Editing Kidney functions

*started here on 03/22/11


==Kidney functions==

===The National Kidney Disease Education Program===
*300K+ people have end stage kidney disease.
*It is expensive to take care of end stage kidney disease: 28 billion in 2010 (8% of the Medicare/caid budgets).
*11% of the US population has chronic kidney disease.
*Testing and therapy for chronic kidney disease are inadequately applied.
*Symptoms don't result until renal failure is well progressed.
**Get regular checkups.

===Homeostasis===
*Claude Bernard suggested the idea of homeostasis: "constancy of the internal milieu is the essential condition to a free life".
*Walter Canon developed the idea of homeostasis and gave it said name.
*Homer Smith explains why the kidney filters everything and then has to reabsorb most of it.
**"Recognizing that we have the kind of blood we have because we have the kind of kidneys we have, we must acknowledge that our kidneys constitute the major foundation of our physiological freedom."
*Recall that mammal (and all land animals) came from sea animals.
*The kidneys have evolved from an environment where there was too much water (sea) to an environment where there is too little water (land).
**And many diverse animals keep their ions (Na, K, Ca, Mg, and Cl) at very consistent proportions.
**And close to the concentrations of sea water.

===Drinking urine is good for you===
*Drinking urine is NOT good for you!

===Kidney functions===
*The kidneys have many functions, all of which focus on homeostasis of the fluid.
**Most important the amount of Na.
**Results in regulation of the amount of water retained.
*The kidneys regulate the osmotic pressure of the body fluids by retaining or losing water.
*The kidneys regulate concentrations of 8 major ions / molecules: Na, K, Mg, Ca, Cl, HCO3- (and therefore H+), phosphate (PO3-) and sulfate (SO4-).
*The kidneys eliminate waste products and foreign compounds (think drugs and urea).
*The kidneys regulate extraceullar fluid volume.
*The kidneys regulate arterial blood pressure.
*The kidneys have specialized metabolic functions:
**Gluconeogenesis
**Degradation of polypeptide hormones
**Synthesis of ammonia from aas.
*The kidneys add important substances to the blood:
**Erythropoietin
**1,25OH VitD (calcitriol)
**Prostaglandins and thromboxane
**Renin
**Kallikrein

===Erythropoietin===
*Erythropoietin (EPO) is released by cells of the renal cortex in response to hypoxia.
*EPO (erythropoietin) acts on the bone marrow to increase RBC proliferation, matruation and release.
*As more RBCs are made, oxygen carrying capacity goes up.
*In chronic renal disease, too little EPO is generated by the kidney and anemia results.
*In blood doping, EPO was used to increase oxygen carrying capacity until we became able to determine the difference between endogenous and exogenous EPO.
*Treatment of anephritic patients with EPO is far more effective than the cycles of transfusion that would otherwise be required.

===Vitamin D===
*Vitamin D is hydroxylated once at the liver and once at the kidney.
**Recall that 7-dehydrocholesterol is obtained from the diet, converted to vitamin D3 at the skin, hydroxylated at the 25 position at the liver, and then at the 1 position in the kidney.
*'''The kidney adds the second hydroxyl group at the 1 position.'''
*'''Calcitriol (1,25OH vit D) is the biologically active form of vitamin D.'''
**Cacitriol causes increased Ca absorption at the gut and increased Ca mobilization at the bone (by potentitiating PTH's action, from the parathyroid).


*In renal disease, vitamin D is not hydroxylated well and so the body has '''too little biologically active vitamin D (calcitriol)'''.
**As the kidney fails, increased phosphate in the blood (''hyperphosphatemia'') and decreased renal tubular mass lead to decreased ability of the kidney to hydroxylate 25OH VitD to calcitriol (1,25 vit D3).
**Phosphate levels go up because phosphate cannot be lost in the filtrate.
*Also, high phosphate can crystalize and cause kidney problems.


*Decreased calcitriol generation has a '''series of effects (literally, a series)''':
**This results in '''poor calcium absorption at the gut'''.
**Because there is poor Ca absorption at the gut, there is also '''hyperparathyroidism''' as the parathyroid works overtime to signal to the gut and bone to keep the Ca levels high despite poor absorption.
**And because the parathyroid is calling on the bone to release lots of Ca to keep serum levels normal, the bone becomes demineralized (bone disease).
**Finally, there is vascular calcification.
 Why is there calcium calcification?
 "Patients with chronic kidney disease are at risk for vascular calcification because of multiple risk factors that induce vascular smooth muscle cells to change into a chondrocyte or osteoblast-like cell; high total body burden of calcium and phosphorus due to abnormal bone metabolism; low levels of circulating and locally produced inhibitors; impaired renal excretion; and current therapies." per [http://jasn.asnjournals.org/content/19/2/213.full JASN]

===Prostaglandins and Thromboxanes===
*Prostaglandins and thromboxanes are made from phospholipds via cyclo-oxygenase enzymes like COX1 and COX2.
*Cyclo-oxygenase enzymes (COX1 and COX2) are constitutively activated in the kidney.
*The kidneys make lots of prostaglandins and thromboxanes which have effects on the kidney, itself.
*Prostaglandins:
**Prostaglandins increase renal blood flow.
**Prostaglandins increase Na excretion (increases water reabsorption, increases blood pressure).
**Prostaglandins increase renin release (increases water reabsorption, increases blood pressure).
***Recall that renin converts angiotensinogen to angiotensin 1 which gets converted to antiotensin 2 (by ACE in the lung) which causes blood vessels to constrict (elevates blood pressure) and causes release of aldosterone (from the glomerulosa zone of the adrenal cortex) which causes the kidney to reabsorb more Na and therefore more water (elevates blood pressure).
**Prostaglandins inhibit the actions of ADH on the kidney (decreases water absorption, decreases blood pressure).
***Recall that ADH (anti-diuretic hormone, AVP arginine vasopressin, from the '''posterior pituitary''') causes the kidney to reabsorb water.
*Thromboxanes are vasoconstrictors (increases blood pressure).
*'''PGE2 and PGI2 are the main prostaglandins.'''

===Renin-angiotensin system===
*The overall scheme is that angiotensinogen is present in the blood, renin cuts it into angiotensin 1, ACE cuts angiotensin 1 into angiotensin 2.
**Note that angiotensinogen comes from the liver, renin comes from the kidney, and ACE (angiotensin converting enzyme) comes from the lungs.
 Did Homor Smith explain why it makes sense that one enzyme should come from the lungs (ACE) and the other from the kidneys (renin)?
 No...
*Angiotensin 2 is all about increasing blood pressure and therefore has effects on the vasculature (think constriction), the adrenal cortex (think aldosterone, and the brain (think thirst).
**Angiotensin 2 causes vasculature to constrict, thus increasing the blood pressure.
**Angiotensin 2 causes the adrenal cortex (the zona glomerulosa) to release aldosterone which causes the kidney to increase Na reabsorption (and therefore water reabsoprtion), thus increasing the blood pressure.
**Angiotensin 2 causes the brain (posterior pituitary) to release AVP (arginine vasopressin = ADH) which causes the kidney to put more aquaporin proteins on the renal tubule epithelial cells which increases water reabsorption, thus increasing the blood pressure.


*ACE inhibitors inhibit the conversion of angiotensin 1 to angiotensin 2 and thus help keep blood pressure low (by decreasing water reabsorption (reduced aldosterone and AVP) mostly and also by decreasing vascular constriction).

===Renal kallikrein enzyme system===
*'''The renal-kallikrein system serves to dilate the vasculature''' (so it has mostly an opposite affect as the renin-angiotensin system, in terms of the vasculature).
*The general pathway is kininogen to kinins via kallikrein, then kinins to inactivated peptides via kininases.
**Kininogens are made primarily by the liver, but also by some other tissues.
**'''Kallikrein is made by the kidney.'''
**The active molecules are the kinins, like bradykinin.
**'''Bradykinin increases production of NO and prostaglandins''' that act on the smooth muscle cells of the vasculature and therefore kinins are potent vasodilators.
***Recall that the kidney makes lots of prostaglandins through the cyclo-oxygenase genes.


*ACE (recall that it converts angiotensin 1 to angiotensin 2 which goes on to increase blood pressure in many ways) is a kininase so it helps to increase blood pressure by getting rid of the kinins (like bradykinin) that are floating around trying to decrease the blood pressure.

===The nephron===
*The nephron is the basic structural and functional unit of the kidney.
*Each kidney is supplied by a renal artery, a renal vein, and a ureter which enter at the renal hilus.
*The outside of the kidney is the renal capsule.
*Deep to the capsule is the cortex.
*Within the cortex framework are medullary pyramids in which are the medulla.
*The beginning of the drainage structures are the minor calyces, then the major calyces, then the renal pelvis, and finally the ureter.
**The area of the renal pelvis and the calyces combined is the renal sinus.

===Blood vessels of the kidney===
*Recall that there is the cortex and medulla of the kidney.
**The cortex and medulla are histologically distinct.
**Within the medulla, we define two distinct areas: the outer medulla and the inner medulla.


*The kidney blood supply is specialized to allow the kidney to perform it's filtering duties.
*Each nephron has its own blood artery and vein.
*The overall flow is renal artery -> arcuate artery -> cortical radial artery -> afferent arteriole (one for each glomerulus) -> glomerulus (either a superficial cortical glomerulus or a juxtamedullary glomerulus) -> efferent arteriole -> peritubular arteries -> arcuate vein -> renal vein.
**The peritubular capillaries deliver oxygen to the cells of the tubule and serve to reabsorbed material from the interstitial fluid back into the blood.
**The superficial cortical glomerulus and the juxtamedullary glomerulus differ in their function and in their location within the kidney.
**The descending vasa recta provide another route for blood.
***The descending vasa recta branch off the efferent arterioles (that is, distal to the glomerulus) '''of the juxtamedullary glomeruli'''.
***The descending and ascending vasa recta lie parallel to an individual tubule.


*Note that the bowman's capsule is the set of epithelial cells that surround the gomerular capillaries.


*The functional unit of the kidney is the nephron, of which there are about 1 million in each kidney.
**85% of the nephrons proceed from the superficial cortex to the outer medulla and have superficial cortical glomeruli.
**15% of the nephrons proceed from the deep cortex to the inner medulla and have juxtamedullary glomeruli.
**The tubule (which has descending thick, descending thin, and ascending thin, ascending thick segments) leads to the collecting duct.

===Renal osmolarity gradient===
*The through filtration and blood flow, the kidney maintains an osmotic gradient along the cortex-medulla axis.
*There are lots of capillaries surrounding the nephrons.

===Blood flow to the kidneys is high===
*25% of the cardiac output goes to the kidneys.
**Flow by gram of tissue is higher than the brain!
*High blood flow is important for driving a high filtration rate.
**The 3 liters of ''plasma'' is filtered every 24 minutes (which is 50-60 times per day).

===Major processes involved in urine formation===
*The blood is '''"filtered"''' at the glomerulus; small particles flow out of the blood into the '''"filtrate"'''.
*Some material from the filtrate is '''"reabsorbed"''' in the kidney tubule; epithelial cells reabsorb ions and such back into the interstitial fluid / blood.
*Some materials are '''"secreted"''' into the filtrate; epithelial cells can put metabolites and such into the filtrate (urine).

===Proximal tubule===
*2/3 of the filtrate is reabsorbed in the proximal tubule.
*The proximal tubule is the epithelial tract that is nearest the glomerulus.
*The proximal tubule is a specialized tissue for reabsorption and secretion:
**Neighboring epithelial cells have tight junctions to keep "stuff" from passing without an active transport mechanism (either reabsorption or secretion).
**The epithelial cells have microvilli (a brush border) to increase the surface area and the ability to reabsorb / secrete.
**The epithelial cells have many microvilli to produce lots of ATP for all the active transport that must occur.
***Also, lots of Na / K ATPase activity to maintain a Na gradient to run all the active transport.
**The epithelial cells sit on a basement membrane to provide structure and order to the single layer of cells.

===The juxtaglomerular apparatus (JGA)===
*The juxtaglomerular apparatus is important for two major functions: the release of renin and feedback on the tubulo-glomerular feedback.
**Recall that the release of renin will convert angiotensinogen to AT1 (angiotensin 1) which will get converted to angiotensin 2 (at the lungs by ACE) which will cause blood vessels to constrict and aldosterone to be released, thus '''increasing blood pressure'''.
*The juxtaglomerular apparatus is called an apparatus because it functions by the coordinated activity of three cell types from two separate structures of one nephron.
**Macula densa cells are epithelial cells found on the thick ascending tubule of the nephron.
***The ascending tubule is coming up (toward cortex) from the ''loop of Henle''.
***Macula densa cells seem to be more columnar in shape than their more cuboidal, normal endothelial cells.
**Extraglomerular mesangial cells are also found on the thick ascending tubule.
***Extraglomerular mesangial cells hold the JGA structure together.
***Extraglomerular mesangial cells may also convert stuff released by the macula densa.
**Granular cells (also called juxtaglomerular cells) are endothelial cells found in the wall of the afferent arteriole.

===Tubulo-glomerular feedback===
*Tubulo-glomerular feedback describes how the concentration of NaCl in the tubule (that is, in the filtrate) can be used to affect the GFR (glomerular flow rate) by changing the diameter of the afferent arterioles that lead to the glomerulus.
**Note that this it taking place within a single nephron; as the tubule ascends back toward the cortex, it passes by it's own glomerulus and therefore can have a very rapid affect on the GFR.
**The '''macula densa''' cells detect the NaCl concentration in the tubule and send molecular signals to the afferent arterioles.
***Sensing of the NaCl concentration is a model of filtrate flow.


*Why detect the NaCl?
**Recall that the tubule is all about reabsorbing important ions and molecules from the filtrate, including Na and Cl (the body doesn't want to lose them).
**So if NaCl concentration is high at the distal tubule (that is, near the macula densa), then we know the filtrate needs to move more slowly in order to reabsorb more of the Na and Cl.
**If NaCl concentration is low at the distal tubule, then we know the filtrate can be moved along more quickly.
**Now recall that the flow rate of the filtrate is a function of glomerular filtration rate which is a function of the blood pressure difference between the afferent and efferent arterioles of the glomerulus.
**So, we should change the blood pressure of the afferent arteriole if we want to change the flow rate of the filtrate (and therefore affect the reabsorption levels).


*The macula densa cells can respond to both high and low NaCl concentrations:
**When NaCl concentrations are low, filtrate flow rate is too slow. The macula densa cells signal to the granular cells to release renin.
***Recall that renin will increase blood pressure systmeically because angiotensin 2 causes vasoconstriction, aldosterone release at the adrenal gland, and AVP release at the posterior pituitary.
***It makes sense that low flow rate should lead to release of renin by the granular cells because increased blood pressure (at the afferent arteriole) causes an increase in filtrate formation (increased blood flow will push more fluid through the fenestrations at the glomerulus and thus generate more filtrate).
***Note that this will not cause immediate vasoconstriction, because the renin-angiotensin pathway must run its course, which includes a trip through the lungs (think ACE).
***Note that macula densa cells signal to granular cells via PGE2, a prostaglandin produced by COX2 in the macula densa cells.
***The '''granular cells have the EP4 receptor for PGE2''' from the macula densa cells.
***The '''granular cells''' of the afferent arteriole are well named because they have granules full of '''renin'''.
**When NaCl concentration levels are high, filtrate flow is too fast.  The macula densa cells signal to the endothelial cells of the afferent arteriole to vasoconstrict.
***'''ATP''' is released by the macula densa cells and is converted to '''adenosine (a vasoconstrictor)''' to decrease blood flow of the afferent arteriole and thus decrease filtrate production.
***Adenosine binds to the A1 receptors of the endothelial cells of the afferent arteriole to cause vasoconstriction.

===Angiotensin 2===
*Recall that angiotensin 2 causes systemic vasoconstriction, release of aldosterone at the adrenal cortex (glomerulosa), and release of ADH (AVP) at the posterior pituitary.
*At low concentrations, angiotensin 2 causes efferent arteriole constriction.
**This causes a decrease in renal blood flow (RBF).
**This will cause an increase in the difference between the afferent arteriole blood pressure and the efferent arteriole blood pressure, and thus '''and increase in GFR'''.
*At high concentrations (as in trauma and emergencies), both the afferent and efferent arterioles vasoconstrict.
**This causes a decrease in RBF (renal blood flow).
**This causes a decrease in GFR (glomerular filtration rate).
***This makes sense because you want to conserve all the fluid you can in an emergency.
**Angiotensin 2 levels are severely elevated in emergency situations because sympathetic nerves directly stimulate the granular cells of the juxtamedullary apparatus to release their renin and thus much more angiotensin 2 is generated than when macula densa cells signal for renin release.

===Micturition = Urination===
*Micturition is a voluntary control in adults.
*Children do not obtain voluntary control of micturition until 2-3 years of age.
*The tension in the wall of the bladder adjusts as the bladder fills to keep pressure from building up.
*One generally feels the need to micturate at about 150-250 ml and loses control of voluntary micturition at 700 ml.
*The ureters have a smooth muscle layer that forces urine along the tract.
**This is important for outer space travel and to counteract the counter pressure of the fluid already in the bladder.

===Renal plasma clearance===
*There are multiple forces that cause a net movement of plasma out of the blood at the glomerulus into the filtrate:
**Pi is the colloid osmotic pressure of the blood (forces into the blood)
**P<sub>GC</sub> = Glomerular capillary pressure is the hydrostatic pressure from blood flow (forces into filtrate)
**P<sub>BS</sub> = '''B'''owman '''space''' hydrostatic pressure; that is, the hydrostatic pressure of the filtrate (forces into the blood)
*One measure of renal function is the renal plasma clearance, defined as ml plasma / min that are cleared of a substance.
*The equation is C * P = U * V where
**C = clearance of the substance (the unknown, the indicator of kidney function)
**P = plasma concentration of the substance
**U = urine concentration of the substance
**V = urine flow rate
**C = UV/P
*As an example: the plasma concentration is 2 mg/ml, the urine concentration is 6 mg/min.
**C = UV/P = 6 mg/min / 2 mg/ml = 3 min/ml
**Note that v-dot (a "v" with a dot over it) is commonly used to denote a rate of flow; the dot distinguishes it from a volume.


*Inulin is a good test compound because it is biologically inert and the kidney reabsorbs nearly zero of the filtered inulin.
**Because very little inulin is reabsorbed, the amount of filtered inulin is equal to the amount of excreted inulin.
**Therefore, the GFR = C = UV/P.


*One might wonder why the urinary inulin is more concentrated than the plasma inulin.
**Its because while none of the inulin gets reabsorbed, so many of the other filtered molecules (including water) ''do get reabsorbed''.


*stopped here on 03/22/11
*started here on 03/23/11

===Endogenous creatinine clearance===
*Creatinine is a useful endogenous molecule for measuring kidney function because there is little to no tubular reabsorption of creatinine.
**We can't use inulin with humans.
*In fact, creatinine is easily filtered and even actively secreted in the proximal tubule.
*Therefore, when plasma creatinine levels rise it is usually the result of poor renal function and a decreased GFR.
**When plasma creatinine levels double, GFR has decreased by 1/4 (25%).

===MDRD equation for estimating GFR===
*This is a well studied equation.
*Age, gender, and AA race are taken into account.
*As GFR declines, creatinine goes up.

===Example GFR data===
*A normal GFR is about 125 ml plasma / min.
*A normal day has about 1440 minutes in it.
*So a normal kidney filters 125 ml plasma / min * 1440 min = 180 L / day.
**And we have about 3.5 L of '''plasma (filtered 50 times per day''') and 14 L of '''extracellular fluid (filtered 13 times per day''').

===Filtration fraction===
*Another useful metric for renal function is the ratio (fraction) of fluid filtered to ''renal plasma flow'' ('''filtration fraction = GFR / 55% of RPF''').
**This fraction will tell us how much of the plasma is filtered with each pass of a unit of blood through the kidney.
**Recall that a normal GFR = 125 ml plasma / min.
**Recall that a normal RPF = 660 ml / min.
***Note that a normal RBF (renal ''blood flow'') is 1200 ml blood / min and that 55% of the volume of blood is plasma so 0.55 * 1200 = 660 ml of plasma.
**So a normal fraction is 125 / 660 = 0.19.
***So around 20% of the plasma is filtered with each pass through the kidney.

===PAH clearance===
*The clearance of '''p-aminohippurate (PAH)''' has been shown to model well the renal plasma flow (RPF).
*Note that PAH is not normally found in blood plasma.
*Also, PAH is cleared in a single pass through the kidney because it is filtered '''and highly secreted'''.
**More than 90% of the PAH is cleared in one cycle of the blood through the kidneys.
*An '''extraction ratio''' is the amount of a compound entering the kidney versus the amount excreted in the urine.
*PAH has an extraction ratio of nearly 1, meaning that nearly all of the PAH that enters the kidney gets filtered out into the filtrate urine.
*Therefore, the clearance rate of PAH is a good estimate of the renal plasma flow (note that this is not the same as renal blood flow, this is how much plasma is flowing through the kidney).

===Renal blood flow versus renal plasma flow===
*Renal blood flow and renal plasma flow are not the same value!
*'''RBF = RPF / (1 - hematocrit)'''
*Recall that a normal renal plasma flow (RPF) is 660 ml plasma / min.
*Recall that a normal plasma / hematocrit ratio is 0.45.
*So a normal RBF (renal blood flow) is 660 ml plasma / min / (0.55 ml plasma / ml blood) = 1200 ml blood / min.

===PAH and renal blood flow===
*We can calculate the renal blood flow using PAH administration.
*Give PAH until the plasma level is steady.
*Collect a timed urine sample and a blood sample.
*Measure the concentration of PAH in the plasma and the urine.
*Calculate the clearance rate of PAH (C).
**Recall that C = UV/P.
***Remember that V = urine flow rate, not the volume!
**This is the effective renal plasma flow (eRPF).
*Measure the blood hematocrit (Hct)
*Then calculate the renal blood flow (RBF).
**RBF = RPF / (1 - Hct)


*continued on to [[Renal blood flow, glomerular filtration]] on 03/23/11.