Renal Flashcards
What is the most obvious function of the kidney?
handle the key elements found in plasma:
- Blood volume and pressure (water concentration, inorganic ion composition)
- acid/base balance
What are the different body fluid compartments? (3)
- plasma: non cellular part of blood, fluid inside blood vessels
- extracellular fluid (ECF): fluid outside the cell - plasma+interstitial fluid+cerebrospinal fluid
- intracellular fluid (ICF): fluid inside the cell
What are the ionic compositions of the body fluid compartments?
Extracellular: high in Na+, Cl-, bicarbonate and phosphate
Intracellular: high in K+, Mg2+, phosphate and protein
Explain what diffusion and osmosis is
diffusion: process in which movement of molecules from one location to another occur as a result of their random thermal motion
osmosis: net diffusion of water across a selectively permeable membrane from high water concentration → lower water concentration
What is osmotic pressure?
pressure necessary to prevent solvent movement
What is tonicity?
- determined by concentration of non-penetrating solutes of a solution relative to the inside of a cell
- solute concentrations may influence changes in cell volume
- isotonic (same conc), hypertonic (higher out) and hypotonic (higher in) solutions
- water flows from lower osmolarity to higher osmolarity
normal osmolarity inside a cell is about
300 mOsm/L
What factors determine water movement accross blood vessels?
factors moving water out of capillaries:
1. capillary hydrostatic pressure (Pc)
2. osmotic force due to interstitial fluid protein concentration (πIF)
factors drawing water into capillaries
3. interstitial fluid hydrostatic pressure (PIF)
4. osmotic force due to plasma protein concentration (πc)
- more filtration occcurs at the arterial end of capillaries due to high Pc (net + filtration pressure)
- more absorption occurs at the venous end of capillaries due to loss of Pc along the blood vessel - πc draws fluid into the vessel (net negative filtration pressure)
filtration: move of solute/water out of plasma
absorption: move of solute/water into plasma
What is homeostasis? Why is it important to maintain the fluid volume inside the body within a given range?
homeostasis: total body balance of any substance
- there is a fixed volume of water and inorganic ion composition in our body
- water + ions are gained through ingestion or produced by metabolism → must be lost through excretion or metabolized
explain the general anatomy of the kidney
- retroperitoneal (towards the back)
- covered with a capsule-like structure
- 2 regions: outer cortex & inner medulla
- nephron: where urine is made, functional unit
micturition: process of releasing urine outside the body
slide 29
what are the associated organs of the urinary system
- ureter: drain the formed urine from the kidneys and empty into the bladder
- bladder: storage organ or a sac for the formed urine - recieves innervation from ANS
- urethra: where urine empties out of the body
What is the structural unit of the kidney? How many types of nephrons are found in the kidney?
Nephron: where urine is made
- parts of nephrons form parts of the cortex and medulla
- fuse with other nephrons to form collecting ducts which empty their contents into the renal pelvis
- 1 million nephrons in the kidney
What are the different parts of the nephron and what are their functions?
renal corpuscle:
- glomerulus (capillary tufts/loops) sit in a cup-like structure called bowman’s capsule, together called the renal corpuscle
- bowman’s capsule leads into the renal tubule
renal tubule:
- proximal convoluted tubule: twisted, close to corpuscle
- loop of henle: hairpin that bends, descnding limb ↓ and ascending limb ↑ (ascending has a thicker and thinner segment)
- distal convoluted tubule: far from corpuscle, drains contents into a collecting duct
- collecting duct: where a number of nephron renal tubules drain their contents, empties into renal pelvis of the kidney
What is the filtering unit of the nephron? What are the specific ultra structural features that make up the filtering unit?
renal corpuscle (glomerular capillaries and bowman’s capsule):
- podocytes are cells that surround the glomerulus: foot processes of one podocyte interlock with those of another - magnifying the surface area for filtration. in b/w interlocking foot processes are filtration slits
- bowman’s space is in b/w podocytes and epi cells: filtrate enters into bowmans space once the blood has been filtered
- flat epithelial cells make up the outer wall of bowman’s capsule and surround bowman’s space: continues on to form tubules where further processing forms the urine
blood enters corpuscle through an afferent arteriole → goes through several twists and turns of the fenestrated glomerular capillaries before exiting through the efferent arteriole
slide 35
What is the functional significance behind the anatomy of the glomerulus?
3 layers:
- endothelial fenestrated to allow for filtration, sits on a basement membrane
- basement membrane: gel-like mesh structure composed of collagen and glycoproteins
- podocytes: found outside the basement membrane, fluid moves through filtration slits that are covered with fine semiporous membranes (made of nephrins & podocins), has many foot processes to increase surface area of filtration
3 stages of renal corpuscle development
- nephrons develop as blind-ended tubules made of a single epithelial layer
- growing tuft of capillaries penetrate the expanded end of tubules - basal lamina trapped b/w endo cells of capillaries and epi. layer - epi. layer differentiates: parietal (outer) and visceral (inner) layers
- Parietal layer flattens to become wall of bowman’s capsule, visceral layer becomes podocytes
What are the different capillaries that remain associated with nephrons?
- Glomerular: recieves blood coming from the afferent arteriole, surrounds glomerulus
- Peritubular: capillaries formed by branches of the efferent arteriole surrounding the proximal convoluted tubule
- Vasa recta: found mostly associated with juxtamedullary nephrons in the medullary portion of the kidney (loop of henle)
blood enters into the glomerular capillary and exits the glomerulus through the efferent arteriole
3 basic renal processes involved in urine formation
- Glomerular filtration: blood is filtered across the capillaries of the glomerulus and into bowman’s space
- Tubular secretion: movement of non-filtered, unwanted substances from the capillaries into the tubular lumen
- Tubular reabsorption: the movement of a substance from inside the tubule into the blood (eg glucose)
amount excreted = amount filtered + amount secreted -amount reabsorbed
2 types of nephrons
- cortical 85%: basic functions, closer to cortex
- juxtamedullary 15%: basic functions, regulate concentration of urine, closer to medulla
basic functions: filtration, reabsorption, secretion
What is filtered through the glomerulus? Ultrafiltrate? Proteinuria?
- filtered substances: water, electrolytes, glucose, waste products etc..
- unfiltered substances: plasma proteins and blood cells, large anions (pores have - charges and do not allow - proteins to pass)
- Ultrafiltrate: the cell-free fluid that comes into bowman’s space, contains mostly all substances (except for proteins) at the same concentrations as in the plasma
- Proteinuria: proteins being filtered and showing up in the urine
Forces involved in the filtration of the plasma through the filtering unit
net GF pressure is always positive favouring filtration
forces favouring filtration:
- glomerular capillary blood pressure (Pgc)
forces opposing filtration:
- fluid pressure in bowman’s space (Pbs)
- osmotic force due to protein in plasma (πgc)
net GF filtration pressure = Pgc - Pbs - πgc
Composition of the filtrate
water, electrolytes, glucose, waste products.. mostly everything aside from blood cells, plasma proteins and large anions
What is filtration fraction? Is it different from renal fraction?
20% of plasma get’s filtered, 80% goes back into the main circulation
- 19% of filtrate is reabsorbed and enters the peritubular capillaries
- renal fraction: less than 1% of the volume filtered is excreted to the external environment
What is GFR?
volume of fluid filtered into bowman’s space per unit time
What are factors that can influence GFR? (4)
- net glomerular filtration pressure
- neural and endocrine control
- permeability of the corpuscular membrane
- surface area available for filtration
What is autoregulation of GFR? How is it achieved?
how the body keeps GFR fairly constant despite large changes in arterial pressure or renal blood flow
alteration of arteriolar resistance (AR):
- restriction of AA and dialation of EA = ↓GFR
- dialation of AA and restriction of EA = ↑GFR
mechanisms which change AR:
- myogenic response: arteriole smooth muscle contracts/relaxes in response to BP changes
- hormones/neurotransmitters from ANS
- tubular glomerular feedback: alters autoregulatory processes in response to volume that is flowing through - affects GFR
AA - afferent arteriole
EA - efferent arteriole
BP - blood pressure
Juxtaglomerular apparatus
specialized structure formed by distal convoluted tubule and the glomerular afferent arteriole, next to the glomerulus
cell types of JGA:
- macula densa: beginning of distal tubule
- juxtaglomerular/granular cells: sits on top of afferent arteriole
- mesangial cells: not considered part of JGA; found in triangular region between AA and EA
How is JGA involved in controlling GFR?
macula densa:
- senses increased Na+ load and flow of fluid through the tubule
- paracrine effects: secretes vasoactive compounds (adenosine) which have an effect on arteriolar resistance, signals to JG cells
juxtaglomerular/granular cells:
- innervated by sympathetic nerve fibers which can change AA resistance
- release renin which controls AA resistance
mesangial cells:
- contract and allow podocytes to contract; shirnks the surface area of the GF surface
- GFR affected by a decrease in filtration surface area
What is the tubuloglomerular effect?
When increased fluid volume flows through the distal tubule, there is a feedback effect
on the glomerular structure in controlling the GFR
increased GFR → increased flow to the tubule → more flow past the macula densa → paracrine factors released and act on the AA → AA constricts, resistance in the afferent arteriole increases → PGC drops → GFR rate decreases
Filtered load
- total amount of non-protein or non-protein bound substance filtered into bowman’s space
FL = GFR x [substance in plasma]
- filtered load for glucose = 180L/day x 1g/L = 180g/day
- indicates resorption when substance in urine is less than in the filtered load
- indicates secretion when substance in urine is more than in the filtered load
Ways that renal processing handles excretion of different substances
- Filtration only: - 20% is filtered and all of which get’s excreted (inulin, creatinine)
- Filtration + secretion - 20% of the substance gets filtered, the rest is secreted from the peritubular capillaries (organic acids and bases)
- Filtration + partial reabsorption - 20% is filtered, some of which gets reabsorbed back into the peritubular capillaries (electrolytes)
- Filtration + complete reabsorbtion - 20% is filtered and is fully reabsorbed into the peritubular capillaries (ideal for glucose, amino acids)
Reabsorption
- re-entrance of a substance from the ultrafiltrate of the renal tubules to the peritubuilar capillaries
How is sodium processed by the renal tubules
- Na passively moves across the luminal surface of the cell down it’s concentration gradient
- actively transported out of the cell across the basolateral membrane via the Na⁺/K⁺ pump
- Na moves into P.C through bulk flow down it’s conc. grad. (membrane proteins)
P.C - peritubular capillaries
Transcellular and paracellular transport
how reabsorption is mediated
trancellular (major): involves the use of transport proteins to move the substance from the lumen, into the cell, out into the IS and into the peritubular capllaries
paracellular (minor): diffusion of the substance between adjacent epithelial cells through tight junctions
IS - interstitial space
How is glucose processed
In the proximal tubule:
- active transport on the luminal side by SGLT protein (secondary AT)
Na/K ATPase maintains low cellular Na for SGLT transporter
- facilitated diffusion on the basolateral side using carrier protein GLUT
What is transport maxiumum and renal threshold
transport maximum: limit of substance that can be transported/unit time; binding sites of transport proteins become saturated; filtered load exceeds the limit of reabsorption
renal threshold: the plasma concentration at which saturation occurs
example: glucose
- reabsorption of glucose is linear up to ~300mg/100mL plasma, afterwards it reaches it’s transport max
- beyond renal threshold, glucose shows up in the urine
- body’s normal range of reabsorbing glucose is b/w 100-200 mg/100mL plasma
Glucosuria - what are the two conditions that cause glucose to appear in the urine
- Diabetes mellitus: capacity to reabsorb glucose is normal but filtered load is greatly increased and beyond the threshold level to reabsorb glucose by the tubules
- Renal glucosuria: genetic mutation of Na+/glucose cotransporter (SGLT), that normally mediates active reabsorption of glucose in the proximal tubules
How is urea processed by the renal tubules?
urea reabsorption is dependant on water reabsorption
- sodium is reabsorbed by AT and electrochemical gradients drive anion reabsorption (eg Cl)
- sodium/anions moving out of the lumen into the extracellular fluid → creates a concentration gradient
- water flows out of the lumen by osmosis
- urea will diffuse down it’s concentration gradient due to movement of water
What is renal clearance?
way of measuring/quantifying how well the kidney’s are functioning by clearing/removing substances
- measures the volume of plasma from which a substance is completely removed from the kidney per unit time
- L/hour or mL/min
Clearance of S = Us x V / Ps
- Us: concentration of substance in urine
- V: volume of urine passed, mL/min
- Ps: concentration of substance in plasma
example: glucose
- clearance = 0, concentration of glucose in urine is 0 (for a healthy person)
How renal clearance measured?
inulin: polysaccharide not found normally in the body, get’s filtered but not reabsorbed/secreted by the tubule → fully urinated
Clearance vs GFR
- inulin clearance: 7.5L/h
- inulin clearance in one day is equal to the GFR (180L/day or 125mL/min)
- measuring the clearance of inulin will provide a measure of the GFR
- if the clearance of a substance is greater than GFR of 125 mL/min = secretion
- if the clearance of a substance is less than the GFR of 125 mL/min = reabsorption
sources of input and output in maintaining water balance
water input:
- ingested liquid
- water from oxidation of food
water output:
- skin, respiratory airways (insensible)
- sweat
- GI tracts, urinary tract, menstrual flow
How is water processed in different segments of the renal tubule?
- proximal convoluted tubule: reabsorbs majority of the water (67%) and non-waste plasma solutes; aquaporins are always open in PCT
- loop of henle: creates an osmotic gradient in the interstitial space; some water reabsorption (15%) occurs in the desending limb of the LOH via AQ1; ascending limb is impermeable to water but reabsorbs solutes
- distal tubule: major homeostatic mechanisms to control water and solute to produce urine; no water reabsorption
- large distal tubule & collecting duct: reabsorbs 8-17% of the filtered water; has different types of aquaporins controlled by vasopressin/ADH
AQP-1 - aquaporins
What is the role of the proximal convoluted tubule?
water moves from the lumen side of the tubule into the interstitial side via sodium reabsorption
- Na/K pump on the basolateral side of the tubule pumps Na out of the cell - providing a gradient for Na to move into the cell from the lumen
- water concentration goes up in the luminal side of the membrane → moves into the interstital space through AQ1 or tight junctions
What is the role of the Loop of Henle? (descending & ascending)
descending limb: allows water to diffuse out from the tubule lumen into the interstitial space
ascending limb: is impermeable to water
- creation of the countercurrent multiplication
countercurrent multiplier mechanism
ascending and descending limb of the loop of henle are very close in proximity; their different permeabilities to water create an osmotic gradient
- multiplication of the gradient down the length of the LOH: caused by water leaving the tubule
- highest osmolarity found at the botton of the hairpin loop - 1400 mosm
- fluid in the tubule dilutes again as it ascends the LOH
a hyperosmotic interstitial gradient is created in order to absorb water into the interstitial space
factors involved in maintaining the countercurrent mechanism
- descending limb: concentrates the fluid at the bottom of the LOH by allowing water to flow into IS (multiplication of the gradient)
- ascending limb: impermeable to water; actively transports NaCl into IS; when fluid reaches the top osmolarity = 100 mOsm (hyporosmolar)
there is always 200 mOsm difference between descending and ascending limb
outcome of having a countercurrent multiplier mechanism in the kidneys
- counter current multiplier is important to keep water in the body and give out, or produce a very hyperosmotic urine or a concentrated urine
role of vasa recta in countercurrent exchange
vasa recta: blood vessels that run parallel to the LoH; blood flow runs in opposite direction to fluid flow in the loop of henle
- create loop-like circuits at each gradient level, to maintain the salt gradient that the nephron tubules have created
- freely permeable to ions, urea and water
mechanism:
- water moves out of the descending limb of the LoH and then enters the ascending limb of the vasa recta
- NaCl enters the descending limb of the vasa recta; as NaCl leaves the ascending limb of the LoH
- water diffuses out of the descending limb of the vasa recta back into the ascending limb
- blood is only slightly higher in osmolarity when it leaves the vasa recta compared to when it enered the vasa recta
how is urea trapped in the medulla? how is urea ultimately excreted?
urea is a waste product that gets trapped in the I.S to maintain the gradient
- urea gets reabsorbed in the proximal tubule; that same amount gets secreted in the LoH; all of urea enters the DT; most of it gets reabsorbed from the CCD and IMCD (with help from ADH); very small amounts diffuses out to vasa recta
- minimal uptake of urea by vasa recta and recycling urea in the I.S helps maintain high osmolarity in the medulla
- 15% of the original amount gets excreted as the rest is recycled
see diagram on slide 123
role of the late distal and collecting ducts
distal convoluted tubule:
- no aquaporins, NaCl is pumped out
- fluid becomes extra hypoosmolar at 80 mOsm
cortical collecting duct:
- physiological control of water movement by ADH which allows for water to be reabsorbed out of the tubules → filtrate becomes isoosmotic with I.S
- filtrate becomes hyperosmolar again as it moves down the collecting duct; high osmolarity gradient in I.S helps water permeate out of the medullary collecting tubule
relationship b/w plasma volume and Na+ concentration
- water reabsorption is dependant on Na+ reabsorption
- [Na] and extracellular fluid volume are closely linked
- any changes in total body [Na] cause changes in blood volume and blood pressure
- plasma osmolarity is mainly determined by measuring plasma [Na]
regulation of water volume by ADH, what is the source of ADH
- peptide hormone made in the hypothalamus (SON)
- cells in hypothalamus sense the osmolarity+volume of plasma and release ADH
- ADH site of action = collecting duct
SON - supraoptic nucleus
mechanism of ADH action
- ADH binds to receptor on cell and through G-protein coupled mechanism, transcription factors are activated and AQP-2 is up-regulated
- Water moves across apical membrane through AQP-2 and out basolateral membrane through AQP-3 and -4
- AQP-2 is under the control of ADH but AQP-3 and -4 are not
- If levels of ADH are very low, AQP-2 channels will be recycled or taken back by
endocytosis
Diabetes insipidus - What are the 2 types?
(1) central diabetes insipidus
- failure to release the ADH from the posterior pituitary
- lots of water is lost in urine
(2) nephrogenic diabetes insipidus
- ADH secreted in a normal manner but hormone doesn’t function normally
- can be a problem with the receptor, intracellular signaling, or the cells of the nephron
osmotic and water diuresis
diuresis: increased volume of urine production
Osmotic:
- excess solute appears in urine; associated with high levels of water excretion
- uncontrolled diabetes mellitus
Water:
- only excess water is excreted without excess solute in urine
regulation of Na+ levels
sodium is never secreted into renal tubules, it is only excreted from filtered fraction
mechanism:
LOW [Na] IN PLASMA:
- short term: baroreceptors regulate GFR
- long term: aldosterone promotes Na reabsorption (renin, angiotensin II needed for aldosterone secretion)
HIGH Na IN PLASMA
- ANP regulates GFR and inhibits Na reabsorption
- ANP also inhibits aldosterone actions
what are baroreceptors, how are they involved in Na+ regulation
- used for short-term regulation of low plasma volume
- have nerve endings that are sensitive to stretch
- low plasma [Na]
- low plasma volume
- low arterial BP
- reduced firing of baroreceptors
- increased activity of sympathetic renal nerves → constriction of arterioles
- decreased GFR
- increased Na reabsorption → increased Na in plasma
how and where is aldosterone synthesized? what is the role of aldosterone in Na+ regulation
- steroid hormone secreted from adrenal cortex
- low plasma volume associated with low plasma [Na] triggers its release
- long term regulation of Na reabsorption
site of action: late DT and CCD
actions: induces synthesis of Na transport proteins, stimulates Na reabsorption, reduced Na secretion
- angiotensin II acts on the adrenal cortex to control the secretion of aldosterone
role of renin-angiotensin system
- renin gets secreted from the JG cells of the JGA in the kidney as well as the liver when [NaCl] is low
- renin converts angiotensinogen into angiotensin I
- ACE converts angiotensin I into ATII
- ATII acts on the adrenal cortex to release aldosterone
initiated in response to:
1. sympathetic stimulation of renal nerves
2. decrease in filtrate osmolarity (eg Na)
3. decreased blood pressure
role of atrial natriuretic peptide (ANP) in Na+ regulation
What is the source of ANP?
- made and secreted by cardiac atria
- inhibits Na reabsorption
- increases GFR and Na excretion
site of ANP action: on cells of several tubular segments
stimulated by: increased Na conc, increase blood volume, atrial distention
mechanisms regulating K+
- most of the filtered K+ is reabsorbed in the PT and LoH; collecting duct secretes a small amount of K
- hyperkalemia: excess K in the blood
↑ extracellular K+ → ↑aldosterone (adrenal cortex) → more K+ excretion in urine
↓ extracellular K+ → ↓ aldosterone → less K+ in urine
aldosterone stimulates Na reabsorption and K secretion in the CCD
pH and its relation to H+ concentration
pH = -log[H⁺]
- pH for ECF is 7.35-7.45
- plasma pH < 7.35 = acidosis
- plasma pH > 7.45 = alkalosis
role of pH in body functions
why is it important to maintain the plasma pH within a given range?
small changes in pH cause proteins to change shape
- changes in enzymes alter their activity
- changes in neuronal activity
- coupled to K+ imbalances
- Irregular cardiac beats
pH < 6.8 and > 7.8 is fatal
what is an acid? what is a base? what is a buffer?
- acid: releases H+ in solution
- base: accepts H+ in solultion
buffer:
- any substance that binds to H+; composed of a weak acid and it’s conjugate base
- buffers modify/adjust the change in pH following addition of acids/bases
- CO₂/HCO₃- is the extracellular buffer system
- phosphate ions & proteins (like hemoglobin) are intracellular buffers
acidosis and alkalosis
acidosis:
- when arterial plasma pH < 7.35
alkalosis:
- when arterial plasma pH is > 7.45
sources of H+ gain or loss
Gain:
- generation of H from CO₂
- production of non volatile acids from metabolism of proteins and other organic molecules
- gain of H+ due to loss of HCO3- in diarrhea or other nongastric GI fluids
- gain of H+ due to loss of HCO3- in urine
Loss:
- utilization of H+ in metabilism of organic anions
- loss of H+ in vomitus
- loss in urine
- hyperventilation
role of lungs and kidneys in H+ balance
Regulation of H+ by the kidney
key concept: when 1 H+ ion is lost from the body, 1 HCO3- is gained
alkalosis: causes kidneys to excrete more bicarbonate
acidosis: causes kidney to synthesize new bicarbonate and send it to blood
describe reabsorption of bicarbonate
reabsorption of HCO3-:
- depends on H+ secretion; active process
- normally most of HCO3- is reabsorbed
- occurs in PT, ascending LoH and CCD
mechansim:
- water and carbon dioxide make carbonic acid in the tubular epi cells; carbonic acid dissociates into H+ and HCO3-
- HCO3- is passively transported into the IF (reabsorption)
- H+ is actively transported into the tubular lumen where it combines with filtered bicarbonate to create carbonic acid
- carbonic acid dissociates into water (excreted in urine) and CO2 (reabsorbed)
mechanisms of acid/base balance
response to acidosis: more H+ is secreted than there is HCO3- in the lumen
mechanism 1:
- extra H+ binds to filtered HPO42- (= H2PO4-)
- H2PO4- is acidic and excreted in the urine
- HCO3- is still generated by tubular cells and diffuses into plasma
- NET gain of HCO3- in plasma
mechanism 2:
- only cells from PT are involved
- uptake of glutamine from glomerular filtrate or peritubular capillaries
- Glutamine dissociates into NH4+ and HCO3- inside the cells
- NH4+ is actively secreted via the Na+/NH4+ counter transport into the lumen (excretes H+ in the form of ammonium)
- HCO3- is added to plasma
response to alkalosis:
- few ions present in the filtrate, thus bicarbonate is lost in the urine
- decrease of glutamine metabolism and ammonium excretion
- net result: bicarbonate is lost in the urine, plasma bicarbonate dcreases, plasma pH returns to 7.4 while urine pH is alkaline
respiratory acidosis/alkalosis
acidosis:
- result of decreased ventilation
- increase in blood Pco2
- occurs in emphysema
- kidneys compensate by secreting H+ to lower plasma [H+]
alkalosis:
- result of hyperventilation
- decreased blood Pco2
- happens in high altitudes
- kidney compensates by excreting HCO3-
metabolic acidosis/alkalosis
acidosis:
- occurs in diarrhea (loss of bicarbonate)
- severe exercise
- diabetes mellitus
- causes increased ventilation
- results in increased H+ secretion
alkalosis:
- occurs after prolonged vomiting
- results in decreased ventilation
- results in increased HCO3- excretion
