Physiology / general Flashcards
Where is aldosterone produced? What stimulates / inhibits its production?
- Zona glomerulosa of the adrenal cortex
- Stimulates: angiotensin II, hyperkalemia, ACTH
- Inhibits: ANP, dopamine
What are the effects of ANP to stimulate natriuresis
- Dilation of afferent arteriole and constriction of efferent arteriole -> increased GFR
- Inhibition of sodium reabsorption in collecting ducts
- Inhibition of renin secretion
- Inhibition of aldosterone secretion
What is the effect of catecholamines on natriuresis
Catecholamines increase sodium reabsorption by:
- vasoconstriction the efferent arteriole (-> lower hydrostatic pressure in peritubular capillaries and increased reabsorption)
- stimulation of Na reabsorption in the proximal tubule (alpha1-adrenergic effect)
- stimulation of renin release (beta1-adrenergic effect)
What vasopressin receptors are found in the kidneys and where? What is their effect?
V2 receptors (Gs type of G protein coupled receptor), on the principal cells in the late distal convoluted tubule and collecting duct
Trigger expression of aquaporin 2 on the luminal membranes on the principal cells
Name causes of central and nephrogenic diabetes insipidus
Central:
- Congenital
- Traumatic
- Neoplastic
- Idiopathic
Nephrogenic:
- Congenital
- Glucocorticoids
- E Coli endotoxin
- Hypercalcemia
- Hyperthyroidism
- Liver insufficiency
- Hypoadrenocorticism
- Post-obstructive diuresis
- Polycystic kidney disease
- Chronic nephritis
What is the clearance of a substance
The volume of plasma that is cleared from the substance per unit of time
Formula for renal clearance of a substance
Clearance (mL/min) = [urine concentration (mg/mL) * urine output (mL/min)] / plasma concentration (mg/mL)
What fraction of CO is the renal blood flow? How is it separated between cortex and medulla?
22-25% of CO
Medullary blood flow is only 1-2% of entire blood flow (cortex gets most of it)
Name hormones / molecules causing vasoconstriction / vasodilation of renal arterioles. Indicate if there is a difference between afferent and efferent arterioles.
Vasoconstriction:
- Norepinephrine, epinephrine (both but slightly more efferent)
- Angiotensin II (more efferent)
Vasodilation:
- Dopamine
- Prostaglandins E2 and I2
- Bradykinin
- NO
- ANP (afferent only with slight vasoconstriction of efferent)
What are the 2 mechanisms of auto-regulation of renal blood flow
- Myogenic (afferent arteriole contracts in response to stretch)
- Tubuloglomerular feedback:
–> decreased Cl in tubule is sensed by the cells of the macula densa in the thick ascending limb of the loop of Henle -> juxtaglomerular cells in the afferent arteriole trigger dilation of afferent arteriole and release of renin (-> angiotensin II -> constriction of efferent)
–> increased renal arterial pressure –> increased delivery of fluid to macula densa –> constriction of afferent arterial
What is the renal filtration fraction? What is it normally?
Fraction of renal plasma flow that is filtered across the glomerular capillaries
FF = GFR / RPF = GFR / [RBF * (1 - Hct)]
with RPF = renal plasma flow and RBF = renal blood flow
Normal is 20% (varies for each solute)
What law determines glomerular filtration
Starling’s law
Jv = Kf*[(Pc-Pi) - s(pc-pi)]
where the interstitial space is the Bowman’s space here
How to calculate the reabsorption rate of a substance
Reabsorption rate = filtered load - excretion rate
Filtered load = GFR * plasma concentration of substance
Excretion rate = UOP * urine concentration of substance
At what urine pH will weak acids / weak bases be better excreted in urine
- Weak acids in alkaline urine
- Weak bases in acidic urine
Because they are in ionized form in the urine and cannot “back-diffuse” in the blood
Explain glomerulotubular balance
It means that the proximal tubular reabsorption rate of Na+ changes with the glomerular filtration rate to maintain a constant fractional reabsorption of Na and H2O.
When GFR increases, the oncotic pressure in the peri-tubular capillaries increases (proteins are more concentrated due to higher fluid filtration). Following Starling’s law, this increases reabsorption of water and solute in the peri-tubular capillary, which maintains the osmotic gradient between the peri-tubular space and the tubular cell, which promotes re-absorption of water and solutes.
In what tubular segments is Na reabsorbed? In what proportions and with which other solutes?
- Proximal tubule: 2/3 (67%)
- Early proximal tubule:
Cotransport with glucose, amino-acids, HCO3-, and water (absorbed proportionately with water, no change in osmotic pressure)
Countertranspport with H+ - Late proximal tubule:
Cotransport with Cl - Thick ascending limb of the loop of Henle: 25%
Cotransport with K and Cl (Na-K-2Cl transporter)
Absorbed without water - Distal tubule and collecting duct: 8%
- Early distal tubule (5%):
Cotransport with Cl - Late distal tubule and collecting duct (3%): Na channels under influence of aldosterone (Principal cells)
What is the excretion fraction of Na and K
Na: < 1% (freely filtered but almost fully reabsorbed)
K: variable (1-110%)
In what tubular segments is K reabsorbed/secreted? In what proportions?
- Proximal convoluted tubule: reabsorbs 2/3 (67%)
- Thick ascending loop of Henle: reabsorbs 20% (Na-K-2Cl transporter)
- Late distal tubule:
- secretion based on aldosterone and acid-base status (Principal cells)
- or re-absorption (countertransport with H+ in intercalated cells) only in situations of K depletion
What factors influence K+ distal tubular excretion
- Aldosterone (influences secretion from Principal cells)
- Acid-base status (influences secretion in intercalated cell based on H+-K+ countertransport)
- Dietary K+ (influences reabsorption in intercalated and principal cells based on intracellular K)
- Diuretics:
- loop / thiazide diuretics (due to increased tubular flow rate and Na delivery to distal tubule)
- potassium sparing diuretics (decrease K secretion from Principal cells)
- Luminal anions: increased tubular anions (HCO3) increase K secretion
Why does alkalosis increase renal K excretion
- Decreased H+ secretion so decreased K+ reabsorption by H+-K+ transporter in intercalated cells of late distal convoluted tubule
- Increased K+ secretion in distal convoluted tubule due to more negative tubular fluid (presence of HCO3)
What is the action of loop diuretics / thiazide diuretics on urinary Ca excretion
- Loop diuretics: inhibit Ca reabsorption in the thick ascending loop of Henle
- Thiazide diuretics: increase Ca reabsorption in early distal tubule
What are the 2 mechanisms required for establishment of the corticomedullary gradient? What hormone influences these mechanisms?
- Countercurrent multiplier (loop of Henle, requires vasa recta)
- Urea recycling (inner medullary collecting duct)
Both under the influence of ADH
What is the urine osmolality in the different tubular segments in the presence / absence of ADH?
- Without ADH:
- Proximal convoluted tubule: 300 mOsm/L
- Thick ascending limb of loop of Henle: 100
- Late distal convoluted tubule: 100
- Collecting duct: 50 - With ADH:
- Proximal convoluted tubule: 300
- Descending limb of loop of Henle: progressively increases to 1000-1200
- Ascending limb of loop of Henle: progressively decreases to 300
- Distal convoluted tubule: 100
- Collecting duct: progressive increase up to 1200
What are the most important tubular segments for urine dilution / urine concentration
- Urine dilution: thick ascending limb of loop of Henle +/- early distal convoluted tubule
- Urine concentration: collecting ducts
What hormones act on the kidney? What are their actions?
- Aldosterone:
- Increased Na reabsorption from distal tubule principal cells
- Increased K secretion from distal tubule principal cells
- Increased H+ secretion from distal tubule intercalated cells - Angiotensin-II: increased Na reabsorption and H+ secretion (=HCO3 reabsorption) in proximal tubule
- ADH: increased water permeability in late distal tubule and collecting duct principal cells (V2 receptors)
- ANP: decreased NA reabsorption
- PTH: increases Ca reabsorption from distal convoluted tubule, decreases P reabsorption from proximal convoluted tubule (+ stimulates 1alpha-hydroxylase to produce calcitriol in proximal tubule)
Where is HCO3 reabsorbed? By what mechanism?
Proximal tubule
- HCO3- + H+ -> CO2, H2O in tubular lumen
- CO2 diffuses in tubular cell
- CO2 + H2O -> HCO3- + H+ in cell
- H+ gets excreted in exchange for Na+, HCO3- gets reabsorbed across baso-lateral membrane
/!\ allows HCO3 reabsorption but not H+ excretion
What is the renal mechanism of respiratory acidosis / alkalosis compensation
Respiratory acidosis:
- Increased pCO2 -> increased H+ in cells (including proximal tubular cells)
- Increased H+ excretion in proximal tubule (against Na+)
- H+ + HCO3- -> H2O + CO2 in tubular lumen
- CO2 diffuses in tubular cell, CO2 + H2O -> HCO3- + H+
- HCO3- reabsorbs at baso-lateral membrane of tubular cell -> metabolic alkalosis
Opposite for respiratory alkalosis
Also causes increased H+ secretion in distal convoluted tubule and collecting duct
What are the 2 mechanisms of H+ excretion in the distal tubule and collecting duct
- Excretion as a titratable acid (H2PO4-)
- Excretion as NH4+
In both cases H+ is secreted from intercalated cells by H+ ATPase (under control of aldosterone) while HCO3- is absorbed (“new” HCO3- for the body). H+ then combines with HPO4-2 or NH3 and is eliminated in urine (cannot diffuse back in cells)
What regulates H+ excretion in the distal tubule / collecting duct
- Aldosterone (increases H+ ATPase activity)
- Acidosis (increases NH3 production)
- Kalemia (hyperkalemia inhibits NH3 synthesis, hypokalemia stimulates NH3 synthesis)
What is the normal GFR in cats and dogs
3 mL/kg/min
What is the normal urine osmolality in cats and dogs
Cats: 1250-2100 mOsm/kg
Dogs: 500-1400 mOsm/kg
What hormones are produced in the kidney
- Renin
- Erythropoietin
- Calcitriol
What are the components of the renal vasculature
- Renal artery
- Lobar artery
- Arcuate arteries
- Interlobular arteries
- Afferent arteriole
- Efferent arteriole
- Peritubular capillaries (vasa recta)
- Venous system
What is the molecular size limit for glomerular filtration
70 kDa
What are the hydrostatic / oncotic pressures in the glomerular
capillaries, Bowman’s capsule, peritubular capillaries, and peritubular interstitium? Where does filtration / absorption happens
- Filtration in glomerulus
- Absorption in tubules
See picture (but oncotic pressure in glomerular capillary should be 25)
What is the transport maximum capacity? What is it for glucose?
Concentration of a solute at which transporters for tubular reabsorption become saturated
For glucose: 10 mmol/L in dogs, 13-16 mmol/L in cats
What is the range of BP for which renal auto-regulation is possible
MAP 80-180 mmHg
What part of the loop of Henle is permeable to water
Thin descending limb of the loop of Henle (thin ascending and thick ascending are impermeable)
Where is urea recycled in the nephron and under the influence of what hormone
Gets reabsorbed from the inner medullary collecting duct and joins the thin ascending loop of Henle (recycle)
Urea reabsorption stimulated by ADH (stimulates UT1 - transporter for urea)
(/!\ 50% of filtered urea is reabsorbed in proximal tubule, but recycling happens in the collecting duct)
How is GFR measured
GFR = renal clearance of a substance that is not reabsorbed or secreted -> substance measured in urine for 24h to calculate clearance
Clearance = (concentration in urine * volume of urine in defined time) / plasma concentration
Theoretically should use inuline. In practice can estimate with creatinine at steady state.
How is the relationship between GFR and creatinine
Logarithmic (when creatinine is low, an increase in creatinine indicates a major drop in GFR)
Where is renin produced? Under what influence?
- Juxtaglomerular cells of the renal afferent arteriole
- Influence of:
- Tubuloglomerular feedback (Cl delivery to the cells of the macula densa in the thick ascending limb of the loop of Henle)
- Baroreceptors: carotid sinus, aortic arch, atrial stretch receptors (decrease in BP)
- Decreased stretch in renal afferent arteriole
What solute is preferentially reabsorbed in the loop of Henle
Magnesium
What fraction of urea is reabsorbed in the proximal tubule
50%
(More can be reabsorbed in the medullary collecting duct for urea recycling)
What fraction of phosphorus is reabsorbed in the proximal tubule
85%
(Not reabsorbed anywhere else - 15% gets excreted in urine)
What is ammonium produced from and where
Glutamine, mostly in the proximal tubule cells
Where can H+ be secreted in the nephron? Under which form?
- Proximal tubule: excreted as NH4+
- Cortical collecting duct (intercalated cells): secreted as H+ and complexed with NH3 or HPO4-2 in tubule
Where is HCO3 mostly excreted in case of metabolic alkalosis
Intercalated cells (type B) of the cortical collecting duct. It is exchanged for Cl-
Name 2 causes of refractory metabolic alkalosis
- Hypoakalemia
- Hypovolemia
What are the 3 layers of glomerular capillaries
- Endothelium + glycocalyx (with fenestrae)
- Basement membrane
- Epithelium (discontinuous podocytes)
What is the USG of isosthenuric urine
1.007 - 1.015
How can ultrasound be used to assess urine output
Measure bladder before and after urination
Urine volume = lengthwidthheight0.2pi
What are the 3 determinants of urine output
- Glomerular filtration rate
- Tubular reabsorption of water and solutes
- Impedance to flow
How to differentiate hemoglobinuria from myoglobinuria (4 indicators)
- Serum color: pink/red for Hb, colourless for Mb
- Hyperbilirubinemia with hemoglobinuria
- Increased AST / CK with myoglobinuria
- Anemia (+/- Heinz bodies, agglutination, schistocytes) with hemoglobinuria
What keto-acids are detected on urine dipstick
- Aceto-acetate
- Acetone
What is the formula to measure urinary fractional excretion of a solute
Fractional excretion = (urine concentration of solute * plasma creatinine) / (urine creatinine * plasma concentration of solute)
It is the amount of filtered solute that ends up excreted in urine (/!\ different from filtration fraction)
A low fractional excretion = tubular reabsorption functions are working
Where does renal glucose reabsorption happen? What are the transporters involved?
Proximal tubule
- Cotransport with Na from tubule to tubular epithelial cell via SGLT transporters
- Passive diffusion out of tubular cell towards interstitium and peritubular capillary via GLUT
How is urea reabsorption determined in the proximal tubule
Reabsorbed by passive diffusion -> determined by tubular flow (urea is more reabsorbed if water is more reabsorbed)
By what mechanisms does angiotensin II lead to renal sodium reabsorption
- Stimulation of aldosterone (-> Na reabsorption in principal cells of distal tubule / collecting duct)
- Direct stimulation of Na+/H+ transporter and Na/K ATPase in proximal tubule
- Vasoconstriction of efferent arteriole -> decreased hydrostatic pressure in peritubular capillary -> increased reabsorption (Starling’s law)
- Vasoconstriction of efferent arteriole ->increased GFR -> increased oncotic pressure in peritubular capillary -> increased reabsorption (Starling’s law)
What is the difference between glomerulo-tubular balance and tubulo-glomerular feedback
- Glomerulotubular balance = adjustment of reabsorption of solutes to the GFR (based on difference of oncotic pressure in peritubular capillaries)
- Tubulo-glomerular feedback = adjustment of GFR to delivery of Cl in the distal tubule (based on regulation of tone of afferent and efferent arterioles)
How do peri-tubular physical forces influence renal solute and water reabsorption
- Hydrostatic pressure in peritubular capillaries depends on BP and vascular tone of efferent arteriole (constriction of arteriole(s) -> decreased hydrostatic pressure in capillary -> increased reabsorption OR increase in BP -> increased hydrostatic pressure -> decreased reabsorption)
- Oncotic pressure in peritubular capillaries depends on proteinemia and filtration fraction (GFR / renal blood flow) (higher filtration fraction -> higher oncotic pressure -> increased reabsorption)
Explain pressure natriuresis
- Increased BP -> increased hydrostatic pressure in glomerular capillaries -> increased GFR (including increased filtered Na and water)
- Increased BP -> increased hydrostatic pressure in peritubular capillaries -> decreased reabsorption of solutes (including Na and water)
- Inhibition of angiotensin II release
Explain mechanisms of urine dilution
- Ascending limb of loop of Henle is impermeable to water -> solutes get reabsorbed (active transport) without movement of water -> dilution of urine in the tubule
- In the absence of ADH, the distal tubule and collecting ducts are impermeable to water -> delivers dilute urine
What are requirements to produce concentrated urine
- Hyperosmotic inner medulla (thanks to countercurrent multiplier of the loop of Henle with the action of the vasa recta + urea recycling between medullary collecting duct and loop of Henle under the influence of ADH)
- ADH to allow expression of aquaporins on principal cells of distal convoluted tubule and collecting duct to reabsorb water
Why does BUN increase more than creatinine in pre renal azotemia?
Hypovolemia increases urea reabsorption in the proximal tubule
True or false: if the filtered load is greater than the excretion rate, net reabsorption of the substance has occurred. If the filtered load is less than the excretion rate, net secretion has occurred
True
What is the difference between Tm and threshold?
Tm: reabsorptive rate at which the carriers are saturated
Threshold: plasma concentration at which solute first appears in the urine
What does it mean to have a high clearance, low clearance, clearance = to GFR?
Order the following substances from lowest clearance to highest clearance:
K+
inulin/creat
urea
Na+
glucose, amino acids, and HCO3-
High clearance: substances that are both filtered across the glomerular capillaries and secreted from the peritubular capillaries into urine
Low clearance: substances that either are not filtered (ex: protein) or are filtered and subsequently reabsorbed into peritubular capillary blood (ex: Na+, glucose, Cl-, HCO3-)
= to GFR: substances that are freely filtered, but not reabsorbed or secreted - biomarkers! (ex: creat)
glucose, amino acids, and HCO3- < Na+ < urea < inulin/creat < K+
What is the mechanism of action of carbonic anhydrase inhibitors?
Diuretics that act in the early proximal tubule by inhibiting the reabsorption of filtered HCO3−
How does ECF volume affect tubular reabsorption?
ECF volume contraction increases reabsorption
- Decreased Pc & increased pc
ECF volume expansion decreases reabsorption
- Increased Pc & decreased pc
Which parts of the nephron are normally impermeable to water and are considered diluting segments?
- Thick ascending limb of the loop of henle
- Distal tubule and collecting duct
How does ADH increase the principal cells’ permeability to H2O?
by directing the insertion of aquaporin 2 (AQP2) H2O channels in the luminal membrane.
In the absence of ADH, the principal cells are virtually impermeable to water.
Where does secretion of K+ occur in the nephron?
Principle cells of the collecting ducts
How does aldosterone increase K+ secretion by the principle cells?
Increased Na+ entry into the cells across the luminal membrane
–> Increased pumping of Na+ out of the cells by the Na+–K+ pump
–> Via the Na-K pump, increase in intracellular K+
–> Increased driving force for K+ secretion
*** Aldosterone also increases number of luminal K+ channels
How do diuretics cause hypokalemia?
- Increase flow rate through the late distal tubules and collecting ducts –> dilution of luminal K+ –> increases driving force for K+ secretion
- Increase Na+ delivery to late distal tubule an collecting ducts –> increase intracellular K+ via Na-K pump –> increases driving force for K+ secretion
What is the effect of fibroblast growth factor (FGF23)
Secreted by bone and inhibits Na+–phosphate cotransport in the early proximal tubule.
What is the effect of PTH on phosphorus and calcium in the kidney?
Inhibits phosphate reabsorption in the early proximal tubule by activating adenylate cyclase, generating cyclic AMP (cAMP), and inhibiting Na+–phosphate cotransport
Increases Ca2+ reabsorption by activating adenylate cyclase in the distal tubule.
Describe the relationship between magnesium and calcium in the nephron
In the thick ascending limb of the loop of henle, Mg and Ca compete for reabsorption
Hypercalcemia causes an increase in Mg2+ excretion
Hypermagnesemia causes an increase in Ca2+ excretion
What is the role of the macula densa in the kidneys?
Constriction of the nearby afferent arteriole via the juxtaglomerula when it senses increased fluid load (via Cl-)
Dilation of afferent arteriole and release of renin (-> angiotensin II -> constriction of efferent) when it senses decreased Cl
Name 5 functions of the kidneys
- Removal of waste material and excretion in urine
- Control volume and composition of body fluids
- Production and secretion of hormones (renin, calcitriol, erythropietin)
- Gluconeogenesis
- Regulation of arterial BP
What quantity of plasma volume is cleared/day?
60X
3 factors that determine the filtering of molecules at the glomerular capillary
- Size
- Charge
- Shape
What are the 3 stimuli for ADH secretion?
Which is more sensitive?
- Increased osmolarity (more sensitive - responds to 1% change)
- Decreased ECV (more robust response)
- SIADH
Which 3 receptors mediate ADH effects and how?
- V1 in vasculature - vasoconstriction
- V2 in the kidney - aquaporine-2 in the collecting ducts –> H2O reabsorption
- V1b hypothalamus/pituitary gland - facilitates ACTH release
What are the mechanisms that lead to thirst?
- Increased osmolarity –> intracellular dehydration of osmoreceptors in the thirst centres
- Decreased ECV
- Dry mouth
- Angiotensin II
What is the expected urinary Na+ concentration in the face of reduced ECV?
Urinary Na+ < 25 mEq/L
In which non-pathological situation is auto-regulation of renal blood-flow lost?
General anesthesia
What are the components of the juxtaglomerular apparatus?
- Macula densa cells (thick ascending limb of the loop of henle)
- Granule cells (aff. arteriole –> release renin)
- Mesangial cells (relay signal between the 2 other cells)
What part of the nephron is impermeable to NaCl?
Thin descending limb of the loop of henle
For each tubular segment, what percentage of Na is reabsorbed,by what mechanism and what are the major regulatory factors?
If protein is filtered in the proximal tubule, how will it be reabsorbed? (mechanism)
Pinocytosis
What is the role of calcitriol in the kidney?
- Increases calcium reabsorption in the distal tubule by increasing expression of transport proteins
- Increases reabsorption of phosphate
In what clinical scenario does urea recycling contribute to a large portion (40-50%) of creating a hyper osmotic renal medulla?
In a state of water deprevation
Briefly explain medullary washout
Administration of large volumes of fluid –> increased medullary blood flow –> medullary washout –> inability of kidneys to concentrate urine
What are the determinants of GFR?
Hydrostatic and osmotic forces across the glomerular membrane
Surface area + permeability of the membrane
