Bonus Episode: What do you think of these new USMLE Podcasts? Doctor Dan teaches pathophysiology and physiologic responses of the kidney to various disease states, including primary aldosteronism, DKA, SIADH and diabetes insipidus as examples.
Listen to the podcast here…
ECF (1/3) = extracellular fluid of two compartments – vascular (1/3) and interstitial (2/3)
ICF (2/3) = intracellular fluid compartment
Example: how many liters of isotonic saline do you have to infuse to get 1 liter into the plasma? 3 Liters (2/3:1/3 relationship); 2 liters in interstial space, and 1 L would go to the vascular space; it equilibrates with interstial/vascular compartments.
B. Osmolality =
Measure of solutes in a fluid; due to three things: Na, glucose, and blood urea nitrogen (BUN) – urea cycle is located in the liver, partly in the cytosol and partly in the mitochondria; usually multiply Na times 2 (b/c one Na and one Cl). Normal Na is 135-140 range, times that by 2 that 280. For glucose, normal is 100 divide that by 18, let’s say it’s roughly 5, so that’s not contributing much. BUN: located in the liver, part of the cycle is in the cytosol and part of it is in mitochondria. The urea comes from ammonia, that’s ammonia is gotten rid of, by urea. B/c the end product of the urea cycle is urea. The normal is about 12; divide that by 3, so we have 4. Therefore, in a normal person Na is controlling the plasma osmolality. To measure serum osmolality: double the serum Na and add 10.
C. Osmosis =
Among intracellular, intravascular, and interstitial spaces, 2 of these 3 are limited to the ECF compartment. One can equilibrate between ECF and ICF across the cell membranes – urea; therefore, with an increased urea, it can equilibrate equally on both sides to it will be equal on both sides; this is due to osmosis.
B/c Na and glucose are limited to the ECF compartment, then changes in its concentration will result in the movement of WATER from low to high concentration (opposite of diffusion – ie in lungs, 100 mmHg in alveoli of O2, and returning from the tissue is 40 mmHg pO2; 100 vs. 40, which is bigger, 100 is bigger, so via diffusion, O2 moves through the interspace into the plasma to increase O2 to about 95mmHb). Therefore, in diffusion, it goes from high to low, while in osmosis, it goes from low to high concentration.
Example: In the case with hyponatremia – water goes from ECF into the ICF, b/c the lower part is in the ECF (hence HYPOnatremia); water goes into the ICF, and therefore is expanded by osmosis. Now make believe that the brain is a single cell, what will we see? cerebral edema and mental status abnormalities via law of osmosis (the intracellular compartment of all the cells in the brain would be expanded)
Example: hypernatremia – water goes out of the ICF into the ECF, therefore the ICF will be contracted. So in the brain, it will lead to contracted cells, therefore mental status abnormalities; therefore, with hypo and hypernatremia, will get mental status abnormalities of the brain.
3. Diabetic ketoacidosis
Example: DKA – have (1000mg) large amount blood sugar. Remember that both Na and glucose are limited to the ECF compartment. You would think that glucose is in the ICF but it’s not. You think that since glycolysis occurs in the cytosol therefore glucose in the ICF (again its not) b/c to order to get into the cell (intracellular), glucose must bind to phosphorus, generating G6P, which is metabolized (it’s the same with fructose and galactose, which are also metabolized immediately, therefore, there is no glucose, fructose, or galactose, per se, intracellularly). So, with hyperglycemia, there is high glucose in the ECF, so water will move from ICF to ECF. Therefore, the serum Na concentration will go down – this is called dilutional hyponatremia (which is what happens to the serum sodium with hyperglycemia).
Therefore the two things that control water in the ECF are Na and glucose; but a normal situation, Na controls. Urea does not control water movements b/c its permeable, and can get through both compartments to have equal concentrations on both sides.
D. Tonicity =
Isotonic state, hypotonic state, and hypertonic state. We have all different types of saline: Isotonic saline, hypotonic saline (1/2 normal saline, ¼ normal saline, 5% dextrose in water), and hypertonic saline (3%, 5%); normal saline is 0.9%. We are referring to normal tonicity of the plasma, which is controlled by the serum Na. These are the three types of tonicity (iso, hypo, and hyper). Serum Na is a reflection of total body Na divided by total body H20. For example: hypernatremia is not just caused by increased total body Na; it can also be caused by decreasing total body water with a normal total body Na, therefore there is an increase in serum Na concentration. It is really a ratio of total body Na to total body H20. To determine serum Na, just look at serum levels. With different fluid abnormalities, can lose or gain a certain tonicity of fluid.
1. Isotonic loss of fluid
– look at ratio of total body Na and water; in this case, you are losing equal amounts of water and Na, hence ISOtonic. This fluid is mainly lost from the ECF. The serum Na concentration is normal when losing isotonic fluid. ECF would look contracted. There would be no osmotic gradient moving into or out of the ECF. Clinical conditions where there is an isotonic loss of fluid: hemorrhage, diarrhea. If we have an isotonic gain, we have in equal increase in salt and water; ie someone getting too much isotonic saline; normal serum Na, excess isotonic Na would be in the ECF, and there would be no osmotic gradient for water movement.
2. Hypotonic solutions
A hypotonic solution, by definition, means hyponatremia. Hypoglycemia will not produce a hypotonic condition.
MCC of low osmolality in plasma is hyponatremia. How? Lose more salt than water, therefore, serum Na would be decreased. If losing more salt than water, kidney is probably the location of where/why it is happening. Main place to deal with sodium (either to get rid of it or to get it back) is in kidney, esp when dealing with diuretics (Furosemide and HCTZ). The tonicity of solution you lose in your urine is HYPERtonic, so that’s how you end up with hyponatremia with a hypotonic condition. ECF concentration is low with hyponatremia, therefore the water will move into the ICF compartment. (Osmosis-remember low to high)
Syndrome of Inappropriate Andidiuretic Hormone (SIADH):
Example: If you gained pure water, and no salt, you have really lowered your serum Na: MCC = SIADH – in small cell carcinoma of the lung; you gain pure water b/c ADH renders the distal and the collecting tubule permeable to free water. With ADH present, will be reabsorbing water back into the ECF compartment, diluting the serum Na, and the ECF and ICF will be expanded. The ECF is expanded due to water reabsorption, and the ICF is expanded b/c it has a high concentration levels (its levels are not diluted). This can lead to mental status abnormalities. Therefore, the more water you drink, the lower your serum Na levels would be. The treatment is by restricting water. Don’t want to restrict Na b/c the Na levels are normal. When ADH is present, you will CONCENTRATE your urine b/c taking free water out of urine; with absent ADH, lose free water and the urine is diluted. Therefore, for with SIADH, water stays in the body, goes into the ECF compartment, and then move into the ICF compartment via osmosis. The lowest serum sodium will be in SIADH. On the boards, when serum Na is less than 120, the answer is always SIADH. Example: pt with SIADH, not a smoker (therefore not a small cell carcinoma), therefore, look at drugs – she was on chlorpropramide, oral sulfylureas produce SIADH.
Right Heart Failure and Hepatic Cirrhosis:
Example: Gain both water and salt, but more water than salt, leading to hyponatremia – these are the pitting edema states – ie RHF, cirrhosis of the liver. When total body Na is increased, it always produces pitting edema. What compartment is the total body Na in? ECF What is the biggest ECF compartment? Interstial compartment. Therefore, increase in total body Na will lead to expansion of interstial compartment f the ECF, water will follow the Na, therefore you get expansion via transudate and pitting edema; seen in right HF and cirrhosis.
- Example: hypertonic loss of salt (from diuretic) leads to hyponatremia
- Example: SIADH (gaining a lot of water) leads to hyponatremia
- Example: gaining more water than salt will lead to hyponatremia: pitting edema
3. Hypertonic state
A hypertonic solution, by definition means too much Na (hypernatremia) or hyperglycemia. Unlike in a hypotonic solution, you can have glucose contribute to this state. For example, a patient with DKA has a hypertonic condition, which is more common than hypernatremia. With hypernatremia, what does ICF look like? It will always be contracted or shrunken.
Gain more salt and water.
Lose pure water (vs. gaining pure salt in SIADH). If you lose more water than salt in the urine, you have osmotic diuresis – mixture. When there is glucose and mannitol in the urine, you’re losing hypotonic salt solution in urine.
Hypotonic salt solution (adult diarrhea is isotonic), therefore, if baby has no access to water and has a rotavirus infection, serum sodium should be high because losing more water than salt, leading to hypernatremia. However, most moms give the baby water to correct the diarrhea; therefore the baby will come in with normal serum Na or even hyponatremia b/c the denominator (H2O) is increased. Treatment is pedialyte and Gatorade – these are hypotonic salt solution (just give them back what they lost). What has to be in pedialyte and what has to be in Gatorade to order to reabsorb the Na in the GI tract? Glucose b/c of the co-transport. With the co-transport, the Na HAS to be reabsorbed with glucose or galactose. Example: cholera, in oral replacement, need glucose to reabsorb Na b/c co-transport pump located in the small intestine. Gatorade has glucose and sucrose (which is converted to fructose and glucose).
Hypotonic salt solution; if you are sweating in a marathon, you will have hypernatremia.
E. Volume Compartments
Physiologic response to hypovolemia:
Arterial blood volume is same as stroke volume and CO (cardiac output). When Cardiac Output decreases, all physiologic processes occur to restore volume. With decrease CO (ie hypovolemia), oxygenated blood will not get to tissues, and we can die. Therefore, volume is essential to our bodies.
We have baroreceptors (low and high pressure ones). The low pressure ones are on the venous side, while the high pressure ones are on the arterial side (ie the carotids and arch of aorta). They are usually innervated by CN 9 and 10 (the high pressure ones). When there is a decrease in arterial blood volume (decreased SV or CO), it will under fill the arch vessels and the carotid; instead of 9th or 10th nerve response, you have a sympathetic NS response, therefore catecholamines are released. This is good b/c they will constrict the venous system, which will increase blood returning to the right side of the heart (do not want venodilation b/c it will pool in your legs).
Catecholamines will act on the beta adrenergic receptors on the heart, which will increase the force of contraction, there will be an increase in stroke volume (slight) and it will increase heart rate (“+” chronotropic effect on the heart, increase in systolic BP). Arterioles on the systemic side: stimulate beta receptors in smooth muscle. Diastolic pressure is really due to the amount of blood in the arterial system, while you heart is filling with blood.
3. Arterioles: The gatekeeper of tissue perfusion
Who controls the amount of blood in arteriole system, while your heart is filling in diastole? Your peripheral resistance arterioles – that maintains your diastolic blood pressure. So, when they are constricted, very little blood is going to the tissues (bad news); good news: keep up diastolic pressure – this is important b/c the coronary arteries fill in diastoles. This is all done with catecholamines.
4. Renin-Angiotensin System
Renin system is activated by catecholamines, too; angiotensin II can vasoconstrictor the peripheral arterioles (therefore it helps the catecholamines). AG II stimulates 18 hydroxylase, which converts corticosterone into aldosterone, and stimulates aldosterone release, which leads to reabsorption of salt and water to get cardiac output up. With decreased SV, renal blood flow to the kidney is decreased, and the RAA can be stimulated by this mechanism, too. Where exactly are the receptors for the juxtaglomerlur apparatus? Afferent arteriole. There are sensors, which are modified smooth muscle cells that sense blood flow. ADH will be released from a nerve response, and pure water will increase but that does not help with increasing the cardiac output. Need salt to increase CO.
Example: bleeding to death and there is a loss of 3 L’s of fluid – how can you keep BP up? Give normal saline is isotonic therefore the saline will stay in the ECF compartment. Normal saline is plasma without the protein. Any time you have hypovolemic shock, give normal saline to increase BP b/c it stays in the ECF compartment. Cannot raise BP with ½ normal saline or 5% dextrose; have to give something that resembles plasma and has the same tonicity of plasma. Normal saline is 0.9%. Peritubular capillary pressures: you reabsorb most of the sodium in the proximal tubule (60- 80%). Where is the rest absorbed?; in the distal and collecting tubule by aldosterone. The Na is reabsorbed into the peritubular capillaries. Starling forces in the capillaries must be amenable to it. Two starling forces: oncotic pressure (keeps fluids in the vessel) and hydrostatic (pushes fluids out of vessel).
Example: When renal blood flow is decreased (with a decreased SV and CO), what happens to the peritubular capillary hydrostatic pressure? It decreases. Therefore, the peritubular oncotic pressure is increasing (ie the force that keeps fluids in the vessel), and that is responsible for reabsorption of anything into the blood stream from the kidney. This is why PO (peritubular oncotic pressure) > PH (hydrostatic pressure of peritubular capillary), allows absorption of salt containing fluid back into blood stream into the kidney. Tonicity of fluid reabsorbing out of proximal tubule is isotonic (like giving normal saline). ADH is reabsorbing isotonic salt solution, but not as much as the proximal tubule. ADH contributes pure water, therefore, with all this reabsorption you have an isotonic sol’n add the ADH effect and the pt becomes slightly hyponatremic and hypotonic, therefore absorbs into the ECF compartment when there is a decreased CO.
Opposite Example: increased SV, and increase arterial volume, will lead to stretch of baroreceptors (innervated by 9th and 10th nerve), and a parasympathetic response will be elicited, instead of a sympathetic response. There will not be any venuloconstriction nor any increase in the force of contraction of the heart. This is fluid overload; therefore we need to get rid of all the volume. There is increased renal blood flow, so the RAA will not be activated. Fluid overload does not ADH be released. The peritubular hydrostatic pressure is greater than the oncotic. Even of the pt absorbed salt, it wouldn’t go into the blood stream, and it would be pee’d out. Therefore pt is losing hypotonic salt solution with increased in arterial blood volume. Need to know what happens if there is decreased CO, what happens when ANP is released from the atria, and give off diuretic effect; it wants to get rid salt. ANP is only released in volume overloaded states.
Example: pt given 3% hypertonic saline: what will happen to osmolality? Increase. What will that do to serum ADH? Increase – increase of osmolality causes a release of ADH.
Example: What happens in a pt with SIADH? decreased plasma osmolality, high ADH levels.
Example: What happens in a pt with DI? no ADH, therefore, serum Na increases, and ADH is low How to tell total body Na in the pt: Two pics: – pt with dry tongue = there is a decrease in total body Na, and the pt with indentation of the skin, there is an increase in total body Na. Dehydration: Skin turgur is preformed by pinching the skin, and when the skin goes down, this tells you that total body Na is normal in interstial space. Also look in mouth and at mucous membranes. If you have dependent pitting edema that means that there is an increase in total body Na.
SIADH – gaining pure water, total body sodium is normal, but serum Na is low; have to restrict water.
Right HF and dependent pitting edema – fluid kidney reabsorbs is hypotonic salt solution with a decreased CO (little more water than salt), therefore serum Na will low. Numerator is increased for total body sodium, but denominator has larger increase with water.
What is nonpharmalogical Rx of any edema states? (ie RHF/liver dz) – restrict salt and water What is the Rx for SIADH = restrict H2O. What is the Rx for any pitting edema state? Restrict salt and water. Pharmacological Rx for pitting water – diuretics (also get rid of some salt).