Lectures Flashcards
Describe the structure of the kidney.
The capsule surrounds the cortex, which surrounds the medulla. The tips of the medulla are called papilla, which point inwards to each calyx. The calyces all collect into the renal pelvis, which exits into the ureter. Near the renal pelvis is where the renal vein and artery pass through.
Describe the nephron structure.
Blood flows through the glomerulus, which filters into the proximal convoluted tubule, which passes into the medulla via the pars recta, before becoming the thin descending limb, thin ascending limb, and thick ascending limb (all part of the Loop of Henle). The thick ascending limb goes back into the cortex, passes next to the glomerulus with Macula Densa cells lining it, before becoming the distal convoluted tubule which drains into the cortical collecting duct and medullary collecting duct.
Describe the different types of nephrons.
Describe the two capillary networks.
In humans, the short-loop nephrons with short loops of Henle make up 7/8 of the nephrons, and the long-loop nephrons with long loops of Henle make up 1/8 of our nephrons.
The afferent arteriole becomes the Glomerular capillary network, but because this is high pressure filtration environment, the efferent arteriole reduces pressure before entering the peritubular capillary network (where pressure is low enough for reabsorption).
Describe the filtration of urine.
Filtration occurs at the glomerulus (180L per day). The structural barrier is via a three layer membrane (endothelium / basement membrane / podocyte cells with filtration slits. Anything under 5,000 MW can pass through, above 70,000 MW cannot.
The electrical barrier means that the Podocyte layer and basement membrane have negatively charged glycoproteins, repel negatively charged plasma proteins, thus less charge lets proteins pass and causes proteinuria.
Describe the reabsorption of water.
67% of it is reabsorbed in the proximal tubule, and 8-17% is reabsorbed in the distal tubule and collecting duct (where fine tuning occurs).
Much of it goes around the cells through a special type of tight junction, through the lateral intercellular space, and follows sodium into the peritubular capillaries. A little bit of water does leak back through the tight junctions, however. If the spaces swell, the passive back leak will increase.
Describe the dynamics of filtration.
GFR means Glomerular filtration rate, and may be 125 mL/min. The filtration fraction (FF) may be 20%, or 20% of the plasma that passes through the glomerulus gets filtered. But enough is reabsorbed that only 1% overall stays in the tubule. FF therefore refers to the percentage of plasma, not blood, that is filtered. Hydrostatic pressure resists entry of fluid, and oncotic pressure pulls fluid in. The major force by far is the Glomerular capillary hydrostatic pressure. This is a disequilibrium capillary thus the pressures never balance, so there is always filtration.
How do you calculate the direction of fluid flow in filtration?
Add up oncotic pressures and hydrostatic pressures in favor of filtration, and subtract from them the hydrostatic and oncotic pressures opposing filtration, and see if the sum favors or disfavors filtration.
Describe factors that affect GFR and renal blood flow.
Increasing renal blood flow will increase GFR.
Relaxing the afferent arteriole will increases GFR and RBF. Constricting it will decrease GFR and RBF. Relaxing the efferent arteriole will increase RBF but decrease GFR. Constricting it will decrease RBF but increase GFR.
Higher Bowman’s capsule hydrostatic pressure will decrease GFR, as will higher plasma oncotic pressure. Higher membrane permeability or surface area will increase GFR.
Describe the autoregulation of GFR.
GFR and RBF remain mostly stable in a range of blood pressures. Thus arteriole tone can keep a steady rate of filtration (myogenic theory). Or the tubule triggers regulation by getting the macula densa to detect a higher sodium delivery rate and control the afferent arteriole via a paracrine effect (tubuloglomerular / Macula Densa feedback theory).
Extrinsic factors like sympathetic nerves / angiotensin II / vasopressin can override and shut down this autoregulatory mechanism.
Briefly describe reabsorption.
Reabsorption occurs at the tubules into the peritubular capillaries (99% of the filtered volume).
Describe renal clearance and how it is measured.
Clearance is the volume of plasma that was cleared of this substance per unit time. This tells you how efficiently the kidney cleans up the plasma. You can use clearance to indirectly measure GFR is your substance is freely filtered by the glomerulus, does not get reabsorbed or secreted (which would bias the result), and does not get metabolically destroyed or produced. Inulin (a polysaccharide) can do this. Excreted inulin therefore equals the filtered inulin.
Describe a tricky concept of inulin.
Describe using inulin clearance as a benchmark.
Explain why we use the terms ‘net’ secretion and absorption.
The clearance of inulin is constant regardless of plasma concentration because the GFR is constant (and because clearance refers to a volume not a concentration).
If a substance has higher clearance than inulin, there is net secretion. If a substance has a lower clearance than inulin, there is net absorption.
The net effect is measured, but even a substance that has net secretion may be absorbed in some places and secreted in others.
Describe what creatinine can tell you.
Creatinine is filtered but a little bit is also secreted as well, thus it overestimates the GFR by about 15-20%. Ccr is 15-20% higher than Cin and GFR. Although creatinine clearance is less accurate than inulin clearance, it is most commonly used because it is an endogenous substance and doesn’t have to be infused.
Furthermore, elevated plasma creatinine tells you that the kidneys are suffering from low GFR (but it only rises after 50% of renal function has been lost).
Explain how you measure renal plasma flow.
Para-aminohippurate (PAH) and Diodrast are freely filtered and also highly secreted from the peritubular capillaries, thus almost all of the renal plasma loses its PAH / Diodrast. So the PAH / Diodrast in the urine tells you the total amount of plasma that flowed through the nephron.
Describe renal micropuncture.
Needles can measure or inject materials into different parts of the tubule. You can compare the concentration of these substances in the tubule fluid relative to plasma concentration to see what happened (TP/F ratio). This only tells you if something has been reabsorbed or secreted faster than water (TF/P ratio starts at 1 and becomes non unity). If the TF/P ratio stays at one, it may still have been reabsorbed or secreted, it’s just doing so at the same rate as water.
Name two things with a TF/P ratio that starts at 1 but drops to 0.
Name something with a TF/P ratio that starts at 1 but rises to 3?
What has the highest TF/P?
Glucose (because all of it leaves the tubule fluid) and amino acids. Both of these are reabsorbed much faster than water.
Inulin (because water is reabsorbed without inulin, this concentrating inulin in the tubule fluid). It is concentrated three fold (1 to 3), thus 2/3 of the water was reabsorbed in the proximal tubule.
PAH (because it gets concentrated when all of the water gets reabsorbed, and then additional PAH is secreted, thus concentrating it even more).
Describe sodium reabsorption.
90% of sodium is reabsorbed in the proximal tubule (thus it is the major driving force for water reabsorption here). The sodium / proton antiporter (which makes urine acidic) and sodium / glucose / amino acid symporters (which explain why glucose and amino acids are so rapidly absorbed) pull sodium from the lumen.
The sodium potassium ATPase then moves sodium into the peritubular capillary.
Describe the transport of potassium.
Describe the transport of urea.
Like water, 67% is reabsorbed in the proximal tubule. This is because potassium follows water through passive paracellular movement, thus 67% of water pulls 67% of potassium along with it. More is reabsorbed in the thick ascending limb and the early distal tubule, but some potassium is eventually secreted in the late distal tubule to re-enter the urine.
50% is reabsorbed passively in the proximal tubule, secreted into the thin ascending limb.
Describe glucose and amino acid transport.
99% of glucose and amino acids are reabsorbed in the proximal convoluted tubule through sodium symporters, like the SGLT2 (sodium glucose luminal transporter) in the early proximal convoluted tubule, and the SGLT1 in the late proximal convoluted tubule.
Describe the function of the distal nephron.
The distal nephron is more of the fine tuning portion. In the early distal tubule, sodium and chloride are reabsorbed through a cotransporter, where water cannot follow them (not water permeable). A sodium potassium pump, with a chloride channel, then move sodium and chloride into the peritubular capillary.
In the late distal tubule and collecting duct, principal cells reabsorb sodium and secrete potassium (due to aldosterone). Intercalated cells secrete protons and reabsorb bicarbonate to acidity urine (and may even reabsorb potassium).
Describe the glucose reabsorption curve.
At low plasma glucose concentrations, the glucose reabsorption scales linearly as a straight line (all glucose is reabsorbed) and the glucose excretion curve remains at zero (none makes it into the urine). But as plasma glucose increases, the glucose reabsorption maxes out to a flat line (transporters are saturated) and the glucose excretion begins to rise up from zero (extra glucose begins making it into the urine).
Describe osmotic diuresis.
Describe the reabsorption rate.
Calculate excretion.
An excess of solute which is normally reabsorbed (glucose) pulls water out with it, or a solute that cannot be reabsorbed (mannitol) pulls water out with it, or reabsorption of the solutes are inhibited (by a diuretic drug).
Take what is filtered and subtract from it what made it out (excretion).
Excretion = filtration plus secretion minus reabsorption.
Describe the PAH secretion curve.
Describe how units may trick you.
PAH secretion scales linearly with the plasma concentration, but eventually the secretion mechanism maxes out, thus the secretion curve flattens our. However, the amount of PAH that is excreted will still continue to increase because more is still being filtered out (even if secretion has already reached a maximum).
Clearance is a volume per time (L / minute) whereas secretion / excretion / reabsorption / filtration are all an amount per time (so that they can all be in the same equation as each other).
Describe the body fluid compartment breakdown.
The body has 60% of their weight composed of water.
2/3 is Intracellular fluid, 1/3 is extracellular fluid. Of the extracellular fluid, 3/4 is interstitial and only 1/4 is plasma.
Transcellular fluid includes CSF / synovial fluid / intraocular fluid / pericardial fluid, which is outside of cells but separated from the plasma by more than just the endothelium.
Describe the types of fluid loss.
Insensible water loss (water leaks through skin and lungs) for about 900ml per day.
Sweat means water lost through glandular secretion, it about 100mL per day, but exercise can dramatically increase this. Note that sweat is hypotonic relative to plasma, thus you lose more water than solutes.
Feces loses about 100mL per day, whereas urine loses about 1,500 mL per day. Urine is the only one that can be adjusted physiologically, thus it is the most important source of water loss.
Describe the function of the Loop of Henle.
It dives from the isotonic cortical interstitial fluid to the hypertonic medullary interstitial fluid. Water is sucked out of the thin descending loop of Henle, which is water permeable, but slightly permeable to urea, and completely blocks sodium. So the tubular fluid osmolarity increases. In the thin ascending limb the opposite is true. Sodium is permeable, urea is moderately permeable, and it blocks water. So sodium gets pulled into the interstitial fluid, and some urea (concentrated in the interstitium) gets pulled from** the interstitial fluid. Then sodium is actively transported out of the thick ascending tubule (diluting section), which decreases osmolarity.
Describe the function of the late distal tubule and collecting duct.
ADH makes the late distal tubule and cortical collecting duct water permeable by fusing aquaporin II vesicles with the luminal membrane through a cAMP mechanism, thus water flows through them to the higher osmolarity interstitial fluid and concentrates urine. In the inner medullary collecting duct, ADH will also cause urea to diffuse into the deep interstitium thus diluting urine. This establishes high concentration of urea in the medullary interstitium.
Define free water clearance.
What can tell you that there is no free water clearance? Diluted urine tells you what?
The excess of deficit of pure water that has been added to the urine flow. The equation is:
Free water clearance = urine volume that comes out minus osmolar clearance that entered nephron to begin with. (Thus positive free water clearance adds water to the urine, whereas negative free water clearance reabsorbs water and concentrated urine).
If the urine osmolarity and plasma osmolarity are equivalent, then the free water clearance is zero because no water has been added to dilute the urine. Diluted urine indicates positive free water clearance.
Describe the control of ADH secretion.
There is osmotic control and volume control. Osmotic control has osmotic receptors in the hypothalamus trigger more water to be retained if the blood is too concentrated, by releasing ADH. Volume control has high pressure arterial baroreceptors (aorta) and low pressure cardiopulmonary baroreceptors (atrium) release ADH to increase blood pressure.
Describe the control of extracellular fluid sodium concentration.
Sodium salts result in 90% of the ECF osmolarity. Thus there are two mechanisms that control sodium concentration. ADH and thirst. ECF sodium concentration is adjusted by changing the amount of the water, not the amount of the sodium. Thus high sodium causes high blood pressure or dilute it out, by triggering ADH. The ADH control of water kicks in before you feel thirsty, at a lower plasma osmolarity threshold. When ADH reaches maximal responsiveness and cannot concentrate urine any more, then you get very thirsty.
Describe the sensitivity of ADH release.
Only at high levels, ADH functions as a what? So what is it called?
Describe the role of the sympathetic nervous system in sodium control.
ADH release is not that sensitive, as it requires a 10% decrease in blood volume to trigger ADH. ADH increases much more sharply with hypovolemia or hypotension, and increases much more gradually with hypervolemia or hypertension.
Vasoconstrictor, vasopressin.
If blood pressure is low, renal sympathetic nerves will constrict afferent arterioles to decrease GFR and RBF, stimulate RAAS system, and directly stimulates sodium reabsorption in the proximal tubule (minor effect). All of these increase blood pressure.
Describe the RAAS system.
The renin-angiotensin-aldosterone-system has dehydration lower blood volume, which lowers blood pressure, which releases angiotensinogen from the liver and renin from the juxtaglomerular kidney cells. Renin turns angiotensinogen into angiotensin I, which ACE from the lungs turns into angiotensin II, which can directly constrict efferent arterioles to lower RBF (while paradoxically maintaining GFR for normal kidney function), and also trigger the adrenal cortex to release aldosterone which increases sodium and water reabsorption.
Describe renin release triggers.
Describe why ACE inhibitors may make stenosis even worse.
Renin can be released when the sympathetic nerves directly stimulate the kidneys, when the afferent arteriole has less stretch due to low pressure, and lower GFR decreases macula densa sodium load (due to lower blood pressure).
Stenosis decreases blood flow to the kidneys. Angiotensin II constricts the efferent arteriole to maintain GFR, but ACE inhibitors relax the efferent arteriole and can drop the kidney perfusion pressure to dangerously low levels.
Describe the effect of aldosterone.
More aldosterone increases sodium reabsorption and secretes potassium (thus preserving sodium).
Less aldosterone causes more sodium to be excreted in the urine, and less potassium to be excreted (thus preserving potassium).
Describe the natriuretic peptides.
These have the opposite function of the RAAS system, and cause blood pressure to decrease by triggering more urination. Atrial natriuretic peptide (surprisingly more in the ventricle than the atrium) and brain natriuretic peptide will dilate vessels, decrease renin / ADH / aldosterone, increase the GFR and decrease sodium reabsorption, thus all of this decreases blood pressure.
High pressure baroreceptors mainly increase blood pressure by what means?
Low pressure baroreceptors mainly increase blood pressure by what means?
Juxtaglomerular apparatus mainly increases pressure by what means?
Activating the sympathetic nervous system to excite the heart and trigger cardiac muscle.
Increasing ADH (and not the sympathetic nervous system).
Triggering the RAAS system by releasing renin (hence renal control of the RAAS system).
Define acidemia.
Define alkalemia.
Define acidosis.
Define alkalosis.
Acidemia means the plasma pH is less than normal.
Alkalemia means the plasma pH is greater than normal.
Acidosis describes a process where there is a net gain of protons.
Alkalosis describes a process where there is a net loss of protons.
Describe the systems that regulate body pH on different time scales.
Describe the effect of pH on ventilation.
Buffer systems immediately regulate pH changes within seconds. The lungs regulate pH over several minutes by modifying CO2 removal. The kidneys regulate pH changes over hours by modifying proton secretion and bicarbonate reabsorption.
Low pH increases ventilation, which reduces the CO2 in the blood, thus raising the pH.
High pH slows down ventilation, which causes Co2 to accumulate in the blood, thus lowering the pH.
Loosely describe the renal regulation of pH.
Name the three mechanisms that do this.
The kidneys secrete protons and reabsorb and generate new bicarbonate. They must generate additional bicarbonate because the amount being reabsorbed is insufficient to keep our blood buffered.
Proximal tubular mechanism, the collecting duct mechanism, and the loop of Henle mechanism.
Describe the proximal convoluted tubule mechanism for bicarbonate.
Proximal tubular mechanism = filtrated bicarbonate binds with secreted protons (sodium proton exchanger) to make carbonic acid, which carbonic anhydrase turns into water and CO2, which easily diffuses into the cell to reform bicarbonate. 80-85% of the bicarbonate reabsorption happens in the PcT, and it is reabsorbed faster than water thus it has a TF/P ratio is less than one.
Describe the collecting duct mechanism for bicarbonate.
Describe tubular secretion of bicarbonate.
Collecting duct mechanism = the alpha intercalated cells actively pump protons into the tubule fluid, which reacts with the bicarbonate to for carbonic acid that degrades on its own (without carbonic anhydrase) to form water and Co2.
Beta intercalated cells turn CO2 and water into carbonic acid, which carbonic anhydrase turns into bicarbonate and a proton. They then secrete the bicarbonate ion into the tubule fluid (in exchange for chloride to balance the negative charge), which also pushes protons into the blood.
Describe the loop of Henle mechanism for bicarbonate.
The same sodium / proton exchanger as in the proximal tubule secreted protons, but just like in the collecting duct, there is no carbonic anhydrase.
Describe the mechanisms that actually create new bicarbonate, beyond just retaining old bicarbonate.
In the proximal tubule, the titratable acid excretion generates carbonic acid, which is split into a proton and bicarbonate. The bicarbonate is secreted into the blood and the proton is secreted into the tubule fluid (hydrogen sodium exchanger), which joins HPO4 to make H2PO4 (called the phosphate buffer system) which buffers tubule fluid before it is excreted.
The same mechanism happens in the collecting duct, but the only difference is that an ATPase actively pumps the proton into the tubule fluid without using a sodium/proton antiporter.
What renal mechanism can increase in an acidosis, with what limits?
What mechanism cannot increase in acidosis?
The titratable acid excretion mechanism can increase to add more bicarbonate in the blood, but as it pumps more protons into the tubule fluid, you run out of HPO4 to accept it in the tubule fluid. This mechanism can therefore only increase slightly (2-3 fold).
The bicarbonate reabsorption mechanism cannot increase at all.
Describe the ammonium excretion mechanism.
This is the most flexible mechanism for excreting protons. In the proximal tubule, glutamine makes ammonia and bicarbonate. The new bicarbonate enters the blood, whereas the ammonia is secreted as ammonium.
The ammonium reaches the loop of Henle, which gets reabsorbed (with sodium and two chlorides to balance charge), and becomes ammonia that enters the blood to be reused.
In the collecting duct, ammonia or ammonium enters the cell, but ammonia enters the tubule to accept a proton. This is the most important means to increase hydrogen excretion in acidosis, because it can increase 10 fold.
Describe the factors that can increase proton secretion.
Lower Intracellular pH and higher Co2 will secrete more protons. aldosterone will also trigger the proton ATPase to secrete more protons.
Describe metabolic acidosis.
Metabolic acidosis is not due to CO2 retention and is therefore not due to a respiratory cause. This is anything that tips the scale to a lower pH. If uncompensated, there will be a low pH with normal CO2. But the lungs will increase their ventilation rate to reduce CO2, so if compensated, there will be low pH with low CO2 (the lungs compensated by releasing CO2 / respiratory compensation). Bicarbonate will also decrease due to buffering acidic blood, as well as due to the loss of CO2. Kidneys will retain as much bicarbonate as they can, form more bicarbonate, and create more ammonium to secrete protons.
Describe metabolic alkalosis.
Alkalosis that does not result from too much ventilation / Co2 removal. If uncompensated, the pH will be too high but the CO2 will be normal. As the lungs compensate, however, breathing rate will slow and the pH will be too high with high CO2. Bicarbonate will increase as it has fewer protons to buffer, so kidneys will reabsorb less bicarbonate and secrete fewer protons (to acidity blood). Some bicarbonate will therefore be excreted in the urine. Less ammonia will be secreted thus carrying away fewer protons with it.
Describe respiratory acidosis.
This is due to CO2 retention resulting from hypoventilation. Increases CO2 has decrease pH. The problem is this acidosis cannot be buffered by bicarbonate, because this CO2 is already being converted into carbonic acid. It cannot buffer itself, thus the major form of buffering is Intracellular. Furthermore, the lungs cannot compensate because they are the problem, so the kidneys must compensate. They secrete more protons, secrete more ammonia, more bicarbonate is filtered out but also more of it is also reabsorbed. So this does increase bicarbonate even more, but it doesn’t matter because we lost protons.
Describe respiratory alkalosis.
The lungs are breathing too quickly and eliminate too much CO2, raising blood pH. Buffering will mainly be Intracellular because the bicarbonate level is the issue, and the lungs cannot compensate. So the decrease in CO2 leads to decreased bicarbonate filtration, and therefore decreased reabsorption, but bicarbonate secretion increases to get rid of excess bicarbonate from basic blood thus more bicarbonate is excreted in the urine. There is decreased tubular secretion of protons and ammonium to make the blood more acidic.
Explain the Davenport diagram.
It describes the arterial pH on the X-axis, and the bicarbonate concentration on the Y axis. The lines curving up and to the right represent the arterial partial pressure of CO2. pH below 7.35 represents acidosis, and pH above 7.45 is alkalosis. The six quadrants are metabolic acidosis / alkalosis, acute (uncompensated) respiratory acidosis / alkalosis, and chronic (uncompensated) respiratory acidosis / alkalosis. ARAcid is left because left means acidosis and bicarbonate hasn’t had time to increase. CRAcid is upper left because bicarbonate had time to increase. ARAlka is right because right is alkalosis and it hasn’t had time to lower bicarbonate. CRAlka is lower right because bicarbonate has decreased. Metabolic acid = lower left because low bicarbonate decreases pH. Metabolic alkal = upper right because high bicarbonate increase pH.
Describe the equilibrium point of the salt / water relationship.
What is the endpoint mediator of sodium secretion? What does it do?
What regulates water via a separate system? Describe it.
Describe why it is stored in the posterior pituitary.
There is a single blood pressure at which the intake of salt and water equals the output of salt and water.
Aldosterone, increased aldosterone increases sodium reabsorption, thus increasing sodium in the blood and decreasing urine output, increasing blood pressure and extracellular volume.
ADH (vasopressin), manufactured in the supraoptic nucleus and PVN to be released from the posterior pituitary.
So that it can be released at a moments notice due to increased plasma osmolality.
What are two major separate balance issues with the fluid?
Sodium concentration does not equal what?
Describe three volume statuses and their symptoms.
Salt balance and water balance (these are separate things).
Does not equal volume of their plasma (sodium concentration tells you nothing about their blood volume).
Hypovolemia / hypervolemia, these are easy to spot clinically so we look at these first. Hypervolemia causes edema / ascites / JVD / displaced PMI. Hypovolemia causes tachycardia / decreased skin turgor / dry membranes / thirst. Euvolemia (normal) means they have none of these symptoms.
Describe the four possible factors of hyponatremia.
Hyponatremia (low blood sodium concentration) could be ADH reabsorbing water, insufficient sodium intake, excessive water intake, or impaired urine diluting capacity.
Thus hyponatremia is most often the result of what two things?
With what three exceptions?
If it’s not these exceptions, then what do you know it must be?
Thus hyponatremia is mostly caused by impaired diluting capacity and inappropriate ADH sucking water into the blood.
1) Polydipsia = Patient is releasing plenty of water in their urine but is simply drinking too much extra water.
2) Tea and Toast syndrome = Patient is making urine with plenty of water in it but is simply not eating enough solute.
3) Hypovolemic hyponatremia = Severe blood loss (tons of symptoms) causes low sodium.
Plain old hyponatremia due to impaired diluting capacity with inappropriate ADH.
Name some mechanisms that contribute to maximally dilute urine.
Why are these important to keep track of?
High GFR / minimum sodium resorption at the PCT / preserved activity of Na-K-2Cl in thick ascending limb / preserved activity of Na-Cl in DCT / minimum water resorption in cortical collecting duct.
Any one of these could be impaired thus causing hyponatremia (too much water being reabsorbed or too little salt being reabsorbed).
Describe SIADH.
Describe what you must exclude.
Syndrome of inappropriate ADH secretion means too much ADH is released thus causing too much water to be pulled back into the blood which causes hyponatremia.
To diagnose SIADH, you must exclude hypothyroidism (which impairs cardiac output thus lower blood volume causes ADH to be released) and adrenal insufficiency (which causes too much water to be filtered out thus ADH is secreted). Once these are excluded, we can consider SIADH.
