends towards increased mortality in AKI in humans
What are some ways to measure urine other than closed collection/indwelling catheter?
collection of naturally voided urine, metabolic cage, weighting cage bedding and litter pans, using body weight before/after natural voiding
insensible losses estimate? how many ml/kg/day?
12-29 ml/kg/day
what is the calculation for the dose of bicarbonate?
0.3 x body weight (kg) x base deficit=bicarb (meq/L)
fluid rates will typically need to be administered at higher rates during what phase of AKI?
recovery`
List 4 triggers of ADH secretion
Elevated plasma osmolality, hypovolemia/hypotension, nausea, increased Angiotensin II concentration
What are 2 triggers for ADH suppression and diuresis?
Atrial natriuretic hormone and ethanol
What are 3 components ADH requires to perform it’s anti diuretic function?
Functional tubular system, a medullary concentration gradient of Na and urea, and a functional ADH receptor system to use this gradient
Which diuretic affects mainly the proximal tubule with some action on the late distal tubule?
Carbonic anhydrase inhibitors ie acetazolamide
What are 2 drug classes that affect the late distal tubule and collecting duct?
Aldosterone antagonists, distal diuretics
What is the site of action of mannitol?
All segments of the nephron but mainly the loop of Henle
What is the one diuretic discussed that expands the ECF?
Mannitol
What are 2 diuretics that may potentially increase calcium?
Amiloride, and triamterene
What are 2 diruretic classes that may cause a metabolic acidosis?
Aldosterone antagonists and carbonic anhydrase inhibitors
Which diuretic does not reach it’s tubular site of action through the urinary space?
Spironolactone
Why would a dog with CHF and severe proteinuria be more difficult to treat than one without proteinuria?
Serum diuretic concentration remains low due to Hypoproteinemia which results in decreased tubular secretion of the diuretic which is then partially neutralized by binding to urinary proteins
T/F: Mannitol is freely filtered by the glomerulus and does not undergo tubular reabsorption, resulting in increased tubular flow rate and diuresis
T
How is mannitol potentially useful in recovering metabolic stability in decompensated chronic renal disease unrelated to oliguria?
The increased urine flow rate induced by mannitol reduces tubular resorption of urea, which increases urea’s urinary clearance, thus decreasing it’s serum concentration
List 4 other potential benefits for mannitol in AKI
Decreased renal vascular resistance, decreased hypoxia cellular swelling, decreased renal vascular congestion, decreased tendency of erythrocytes to aggregate, protection of mitochondrial function, decreased free radical damage, and potentially renoprotection if administered before a toxic or ischemic insult
What is acetazolamide’s mechanism of action?
Inhibits type II (cytoplasmic) and type IV (membrane) CA’s from the proximal tubular epithelium, leading to a net decrease in the proximal reabsorption of Na bicarbonate.
What is the main clinical application of carbonic anhydrase inhibitors?
Treatment of elevated intra ocular pressure in glaucoma
How are thiazides potentially useful in diabetes insipidus?
They paradoxically reduce urine production in severely polyuric animals by inducing a mild hypovolemia and increasing proximal tubular sodium conservation
What are aquaretics?
Diuretics that antagonize V2 receptors in the kidney and promote solute-free water clearance
Why specifically should K be monitored carefully when potassium-wasting diuretics are used in patients with cardiac disease?
Hypokalemia increases the risk of digoxin toxicity
Why does end stage liver disease lead to ascites and edema?
Hypoalbuminemia, activation of RAAS, and portal hypertension
What are the diuretic goals in urinary diseases such as cystitis and what is the recommended diuretic strategy?
Increase urine flow; water +/- salt, thiazides
What is the main diuretic goal in liver failure and what is the recommended diuretic strategy?
Decrease interstitial fluid volume; spironolactone +/- furosemide
List 9 indications for diuretic therapy
Oligoanuria (ARF), uremic crisis, nephrotic syndrome, urinary diseases (stones, cystitis), CHF, hypertension, liver failure, hypercalcemia, hyperkalemia, iatrogenic fluid overload, intracranial pressure, glaucoma, diabetes insipidus
Name the 7 major functions of the kidney
- Regulation of water and electrolyte balance
- Excretion of metabolic waste
- Excretion of bioactive substances (hormones, foreign substances)
- Regulation of arterial blood pressure
- Regulation of red blood cell production
- Regulation of vitamin D production
- Gluconeogenesis
By which mechanisms the kidney participates to the regulation of blood pressure?
- Regulation of blood volume (maintenance of sodium and water balance)
- Generation of vasoactive that regulate smooth muscle in the peripheral vasculature
Which organs produce EPO?
- Kidneys (mainly)
- Liver (small amount)
In which condition the renal EPO secretion is stimulated?
Reduction of partial pressure of oxygen in the kidneys (particularly a group of cells in the interstitium) as in anemia, arterial hypoxia and inadequate renal blood flow
How do kidneys contribute to the formation of Vitamin D?
Last biochemical transformation to the active form of vitamin D
What part of the nephrons does the cortex contain?
Glomeruli + thick ascending limb of Henle’s loop + cortical collecting duct
What part of the nephrons does the medulla contain?
Collecting ducts (except thick ascending limb of Henle’s loop and cortical collecting duct)
Name the component parts of the nephron
Glomerulus - Proximal convoluted tubule - Straight proximal tubule - Descending thin limb of Henle’s loop - Ascending thin limb of Henle’s loop - Thick ascending limb of Henle’s loop - Distal convoluted tubule - Connecting tubule - Cortical collecting duct - Medullary collecting duct
What are the 3 layers of the renal filtration barrier?
capillary endothelium of the capillaries, basement membrane, single-celled layer of epithelial cells (podocytes)
What is the role of the glomerular mesangial cells in the central part of the glomerulus between and within capillary loops?
Phagocytosis and removal of trapped material from the basement membrane
Contraction (large number of myofilament) influencing filtration by the renal corpuscles
How is the concentration of the ions and low-molecular-weight organic solutes in the glomerular filtrate compared to blood plasma
Similar
What is the meaning of “freely filtered” substances.
Substances that move between the plasma and the glomerular filtrate. The amount filtered is in exact proportion to the fraction of plasma volume that is filtered.
Name at least 9 substances that are “freely filtered”
Ions: sodium, potassium, chloride, bicarbonate
Glucose, urea, aminoacids
Peptides: insuline, ADH
What is GRF? Definition, normal value
The volume of glomerular filtrate, it has a volume of 180L/day in a healthy adult(human)
What is the percentage of this substances absorption in the tubules? H2O Sodium Glucose Urea
H2O –> 99.0%
Sodium –> 99.5%
Glucose –> 100%
Urea–> 50%
Name three metabolic processes that occur in the tubular cells.
1 Gluconeogenesis
2 Synthesis of ammonium from glutamine
3 Production of bicarbonate
name the three types of signals/messenger that regulate the renal function
Neural signals, hormonal signals and intrarenal chemical messengers
name the glands/organs involved in secretion of hormonal signals and which are this hormones
adrenal gl: aldosterone, cortisol, epi and norepi pituitary gl: ADH parathyroid heart: natriuretic peptides
which two hormones participate in the regulation of sodium excretion by the kidney??
aldosterone and the natriuretic peptides
How is the oncotic pressure at the beggining of the glomerular capillaries compared to the systemic arterial plasma? how does it change as it advances through the capillaries
Similar at the beggining, then increases as protein-free fluid filters out of the capillary, concentrating the protein.
Does a low RBF (renal blood flow) increases or decreases the oncotic pressure in the glomerular capillary? why? how this affects the NFP and GRF
It increases as more fluid is removed in the filtration proccess. It lowers the net filtration pressure, hence the glomerulate filtration rate.
what is the filtration fraction?
the variations in the relative amount of plasma that are filtered, the ratio RPF/GFR, which is normally 20%. (20% of the plasma entering the kidney is removed from the blood)
what is the Filtered Load?
the amount of substance that is filtered per unit time. GFR × plasma concentration= filtered load (for freely filtered subst)
name the most important factor tending to change the GFR
renal artery pressure=systemic art pressure (in healthy kidney)
how does the kidney (and other organs) autoregulate to counteract increases in arterial blood pressure
By a rise in vascular resistance.
why is creatinine a good indicator of GFR
Because the amount of creatinine produced is he same as the creatinine excreted each day.
What happens with the plasma creatinine when there is a decrease of GFR by 50%
it doubles the plasma concentration (1mg/dL to 2mg/dL) to keep excreting the same amount.
What happens to most major cellular nutrients in the glomeruli?
They are freely filtered
Where and how are most of the major filtered cellular nutrients reabsorbed?
Proximal tubule
Actively transported via a symporter with sodium across the luminal membrane (most of them are Tm systems = tubular maximum-limited)
What are the characteristics associated with Tm systems (tubular maximum-limited system)? (= What should we expect?)
- Luminal concentration can be reduced virtually to 0
- The kidneys do not help regulate their levels in the body
- If filtered load > Tm, excretion in the urine (ex: glucose, acetate, beta-hydroxybutyrate)
- Transporter specificity (except for amino acids)
- Inhibition by drugs and monogenetic diseases (ex: heavy metal)
What are the receptors responsible for glucose reabsorption?
Apical membrane: SLGUT sodium-dependent glucose symporter
Basolateral membrane: GLUT uniporter (gradient)
Are tight junctions permeable to glucose?
No (no back-leak)
What is the reabsorptive capacity of glucose in cats-dogs?
Cats: 260-280 mg/dL
Dogs: 180-220 mg/dL
What are the 2 major solutes in the extracellular fluids?
Sodium and chloride
Briefly summarize the tubular mechanisms for reabsorption of sodium, chloride and water
- Sodium: mainly an active, transcellular process driven mostly by Na-K-ATPase at the basolateral side
- Chloride: passive (paracellular) and active (transcellular), directly or indirectly coupled with the reabsorption of sodium
- Water: reabsorption by osmosis
Where is the sodium reabsorbed in the nephron (and which percentage for each portion)? (same values for Chloride)
- 65% proximal tubule
- 25% thin and thick ascending limb of Henle’s loop
- 10% distal convoluted tubule and collecting duct system
What are the transporters for sodium found on the basolateral membrane?
- Na-K-ATPase pumps to keep the intracellular sodium concentration lower than the surrounding media
(- Na-HCO3 multiporter in the proximal tubule -> symport for 1 Na and 3 HCO3)
What are the transporters for sodium found on the luminal membrane?
- Na-H antiporter (majority)
- Na-nutrient symporter
- Na-phosphate symporter
- Na-sulfate symporter
- Sodium channel
Where is the water reabsorbed in the nephron (and which percentage for each portion)?
- 65% proximal tubule
- 10% descending thin limb of Henle’s loop
- (Variable) collecting-duct system
What are the different routes for water movement?
- Net diffusion through the lipid bilayer
- Through aquaporins in plasma/basolateral membranes
- Through the tight junctions between the cells
What are the segments of the renal tubule with 1. a high permeability to water, 2. a low permeability to water, 3. a variable permeability to water (on the luminal side -> basolateral side always permeable due to aquaporins)
- Proximal tubule / Descending thin limb of Henle’s loop
- Ascending thin and thick limb of Henle’s loop / Distal convoluted tubule
- Collecting-duct system
What happens when the collecting-duct system’s water permeability is very high instead of very low?
As the hypo-osmotic fluid entering the collecting-duct system from the distal convoluted tubule flows through the cortical collecting ducts, water is rapidly reabsorbed
This is because of the large difference in osmolality between the hypo-osmotic luminal fluid and the iso-osmotic (285 mOsm/ kg) interstitial fluid of the cortex.
what hormone is the responsible of controlling the reabsorption in the collecting - duct system?
ADH can make the reabsorption of water very high or very little.
How is the water reabsorption in tubular segments beyond the loop of Henle?
The water permeability of the distal convoluted tubule is always very low and unchanging, similar to that of the ascending limbs of Henle’s loop. hypo-osmotic fluid entering the distal convoluted tubule from the thick ascending limb of Henle’s loop becomes even more hypo-osmotic
How does ADH convert epithelial water permeability from very low to very high?
In the absence of ADH, the water permeability of the cortical and outer medullary collecting duct is very low, and little if any water is reabsorbed from these segments, resulting in water diuresis.
in the presence of high plasma concentrations of ADH, the water permeability of all regions of the collecting ducts is great, and only a small volume of maximally hyperosmotic urine is excreted.
where are the renal receptors for ADH, called vasopresine Type 2 receptors in the collecting ducts?
in the basolateral membrane of the principal cells and are different from the vascular receptors (vasopressin type 1)
how do the kidneys generate a hyperosmotic medullary interstitium?
there is a gradient of osmolality, increasing from a nearly iso-osmotic value at the corticomedullary border, to a maximum of greater than 1000 mOsm/kg at the papilla.
What are the parameters affected by the regulation of total body salt and water? (4)
- Water balance
- Salt balance
- Osmolality
- Blood pressure
What are the 4 effectors of blood pressure regulation?
- Heart (contractility, rate)
- Peripheral arterioles (resistance)
- Large veins (compliance and capacity to hold blood)
- Kidneys (output of salt and water)
What are the two major sets of detectors for the short-term control of blood pressure? Which one serves as de facto blood volume detectors and play an important role in regulating salt and water? Where is the neural information sent to for integration?
- Mechanoreceptor (= classic baroreceptor) in the carotid arteries and arch of the aorta
- Cardiopulmonary baroreceptor in the cardiac atria and parts of the pulmonary vasculature -> +/- blood volume detectors pressure in the atria and pulmonary vessels rise when blood volume increases and vice-versa)
- Brainstem vasomotor center for both sets of detectors
- Hypothalamus for cardiopulmonary baroreceptors (ADH)
What are the fast, intermediate and slow mechanisms involved in arterial blood pressure regulation?
- Fast (seconds): Baroreceptor reflex -> cardiac and vascular actions (increased HR, increased arterioles resistance, decreased venous compliance)
- Intermediate (minutes to hours): Renal actions -> peripheral resistance
- Slow (hours to days): Renal actions -> excretion of salt and water
What other set of detectors are involved in the intermediate-term control of blood pressure? What type of cells are they?
- Intrarenal baroreceptors in renal afferent arteriole (not neural baroreceptors but granular cells, aka juxtaglomerular cells)
The reflex control of GFR is mediated by what?
Afferent and efferent arteriolar resistance
What causes changes in afferent and efferent arteriolar resistance?
Changes in sympathetic nerve activity and circulating levels of angiotensin II
When plasma volume is increased, renal sympathetic nerve activity is ________ and renin secretion is ____________
Both are decreased
By what 3 mechanisms does angiotensin II exert its sodium-retaining effects in the kidney?
- Vasoconstriction of renal arterioles thereby reducing renal blood flow and GFR
- Constriction of glomerular mesangial cells, thereby reducing GFR
- Stimulates sodium reabsorption in the proximal tubule by stimulating Na-H exchange
When the level of angiotensin II is high, do the kidneys excrete more or less sodium?
The kidneys filter less sodium (due to decreased GFR), and reabsorb more sodium, resulting in less excretion of sodium
What is the term for the mechanism by which angiotensin II directly alters proximal tubule reabsorption of sodium in response to high pressure?
Pressure natriuresis
How does pressure natriuresis work?
Increases in renal artery pressure are detected by the intrarenal baroreceptors and decreases the amount of intrarenal angiotensin II. This causes the Na-H exchangers to be withdrawn, along with a reduction in the activity of the basolateral Na-K-ATPase.
What is the net result of high renal artery pressure in regards to sodium?
Less sodium absorption and more presentation of sodium to the loop of henle, and therefore more sodium excretion
True or False: The degree of pressure natriuresis varies with the volume status of the ECF compartment
TRUE
If ECF is normal or high and renal artery pressure rises, pressure natriuresis and diuresis are effective in increasing sodium and water and reducing blood volume
If ECF is low and renal artery pressure rises, there is a decreased loss of sodium and water
Fluid loss from the body results in what 3 changes that lower GFR?
- Increased constriction of the afferent and efferent arterioles (mediated by renal nerves and angiotensin II)
- Decreased arterial hydraulic pressure
- Increased arterial oncotic pressure
Hydraulic pressure of the peritubular capillary (Ppc) is determined by what?
- Arterial pressure
2. Combined vascular resistance of the afferent and efferent arterioles
Oncotic pressure of the peritubular capillary is determined by what?
- Arterial oncotic pressure
2. Filtration fraction (GFR/RPF)
Fluid loss from the body results in what 3 changes that lower GFR?
- Increased constriction of the afferent and efferent arterioles (mediated by renal nerves and angiotensin II)
- Decreased arterial hydraulic pressure
- Increased arterial oncotic pressure
When the ECF is expanded, what three changes have occurred to increase GFR and sodium excretion?
- Decreased plasma oncotic pressure (from dilution of plasma proteins)
- Increased arterial pressure
- Renal vasodilation secondary to decreased activity of the renal sympathetic nerves and decreased angiotensin II
3 separate, redundant mechanisms regulating renin secretion
- neural signals
neural baroreceptors (detector) produce signals via renal sympathetic nerves (beta 1 adrenergic receptor) that stimulate granular cells of the afferent arteriole to stimulate rein secretion
beta 1 adrenergic receptors on the granular cells stimulate renal secretion - afferent arteriolar pressure
pressure falls, renin production increases
granular cells act as “intrarenal baroreceptor”. They respond to changes in pressure in the afferent arterioles. both as detectors and as signal generator (releasing renin) - NaCl at the macula densa
This is also intrarenal, It detects sodium, but does not detect blood pressure
Macula densa cells in the thick ascending limb sense sodium chloride delivery by changing the uptake of salt, with subsequent osmotic swelling. Change in cell volume lead to release of chemical transmitters that alter renal secretion.
it measures the amount of sodium chloride that leaves the thick ascending limb directly bathing the macula densa cells of juxtaglomelular apparatus and delivered to the distal convoluted tubule
Among 3 regulators of renin secretion (1. neural signal, 2. afferent arteriolar pressure, 3. NaCl at the macula densa) which one is the most significant actions of circulating angiotensin 2 produced by global RASS
General arteriole vasoconstriction (1. neural signal)
Which one is responsible for determining the setpoint for mean blood pressure: 1, brainstem versus 2. kidney,
Then how?
- Kidney, by controlling the amount of sodium- hence volume in the vascular space on a long term basis
Where are most osmoreceptors located?
In the tissues surrounding the 3rd cerebral ventricle
What happens when baroreceptor and osmoreceptor inputs oppose each other? (i.e. plasma volume and osmolality are decreased)
In general, because of the high sensitivity of the osmoreceptors, the osmoreceptor influence dominates when changes in osmolality and plasma volume are small to moderate.
When there is a very large change in plasma volume, maintaining plasma volume will predominate
What other factors can influence ADH secretion (other than plasma volume and osmolality)?
Pain, fear, and drugs such as alcohol
In diabetes insipidus, what changes are seen with ADH?
Either ADH production is low or absent, or the cells cannot respond to ADH
True or false: The same stimulants for ADH secretion (decreased plasma volume and increased osmolality) are stimulants for thirst
TRUE
Angiotensin II also stimulates thirst
Describe the effects of the RAAS system and natriuretic peptides in congestive heart failure
The RAAS system is increased resulting in increased fluid volume and edema. The large fluid volume is sensed by the baroreceptors and should normally result in decreased ADH secretion; however, these signals are increased, and the kidneys operate under a new set point in which normal sodium excretion only occurs at the expense of excessive fluid volume.
High levels of natriuretic peptides are also seen which partially counteracts the sodium-retaining signals to the kidney
Give three reasons for excessive blood volume leading to hypertension
- Renal glomerular disease leading to increased release of renin
- Tumor of the adrenal cortex that leads to excessive aldosterone production
- Gain of function mutation in the sodium reabsorptive mechanism in the collecting ducts
Explain the concept of ‘‘glomerulotubular balance’’
A change in GFR automatically induces a proportional change in the reabdorption of sodium by the proximal tubules -> the fraction of sodium reabsorbed proximally remains relatively constant (about 65%) but not the total amount (Rq: if that fraction changes, it is because of factors other than GFR)
What are the two lines of defense preventing changes in renal hemodynamics from causing large changes in sodium excretion?
- Autoregulation of GFR (prevents GFR from changing too much in direct response to changes in blood pressure)
- Glomerulotubular balance (blunt the sodium-excretion response to GFR changes)
What is the effect of aldosterone and where?
- Increases reabsorption of sodium in the connecting tubules and collecting ducts of distal nephrons, and more specifically by the principal cells -> increases blood volume and mean blood pressure, ‘‘fine tuning’’
- Stimulates sodium transport and retention by other epithelia (sweat, salivary ducts, intestine)
What stimulates/inhibits the secretion of aldosterone?
Stimulates: - Angiotensin 2 - Hyperkalemia Inhibits: - Atrial natriuretic factors
What is the percentage of the filtered sodium already reabsorbed when the urine passes through the collecting duct system? What is the percentage on the influence of aldosterone?
- 90%
- About 2% on the influence of aldosterone -> regulation of sodium reabsorption in the collecting duct system is a ‘‘fine-tuning’’
How does aldosterone act to modulate sodium reabsorbtion?
Increases the activity or number of luminal membrane sodium channels and basolateral membrane Na-K-ATPase pumps
What is the major function of the ADH with respect of water and sodium absorption.
to increase the permeability of the cortical and medullary collecting ducts to water, thereby decreasing the excretion of water. In addition to this effect, ADH also increases sodium reabsorption by the cortical collecting duct, one of the same segments influenced by aldosterone.
Which hormones enhance sodium reabsorption and which decrease it?
Cortisol, estrogen, growth hormone, thyroid hormone, and insulin enhance sodium reabsorption, whereas glucagon, progesterone, and parathyroid hormone decrease it.
Name and explain the two categories of mechanisms of sodium excretion
(1) proximal nephron mechanisms (control of GFR, pressure natriuresis, and, to a lesser extent, changes in Starling forces) that lead to coupled changes in sodium and water excretion and (2) distal nephron effects in which sodium can be reabsorbed independently of water.
The proximal mechanisms are primarily involved in excreting excess ECF volume, whereas the distal mechanisms alter sodium excretion when ingestion of sodium is not balanced by ingestion of water. Both types of mechanisms can alter blood pressure
Name the three categories of renal nerve effects
1-Stimulates renin secretion via a direct action on β1
-receptors of granular cells.
2- Stimulates sodium reabsorption via a direct action on tubular cells (multiple receptors); one site affected is the proximal tubule.
3- Stimulates afferent and efferent arteriolar constriction (α-adrenergic receptors).
Describe how water excretion or water output is regulated. Is it regulated by water intake?
No, water output is not regulated by the inputs. The major signals regulating water excretion originate from baroreceptors that assess vascular fullness and osmoreceptors that assess plasma osmolality
What are the two components of water excretion?
1 proximal
nephron component, in which water is absorbed along with sodium as an isotonic fluid,
2 distal nephron component, in which water can be reabsorbed independent of sodium.
*The proximal nephron component is primarily a mechanism to regulate ECF volume in response to changes in blood pressure, while the distal nephron rate of water reabsorption is independent of sodium reabsorption. It is determined mainly by ADH, which increases the water permeability of the collecting ducts.
What is ADH, where is it produced and how is its production regulated (name the receptors and where they are
ADH is a peptide produced by a discrete group of hypothalamic neurons whose
cell bodies are located in the supraoptic and paraventricular nuclei and whose axons terminate in the posterior pituitary gland, from which ADH is released into the blood. The most important of the inputs to these neurons are from cardiovascular (cardio pulmonar and arterial )baroreceptors and osmoreceptors.
How does sodium delivery to the distal nephron affect potassium secretion?
If more sodium is delivered, more sodium is taken up by the principal cells; therefore, more sodium is pumped out by the Na-K-ATPase, which causes more potassium to be pumped in
How does distal nephron flow rate affect potassium secretion?
Increased flow in the distal nephron is detected by the mechxnosensitive elements of the principal cells This results in bending of the cilia which results in intracellular calcium release and activation of BK channels. Usually increased flow is due to increased sodium.
Increased flow also sweeps potassium away that reaches the tubule by secretion, which maintains the gradient for continued secretion
How does the concentration of non chloride anions affect potassium secretion?
If sodium reabsorption is restricted due to replacement of luminal chloride with other anions (which cannot accompany the sodium), the luminal membrane becomes depolarized which increases the driving force for potassium secretion
How does dietary potassium affect potassium secretion?
High-potassium diets lead to insertion of ROMK channels which leads to higher potassium secretion
In chronic low potassium ingestion, the H-K-ATPase activity in the intercalated cells is increased, which leads to more efficient reabsorption of filtered potassium
True or false:
Diuretics that act in the proximal tubule and loop of henle inhibit potassium reabsorption
TRUE
These diuretic inhibit sodium reabsorption and potassium reabsorption.
Why is there increased potassium secretion when diuretics that affect the proximal tubule and loop of henle are used?
These diuretics result in increased flow and increased delivery of sodium to the distal nephron which results in increased potassium secretion
What happens to potassium when a patient with CHF (and high aldosterone) its given diuretics?
The diuretics increase fluid delivery to the distal nephron so the patient now has increased flow and increased aldosterone. This results in marked increases in potassium secretion and excretion
In a patient with CHF and increased aldosterone, why do they not eliminate large amounts of potassium?
They have increased aldosterone which increases potassium secretion, but they also have reduced flow to the distal nephron
How can we prevent excessive potassium secretion in patients with CHF that need diuretics?
Drugs that block the actions of aldosterone can be given (they act by inhibiting the sodium reabsorption and by blocking aldosterone’s stimulation of potassium channels)
True or false:
Blocking sodium reabsorption in the proximal nephron results in increased potassium secretion, whereas blocking sodium reabsorption in the distal nephron does not
TRUE
How does alkalosis affect potassium levels?
During alkalosis, low extracellular hydrogen ion concentrations induces the influx of hydrogen ions that are normally bound to intracellular buffers. The loss of positively charged hydrogen ions is balanced by the uptake of other cations, such as potassium
How does low intracellular pH affect potassium levels?
The low intracellular pH inhibits pumps, which allows potassium to escape from cells (muscle cells in particular) to increase plasma potassium.
Normally this increase in plasma potassium would stimulate potassium uptake by Na-K-ATPase in principal cells, but the low intracellular pH also inhibits these pumps
What is the typical cytosolic concentration of potassium ? extracellular concentration of potassium?
- 140-150 mEq/L
- 4 mEq/L
What does the intracellular to extracellular potassium ratio influence?
Resting membrane potentials -> excitability of nerves and muscle
(a raise in the EC potassium depolarizes the resting membrane potential / a decrease hyperpolarizes)
What are the possible sources of loss for potassium?
- urine
- feces
- sweat
- vomiting
- diarrhea
What is the tissue contributing most to the sequestration of potassium?
Muscles (largest intracellular volume)
What are the (4) major factors involved in potassium homeostasis? Briefly explain the mechanism
- GI tract (‘‘gut brain’’) -> send hormonal and neural messages to target organs such as kidneys
- Insulin -> stimulate K+ intracellular movement by activating more N-K-ATPase channel
- Epinephrine -> stimulate N-K-ATPase channel, especially during exercise and trauma (K= leaked out due to firing action potentials and tissue damage)
- ECF H+ concentration: acidosis is associated with extracellular movement of K+ (vice and versa)
major 3 differences between the renal handling of sodium and potassium
- filtered load: Na is x30-40 greater than potassium
- Na in only excreted, never secreted - K is both reabsorbed and secreted and regulation is primarily focused on secretion
- renal handling of Na: much greater effect on potassium than vice versa
Which plays a major role when it takes into account potassium regulation, between reabsorption and secretion?
regulation is primarily focused on secretion
What is a daily filtered load if normal plasma K level 4 mEq/L x GFR 150 L/day
600 mEq/day
How much potassium is reabsorbed in proximal tubule and thick ascending limb, respectively?
65%, 25%
which location plays a major role in K secretion when total body potassium is high?
distal nephron (distal convoluted tubule and connecting tubule, can secret 20-150% when normal or high potassium diet, little secretion when low-potassium diet or potassium depletion)
name the cells in charge of secretion and absorption of potassium and which pumps or channels they use.
Secretion of potassium by principal cells involves the uptake of potassium from the interstitium via the Na-K-ATPase and secretion into the tubular lumen through channels.
Type A intercalated cells reabsorb potassium via
the H-K-ATPase in the luminal membrane, which actively takes up potassium from the lumen and then allows potassium to enter the interstitium across the
basolateral membrane via K channels.
Name the two major K channels in the principal cells
ROMK (standing for renal outer medulla, because that is where they were first identified) and BK
(as each channel has a “big” capacity to secrete potassium)
Are both channels ROMK & BK regulated in the same way ??
No, it depends on the rate of secretion. they will both be closed in a low dietary load K. In the case of a normal load just the ROMK will be open and if there is a high excretion rate.
What is the role of aldosterone in potassium secretion?
Aldosterone, as well as increasing expression of the Na-K-ATPase, also stimulates the expression of ROMK channels in the distal nephron. Both actions have the effect of increasing potassium secretion. Greater pumping by the Na-K-ATPase supplies more potassium from the interstitium to the cytosol of the principal cells, and more ROMK channels provide more pathways for secretion
What are the 3 different routes for the entry of acids or bases?
- Processing of ingested food
- Secretions of the GI tract
- Generation of acids and bases from metabolism of stored fat and glycogen
What are the 3 components of a buffer system?
- Weak acid
- Conjugate base
- Free protons
Where buffers can be found in the body?
- ECF
- ICF (cytosol of various cells)
- Matrix of bone
What are the 2 more important buffers in the ECF?
Phosphates and albumin
What circulating cells act like an important acid-base buffer?
Red blood cells (uptake or release of H+ by hemoglobin depending of pH -> dissociation curve)
What are the 2 ways the kidneys balance the excretion of bicarbonate.
(1) allow some filtered bicarbonate to pass through to the urine and (2) secrete bicarbonate via Type B intercalated cells
How do the kidneys excrete acid load?
Hydrogen ions are secreted and combine with the conjugate base of buffers in the tubular lumen other than bicarbonate, thereby generating the acid form of the buffer. The acid form of that buffer is excreted in the urine.
what are the two sources for non-bicarbonate buffers
Filtration and synthesis. Normally, the most important of the filtered buffers is phosphate, while ammonia is the most important synthesized buffer
T/F: addition or removal of hydrogen ion alters total body bicarbonate
True (for every hydrogen ion, added to the body, one bicarbonate disappears. Therefore, to maintain balance it is necessary to generate a new bicarbonate to replace the one that was lost: This is responsibility of kidneys)
T/F: unlike other buffer system in the body, in CO2-bicarbonate system, the concentration of the weak acid (CO2) is essentially constant
True (this is because partial pressure of CO2 is regulated by respiratory system to be about 40 mmHg)
T/F: input and output of CO2 and bicarbonate are handled independantly
True (one cannot be excreted as the other). If CO2 is excessively generated, CO2 cannot be converted into fixed acid and excreted by kidneys. Increased CO2 input must be balanced by increased CO2 exhalation from lungs
T/F: normally, the sum of GI tract secretions is nearly acid-base neutral, i.e. the secretion of acid in one site (for example stomach) and is balanced by the secretion of bicarbonate elsewhere.
True (typically, there is a small net secretion of bicarbonate into the lumen of GI tract, resulting in the addtion of protons to the blood.
What does the liver transform ammonium into?
Urea and glutamine
Is the renal handling of urea acid-base neutral?
Is the renal handling of glutamine acid-base neutral?
Yes (urea)
No, glutamine = bicarbonate + ammonium
How does glutamine enter into the tubular lumen?
Filtration and secretion from renal interstitium
What happens to glutamine in the proximal tubule cells?
Transformed back into bicarbonate (reabsorbed into interstitium and blood) + ammonium NH4+ (secreted back into the lumen)
How does ammonium cross cellular membranes?
Hydrated ion -> channels or transporters
- NHE-3 antiporter in exchange for sodium
- NH4+ can use channels and transporters not completely selective for their ions (K+ or H+, ex. Na-K-2Cl)
What happens to ammonium in the thick ascending limb?
80% of the tubular ammonium is reabsorbed, mostly by the Na-K-2Cl multiporter, and accumulated in the interstitium
What happens to ammonium in the medullary interstitium ducts?
Secretion into the lumen, mainly by parallel transport of hydrogen ions and ammonia
How does the increased uptake of calcium from the tubular lumen (in response to increased PTH) result in decreased urinary calcium excretion?
It stimulates basolateral extrusion by a combination of Ca-ATPase activity and Na-Ca antiporter activity
What effect does PTH have on tubular reabsorption of phosphate?
Increased PTH reduces the proximal tubular reabsorption of phosphate leading to increased urinary phosphate excretion and lowered extracellular phosphate concentration
Why does increased PTH not lead to an increased level of phosphate in the plasma?
Although increased PTH stimulates the release of phosphate from the bones and increased intestinal absorption of phosphate, it also acts to inhibit tubular phosphate reabsorption - in fact plasma phosphate may actually decrease when PTH levels are high
Chronic increased levels of PTH have what effect on bone? Intermittent increased levels of PTH have what effect on bone?
Chronic elevations in PTH lead to enhanced bone resorption and bone thinning
Intermittent elevations in PTH lead to increased deposition of calcium into bone
What percentage of plasma phosphate is protein bound?
5-10%
How much of the plasma phosphate is filtered at the renal corpuscle?
90-95%
How much of the filtered plasma phosphate is reabsorbed and where in the kidney is this primarily done?
75% is reabsorbed primarily in the proximal tubule (in symport with sodium)
How does acidosis effect phosphate concentration?
Systemic acidosis promotes the release of calcium and phosphate from bone. This results in an increase in plasma phosphate and an increased filtered load of phosphate which results in more titratable buffer to remove excess hydrogen ions that promoted phosphate release in the first place
What other hormones (not PTH or vitamin D) alter phosphate reabsorption?
insulin increases reabsorption
glucagon decreases reabsorption
How is elevated plasma phosphate in chronic renal failure treated?
By giving large amounts of oral calcium which then complexes with the phosphate and reduces the amount of absorbable phosphate
How does providing vitamin D to a patient with hyperphosphatemia due to chronic renal failure result in a decrease in plasma phosphorus?
Vitamin D should increase GI absorption of phosphate but it also has the ability to lower the synthesis of PTH which is more important (reduces the excessive resorption of bone)
What are the 3 compartments in which Ca is distributed?
Bone (‘‘buffer’’), ECF (crucial for the function of cells), ICF
Which organ predominantly regulates Ca?
GI tract
How do the kidneys play a role in Ca regulation?
- Excretion of Ca
- Transformation of Vitamin D in active form
In which form is Ca in the blood?
- 45% free ionized form (Ca2+)
- 15% complexed to anions such as citrate and phosphate
- 40% bound to proteins
What is the role of Ca in the ECF?
- Triggers rapid exocytosis of hormones and neurotransmitters
- Signals contraction in smooth and cardiac muscle cells
- Regulates the threshold for excitation in nerve and muscle cells
How does pH influence the level of free calcium ions?
(competition between Ca and H to bind anionic sites in albumin) -> high pH -> proton dissociation from albumin -> more Ca bind to albumin -> decreased concentration of free calcium ions
What are the effects of hypocalcemia?
HypoCa fools sodium channels into sensing more depolarization than actually exists, leading to spontaneous firing of motor neurons and inappropriate muscle contraction
What are the effects of hypercalcemia?
Deterioration of excitable cell function, including CNS depression, muscle weakness, and GI tract immotility
What are three key hormones that control calcium and phosphate?
- active form of vitamin D (1,25-(OH)2D): mainly stimulates intestinal absorption of calcium and phosphate
- PTH (parathyroid hormone): regulates what it is in ECF (plasma calcium concentration) by reabsorption of bone and move calcium into blood
- fibroblast growth factor 23 (FGF23)
3 crucial processes how those key hormones (active vitamin D, PTH, FGF23) regulate calcium and phosphate.
- input of calcium and phosphate into body from GI tract
- excretion of calcium and phosphate by kidneys
- movement of both substances between plasma and bone
Which two organs turn vitamin D (cholecalciferol) into its active form (calcitriol) through hydroxylation? And which two hormones regulate this step?
Hydroxylation step occurs in liver and kidney (proximal tubular cells).
This step is regulated by PTH and FGF23. Specifically, PTH stimulates this step, wherease FGF23 inhibits it.
What are major action of calcitriol on effector systems (GI, kidney, and bone)
- GI: stimulate transcellular absorption of calcium, and to a lesser extent, by duodenum
- Kidney: stimulate the renal-tubular reabsorption of both calcium and phosphate
- Bone: permissive for normal bone turnover
Y/N, vitamin D3 is synthesized in the skin by the action of UV, another member, vitamine D2 (ergocalciferol) is ingested in food derived from plants. They are equivalent in terms of their physiological roles in body and can be considered to the same vitamin
Yes
The influences of vitamin D on bone and the kidney are far more important than its actions on the GI tract to stimulate absorption of calcium and phosphate.
No (far less important)
What are three regulators of PTH and how each regulator interact with PTH? (i.e. A regulator inhibit or stimuate PTH). Among three regulators, which one is primary regulator?
- plasma calcium: decreased calcium stimulates PTH secretion, increased calcium inhibit secretion
- plasma phosphate: elevated phosphate stimulates PTH secretion,
- calcitriol: inhibit PTH synthesis
On a moment-to-moment basis, calcium is the primary actue regulator
State 5 distinct effects of PTH on calcium and phosphate homeostasis, depends on which organ and whether rapid or slow process.
- Bone, rapid: acutely increases movement of calcium and phosphate from bone into ECF
- Bone, slow: PTH stimulates bone remodeling process
- Kidney, slow: stimulate kidneys to generate calcitriol
- Kidney, rapid: increases renal tubular calcium resorption
- Kidney, rapid: reduces proximal tubular reabsorption of phosphate, thereby increasing urinary phosphate excretion and decreasing extracellular phosphate concentration
