CVPR-Renal+LOs

//These notes were prepared by James Rose, CO 2011. Note that lecture order and content may have been (substantially) reorganized since these notes were written.//


 * __Renal:__**

Overview of Renal Physiology Tuesday, May 06, 2008 7:54 AM


 * Overview of Renal Physiology, 5/6/08:**


 * Describe in a single sentence the role of the kidney in total body homeostasis
 * "The main physiological function of the kidneys is the maintenance of the composition and volume of the extracellular fluid."
 * The point is this: the kidney's primary role is not limited to excretion.
 * Dr. Levinson: "We carry without ourselves a hot-house environment" that allows our cells to live while we're walking around; the maintenance of this environment is the role of the kidneys.
 * State the volume of each of the major body compartments in a standard-sized, healthy, adult individual.
 * Recall that the major body compartments are the intracellular fluid (ICF) and the extracellular fluid (ECF). For a normal (70 kg) person:
 * **ICF: 27 L**
 * Of that, the fluid inside of cells carried within the blood is about __3 L__; the fluid in noncirculating cells is about __24 L__.
 * **ECF: 15 L**
 * Of that, the blood fluid (plasma) is about __3 L__; the interstitial fluid (ISF) is about __12 L__.
 * Note that we've differentiated these compartments into the portion that circulates or moves around and the portion that more or less stays put.
 * Describe the major components and volumes of daily water intake and loss.
 * Water intake:
 * Ingestion of fluids and water in foods (2.0 L/day)
 * Metabolism (the oxidation of glucose produces CO2 and H2O (about 1/2 a liter per day).
 * Note certain animals in arid climates can actually survive on just the water produced by their metabolism.
 * Water loss:
 * Feces and sweat (0.1 L/day)
 * Through the breath and skin (0.9 L/day)
 * Urine (1.5 L/day)
 * Recall from a variety of lectures, primarily Dr. Betz's in M2M, that the maintenance of ECF ion concentrations is vital to cell life. Since these water intakes and losses can vary significantly, the kidneys need to be able to regulate water retention or release to maintain those concentrations.
 * Identify the processes of water intake and output that are regulated to achieve extracellular fluid homeostasis.
 * Kidney-regulated parameters of the ECF:
 * Volume (as mentioned above)
 * Osmolarity
 * Electrolyte composition- Na+, K+, Ca++, PO4-, etc.
 * Acid-base balance
 * Note that the kidney doesn't directly regulate H+; it regulates the bicarbonate buffer system by regulating HCO3- levels.
 * Excretes wastes- urea, acids, "foreign substances" (various drugs and their metabolites)
 * Identify the basic functional structures of the nephron.
 * Two main parts: vasculature and epithelial tubule.
 * The vasculature consists of two capillary beds in series (one after the other)-- the end of the epithelial tubule sits up against the first capillary bed (the glomerular capillary), while the other capillary bed (the peritubular capillary) kinds of wraps up around the tubule.
 * Filtration takes place across the glomerular capillary loops into Bowman's capsule; the filtrate travels into the proximal tubule, down the descending loop of Henle, up the ascending loop of Henle, through the distal tubule, into the collecting ducts, and thence into the ureters and the bladder.
 * Describe the basic glomerular and tubular processes and how they interact to achieve ECF homeostasis.
 * How this works: you get filtration (__glomerular filtration__) of the plasma in the glomerular capillary into the end of the tubule; essentially everything below a certain size (and of a certain charge-- the epithelium is negatively charged, which tends to repel other negatively-charged compounds like albumin) passes passively through the epithelium into the tubule.
 * Following that, there's an active (energy-dependent) process of __selective and variable reabsorption__ of specific substances out of the tubule into the peritubular capillary. This reabsorption is just enough to maintain the proper water and ion balance in the ECF.
 * Finally, there's the excretion of excess regulated substances (regulated substances are substances that the kidney can reabsorb) and also the excretion of wastes (substances that the kidney doesn't have a reabsorptive process for) into the urine.
 * Note that substances can also leak __into__ the kidney from the peritubular capillary (a process called secretion). More on this later.
 * So:
 * Plasma gets filtered
 * Some of the filtrate gets reabsorbed into the plasma
 * The rest of the filtrate (plus anything secreted into it) gets excreted
 * Notice that kidney activity (filtration, reabsorption) is regulated by various sensors of ECF composition in the interstitial fluid and plasma.
 * For a normal sized healthy individual, state the magnitude of renal blood flow, renal plasma flow, glomerular filtration rate, filtration fraction, and urine flow rate.
 * Renal blood flow: 25% of the total cardiac output (for our normal person, about __1.3__ L/min).
 * Note this is pretty durn high. The kidneys actually get a higher level of oxygenated blood supply than any other organ.
 * However, note that the kidneys' oxygen demands are not in proportion to their blood flow demands. Keep in mind that the reason the blood supply to the kidneys is so high is less because they're extremely oxygen-hungry (though they do consume a fair bit of energy, see below) and more because they're sort of the sieve that maintains the plasma in a state where it can be effective.
 * Renal plasma flow: assuming a hematocrit of 50%, then 1.3 x 0.50 = __0.65__ L/min or about 650 mL/min.
 * Glomerular filtration rate (**GFR** ): the rate at which the plasma is filtered into the glomerulus. Usually about __130__ mL/min.
 * Notice that this means the kidneys filter about __190 liters__ or 50 gallons per day.
 * Filtration fraction: GFR divided by the renal plasma flow (GFR/RPF). Essentially, how much of the plasma that flows through the glomerulus gets filtered into the tubule. For a normal person, about __20%__ or 0.20.
 * [so the renal plasma flow (about .65 L per minute) times the filtration fraction (generally about 0.20) equals the GFR for the kidney.]
 * **Normal urinary output: 1.5 L/day.**
 * That leaves 188.5 L/day unaccounted for-- it's being reabsorbed. Note that this means that > 99% of the filtered volume is being reabsorbed.
 * Since most reabsorption is an active process, this takes ATP; note that about 10% of total ATP output tends to be eaten up by this.
 * Describe regulation of vascular resistance by angiotensin II via the baroreceptor-mediated renin/angiotensin axis.
 * Recall how the renin-angiotensin (+aldosterone, more on that later) axis works:
 * Prohormone __angiotensinogen__ is produced by the liver (13 amino acids). In the presence of a proteolytic enzyme, renin, that's secreted from the juxtaglomerular cells in the kidney, angiotensinogen is cleaved into angiotensin I (10 amino acids long).
 * Angiotensin I is inactive but circulates; in the presence of a converting enzyme (ACE), it is cleaved to an activated, 8 amino acid-long form called angiotensin II.
 * Note that ACE is mainly stored in the lungs, evidently because all the blood passes through there with relative celerity. Interesting.
 * Angio II, recall, is an extremely effective vasoconstrictor; this elevates total peripheral resistance, elevating mean arterial pressure.
 * Decreased mean arterial pressure triggers baroreceptor reflex, resulting in an increase in secretion of renin by the JG cells of the kidneys. More on this next lecture.

Claude Bernard, Homer Smith "From Fish To Philosopher"

Glomerular Filtration and Renal Blood Flow Tuesday, May 06, 2008 8:57 AM


 * Glomerular Filtration and Renal Blood Flow, 5/6/08:**


 * Describe the arteriolar, capillary, and epithelial components of the filtration apparatus.
 * Ok. So you've got arterioles on either side of the first glomerular capillary bed-- the one coming into the glomerulus is called the **afferent arteriole** ; the one going out is called the **efferent arteriole**.
 * Notice that this means that constriction can occur either before or after the glomerular filtration point.
 * This winds up being fairly important, so think of this as a garden hose with a hole in it. The input (where it's connected to the spigot) is the afferent arteriole. The hole is the glomerular filter-- as water flows through the hose, some leaks out into the filtrate. The end of the hose is the efferent arteriole.
 * If you shut off the afferent arteriole, no water gets anywhere (stays in the plumbing of the house). If you shut off the efferent arteriole (put your thumb over the end of the hose), then all the water coming from the spigot is going to have to go out the hole-- that is, you're going to increase filtration. If you partially shut off the afferent arteriole (decreasing flow through the hole), but put your thumb partly on the efferent arteriole to compensate, you can maintain a steady flow of water through the __hole__ even though there's less total water going through the __hose__.
 * This is important because it's of vital importance that your body keeps the GFR (water going through the __hole__) steady. More on why this is a little later.
 * Notice also that there's a special part of the afferent arteriole just at the point where it stops becoming an arteriole and starts to become a capillary-- it's called the **juxtaglomerular apparatus** . This is where the secretion of __renin__ occurs.
 * End of the tubule that engulfs the glomerular capillary: called "**Bowman's capsule** ."
 * So you've got the separated endothelial cells of the capillaries right next to the epithelial surface of Bowman's capsule, separated by a basal lamina (also called basement) layer. The epithelial surface of Bowman's capsule is made up of overlapping 'feet' (thus called "podocytes").
 * As Dr. Lucia will go over in great and enthusiastic detail, the 'feet' of adjacent podocytes interdigitate (like if you interlace your fingers) to form a fairly tight mesh around the basolateral membrane, leaving only small, regular spaces for substances to pass through.
 * Describe the ultrastructural basis for molecular sieving during glomerular filtration.
 * The filtration does not take place at the endothelium-- it's "fenestrated" endothelium and has big ol' holes in it that allow just about everything to leak out at the capillary site.
 * There's some debate about whether or not the podocytes contribute to filtration, and how much. Dr. Lucia's a big believer. Drs. Bendiak and Levinson are more reserved. At the moment, just keep in mind that the podocytes do contribute something, partly due to their negative charge (which repels albumin and other negative compounds) and partly due to their meshlike interlacing around the basolateral membrane.
 * The primary filtration barrier (according to Dr. Levinson) lies in the __basal lamina__ that lies between the endothelium of the capillary and the epithelium of Bowman's capsule. This lamina has pores in it that only allows certain-size compounds through.
 * Describe the Starling forces that drive and oppose glomerular filtration
 * Recall this equation: delta-P = flow times resistance. Thus flow = delta-P divided by resistance.
 * In the glomerulus, resistance is generally constant. Thus:
 * Glomerular flow = delta-P * k, or __glomerular filtration is proportional to delta-P__.
 * Delta-P: On the one side, you have pressure in the capillary (**Pgc** for glomerular capillary pressure). On the other, you have the hydrostatic back-pressure in the tubule ( **Pt** ) and the oncotic pressure (mostly caused by retention of albumin in the capillaries) that directs water back into the capillary ( **Π** **gc** ).
 * So **glomerular flow rate = k * (Pgc - Pt -** **Π** **gc)**.
 * Note this is an adaptation of the Starling law we're already familiar with governing fluid flow in capillary beds.
 * Typically: **Pgc = 46 mm Hg**, **Pt = 10 mm Hg** , **Π** **gc = 30 mm Hg** . Thus normal glomerular flow rate ( **NGF** ) is proportional to __6 mm Hg__. Not a whole lot.
 * The small size of the pressure differential driving glomerular filtration is compensated for by the really huge filtration area in the kidneys.
 * There are about 2 million nephrons (thus 2 million glomeruli) in an average person. That's a whole lot. Two million times 6 mm Hg is a pretty significant rate of filtration.
 * State the Starling equation for glomerular filtration rate.
 * See above.
 * State the typical magnitude of each of the Starling forces and the resultant net filtration pressure.
 * See above.
 * Define the process of autoregulation of GFR and RBF, including the structures involved, the cellular mechanisms, and physiological context and limitations under which this process operates.
 * You want glomerular filtration, thus GFR, to be a constant and unchanging thing. If it wasn't - if you adapted to an abundance or dearth of a particular substrate or fluid by altering the GFR - you'd have to change the reabsorption of everything else. That's a pain. Better to adjust reabsorption of just the one thing and keep GFR constant.
 * Note also that if you raise or lower the pressure of the glomerular capillaries by even 1 mm Hg, since the GFR is determined by that pressure, you're raising or lowering the GFR by about a sixth (6 mm Hg is the normal pressure gradient)-- which, if you recall that the total filtrate per day is 190 L, means you're adding or taking away about 32 liters of fluid to the filtrate. That's a lot of extra work to load onto your kidneys (have you excreted an extra 30 L of urine lately?).
 * All this by way of saying: glomerular filtration rate is more or less a constant under normal circumstances, and is maintained that way by autoregulative processes.
 * So take a normal person under normal circumstances, with a MAP of about 100 mm Hg. Suppose the MAP rises to 115 mm Hg while he's thinking about the bear that ate his slow friend in the pulmonology block.
 * This raises the Pgc up from 46 to 52 mm Hg, which means the normal glomerular flow will be raised from 6 mm Hg to 12 mm Hg, doubling the glomerular filtration rate. This would be bad (an extra 190 L to be processed by the kidneys-- good luck with that).
 * So to keep the GFR stable, **__under conditions of hypertension the afferent arteriole will constrict__** to maintain a steady blood flow to the kidneys. Note that this is a myogenic process (intrinsic to the afferent arteriole smooth muscle).
 * Over a certain range of mean arterial pressure (~75-150 mm Hg) the afferent arteriole can constrict or dilate to maintain a steady glomerular blood flow (which in turn maintains a steady glomerular filtration rate).
 * Note that this is one reason why chronic uncontrolled hypertension can lead to kidney failure-- the MAP is high enough that the nephrons are always having to filter and then reabsorb a higher volume than they're designed to do.
 * Define the process of hypovolemic regulation of GFR and RBF including the structures involved, the cellular mechanisms, and physiological context under which this process operates.
 * In hypovolemia, blood flow is shunted away from peripheral organs to the heart and brain by vasoconstriction.
 * However, you still need the kidney to work well and be able to constantly adapt to new situations (ie. you just stumbled across an oasis in the desert and are gorging yourself with water). This means the kidney needs to maintain its glomerular filtration rate even with reduced blood flow.
 * So there's a compromise which means you can get profound changes in renal blood flow with only small changes in glomerular filtration rate. Here's how it works.
 * We've said that the afferent arteriole can constrict to restrict blood flow to the glomerulus. Note, however, that the efferent arteriole (out of the glomerulus) can also constrict. Note also that the glomerular filtration takes place between these two arterioles. Here's where that garden hose metaphor comes into play.
 * So in hypovolemia, the afferent arteriole constricts, limiting renal blood flow. This would decrease the GFR, which we don't want. So the efferent arteriole also constricts, building up an increased Pgc in the glomerular capillary. This results in increased glomerular filtration (water flow out the hole in the hose) that compensates exactly for the decreased blood flow in order to maintain the same GFR in hypovolemic states.
 * Note that hypovolemia here operates in an opposite direction from the myogenic autoregulation example that we considered before-- you would think a drop in MAP would result in a dilation, not a contraction, of the afferent arteriole. How this works:
 * Both arterioles are innervated by the __renal sympathetic nerve__.
 * In hypovolemia, there's a drop in MAP, triggering a baroreceptor reflex. One of the consequences of this reflex is increased firing in the renal sympathetic nerve.
 * When the renal sympathetic nerve is stimulated, both of the arterioles constrict, dropping renal blood flow but maintaining GFR.
 * In addition, the renal sympathetic stimulation causes an increased renin secretion in the juxtaglomerular apparatus, causing angio II activation and systemic (as well as afferent/efferent arteriole) vasoconstriction.
 * The juxtaglomerular cells also have intrinsic baroreceptors that allow them to increase renin directly in response to decreased blood pressure.
 * So notice that there are three different redundant ways of decreasing renal blood flow but maintaining GFR in hypovolemia:
 * Direct sympathetic stimulation of both sets of arterioles, causing contraction.
 * Sympathetic stimulation of JG cells, causing increased release of renin, causing hormone-mediated arteriolar contraction.
 * Direct baroreceptor stimulation of JG cells, causing increased release of renin, causing hormone-mediated arteriolar contraction.
 * Note also that the rise in TPR due to angio II causes a rise in systemic mean arterial pressure, which helps with the hypovolemia. Very elegant.
 * Notice that GFR actually does fall a little bit, mainly due to the increased Π gc in the doubly-constricted glomerulus. But mostly it's compensated.
 * Here's a question I asked Dr. Levinson: if the baroreceptors respond to a decrease in MAP in hypovolemia to override any arteriolar myogenic dilation, how come they don't respond to an increase in MAP (in hypertension) to override the myogenic constriction? To which he answered that the baroreceptor reflex tied to renal sympathetic nerve activation is one-way-- it doesn't respond to high MAP, just low MAP. So there you go-- renal blood flow in hypertension is largely governed by myogenic autoregulation, whereas in hypotension it's regulated by baroreceptor stimulation and angio II release.
 * Describe the role of renal prostaglandins in the renal response to hypovolemia
 * In hypovolemia, recall, you get an increase in renin levels, both because of juxtaglomerular baroreceptor stimulation and sympathetic nervous stimulation of the JG cells. This is turn causes an increase in angio II levels.
 * Remember that angio II normally causes systemic vasoconstriction. But in the renal interstitial cells between the medulla and the pyramids, angio II causes __renal prostaglandins__ to be secreted that cause the renal arterioles to dilate.
 * The reasons for this seems to be to partially blunt the effects of severe vasoconstriction brought on by sympathetic and angio II stimulation. The renal tubular cells are highly susceptible to ischemic damage, so you want to build in a fudge factor that makes sure they're protected in case of severe hypoxia. In support of this theory, the renal prostaglandins seem to preferentially target the afferent arteriole (thus increasing renal flow).
 * This means that if you give a whole lot of NSAIDs (which block prostaglandin synthesis) to someone with hypovolemia, that person can go into acute renal failure if their levels of angio II are high enough to really choke off renal blood flow. Effectively NSAIDs can remove the vasodilation safety net in the renal arterioles. Good to know.

Kidney Histology Tuesday, May 06, 2008 10:02 AM


 * Kidney Histology, 5/6/08:**

[Upcoming Bendiak talk. A lot of this is going to be me cobbling together bits and pieces of what he referred to, implied, or hinted at but never outright stated. Wiki is a major influence.]


 * Describe the major anatomical regions of the kidney including the renal artery and vein, major and minor calyces, medulla, cortex, renal pyramids and regions containing collecting ducts.
 * Lots of diagrams here. May need to go look it up. The cortex of the kidney is on the outside, under the capsule; the medulla is more interior, punctuating the cortex with the medullary pyramids, which feed into minor calyces at points called the renal papillae-- these feed into major calyxes, which empty into the renal pelvis, which empties into the ureter.
 * Collecting ducts are what the tail ends of nephrons eventually feed into. Some bits of them are in the cortex, but they drain at the papillae in the medulla.
 * Note that glomeruli are in the cortex; they can be either out in the distal cortex or in between the medullary pyramids (in which case they're called juxtamedullar glomeruli).
 * Outline the flow of blood into and within the kidney finishing with its exit in the renal vein
 * The renal artery comes in with the ureter and branches to go between the pyramids (__interlobar arteries__); these arteries then branch further into the proximal cortex as the __arcuate arteries__, which in turn branch into the distal cortex as the __interlobular__ arteries. These interlobular arteries eventually turn into the afferent arterioles at the various glomeruli in the cortex.
 * The efferent arterioles from those cortical glomeruli all come out in this interlinked mess called the __vasa recta__, then follow the sequence back through the interlobular, arcuate, and interlobal veins before running back into the renal vein, which exits the kidney along the renal artery and the ureter.
 * Note that there are glomeruli right next to the medulla, called the juxtamedullar glomeruli, from which the efferent arterioles don't need to run through the vasa recta.
 * Describe the cellular disposition of Bowman's capsule including the glomerulus and the cells and filtration barrier that comprise it and the visceral and parietal epithelia. Illustrate and describe the relationship between glomerular endothelial cells, the filtration barrier, the podocytes, and the mesangial cells. Why are the endothelial cells fenestrated?
 * Recall from "Overview of Renal Physiology" that fenestrated endothelial cells in the Bowman's capsule run along one side of the glomerular basal lamina and that the interdigitated podocytes run on the other.
 * So general idea of Bowman's capsule: a bunch of anastomosing capillaries in the glomerulus, surrounded by the basal lamina (filtration barrier) and podocytes (visceral epithelium), surrounded by a collecting space, surrounded by a parietal epithelium that contains the whole thing. Imagine partly filling a balloon with hair gel then pushing your fist into it: fist + balloon (capillaries, basal lamina, podocytes), gel (collecting space), balloon (parietal epithelium).
 * As I've just hinted, there's a squamous cell layer around the outer ring of the Bowman's capsule; that's called the parietal epithelium. The podocytes are called the visceral epithelium.
 * Within the capillary structures in Bowman's capsule, there are __mesangial__ cells that secrete connective tissue to support the structure of the glomerulus. This winds up being important in pathology later. Note that mesangial cells are in directly contact with the endothelium in the capillaries.
 * Note that the basal lamina is thickened in diseases such as type II diabetes or lupus.
 * The endothelial cells are fenestrated because you need rapid movement of pretty much the entire small-molecule contents of the plasma out the capillary.
 * Describe the functions of later regions of the nephron afterfiltration through the glomerulus. Outline each region and give one example of specialized functions of the different portions of the nephron involved in resorption of solutes. Understand the relationship between the microscopic structure of different endothelial cells in the kidney and their function. Be able to describe where in the kidney (either medulla or cortex) the different resorptive events occur.
 * Outline:
 * The tubule, after leaving the Bowman's capsule, takes a tortuous route through the cortex. This region is called the __proximal convoluted tubule__.
 * After this, there's a region that dips down into the medulla, first thick-walled (the __thick descending loop of Henle__) and then thin-walled (the __thin descending loop of Henle__).
 * Then the loop comes back up into towards the cortex, first thin-walled (the __thin ascending loop of Henle__) and the thick-walled (the __thick ascending loop of Henle__).
 * It then crosses back into the cortex, again taking a tortuous path (the __distal convoluted tubule__).
 * If I'm reading this right, when the distal tubule crosses into the medulla, it turns into a collecting tubule, draining into a collecting duct, which drains into the minor calyces at the renal papillae.
 * Proximal tubule cells:
 * Cuboidal cells. On the one end (luminal side of the tubule, facing the filtrate) they have a whole bunch of microvilli to reabsorb and increase their surface area; on the other they have Na+/K+ ATPases to drive the whole process. Inside they are chock-full of mitochondria to generate the ATP that powers the Na/K pumps.
 * Effectively the proximal tubule __reabsorbs glucose, amino acids, and sodium__.
 * Descending/ascending loop of Henle cells:
 * Thin portions: squamous cells. Thick portions: cuboidal cells.
 * Note that the descending vs ascending thin loops have different permeabilities to Na+, Cl-, and H2O. The thick ascending loop cells have lots of sodium pumps for reabsorption of sodium and lots of mitochondria to power those pumps.
 * Distal tubule cells:
 * Cuboidal cells. "Less extensive versions" of the proximal tubule cells (some, but less, microvilli and mitochondria).
 * These seem to mainly be involved with __acid-base balance__.
 * Note that, contrary to Dr. Levinson, Dr. Bendiak does not describe this portion as being involved in ADH/aldosterone/ANP-regulated variable reabsorption.
 * Collecting tubule cells:
 * Two types of cuboidal cell:
 * "__Principal cell__:" single cilia in lumen, used for sodium/potassium exchange.
 * "__Intercalated cell__:" many cilia in lumen, used for acid/base balance by H+/HCO3- exchange.
 * Collecting duct cells:
 * Non-ciliated **columnar** cells; note that these are the only columnar cells around, so if you're seeing columnar, you're in the collecting duct. Can become more or less permeable to water (more or less aquaporins in membrane) in inverse response to anti-diuretic hormone.
 * Describe the unique epithelium of the ureters and bladder and know its functional significance.
 * There's //transitional epithelium// (remember this little gem from Evans' lectures in M2M?) in the bladder. Recall that it looks cuboidal when it's not being stretched but converts to a squamous appearance under tension.
 * The main effect here is to allow the bladder to stretch to accommodate changes in stored urine volume.
 * There is evidently a lot of elastin in and around the lamina propria in this cell layer, again facilitating enormous stretch capacity.

Urinary Tract Infections and Tubulointerstitial Diseases of the Kidney Tuesday, May 06, 2008 11:07 AM


 * Urinary Tract Infections and Tubulointerstitial Diseases of the Kidney, 5/6/08:**

[Upcoming LaRosa talk. This is more or less straight from his notes.]


 * [Note definition of pyelonephritis: generally an ascending UTI causing inflammation in the renal pelvis (Greek renal = //nephros//, pelvis = //pyelum// , //-itis// inflammation).]
 * Describe the pathogenesis of urinary tract infection in terms of routes of infection, organism virulence factors, host defense mechanisms, predisposing factors, clinical manifestations, and complications.
 * Routes of infection:
 * (1) __Ascending__ (up the urethra): most common cause of UTI, particularly when it involves the bacterial flora of the GI tract and perineum coming in contact with the urethra. For presumably obvious reasons, this tends to be a problem for women more than for men.
 * Most common: **//E. coli//** . However, can also see //Klebsiella//, //Proteus// , //Pseudomonas// , //Serratia// , and //Streptococcus//.
 * Note that since //E. coli// is only about 1% of GI flora but causes about 70% of ascending infections, pathogenic factors must play a role.
 * (2) __Blood-borne__ (descending, hematogenous, down from the kidneys): much less common.
 * Generally occurs in immunocompromised patients or in damaged kidneys.
 * Involves mainly different, Gram-positive organisms (largely **//Staph. aureus//** or group A **//Streptococcus//** ) since they're coming from other areas of the body than the GI tract.
 * Organism virulence factors:
 * (1) Some //E. coli// strains have special pili ("P pili") that allow adhesion to urethral epithelial cells. These get stuck in/climb the urethra real good.
 * (2) "P1 blood group" is an increased risk factor for carrying these strains. "P2 blood group" is not. Whatever that means.
 * (3) Any of your run-of-the-mill antigenic resistance factors to host defenses.
 * (4) Some //E. coli// strains produce endotoxins that inhibit peristalsis in ureters (making it easier for the bacteria to climb them).
 * Host defense mechanisms:
 * (1) Mucosal secretion of urethral glands-- mucus traps bacteria.
 * (2) Mucosal factors-- I think what he's talking about is that IgA dimers are secreted into the urine; also have complement and neutrophil secretion into urine.
 * (3) Urine flow (flush out bacteria).
 * (4) "Valve" between bladder and ureter to prevent retrograde flow. Notice that this isn't an actual valve, just a tissue arrangement that works like one (part of the ureter travels within the wall of the bladder, so that when the bladder contracts, the wall compresses the ureter to prevent backflow).
 * (5) Urine itself is a poor culture medium, at least normally. Notice that big changes in urine composition can change this.
 * Predisposing factors:
 * (1) As mentioned, females get UTIs more than males (proximity of perineum to urethra and relatively easy colonization of vagina, particularly after menopause and cessation of estrogen).
 * (2) Catheterization increases risk of infection, as does sticking a scope up there.
 * (3) Decreased urine flow is an increased risk.
 * (4) Calcifications can cause obstructions to flow and allow bacterial growth in static fluid. Can also damage the surrounding epithelium and predispose them to infection.
 * (5) Vesiculo-ureretal reflux (backflow from bladder into urine, sometimes caused by faulty ureter implantation into bladder causing faulty valve action).
 * (6) Pregnancy
 * (7) Diabetes
 * (8) Other kidney problems (polycystic kidney disease, etc)
 * Clinical manifestations:
 * (1) "Covert bacteriuria"-- I gather this is asymptomatic.
 * 15-20% incidence of pyelonephritis
 * Scarring (of unspecified organs, probably the kidneys but possibly the bladder, urethra, or ureters) usually occurs early in life due to chronic reflux with infection (the reflux possibly due to urinary retention secondary to infection? No real ideas here.).
 * (2) Symptomatic UTI:
 * If organisms haven't ascended higher than the urethra or vesiculo-urethral valve:
 * Dysuria (pain during urination)
 * Difficulty voiding and incomplete emptying
 * Incontinence
 * If organisms have gotten into the bladder:
 * Frequent urinations
 * Pain in suprapubic region
 * If organisms have gotten into the ureters and kidneys:
 * Flank pain and tenderness, often described as abdominal pain
 * Fever and chills
 * Oliguria (decreased urine output)
 * Note that gross hematuria (blood visible in urine) is usually caused by a stone or a tumor, not a UTI.
 * Laboratory features of UTIs:
 * Urinalysis shows lots of white cells, occasionally red cells. Note that if you see 'casts' of white cells, probably pyelonephritic. Much more on this in pathology.
 * Urine culture is usually above 100,000 bacteria/mL and always above 10,000 bacteria/mL (104 - 105+).
 * Complications:
 * Acute pyelonephritis: suppurative (pus-filled) inflammation of the kidney/renal pelvis usually caused by bacterial infection (occasionally fungal).
 * See wedge-shaped regions of suppuration with tiny abscesses.
 * The tubules are filled with neutrophil aggregates (the 'casts' found in urine) and can be damaged or destroyed.
 * Can see edema, neutrophils, and lymphocytes in the interstitium.
 * Note that the glomeruli are generally well preserved until late in the course of the infection (they're out in the cortex).
 * Can see necrosis of the renal papilla (which, recall, are where the medullary pyramids empty out).
 * Perinephric abscesses: generally a sequel to acute pyelonephritis. Chunks of kidney come out in the urine. Not pleasant.
 * Can also see renal scarring or large stones, particularly with //Proteus// infection.
 * Note that once you've had a severe UTI, you're more likely to get another (damage to tissue prevents defenses from working optimally).
 * Compare and contrast the features and pathogenesis of the two major causes of chronic pyelonephritis (urinary tract obstruction and vesico-ureteral reflux).
 * Main causes of chronic pyelonephritis:
 * (1) Urinary tract obstruction
 * Obstruction predisposes to infection and makes getting rid of infection more difficult. Can also see 'pressure-induced ischemia.'
 * Pathogenesis:
 * Intraluminal masses (tumors, calculi [stones], necrotic papilla, blood clots)
 * Inflammation
 * Blocked urethral valves
 * Compression by tumors, fibrosis, trauma, etc
 * Diabetes/neurological dysfunction (for no evident reason)
 * Features:
 * Decreased GFR, irreversible if untreated
 * Hypertension
 * Dilation of the urinary collecting system
 * Atrophy and flattening of the renal papillae and medulaa
 * Fibrosis and atrophy of renal cortex
 * Tubular atrophy, fibrosis, and edema
 * (2) Vesico-ureteral reflux:
 * Two parts, the retrograde urine flow into the renal pelvis and the nephropathy that follows it.
 * Retrograde urine flow pathogenesis:
 * Abnormally short intramural ureteral segments (the part of the ureter that courses through the wall of the bladder) can cause an ineffective 'valve' and cause reflex during urination.
 * Retrograde urine flow features:
 * Generally shows up in infancy and resolves by age 5. Generally genetic. The renal scarring doesn't generally progress much if the reflux gets better.
 * Reflux nephropathy pathogenesis: just mentioned. Urine backflow into the kidneys causes chronic infections.
 * Reflux nephropathy features:
 * Chronic or recurrent infections (like obstruction), pyelonephritis, renal scarring, usually with hypertension.
 * Dilation and scarring of calyces
 * Etc.
 * Note that I presume you can easily get reflux (2) from an obstruction (1), but I think he's mainly talking about congenital or familial reflux here.

Tubular Transport of Na, Cl, and Water Tuesday, May 06, 2008 3:58 PM


 * Tubular Transport of Na, Cl, and Water, 5/7/08:**

So at the end of the loop, the interstitial fluid is still hypertonic to the fluid inside the loop (25% NaCl pulled out but only 15% water pulled out to compensate). § Note that by this point (end of the loop) we’ve reabsorbed 90% of the sodium but only 80% of the water, all obligatory reabsorption. · Note that on the __thick__ ascending loop, you use the Na+ channels to co-transport one K+ and two Cl- ions into the cell with every 1 Na+ ion. The Cl- and K+ passively diffuse out the cell into the interstitium (the Na+ is still actively pumped out into the interstitium). § This is important because this pump, the **Na/K/2Cl pump**, is the target for the diuretic Lasix. More on this later. o __Distal tubule/collecting duct__ (the 'fine-tuning segments'): variable reabsorption, controlled by **aldosterone** and **anti-diuretic hormone** (also known as ADH or vasopressin). Note that Dr. Bendiak draws a much firmer division between these two segments. · In the presence of __aldosterone__ (steroid hormone that enters the cell and binds to its intracellular receptor), the genes that encode sodium pumps and channels are expressed more strongly-- thus more sodium channels open in the apical membrane and more sodium pumps pop up in the basolateral membrane. It may also increase mitochondrial activity (which leads to more ATP to power the pumps). § This leads to increased sodium reabsorption from the distal tubule. · In the presence of __ADH__, water channels (aquaporins) are inserted into the cell membrane. Though there's always a lot of permanent aquaporins in the basolateral membrane, the number of aquaporins in the apical membrane is highly variable-- that's what's affected by the ADH cascade. § This leads to increased water reabsorption, with or without co-activation of aldosterone (remember that the interstitium at this point is still hypertonic, so if you increase aquaporin insertion, the water will flow out into the interstitium). · These segments are where the nephron has some discretion in figuring out how much sodium and water to excrete, up to the maximal rates of excretion (as mentioned in the first LO for this section).
 * State the magnitude and regulated range of NaCl and water handling by the kidneys.
 * Recall that the standard person filters **190 L of water** per day.
 * The same person filters **1.5 kilos of sodium** per day.
 * Range of H2O/Na+ excreted per day: 0.5-25 L water, 0.05-30 g Na+.
 * So the __maximal excretion__ of water and sodium is about 14% and 2%, respectively, of the total amount filtered.
 * So the great majority of both water and sodium that's been filtered is __not under direct regulatory control__-- it must be reabsorbed.
 * This obligatory reabsorption takes place largely in the 'proximal segments': the proximal tubule and descending loop of Henle.
 * [Note you can, under certain conditions, intake more water than you can excrete (as on ecstasy), leading to water toxicity/cerebral swelling. This is fairly rare. But note that it's actually not that hard to take in more sodium than you can excrete (particularly for those of us from the great state of Louisiana), which can lead to chronic hypertension due to fluid overload.]
 * Describe the major epithelial transport mechanisms for NaCl and water reabsorption in each major tubular segment.
 * Recall that in epithelial cells, Na+ flows down its gradient into the apical side of the cell. On the basolateral side of the epithelial cells throughout the nephron, there's a Na+/K+ pump: like all Na/K pumps, it uses ATP to pump Na+ __out__ of the cell and exchanges it for K+ transported __into__ the cell.
 * Note that the net effect of these processes is to transport Na+ from one side of the cell (apical) to the other (basolateral)-- that is, to transport it from the lumen of the nephron to the interstitium around the nephron. This is more or less the energetic basis for everything that follows.
 * Note that when the positive cation (Na) goes from one side of the cell to the other, an anion (Cl) has to follow.
 * Note that when Na and Cl go from one side of the cell to the other, this changes the osmolarity gradient across the cell; thus water follows in the same direction that NaCl has been moved (apical-to-basolateral), both between the cells (paracellular) and through the cell (through aquaporin channels in the cell membranes).
 * Recall that water always moves passively; there are no water pumps. However, what you can do is change the expression of aquaporins in the membrane, which allows you to limit or enhance the water flow. More on this later.
 * Recall also that Na+ flows down its gradient into the cell. The passive transporter that allows this can also co-transport things that wouldn't ordinarily come into the cell (eg. glucose and other metabolites) in along with it. Once they're in the cell, they can passively diffuse out the basolateral side. The active transport of Na+ out the basolateral side keeps the apical channels flowing, which in turn keeps the transport of metabolites up.
 * Note that everything comes back to sodium. Sodium movement dictates passive chloride and water movement; it also dictates mediated transport of glucose, amino acids, and most other reabsorbents.
 * State the relative proportion of water and NaCl reabsorbed in each tubular segment.
 * __Proximal tubule__: 65% of total water and 65% of total NaCl is reabsorbed (obligatory).
 * Note it also absorbs most of the very important metabolites like glucose, by the above-described co-transportation mechanism.
 * (in diabetes, the concentration of glucose can become so high that it can't all be reabsorbed, leading to glucosuria.)
 * Note also that the 'leakiness' of the tight junctions is high in the proximal tubule; there's also a lot of aquaporins. This means a high rate of water movement corresponding to the high rate of sodium transport; this further means that fluid in the proximal tubule is more or less __isotonic__ with the fluid in the interstitium around the proximal tubule.
 * __Descending loop of Henle__: Highly water-permeable (lots of aquaporins). This becomes important in a second, but you lose about 15% of total water here without losing a significant amount of sodium.
 * __Ascending loop of Henle__: Relatively water-impermeable. 25% of total NaCl is actively reabsorbed here, but no water.
 * Note that this makes the interstitial fluid outside the ascending loop __hypertonic__ to the fluid inside the loop.
 * This means that you can pull water out of the nearby descending loop (which is water-permeable) in response to the interstitial hypertonicity.
 * Describe the overall role of each major tubular segment in the regulation of NaCl and water reabsorption.
 * Proximal tubule: main obligatory 'big bite' of reabsorption, both NaCl and water along with other important metabolites.
 * Loop: Establish hypertonicity of interstitial fluid by obligate reabsorption of different amounts of water in the descending limb and NaCl in the ascending limb.
 * Distal tubule/collecting duct: some obligate, some variable water/sodium reabsorption.
 * Identify the major hormones that regulate tubular reabsorption of NaCl and water and their tubular and cellular site of action.
 * Aldosterone and ASH have been mentioned so far. Also note ANP in the next lecture, which counters them both.
 * Describe the molecular mechanism of action of aldosterone and ADH/vasopressin, with respect to NaCl and water transport.
 * Described above.
 * State the Starling equation for the flow of solution from the renal interstitium to the peritubular capillaries. Give values for each of the Starling forces and the net pressure driving the flow.
 * Recall that we already mentioned Starling equations as governing the filtration rate into the nephron. Now we're talking about the same set of equations governing the rate of flow from the interstitial fluid into the peritubular capillaries (ie. the uptake of reabsorbed fluids and substances).
 * Once again, flow is equal to k * delta-P, where delta-P is the difference in pressure between the interstitium and the peritubular capillary.
 * So if **Pint** is the hydrostatic pressure in the interstitium and **Pcap** is the hydrostatic pressure in the capillary, and **Π** **int** is the oncotic pressure in the interstitium and **Π** **cap** is the oncotic pressure in the capillary, then:
 * Flow from interstitium to capillary = k * ((Pint - Pcap) - ( Π int - Π cap))
 * Pint is usually about __7__ mm Hg; Pcap is usually about __11__ mm Hg.
 * Π cap is usually about __35__ mm Hg; Π int is usually about __6__ mm Hg.
 * So flow tends to look like: k * ((7 - 11) + (35 - 6)).
 * Note that this means that the main force acting to allow flow from the renal interstitium into the peritubular capillaries is the **oncotic pressure in the capillaries**, which is turn is largely dependent on the albumin content in the plasma.
 * Note that this can be affected by the liver's albumin production or nephrotic syndromes in which a lot of the plasma albumin is filtered into the nephrons.
 * Describe qualitatively the effects of increasing and decreasing tubular flow on water and sodium reabsorption
 * Reabsorption, whether passive (water) or active (sodium), takes time. Effectively: __increased tubular flow decreases reabsorption__ (less time for it to occur), while __decreased tubular flow increases reabsorption__.
 * This is going to be a different story when we get to __secretion__, particularly of potassium. Keep an eye out.
 * Note that the more water you have in the tubule, the faster the flow goes. Note also that this is a circular system: amount of water in the tubule dictates flow rate, which dictates water flow out of the nephron, which in turn dictates the amount of water in the tubule. Fast flow rates tend not to self-correct, is maybe another way of saying this, and slow flow rates don't either (fast stay fast and slow get slower).
 * This is one reason diuretics (which decrease water reabsorption) also cause decreases in the reabsorption of other ions-- they increase tubular flow, thus decreasing the length of time available for those ions to be reabsorbed. (note also, of course, that some diuretics decrease water retention by directly blocking ion channels, which is a more direct way of limiting ion reabsorption).
 * Define "glomerulotubular balance" and "tubuloglomerular feedback" and describe the role these processes play in the regulation of NaCl and water reabsorption.
 * __Glomerulotubular balance__: the ability of the obligatory reabsorptive mechanisms in the proximal tubule to adapt to changes in the filtrate load. Effectively this means that 65% of the filtrate is reabsorbed in the proximal tubule, regardless of how much or little that is.
 * __Tubuloglomerular feedback__: effectively, individual nephrons can adjust their afferent arterioles to maintain their GFRs. How this works:
 * GFR goes up. Only 65% of the increase is handled by the proximal tubule.
 * That means there's an increased flow through the loop of Henle.
 * That means there's less reabsorption of sodium in the ascending loop.
 * That means there's a higher Na+ concentration in the luminal fluid in the ascending loop.
 * This gets picked up on by receptors in a specialized cluster of the ascending loop (the **macula densa** cells), which are also in contact with the afferent arteriole.
 * If the sodium concentration goes up, the afferent arterioles contract to lower GFR; if it goes down, the afferent arterioles dilate to raise GFR.

Regulation of Sodium and Water in the ECF Wednesday, May 07, 2008 9:03 AM


 * Regulation of Sodium and Water in the ECF, 5/7/08:**


 * State the qualitative effects of adding and subtracting sodium from the ECF on ECF volume and the physicochemical bases for these changes.
 * Note that there aren't sodium receptors in the ECF to directly detect increased or decreased ECF sodium levels. The reason for this will become clear in a moment.
 * If the sodium level in the ECF is increased by 10% (thereby increasing the sodium concentration in the ECF by 10%), that increases the osmolarity of the ECF relative to the ICF, drawing water out of cells and into the ECF to equilibrate osmolarities. But notice that, since the total volume of the ICF is much larger than that of the ECF, the equilibrium favors the transfer of water from the ICF to the ECF-- thus at the new equilibrium the sodium concentration in the ECF is 3% above normal but the volume in which that sodium has been dissolved has gone up 6%.
 * What he's getting at here is that the ICF is going to lose fluid in order to increase its sodium concentration, and the ECF is going to gain fluid in order to decrease its own. But since the ICF is much bigger than the ECF, the equilibrium position is going to favor a smaller change in end-point sodium concentrations and a larger change in end-point fluid volumes. I'm not sure that makes sense to me, but if I squint at it it kind of works.
 * Anyway, the point is that changes in the sodium concentrations of the ECF lead to larger changes in ECF volume than they do to sodium concentrations.
 * This is why there aren't sodium receptors in the ECF; it's much more effective to monitor the __volume__ of the ECF through stretch/pressure receptors in the arteries.
 * Describe the physiological feedback loop involved in the homeostasis of sodium concentration in the ECF.
 * Let's go the other way and consider a loss of sodium instead of a gain:
 * So a loss of sodium from the ECF leads to a decreased in ECF osmolarity..
 * Leading to a shift of water into cells (ICF) from the ECF to balance out..
 * Leading to a decrease in ECF volume..
 * Leading to a decreased mean arterial pressure.

o Decreased mean arterial pressure leads to renin release (see "Glomerular Filtration and Renal Blood Flow").. o Leading to angiotensin II activation.. o Leading to activation of aldosterone.. o Leading to increased retention of sodium in the distal tubule and collecting duct.. o Leading to increased ECF osmolarity.. o Leading to a shift of water out of cells.. o Leading to a compensating increase in ECF volume.. o Leading to a compensating increase in MAP.

o Normalized MAP steadies renin release and stops it from increasing further.

o Got that? Run through it and make sure it makes sense. o This runs the other way, as well (too much sodium leads to hypertension, leading to decreased renin secretion and decreased aldosterone activation). o Note that the MAP is the main regulatory sensor for sodium content.
 * Describe the physiological feedback pathway for the regulation of water content in the ECF.
 * Note normal osmolarity is about 285-295 mOsm/L.
 * __In water regulation, both water volume and osmolarity are monitored__.
 * __Volume__ pathway:
 * A decrease in total water volume (as in excess sweating) leads to a decrease in left atrial filling pressure..
 * Leading to a left atrial baroreceptor reflex..
 * Leading to increased stimulation of ADH-producing regions in the hypothalamus..
 * Leading to an increase of ADH release from the posterior pituitary gland..
 * Leading to increased water reabsorption from the distal tubule and the collecting duct..
 * Leading to an increase in total water volume, leading to decreased left atrial baroreceptor reflex, leading to normalization of ADH levels.

· Note that atrial pressure is the main regulatory sensor for hypovolemia. o __Osmolarity__ pathway: · Note that sweat is hypotonic. Therefore an increase in sweating causes an increase in osmolarity in the ECF.. · Leading to increased stimulation of osmolarity receptors in the hypothalamus.. · Leading to an increase in ADH release from the posterior pituitary gland.. · Leading to all the other stuff just mentioned.

· Note that osmolarity sensors are the main regulatory sensor for changes in plasma osmolarity. o Note that the osmolarity receptors are extremely sensitive and can pick up changes in osmolarity of less than 1%. o Note also that the two pathways mostly work in tandem, but not always. Consider the situation in which a diarrheic patient loses 3 L of isotonic fluid to diarrhea. · This means he's lost about 20% of his ECF volume, triggering left atrial baroreceptors to increase ADH. · Suppose that the patient drinks 2 L of water in an attempt to compensate. Now he's only missing 1 L of fluid, meaning that he's still triggering his volume receptors to produce more ADH. · But since he drank pure water to replace isotonic fluid, that means that his osmolarity has gone down. This triggers osmolarity sensors to __decrease__ ADH secretion, since they want to increase water output to normalize osmolarity. o So which one wins? · Depends on the situation. Over a normal (physiological) range of volume changes, the volume receptors don't really kick in and it's an osmolarity-governed system. But over an abnormal (severe hypovolemic) range of volume changes, the volume receptors become increasingly important and override the osmolarity receptors. · So you can think of volume regulation as an emergency override system. Unless you lose more than 10% or so of your ECF, it's an osmolarity-governed system.
 * Identify the dominant pathway involved in water regulation during normal variations in volume and osmolarity.
 * As mentioned: osmolarity (hypothalamic osmolarity sensors).
 * Identify the dominant pathway involved in water regulation during severe hypovolemia.
 * As mentioned: volume (atrial sensors).
 * [Note that the water/sodium regulation systems don't work independently of each other. Aldosterone helps with volume retention and normalization of osmolarity, and ADH has obvious effects on sodium concentrations.]
 * Describe the pathways involved in the regulation of ECF volume overloads by atrial natriuretic peptide.
 * Note that the atrial baroreceptors involved in increased ADH secretion don't detect __high__ blood volume (increased atrial pressures).
 * The factor involved in responding to high atrial pressure is ANP, or atrial natriuretic peptide, and it causes increased excretion of sodium and water.
 * How this works: the increased ECF volume increases filling pressure in the atria, triggering increased ANP release from granules in the atrial cardiomyocytes.
 * ANP circulates in the plasma and decreases both water reabsorption (by decreasing release of ADH from pituitary and antagonizing ADH action on distal tubule receptors) and sodium reabsorption (by decreasing release of renin from JG cells and blocking the effect of aldosterone in the distal tubule).
 * Decreased water and sodium reabsorption leads to increased sodium and water excretion.
 * One more effect: causes increased constriction of the efferent arteriole (downstream of the glomerulus), causing increased glomerular filtration, causing more water to be excreted.

Sodium: alters MAP (picked up by baroreceptors and JG cells), altering renin/aldosterone

Water (hypovolemia): alters LA pressure, altering post. pituitary ADH Water (osmolarity): alters osmolarity receptors, same Water (volume overload): alters atrial pressure, releases ANP.

Clearance-Based Measurement of Renal Function Wednesday, May 07, 2008 1:23 PM


 * Clearance-Based Measurement of Renal Function, 5/8/08:**


 * [It's a pity this lecture was at 8 AM-- it's more or less what all of our pathophys has come out of so far. Lot of good info here. I also recommend reading his notes carefully.]
 * Describe the physiologic determinants of glomerular filtration rate at a single nephron level as well as for the whole kidney.
 * The rate at which the plasma is filtered (GFR) times the plasma concentration of a substance (Px) is equal to the concentration of that substance in the urine (Ux) times the flow rate of the urine (V).
 * That is, GFR * Px = Ux * V.
 * Rearranging, GFR is equal to the concentration of a substance in the urine, divided by the concentration of a substance in the plasma, all times the urine flow rate.
 * That is, **GFR = (Ux/Px) * V**.
 * The __clearance__ of a substance is equal to the mass of that substance eliminated (XE) divided by the concentration of that substance in the plasma (Px).
 * That is, Clx = XE/Px.
 * But also note that XE equals to the uninary concentration of the substance (Ux) times the volume of urine excreted (V).
 * So substituting: Clx = (Ux/Px) * V. Looks similar to GFR, right?
 * So under certain conditions, clearance rates can equal GFR. But this only applies to substances that are freely filtered at the glomerulus, aren't reabsorbed, and aren't secreted.
 * Urea is freely filtered, and isn't secreted, but is reabsorbed-- thus not a good marker for GFR.
 * Creatinine is freely filtered, isn't reabsorbed, and for the purposes of this class isn't secreted enough to matter. This is why we look at creatinine clearance as a marker for kidney function.
 * Creatinine: breakdown product of muscle metabolism, formed and liberated at a constant rate (thus filtered at a constant rate). Note that it's going to vary a lot based on how much muscle mass an individual has.
 * So you can look at GFR as the concentration of creatinine in the urine, divided by the concentration of creatinine in the urine, times the urine flow rate. Trouble is that this requires a 24-hour urine collection, which can be a hassle. So to approximate creatinine clearance levels on the fly with just some basic patient data and the serum creatinine level alone, we use the "Cockcroft-Gault" formula:
 * **Required formula** for estimating creatinine clearance:
 * **[(A) * (140-age) * weight] / (72 * SCr)**
 * Where:
 * A = 1.0 if male, 0.85 if female
 * Age is in years
 * Weight is in kg
 * SCr = serum creatinine level in mg/dL
 * So much for whole-kidney stuff. Let's look at single-nephron GFRs.
 * Recall that single-nephron GFRs are proportional to the flow dictated by the Starling equation; ie., the difference in hydrostatic pressures minus difference in oncotic pressures: Pgc - Pt - ( Π gc - Π t).
 * According to Dr. Teitelbaum, neither the Pt nor the Π t really matter here. The Π gc is significant but fairly constant. So what he wants us to know is that __GFR of a single nephron is usually proportional to Pgc__ (blood flow to that nephron).
 * If the body's having problems with GFR (under otherwise normal conditions), generally it opens up the afferent arteriole (more water in the hose) and clamps down on the efferent arteriole (more water going out the hole in the hose). It does this more or less with a combination of angio II (constricts both afferent and efferent arterioles) and renal prostaglandins (preferentially dilate the afferent arterioles). Note also that if you get put on ACE inhibitors, the angio II isn't going to work (no constriction of efferent arterioles, thus no increased flow out the hole in the hose); again, if you get put on NSAIDs, the prostaglandins aren't going to work (no dilation of afferent arterioles, thus a decreased rate of water flow into the hose).
 * [**Acute renal failure** : broad term that describes any of a variety of kidney injuries, that result in a rapid reduction in GFR and the loss of ability to maintain homeostasis.]
 * Types:
 * **Pre-renal azotemia** : decrease in GFR due to decreases in renal plasma flow or perfusion pressure.
 * **Post-renal azotemia** / **obstructive nephropathy** : decrease in GFR due to obstruction of renal flow. Note that generally this is only clinically significant when both ureters are affected (if only one ureter, the other kidney will generally compensate).
 * **Intrinsic renal disease** : decrease in GFR due to direct injury to the kidneys.
 * Note that "azotemia" means a buildup of nitrogenous wastes in the blood (BUN and serum creatinine are increased).
 * Note also that "oliguria" is a urine output of less than 400 mL per day in a normal adult and "anuria" is a urine output of less that 50 mL per day in a normal adult.
 * Types of intrinsic renal disease (broken up into types of tissue in kidney):
 * __Vascular__ diseases
 * __Glomerular__ diseases
 * __Tubular__ disease (acute tubular necrosis or ATN - though frequently it's not necrosis, but reversible injury - leading to failure of tubular function.)
 * __Interstitial__ diseases
 * Ways of distinguishing types of renal failure:
 * **Prerenal azotemia** : __low urine sodium concentration__ (increased sodium reabsorption to compensate for perceived hypovolemic state).
 * **Intrinsic renal disease:**
 * **(1) Vasculitis or glomerulonephritis** : __red blood cells and red cell casts__ in urine.
 * **(2) Acute interstitial nephritis** : see __white cell casts__; can also see __eosinophils__ if due to allergies.
 * **(3) Acute tubular necrosis** : __pigmented, coarse, granular casts__ and __renal tubular epithelial cells__.
 * **Obstruction (postrenal azotemia)** : nothing characteristic.
 * Note that "casts" are sloughed-off mucus layers from the insides of the distal convoluted tubules or the collecting ducts. Whatever happens to be inside the tubule/duct at the time of sloughing is sloughed off with it-- so it's kind of a snapshot of what the contents of the tubule or duct look like at a particular moment in time.
 * [Fractional excretion of sodium: of the total filtered sodium, how much has been eliminated, expressed as a fraction of GFR. Ie: clearance of sodium divided by the clearance of creatinine:]
 * **FeNa = (UNa * PCr) / (UCr * PNa)**
 * This rises in ATN due to failure of tubules to be able to reabsorb sodium. It's low in prerenal disease due to attempted compensation for renal hypovolemia.
 * Generally __FeNa is less than 1% in prerenal disease and greater than 2% in intrinsic and postrenal disease__.
 * Describe the mechanisms operant in autoregulation of renal blood flow and glomerular filtration rate.
 * Detailed in "Glomerular Filtration and Renal Blood Flow" and "Tubular Transport of Na, Cl, and Water."
 * Describe how to calculate and/or estimate glomerular filtration rate.
 * Mentioned above.
 * Discuss the concept of balance and the central role of the kidney in achieving sodium, water, potassium and acid balance.
 * There's a balance, see? The kidney is central.

Introduction to Renal Pathology Thursday, May 08, 2008 8:55 AM


 * Introduction to Renal Pathology, 5/8/08:**


 * Understand the structural relationship between the glomeruli, tubules and vessels in the kidney and the significance of this relationship in terms of function and dysfunction
 * I think what he's attempting to get at is that if you take out the part of the kidney that governs (say) filtration (glomerulus), you're going to see a drop in filtration. If you take out the part of the kidney that governs (say) reabsorption of glucose (proximal tubule), you're going to see a drop in reabsorbed glucose… etc.
 * List the normal renal functions and the clinical result of disturbance of these functions
 * Regulation of water and electrolyte (Na+, K+, PO4-, H+) balance. Dysfunction leads to acidosis, fluid overload, and hyperkalemia or hypokalemia.
 * Excretion of waste products and some toxins. Dysfunction leads to azotemia, uremia, etc.
 * Hormones: regulation of blood pressure through renin secretion, regulation of erythrocyte production through erythropoietin secretion, regulation of Ca++ and phosphorus metabolism. Dysfunction leads to hypertension, anemia, secondary hyperparathyroidism, metabolic bone disease.
 * Compare and contrast acute and chronic renal failure in terms of time course, clinical presentation, distribution of nephron injury, causes, reversibility, kidney size and endocrine functions
 * __Acute renal failure__:
 * Fast (GFR goes down to near-0 over hours to days).
 * Shows up as oliguria, fluid overload, hypertension, hyperkalemia, and acidosis.
 * Distribution is universal-- all nephrons at once show reduced single-nephron GFRs.
 * Caused by toxins, severe ischemia, acute inflammation, etc.
 * Often reversible.
 * Usually a normal kidney size.
 * Endocrine function is preserved until late in course.
 * __Chronic renal failure__:
 * Slow (GFR goes down over months to years).
 * Shows up as uremia and hypertension (note hypertension common to both).
 * Distribution is selective-- a few nephrons permanently destroyed at a time.
 * Caused by chronic inflammation, vascular or genetic disease, etc.
 * Seldom reversible.
 * Usually the kidney shrinks as it's damaged.
 * Endocrine function is frequently lost, leading to anemia and bone disease.
 * Define the classification and causes of acute renal failure.
 * As defined earlier, classified three ways:
 * Pre-renal (caused by hypertension, heart failure, vasoconstriction).
 * Post-renal (bilateral obstruction, caused by intraluminal masses, extrinsic compression, or perforation of the bladder/urethra).
 * Intrinsic renal disease:
 * Very severe parenchymal disease-- allergic interstitial nephritis, glomerulonephritis, infection/pyelonephritis, vascular disease.
 * Intratubular precipitation (ethylene glycol intoxication, etc)
 * Renal ischemia
 * Nephrotoxic substances (drugs, heavy metals, organic solvents)
 * Myoglobin or hemoglobin (toxic to kidney)
 * Define the common causes of chronic renal failure.
 * Diabetes (40%)
 * Hypertension (27%)
 * Glomerulonephritis (11%)
 * Etc (interstitial nephritis, polycystic kidney disease, others)
 * Understand the causes of progression in chronic renal disease
 * (1) Could be a continuation or progression of the original insult.
 * (2) Could be a result of hypertension that is itself resultant from the original renal disease.
 * (3) Could be infection.
 * (4) Could just be that enough nephrons are destroyed that the rest are overworked and stressed out (hyperfiltration, resulting in increased single-nephron GFR) and eventually just fail.
 * Define uremia and its manifestations and complications.
 * __Uremia__: a group of clinical abnormalities that occur when there's a severe loss of renal function (often includes, but is not the same as, azotemia, which is specifically due to an over-abundance of nitrogen-containing products like urea and creatinine in the blood).
 * Uremia is only seen after the GFR has dropped by over 75% (when you're pretty bad off) and gets worse with the GFR below this point.
 * Characterized by:
 * **Edema** (unregulated fluid volume)
 * **Acidosis and hyperkalemia**, plus high PO4- and low Ca++, due to lack of solute regulation
 * **Azotemia** (failure to excrete nitrogen-containing compounds)
 * **Lack of drug clearance** (for drugs normally cleared through renal pathway)
 * **Hypertension** caused by abnormal renin secretion
 * **Anemia** caused by decreased erythropoietin secretion
 * **Bone disease** caused by decreased activation of vitamin D
 * Characterized also by a whole slew of other, seemingly unrelated, problems. These include, in addition to the obvious sequellae of the above dysfunctions, pericarditis, neuromuscular problems, GI upset/ulcers, hyperlipidemia, amenorrhea, increased rate of infection, insomnia, etc, etc.

Overview of Glomerular Pathology Thursday, May 08, 2008 9:13 AM


 * Overview of Glomerular Pathology, 5/8/08:**


 * Define the clinical syndromes associated with glomerular diseases.
 * (note that some of these can lead to others-- acute nephritic syndrome can lead to nephrotic syndrome can lead to chronic renal failure.)
 * **(1) Asymptomatic proteinuria and/or hematuria**
 * So if you entirely lost all ability to reabsorb protein, you'd still only have about 500 mg of protein per day in the urine. If you're seeing more than that, there's a problem with your glomeruli themselves (leaking protein into tubule).
 * If red cell casts are found in the urine, that's a specific sign that there's bleeding from the glomerulus.
 * These two are often, not always, associated.
 * **(2) Acute nephritic syndrome**
 * Increased glomerular permeability due to inflammation (note can get proteinuria or hematuria with red cell casts).
 * Loss of GFR (acute renal failure-- azotemia, HTN, Na+/H2O retention, etc)
 * **(3) Rapidly progressing nephritic syndrome**
 * As above but progresses quickly (rapid drop in GFR).
 * **(4) Nephrotic syndrome**
 * Note difference between nephritis (inflammation) and nephrosis (protein leakage).
 * Massive proteinuria (more than liver synthesis can keep up with: around __3.5 grams per day__ is the cutoff for nephrotic syndrome).
 * Leads to decreased plasma oncotic pressure, leading to Na+ and H2O retention, leading to all the things that that leads to.
 * **(5) Chronic renal failure**
 * Nephron loss leading to an irreversible loss of GFR.
 * Explain the most common pathogenic factors involved in glomerular disease.
 * [Recall that there's three layers to the filtration barrier: fenestrated endothelial cells, a basal lamina, and the epithelial podocytes (ie visceral epithelium). Immunoglobulins that attach to the epithelium, since they're not in the bloodstream, are generally non-inflammatory, while immunoglobulins that attach to the endothelium generally tend to be inflammatory (ready access to inflammatory mediators and white cells).]
 * (1) Non-inflammatory mechanisms:
 * Circulating immunoglobulins bind to glomerular epithelium cells (podocytes) or the basal lamina without fixing complement.
 * This can reduce the negative charge of the glomerular epithelium, which is keeping negatively charged proteins (like albumin) from slipping through into the tubule, resulting in proteinuria.
 * These compounds can also be toxic to the glomerular epithelium itself and damage it, forming larger pores and allowing larger proteins to get into the urine.
 * Or you can get an antibody that attacks the glomerular epithelium itself, and fixes complement there, outside the vasculature.
 * This fixes complement, through the alternative pathway, onto the podocytes-- the MAC forms, cutting a hole into the epithelium, again creating a situation in which larger proteins can transfer into the protein. Note that since this is extravascular, it doesn't attract inflammatory cells from the bloodstream.
 * Can also damage the vasculature itself, increasing leakage.
 * (2) Inflammatory mechanisms:
 * Antigen-antibody complexes deposit in glomerular capillaries and activate complement (Type III immunopathology). Can also see type II (Goodpasture's) in which the antibodies are directly attacking the capillary walls.
 * These fix complement in the capillary walls, leading to chemoattraction of inflammatory factors and damage to capillary and surrounding glomerular tissue.
 * After a certain point of capillary damage, fibrinogen is allowed to escape, which leads to a variety of bad outcomes.
 * (3) Hyperfiltration: when glomeruli have to work too hard they can break down.
 * (4) Coagulation: platelet aggregation: clotting of blood vessels in glomerulus (no oxygen/nutrients to tubules, etc), particularly when it spills out into Bowman's space.
 * Note that "crescents" can form in which scar tissue and coagulated fibrin clots fill the Bowman's space around the capillaries.

Kidney Microanatomy Thursday, May 08, 2008 11:01 AM


 * Kidney Microanatomy, 5/8/08:**

[Look, effectively most of this breaks down to "look at the Powerpoint and be able to answer his questions on it." The rest of it was covered in "Kidney Histology."


 * Describe the gross structures of the kidney and blood flow into, through, and out of the kidney
 * Be able to explain the basic structure and function of the nephron
 * Be able to identify the detailed structures of the renal corpuscle and how they relate to function of the nephron, including the ultrastructure of the filtration barrier
 * Be able to identify the detailed structures of the different cell types along the renal tubule and collecting tubules/ducts and how they relate to the function of the kidney
 * Describe the context of the structures and functional relationships of different regions of the nephron to their locations within the cortex and medulla
 * Be able to identify transitional epithelium of the bladder and know its function

Glomerular Pathology II: Nephritic Disease Friday, May 09, 2008 8:00 AM


 * Glomerular Pathology II: Nephritic Disease, 5/9/08:**


 * Define and recognize the 4 morphologic glomerular changes that accompany glomerular injury.
 * [Definitions:]
 * Focal = certain local glomeruli, but not others, are involved.
 * Diffuse = all local glomeruli are involved.
 * Global = all segments of a given glomerulus are involved.
 * Segmental = only some segments of a given glomerulus are involved.
 * Patterns of morphological change:
 * (1) **Cell proliferation**
 * Hypercellularity: endothelial, mesangial, or epithelial cells.
 * Questions to consider on pathology:
 * Are the capillary loops open or are they occluded?
 * Are the mesangial regions hypercellular (contain more than 4 or 5 cells per cluster)?
 * Does the glomerulus as a whole contain a roughly normal number of cells (about 30% of total volume)?
 * Is there a crescent pattern of scarring in Bowman's space?
 * (2) **Leukocytic infiltration**
 * In acute glomerulonephritis, PMNs, macrophages, and/or eosinophils come in, release enzymes, damage glomerulus.
 * (3) **Basement membrane thickening**
 * If the glomerular epithelium (podocytes) is damaged, it tends to produce factors that thicken the basolateral membrane. This tends to make the membrane more, not less, leaky.
 * Notice if the endothelium gets damaged, there's also thickening, of a different kind.
 * Often caused by diabetes.
 * (4) **Scarring/sclerosis**
 * Ischemia can cause scarring (fibrous repair mechanisms).
 * Scars can also develop from inside the mesangium. Not well understood.
 * Understand the role of immunofluorescence, serology and electron microscopy in the evaluation and diagnosis of glomerular disease
 * Immunofluorescence: can identify immunoglobulins by fluorescently labeling them (anti-IgG, anti-IgA), and can do they same thing with complement-- is it an immune-complex problem? Does it involve complement activation?
 * Recall that Goodpasture's is smooth (linear) on the basement membrane while immune complexes are granular (lumpy-bumpy).
 * Electron microscopy: can directly see deposits of antigen-antibodies complexes in the context of the surrounding tissue (is it in the mesangium? the capillaries?)
 * Serological assays: can look at complement levels, ANA for lupus, ANCA for Wegener's or polyarteritis nodosa vasculitides, and anti-streplysin-O for B-hemolytic //Streptococcus// (associated with glomerulonephritis).
 * List the glomerular diseases caused by immune-complex deposition.
 * Nephritic diseases (from milder to more severe syndromes):
 * **IgA nephropathy**
 * Usually presents as __asymptomatic hematuria__.
 * Histologically, looks like mesangial proliferation.
 * Due to extravascular immune complex deposition.
 * Immunofluorescence shows mesangial IgA and C3 and mesangial proliferation ("burning bush").
 * Can progress to end-stage renal disease. Acute cases treated with steroids.
 * **Post-infectious glomerulonephropathy**
 * Usually presents after a //Strep// infection with __acute nephritic syndrome__ (lots of red cells, white cells, and red cell casts in urine, and azotemia).
 * Due to immune complex deposits.
 * Histologically, see diffuse endoproliferative glomerulonephritis.
 * Immunofluorescence and EM show granular IgG deposits in the subepithelium, not so much the endothelium (as you would expect from an inflammatory immune-mediated renal disease). They seem to be transferred out of the endothelium in an attempt to limit inflammatory damage.
 * Prognosis is generally good, without sequellae. Therapy is supportive.
 * **Focal necrotizing and crescentic glomerulonephropathy**
 * (not a specific disease, but a clinical presentation:)
 * Usually presents as __rapidly progressing nephritic syndrome__ (hematuria, lots of red cell casts, significant impairment of renal function, progresses quickly).
 * Histologically, shows a focal, segmental pattern of necrosis and crescents in the glomeruli.
 * Immunofluorescence can show linear staining with Goodpasture's, or granular staining with IgA, lupus, or endocarditis (due to toxic emboli from heart), or no immunostaining at all (due to a vasculitis etiology: Wegener's, Churg-Strauss, or microscopic polyarteritis nodosa).
 * Damage can be due to any of these things, or the inevitable "idiopathic."
 * Therapy depends on etiology, but it's a life-threatening illness. Prognosis is poor, particularly for autoimmune or with lots of crescents.
 * **Lupus glomerulonephropathy**
 * The kidney is a major target of lupus. Unfortunately, it can present as just about anything-- IgA nephropathy in mesangial, focal or diffuse glomerulonephritis, membranous nephropathy, etc. Can have hematuria, proteinuria, nephrotic syndrome, and impairment of GFR.
 * So we talk about it in terms of morphology:
 * Glomerular cell proliferation
 * How much necrosis and how many crescents
 * Abundance of leukocytes
 * Presence of hyaline deposits (nonfunctioning regions)
 * Interstitial inflammation
 * Treated "harshly" with steroids and cytotoxic agents. Prognosis with treatment is generally good, but recurrence risk is high and can progress to end stage renal disease. Also the application of cytotoxics in the population that's most susceptible (young women) can render them infertile.
 * Explain the relationship of morphologic patterns of injury with clinical presentation.
 * I more or less just rolled this into the last LO.
 * Note the terminology of the following patterns of immunofluorescence:
 * Lumpy-bumpy on __basement membrane__: 'starry sky' presentation
 * Lumpy-bumpy on __mesangial cells__: 'burning bush' presentation

Glomerular Pathology III: Nephrotic Disease Friday, May 09, 2008 9:07 AM


 * Glomerular Pathology III: Nephrotic Disease, 5/9/08:**


 * Describe the pathophysiology, clinical manifestations and complications of nephrotic syndrome.
 * Increased permeability of the glomerular capillary wall to plasma proteins.
 * Clinical manifestations:
 * **Albuminuria**
 * **Hypoalbuminemia** (due to insufficiently compensated loss of albumin)
 * **Edema** (due to a loss of oncotic pressure to retain fluid in capillaries)
 * **Hypovolemia** (due to third-spacing of fluid from blood)
 * **Hyperlipidemia** (due to overactivation of hepatic synthesis pathways that also make lots of LDL along with albumin. Can also see fat emboli released from liver.)
 * Note that the pathogenesis can be a physical disruption in the filtration barrier (which would disrupt filtration based on size) or a disruption in the negative charge of the filtration barrier (which would disrupt filtration based on charge).
 * Specifically, recall that there can be non-inflammatory mechanisms that attach and don't fix complement, but screw up the charge of the glomerular membrane (disruption of charge barrier). Or it can result from extravascular complement-fixing anti-epithelial antibodies or immune complexes that form the MAC through the alternative pathway and bore holes through the podocytes (disruption of size barrier).
 * Complications:
 * Increased infection rate (perhaps due to loss of immunoglobulins)
 * Increased thrombosis (perhaps due to loss of anti-coagulant factors like ATIII)
 * Increased drug toxicities (many drugs are bound by albumin)
 * Protein malnutrition, particularly in kids
 * Hyponatremia and hypokalemia (leaking out with edematous fluid)
 * Be able to describe the typical clinical manifestations, morphology, pathogenesis and prognosis of the common glomerular diseases summarized in the handout.
 * Note that accordingly to Dr. Lucia, nephrotic syndrome in an adult is always a "kidney biopsy event."
 * Pediatric:
 * **Minimal change nephropathy** :
 * Light microscopy looks normal. EM shows loss of podocyte foot processes. No immunofluorescence.
 * Can, in principle, be lethal, so want to catch it. But prognosis with steroids is vey good.
 * Note that the factor that causes it - whatever that may be - seems to be able to be activated by application of an endogenous agent (like antibiotics, etc).
 * **Focal segmental glomerulosclerosis**
 * Histologically, see focal segmental dark pink stuff in glomeruli-- that's scarring, or sclerosis. Note can be very focal (5% glomeruli).
 * Caused by unknown agent; therapy has dubious efficacy. Can progress to end-stage renal disease.
 * In adults, get the above two, but also:
 * **Membranous nephropathy** :
 * Histologically, look for basolateral membrane thickening. On EM the membranes also look a little like Swiss cheese.
 * Immunofluorescence shows a granular epithelial pattern, with IgG and C3 fixed on the podocytes.
 * Sometimes associated with tumors, as well as certain medications or connective tissue disorders.
 * Treat with steroids; some still progress to end-stage renal disease.
 * Note can also get mixed nephritic/nephrotic syndromes:
 * **Membranoproliferative glomerulonephritis** :
 * Presents with signs of both nephritic and nephrotic disease (impaired renal clearance along with proteinuria and hypoalbuminemia).
 * Histologically, looks like endocapillary proliferation (hypercellular) with "tram tracks" (deposits between basement membranes).
 * Immunofluorescence shows some mesangial and endothelial depositions of IgG and C3.
 * Caused by lots of things, lupus among them. Treat with steroids; some still progress to end-stage renal disease.

Renal Regulation of ECF Potassium Monday, May 12, 2008 8:00 AM


 * Renal Regulation of ECF Potassium, 5/12/08:**


 * [Note that the kidneys can excrete 0 to 45 g of K+ per day.]
 * [Note also that the kidneys only filter about 30 g of K+ per day.]
 * [This means there's a fairly significant K+ secretion process going on.]


 * Describe the cellular mechanisms for potassium reabsorption and secretion and their tubular location.
 * Potassium reabsorption:
 * Most obligatory K+ reabsorption occurs in the proximal tubule (80%):
 * Recall that Na+ and Cl- are being reabsorbed en masse in the proximal tubule, and that a lot of water is following them, largely through leaky tight junctions.
 * Essentially the K+ in the lumen is swept back into the interstitium along with the water that's following the NaCl.
 * In the thick segment of the ascending loop of Henle, recall that there's Na/K/2Cl co-transporters in the apical membrane; these take K+ in with Na+ and 2 Cl-, and the K+ flows out the basolateral membrane into the interstitium.
 * Recall also that these co-transporters are the target of loop diuretics (which is one reason they're called "potassium wasting"-- they block this K+ reabsorption).
 * About 15% of obligatory K+ reabsorption occurs in the loop.
 * The rest of the obligatory reabsorption occurs in the intercalated cells of the distal tubule/collecting duct. The cells most involved in K+ secretion are the principal cells of the DT/CD.
 * Potassium secretion:
 * Effectively potassium secretion (in the distal tubule) goes by the opposite route as sodium reabsorption:
 * K+ is actively pumped inwards from the interstitium by the Na/K ATPase pump (**step 1** ) and flows out passively into the lumen through ion channels ( **step 2** ), generally to balance the influx of Na+ from the luminal fluid.
 * Note that this is reversed from Na (which enters from the lumen passively and is actively pumped outwards into the interstitium by the Na/K ATPase pump).
 * Note also that if you block the Na+ channels, the K+ loses most of its impetus for leaving the cell (thus lowering K+ secretion). This is the main reason K-sparing diuretics (amiloride, spironolactone) are K-sparing.
 * Describe the feedback pathways that regulate ECF potassium levels via potassium secretion.
 * Path one: Na/K pump correction by the law of mass action.
 * So imagine you eat a really big banana, thus increasing your plasma K+ concentration (ie. your ECF [K+] goes up).
 * That means there's lots and lots of potassium in the plasma in the peritubular capillaries available to bind to the Na/K pump in the basolateral surface of the distal tubule.
 * This is going to increase the pumping rate of the Na/K pump (by the mass action effect), increasing the rate of potassium secretion across the basolateral membrane into the tubular cells.
 * The increased concentration of potassium in the tubular cells increases the K+ gradient between the inside of the cell and the luminal fluid in the tubule, thus increasing the secretion of K+ through its ion channels into the fluid.
 * This works well for correcting large increases in [K+], but it goes pretty slowly. So you have another way of doing this:
 * Path two: correction by alterations in aldosterone secretion.
 * Increased levels of potassium in the ECF cause a release of aldosterone.
 * Aldosterone does three things here:
 * One, it increases the number of Na/K pumps in the basolateral membrane. That increases the rate of pumping as above (affects step 1).
 * Two, it increases the number of Na+ channels in the apical membrane. That allows more Na+ to flow into the cell, which creates an electrochemical gradient for K+ to be secreted out of it (step 2).
 * Three, it increases the number of K+ channels in the apical membrane. That effectively increases the membrane permeability to K+ and increases the secretion rate (step 2).
 * [Note that this means that if you have normal potassium levels, but you're volume-depleted, the aldosterone that's secreted to correct the volume depletion can also increase K+ secretion, resulting in hypokalemia.]
 * [Take-home: **Aldosterone increases potassium secretion.** ]
 * [Not a LO but important: the effects of tubular flow on potassium secretion.]
 * Recall that increased tubular flow __decreases__ sodium reabsorption.
 * Increased tubular flow __increases__ potassium secretion.
 * This works because the driving force for potassium to enter the luminal fluid is dependent on the relative concentrations between intracellular and luminal potassium.
 * With a high rate of flow, the luminal fluid doesn't stick around long enough to significantly change its potassium concentrations, thus the chemical gradient for potassium secretion stays high.
 * With a slow rate of flow, the luminal fluid accumulates more potassium, decreasing the chemical gradient that favors potassium secretion and slowing the secretion process.
 * This is the other reason why loop diuretics waste potassium: they increase water retention in the tubule, which leads to increased flow rates in the tubule and increased potassium secretion.
 * This actually seems to be the main mechanism for potassium wasting in loop diuretics.
 * State the effects of acid/base imbalances on potassium levels.
 * **Alkalosis increases potassium secretion**.
 * Two reasons for this:
 * One, if you recall from a long time back, Dr. Betz told us to pretend that there was a H+/K+ exchanger in cells that was driven by comparative gradients. This is a useful concept here.
 * So if you have a loss of H+ in the ECF (alkalosis), there's a trend towards H+ going out of the cells and K+ going in. This reduces the level of K+ in the ECF (hypokalemia) and also increases the concentration of K+ in the tubular cells (which increases the gradient driving K+ secretion into the luminal fluid).
 * Two, a high pH potentiates potassium channels in the apical membrane (protons inhibit these pumps). So you're increasing secretion that way too.
 * Acidosis can either increase or decrease potassium secretion, dependent on the extent of the acidosis, but is generally associated with __decreased__ secretion.
 * Acidosis inhibits sodium transporters as well as inhibiting potassium transporters-- although the inhibited potassium channels will tend towards decreased secretion, the inhibited sodium channels will decrease sodium and water reabsorption, thus increasing tubular flow rate and tending towards increased secretion.
 * Describe the cellular mechanisms by which acid/base abnormalities can cause hypokalemia and hyperkalemia.
 * See above.

Diseases of Potassium Regulation Monday, May 12, 2008 9:05 AM


 * Diseases of Potassium Regulation, 5/12/08:**


 * Discuss the factors that influence potassium shifts between the intracellular and extracellular fluid spaces.
 * **Insulin** : increased ECF potassium induces insulin, which shifts potassium into cells and out of the ECF.
 * **Beta-2 adrenergic receptor stimulation** : increased ECF potassium induces beta-2 adrenergic stimulation, which also shifts potassium into cells and out of the ECF.
 * **Acidosis/Alkalosis** : As mentioned in the last lecture, alkalosis moves potassium into cells and out of the ECF (acidosis tends to move potassium out of cells and into the ECF).
 * [Also note the following factors affecting secretion inside the kidney itself:]
 * **Flow rate** (as mentioned last lecture, increased flow = increased K+ secretion).
 * **Aldosterone** (as mentioned last lecture, increased aldosterone also = increased K+ secretion).
 * Notice that aldosterone receptors have the potential to also respond to glucocorticoids (cortisol). This is inhibited by an enzyme called 11-beta-hydroxysteroid dehydrogenase, which is why your kidneys don't go nuts every time you eat a cookie.
 * **Epithelial cell integrity** (if the cells are screwed, no secretion's going to happen).
 * [Excretion of anions (like HCO3-) also increase K+ secretion as an obligate cation to ensure electrical balance.]
 * Describe how to diagnostically approach a case of hypokalemia.
 * First thing to do: look for clinical correlates that should go along with hypokalemia. If they're not there, check for possible lab error.
 * Assuming it's real:
 * Dr. Linas: "How-did-it-happen? Why-do-we-care? What-are-you-going-to-do-about-it?"
 * Want to distinguish between internal-balance potassium problems and intake-output problems.
 * Check for existing conditions (diabetes/insulin levels, excess catecholamine release due to stress, etc) that might account for the hypokalemia.
 * If none of the above, look for decreases in total body potassium. This can happen in one of two ways:
 * Inappropriate excretion by the kidney (test electrolytes in urine. If it's high, probably a kidney problem).
 * Lack of dietary potassium (check serum pH. If it's normal, then it's probably this).
 * Inappropriate excretion by GI tract, ie. diarrhea (if in metabolic acidosis, probably this one-- acidosis caused by loss of HCO3-).
 * Why we care: see next LO.
 * Treatment:
 * Potassium is caustic to blood vessels, so generally given orally, but it also absorbs slowly from the oral route, so can use IV in an emergency.
 * Other ways of correcting low K:
 * Recall that beta-2 catecholamines can cause hypokalemia-- so beta-2 blockers can, potentially correct it.
 * Also recall that you can use potassium-sparing diuretics (spironolactone, amiloride) to decrease K secretion.
 * Discuss the physiologic effects of hypo and hyperkalemia, particularly as they relate to excitable tissues.
 * Things you're worried about with __hypokalemia__:
 * Neuromuscular: muscles fail, die of respiratory failure.
 * Also cause a lot of arrhythmias (excess depolarization of cells).
 * So if the guy has a history of heart problems, want to be very careful about this. Look for __U waves__ on the EKG in hypokalemia.
 * Of particular note, __hypokalemia worsens arrhythmic tendencies of patients on digitalis__ (recall that digitalis binds to the K-binding site on the Na/K pump; if the K levels are lowered, there's less competition for the digitalis and it has an increased effect).
 * Other stuff:
 * Hypokalemia suppresses insulin release (probably because insulin lowers potassium levels) and causes intracellular acidosis.
 * It also causes thirst and a renal concentrating defect (polyuria). Can mess up your glomeruli pretty good if it keeps on.
 * Things you're worried about with __hyperkalemia__:
 * Mainly arrhythmias (move cells closer to depolarization threshold). Look for a __peaked T wave, widened QRS complexes, or a 'sine wave' pattern__ on EKG.
 * Can see the same neuromuscular weakness/paralysis as in hypokalemia.
 * Hyperkalemia is rarer but generally more serious than hypokalemia.
 * Describe how to diagnostically and therapeutically approach a case of hyperkalemia.
 * Again, check for clinical correlates and look for lab error if they're not there.
 * If it's real:
 * Again, check for pre-existing conditions that would account for an altered internal balance of potassium.
 * Failing that, look for increases in total body potassium:
 * Look at urine potassium. If it's low, look for a kidney problem; if not, look for a GI or intake problem (been eating too many bananas).
 * Kidney problems:
 * Check if GFR is low (normal nephron function). If the GFR is less than 20 mL/min, that's presumably why the potassium is high and you can move on to trying to save the guy's kidney.
 * If the GFR is normal or not all that low, look for low aldosterone levels (ACE inhibitors, etc).
 * If the aldosterone is normal but if the tubule flow is really small (so that you don't have much flow to the distal tubule), then you're not going to secrete potassium (no flow to secrete it into). Also if you're on an aldosterone blocker like spironolactone, your aldosterone levels can be normal but they're not doing anything.
 * Treatment (this is important):
 * Option 1: shift the potassium into cells with insulin, beta-2 agonists, or by making the patient alkalemic with sodium bicarbonate.
 * Option 2: lower total body potassium by using Kayexelate (ion exchange resin), potassium-wasting diuretics, or dialysis.
 * Option 3: immediate calcium infusion decreases myocardial excitability, lowering the likelihood of arrhythmias.

Role of the Kidneys in Acid/Base Balance Monday, May 12, 2008 1:56 PM


 * Role of the Kidneys in Acid/Base Balance, 5/13/08:**


 * State the production rate of metabolic, nonvolatile acid in a healthy, average-sized individual.
 * (recall that 'nonvolatile' means nongaseous-- ie. H3PO4, H2SO4, etc.)
 * Daily production of nonvolatile acids: about **1 mmol per kg**, or about **60 mmol** for our standard person.
 * State the major acid buffering mechanisms in the ECF.
 * So there's about 60 mmol of H+ produced every day that needs to be neutralized.
 * __This occurs largely through the action of bicarbonate__ (also occurs, minimally, through plasma proteins, mostly albumin).
 * You've already seen the equations for how this works: HCO3- + H+ <--> H2CO3 <--> CO2 + H2O. Effectively you can combine hydrogen and bicarbonate to neutralize the hydrogen and blow it out of the lungs as CO2.
 * However, you wind up losing a bicarbonate ion every time you do this. Note that you've got about 300 mmol of bicarb in the ECF and you're losing about 60 mmol per day to nonvolatile acid production. So making more every day is a good idea.
 * The kidneys synthesize about 60 mmol per day (or however much acid you make) of bicarbonate to maintain steady levels.
 * Note also that, as a small ion, bicarbonate is filtered along with the blood into the kidney. Since you're already losing total bicarb and not becoming acidemic is good, it's also extremely important to reabsorb bicarbonate like crazy from the tubules.
 * Describe the chemical reaction scheme and role of bicarbonate in the buffering of nonvolatile acid.
 * See above.
 * State the role of the kidney in the maintenance of bicarbonate levels.
 * See above. Reabsorption, synthesis.
 * Describe the cellular mechanisms, tubular localization, and daily magnitude of bicarbonate reabsorption.
 * Most of the **reabsorption** occurs in the __proximal tubule__. Here's how it works:
 * HCO3- is hanging out in the lumen of the tubule.
 * A hydrogen ion in the cell is secreted into the lumen by being exchanged for a sodium ion coming into the cell (through a sodium-hydrogen exchanger or NHE).
 * The hydrogen ion combines with the HCO3- to form CO2 and H2O.
 * It does this with great avidity, since there's a ton of carbonic anhydrase (catalyzes the HCO3- + H+ <--> CO2 + H2O reaction) embedded in the apical membrane and apical concentrations favor CO2 formation.
 * The CO2 diffuses into the cell across the apical membrane.
 * The CO2 combines with water within the cell to form HCO3- and H+ again.
 * It does this, again, with great avidity, since there's a lot of carbonic anhydrase inside the cell as well and intracellular concentrations favor HCO3- formation.
 * The HCO3- is co-transported out of the basolateral membrane into the interstitial fluid with a sodium ion by a sodium-bicarbonate co-transporter or NBC.
 * The H+ stays in the cell to be reused for the same process over and over.
 * Note __no net change__ in acid-base status (no loss of H+, co-transport of Na+ along with HCO3- to balance charges) with reabsorption.
 * Note also that this moves a significant amount of sodium along with it-- about 15% of total sodium is reabsorbed along with the bicarbonate. Again, this becomes important in the use of certain diuretics that block bicarbonate resorption.
 * Note also also that the amount of bicarbonate reabsorbed generally far exceeds the amount of bicarbonate synthesized. If you wanted to calculate it out, it would be something like [HCO3-] * GFR * 1440 min/day.. or something. It's a fair amount.
 * Most of the **synthesis** occurs in the __distal tubule and collecting ducts__ (in the intercalated cells). It's a similar process but with some significant differences:
 * Effectively what you want to do is break down CO2 to HCO3- and H+ and excrete the H+.
 * So CO2 comes into the tubular cells from the interstitial fluid and is broken down into HCO3- and H+.
 * The HCO3- is transported back out into the interstitium in exchange for a chloride ion, by the bicarbonate-chloride exchanger or BCE.
 * The H+ is actively transported out the apical membrane by a proton pump (H+ ATPase pump).
 * The H+ that's pumped out into the luminal fluid, recall, will immediately bind to HCO3- if any is around to combine with (all that carbonic anhydrase) and begin the reabsorption cycle. But since all of the bicarbonate reabsorption is generally finished by this point in the tubule system, there shouldn't be any bicarb left to combine with.
 * To emphasize that point-- __you can't synthesize bicarbonate while there's still bicarbonate in the lumen to be reabsorbed__.
 * In bicarb synthesis, in order to prevent the urine becoming crazy acidic and eating away all our good bits, you have to trap the secreted hydrogen ions in some inactive form.
 * So the hydrogen ions excreted into the distal tubule have a couple of options. One is to bind to any acid anions floating around in the urine (H2PO4-, HSO4-, etc). This is fine as far as it goes, but there generally aren't enough of those floating around to sufficiently buffer the excreted hydrogen ions.
 * The other, main, option is to bind to NH3 molecules floating around in the urine, converting it to a relatively stable NH4+ form and trapping the hydrogen ion in the resultant ammonium. Note that since ammonium is charged, it can't pass through the membrane, and is washed out and excreted.
 * [The ammonia in urine comes from the breakdown of glutamine in the tubular cells.]
 * Note that this process __produces a net charge__ since you're excreting out H+ and retaining HCO3-.
 * Describe the renal responses to metabolic acidoses.
 * The increased H+ concentration in the ECF results in a decrease in HCO3- in the ECF (combining into CO2 to be blown off). This decreases the amount of HCO3- in the filtrate.
 * Recall that we said that all the HCO3- has to be reabsorbed before the hydrogen ions can bind to ammonia and be trapped-- reabsorption has to be finished before synthesis can occur.
 * In metabolic acidosis, you're going to reach the end of bicarbonate reabsorption much faster, leaving more time and [H+] available for synthesis to make up the shortfall.
 * I don't think it's actually accurate, but I think of it like you're trying to pick up sandwiches off a conveyor belt. Each of your hands can be either picking up a sandwich off the conveyor belt or making more sandwiches. But you'd rather pick up sandwiches than make them (sandwiches made by someone else taste better). So as long as sandwiches are coming down that belt, both hands are going to be busy picking them up and packing them away. But once there aren't any more sandwiches, then you start making more. If you start running low on sandwiches (bicarbonate), you'll start making more sandwiches (bicarbonate), since there'll now be more time during which your hands aren't picking up sandwiches. If you've got a whole ton of sandwiches, you'll probably stop making them altogether, and some of them may even get by you on the conveyor belt and be wasted, because, you know, you've only got two hands and that's a lot of sandwiches.
 * Note that the pumps that control H+ secretion into the lumen are potentiated in metabolic acidosis (you can make sandwiches quicker when you're running low).
 * Note also that the enzyme that promotes glutamine breakdown (thus ammonia production to trap excess hydrogen ions) is upregulated in metabolic acidosis.
 * Describe the long term effects of primary changes in ECF potassium levels on plasma pH.
 * Recall that alkalosis causes hypokalemia. __Hypokalemia also causes alkalosis__.
 * Work it through with the imaginary H+/K+ exchanger: low serum K+ means more K is removed from cells and more H is added into them (out from the ECF). This lowers the plasma [H+] and thus raises plasma pH (also makes more H+ in the tubule cells available for secretion).
 * Note that this increases the [H+] intracellularly, lowering intracellular pH. A more acidic internal environment increases the activity of the H+ pump, also increasing proton secretion and furthering alkalosis.
 * Finally, __hyperkalemia causes acidosis__. With more K in the plasma, more H will be removed from the ICF to the ECF, resulting in the opposite of the actions just described and leading to a low plasma pH and decreased proton secretion. Also, as mentioned, increased potassium levels decrease ammonia production through glutamine breakdown, further reducing H+ secretion.

HCO3- synthesis: intercalated cells K+ secretion: principle cells

[to sum a couple of things:] o Aldosterone lowers serum potassium. It also causes alkalosis. o Hypokalemia causes alkalosis and decreases insulin secretion. o Alkalosis causes hypokalemia.

Acid/Base Disorders Monday, May 12, 2008 1:56 PM


 * Acid/Base Disorders, 5/13/08:**


 * Understand the definition of simple and mixed acid-base disorders.
 * Simple: you have one (1) respiratory or metabolic problem, either acidosis or alkalosis, that's compensated for by one (1) metabolic or respiratory mechanism.
 * Mixed: you have multiple things going on. Maybe you've got a metabolic acidosis on top of a metabolic alkalosis with some inadequately compensatory respiratory alkalosis.
 * Say I've got lots of lactic acid (metabolic acidosis). This makes me ventilate more to decrease my CO2 (respiratory compensation) to normalize the pH. That's simple.
 * Now say I've got lots of lactic acid (metabolic acidosis) but I'm also vomiting (metabolic alkalosis) and losing bicarbonate to diarrhea (another metabolic acidosis), and I'm trying to compensate for the acidosis through respiratory alkalosis but I've got COPD so it's not working so well. That's mixed. It's a big gigantic pain.
 * What you want to look at is: is the respiratory change proportionate ("appropriate") to the metabolic change? That is, is the change in HCO3- appropriate to the change in CO2? You also need to compare the change in bicarbonate to the anion gap. If all this works out, great, it's probably simple. If not, crap, it's probably mixed. Much more on this below.
 * More about "appropriate" below under the rules of compensation.
 * Know the definition and utility of the serum and urine anion-gaps.
 * Definition:
 * **Anion gap: measured cations minus the measured anions.**
 * Generally this breaks down into Na+ on the cation side and HCO3- + Cl- on the anion side.
 * Note that since K is usually pretty small, it's often not included with the cations.
 * **Normally the anion gap is from 6-12 (9 plus or minus 3).** You can just use 10 as a good round rule of thumb.
 * Note that the anion gap isn't 'real' (you don't actually have 6-12 mmol/L more cations than anions), to the best of my knowledge. It's indicative of a bunch of anions that aren't routinely measured. This will be important in a minute.
 * Utility:
 * Anion gap measurements are usually used only in metabolic acidosis cases.
 * Metabolic acidosis means your concentration of HCO3- is going down. Assuming the total cations and anions still balance, the question is what's making up the difference in anion count-- something measured (ie. Cl-) or something that's not (eg. HSO4-)?
 * __If the serum anion gap is normal__, then you're making up the loss of HCO3- with Cl-. This is what happens when you're losing a lot of HCO3- to diarrhea, or not able to reabsorb HCO3- in the tubule, or not able to secrete H+ in the tubule.
 * This is where the __urine anion gap__ comes in, to test to see if the problem is in the kidneys or not.
 * If the kidneys are working right, you should be excreting protons like crazy (you're trying to make bicarbonate) and trapping them in ammonia. When you excrete hydrogen ions, chloride generally travels with them.
 * This means that your urine electrolyte analysis should show that the relative level of chloride in the urine should be way up. Increased secretion of chloride also means that the __urine__ anion gap should be __negative__ (measured anions way outnumber the measured cations, since NH4+ - the counter-cation to Cl- - isn't routinely measured). If it isn't, then there's a problem with your kidneys.
 * Take-home here: in a person with metabolic acidosis and a normal serum anion gap, get the urine anion gap. If it's __negative__, then the kidneys are normal and you should look for a problem outside them (GI loss of HCO3-, etc). If it's __positive__, then the kidneys are not doing their job properly and that's probably your trouble.
 * __If the serum anion gap is elevated__, then you're making up the loss of HCO3- with something that you don't routinely measure. This is what happens when you're trying to neutralize a bunch of organic acids (you've eaten a chunk of H2SO4, or run a marathon and you've got a ton of lactic acid, or you can't secrete organic acids into the tubules, or you're diabetic and building up way too many ketone acids, or you've chugged a bottle of antifreeze and all that ethylene glycol is starting to build up as oxalic acid). This is generally a big deal and you want to get a follow-up organic acid screen right now.
 * Understand the concept (and rules) of compensation.
 * There are quite a few of these rules, actually. The basic idea is that you should be able to look at the HCO3- and CO2 levels and predict whether the one looks right, given the other. If they're not, then you probably have some kind of mixed acid-base problem.
 * In compensated metabolic acidosis, the change in CO2 should equal 1-1.5 times the change in HCO3-.
 * In compensated metabolic alkalosis, the change in CO2 should equal 0.25-1 times the change in HCO3-.
 * In __compensated (chronic)__ respiratory acidosis, the HCO3- should go up by 4 and the pH should go down by 0.03 for every increase of 10 in CO2.
 * In __uncompensated (acute)__ respiratory acidosis, the HCO3- should go up by 1 and the pH should go down by 0.08 for every increase of 10 in CO2.
 * In __compensated (chronic)__ respiratory alkalosis, the HCO3- should go down by 4 and the pH should go up by 0.03 for every decrease of 10 in CO2.
 * In __uncompensated (acute)__ respiratory alkalosis, the HCO3- should go down by 1 and the pH should go up by 0.08 for every decrease of 10 in CO2.
 * [Note that our small-group guy mentioned this: compensation generally doesn't fully work (the pH is usually still going to be slightly tilted in the direction of the original disorder). If you see a guy with a problem and a completely normal pH, there's probably an underlying disorder somewhere.]
 * [Also note that the CO2 and HCO3- should always move in parallel. If you have a guy where they're going in different directions, that's always going to be a mixed disorder.]
 * Know how to approach simple and mixed acid-base disorders.
 * As much as I hate these six-part diagnostic ladders, this one seems pretty good:
 * (1) Is the patient acidemic or alkalemic? (look at blood pH)
 * (2) Is the primary cause a respiratory or a metabolic problem? (look at PCO2 and bicarbonate levels)
 * If it's respiratory:
 * (3) Is it acute or chronic? (check to see how much the kidneys have compensated for it with bicarb changes)
 * If it's metabolic:
 * (3) Is the respiratory system compensating appropriately? (compare change in bicarbonate to change in PCO2) If not, probably some kind of superimposed respiratory problem.
 * (4) Is the anion gap normal (6-12) or elevated? (measure chloride, sodium, bicarb levels) If it's normal, check urine anion gap, as discussed above.
 * (5) [This is the tricky one] **Compare the change in bicarb to the change in the anion gap.** (This seems to mostly be important in metabolic acidoses.)
 * If they're the same, then you've probably got only the one metabolic disorder.
 * If the change in bicarb is greater than the change in the anion gap, then whatever's causing the change in the anion gap (like organic acid buildup) must only be part of the metabolic acidotic picture and there's another source of bicarb consumption (an additional, non-organic acid, metabolic acidosis).
 * If the change in bicarb is less than the change in the anion gap, then whatever's causing the change in the anion gap must be being partially compensated for by some other mechanism that depletes protons or increases HCO3- (there's an underlying metabolic alkalosis).
 * [recall H-H, simplified: pH is proportional to the concentration of HCO3- over the concentration/pressure of CO2. If the primary problem is metabolic, the pH should directly follow the bicarb levels. If the primary problem is respiratory, the pH should inversely follow the CO2 levels.]
 * [__Yet another set of 'normal' values for us: **pH = 7.4, PCO2 = 40, HCO3- = 24**__ __.__]
 * [__Metabolic alkalosis__: classified as either '**saline-responsive** ' or ' **saline-resistant** .' The idea is to figure out whether or not giving the patients fluids should help. You get this information from looking at the urine chloride concentration:]
 * In volume-depleted patients, the increased levels of aldosterone can result in alkalosis (while I'm not entirely clear on the mechanism, it may have something to do with the fact that you're secreting increased H+ to make up for the increased discrepancy in the 3 Na+-for-2 K+ Na/K pump, which is upregulated with aldosterone release). So if the underlying cause of the metabolic alkalosis is aldosterone release secondary to volume depletion, you can solve the metabolic alkalosis by administering volume. So the question is, how can you tell if the patient is volume-depleted through the urine analysis?
 * In a volume-depleted patient, the kidneys should be strongly reabsorbing Na+ (and thus also Cl-). So __if the Cl- levels in the urine are low (less than 10 mEq/L), that's a sign that the patient needs volume__ (saline-responsive). If the Cl- levels in the urine aren't low, that's a sign that the patient has adequate volume (or their kidneys are screwed enough that more volume won't help), thus 'saline-resistant.'
 * [Four common causes of increased-anion-gap metabolic acidosis:]
 * **K** etones (diabetic ketoacidosis)
 * **A** spirin (salicylic acid)
 * **R** enal failure (retention of sulfate, phosphate, etc)
 * **L** actate (ischemia)
 * [A somewhat more complex acronym:]
 * **M** ethanol
 * **U** remia
 * **D** iabetic ketoacidosis
 * **P** araldehyde
 * **I** sopropanol
 * **L** actic acid
 * **E** thylene gylcol
 * **S** alicylic acids

1-3-4-8 rule of metabolic compensation for respiratory problems

Hypertension/Secondary Causes of Hypertension Wednesday, May 14, 2008 7:39 AM


 * Hypertension/Secondary Causes of Hypertension, 5/14/08:**


 * Understand the operational nature of the term "Hypertension".
 * Recall that some people are going to naturally have higher blood pressures than others. Nevertheless, we set a standard of 140/90. Patients over this mark, but under 160/100, are said to have __stage 1 hypertension__.
 * Generally want to prescribe __thiazide diuretics__ for people in this category.
 * Note that increases in systolic pressure seem to be more highly correlated with morbidity in people over 50 than increases in diastolic pressure.
 * We define 'prehypertension' as a systolic of 120-139 or a diastolic of 80-89.
 * Note __no antihypertensive medications__ are indicated for prehypertensive patients (lifestyle modifications only).
 * There's also a __stage 2 hypertension__ in which you've got a systolic over 160 or a diastolic over 100.
 * Prescription indications: __Thiazide diuretics and some secondary drug__ (ACE inhibitor, beta blockers, angiotensin receptor blockers, calcium channel blockers).
 * Dr. Linus: drugs are great. Lifestyle modifications are OK. My kind of guy.
 * Note that you treat most patients to 140/90. You treat diabetic or chronic kidney disease patients to 130/80.
 * Understand the importance of hypertension and public health.
 * Over 50 million people in the US have hypertension. Most of them know they have it; most of them aren't controlling it to below 140/90.
 * Starting at a blood pressure of 115/75, every increase of 20/10 doubles risk of cardiovascular events. The ones you're particularly worried about are stroke, MI, and heart failure. Controlling hypertension reduces these risks about 35, 20, and 50% respectively.
 * Hypertension: 'targets' heart and arteries (CVD), brain (stroke), kidneys, eyes (retinopathy). Also a big risk factor for dementia and Alzheimer's.
 * Following the above-mentioned guidelines for prescription of hypertensive meds would arguably save more lives and more public spending than smoking cessation. It's a big deal.
 * Understand the pathogenetic role of the kidney in hypertension.
 * The kidney seems to be the culprit organ in essential hypertension (90-95% of hypertension in the US). Some thoughts on why this is in the next LO.
 * Note that a GFR of less than 60 mL/min is a risk factor for developing cardiovascular disease.
 * Note also that, in rat models, if you transplant a kidney from a rat with essential hypertension into a rat without, the hypertension tends to come along. Conversely, if you transplant a normal kidney into a rat with essential hypertension, the hypertension tends to resolve.
 * Know the pathophysiology behind primary and secondary forms of hypertension.
 * Note that we have no real idea what causes primary hypertension. But the physiology behind it is a little more clear. Two schools of thought on this:
 * Guyton Hypothesis (seems to be predominant):
 * __Primary defect in Na excretion__ by kidney leads to increased plasma volume, which (Starling) leads to increased cardiac output, leading to a (myogenic?) autoregulatory increase in total peripheral resistance.
 * The cardiac output normalizes due to the increased TPR, but the peripheral resistance remains (hypertension).
 * Notice that, in support of this theory, the decreased CO from diuretic administration seems to lead to a decreased TPR over time, the main benefit of diuretics in hypertension.
 * Cellular Hypothesis:
 * In vascular smooth muscle cells, the Na/K ATPase pump is inhibited by a sodium transfer inhibitor. This leads to an increase in cell sodium, which screws up the sodium/calcium exchanger, leading to an increased buildup of calcium in the cell. This triggers vascular smooth muscle contraction, leading to increased total peripheral resistance and hypertension.
 * Notice that one is kidney-centric, the other is vascular smooth muscle-centric.
 * At the moment, the prevailing hypothesis is the kidney-centric one.
 * Secondary hypertension:
 * Note this is much more rare than primary or essential hypertension (5-10%).
 * Causes:
 * Drug use
 * Diseases of the kidney:
 * __Renal artery stenosis__ (can hear bruits on auscultation of abdominal arteries). The decreased blood flow to the JG cells due to the stenosis causes an increase in RAA activity, which chronically jacks up systemic hypertension both indirectly due to sodium retention through aldosterone and also directly through angio II activity.
 * Can be due to __atherosclerosis__ (in older patients, usually male) or __fibromuscular dysplasia__ (in younger patients, usually female).
 * Notice that if you have one kidney with a fairly normal renal artery and one with an obstructed artery, you're going to way increase the blood flow to the normal kidney, which can produce a number of additional problems (among others, the higher blood pressure in the normal kidney is going to start to damage its endothelium/parenchyma). Note also that this can create a strange feedback cycle where the one kidney is trying to downregulate RAA and the other is trying to upregulate it.
 * __Parenchymal kidney disease__: glomerulonephritis, polycystic kidney disease, diabetic nephropathy. Essentially if the kidneys are whack, they can either kick out a whole bunch of renin or not be able to excrete much ECF fluid, either of which can cause hypertension.
 * Diseases of the adrenal glands:
 * __Hyperaldosteronism__ (recall this pops up as hypokalemia)
 * (Primary: high aldosterone is the primary cause. Secondary: aldosterone is being driven by high renin levels.)
 * Benign tumors of the adrenal glands (__pheochromocytomas__)
 * Understand the concept of malignant hypertension and its consequences.
 * Malignant hypertension: essentially the "holy shit this is gonna kill you" flavor of hypertension (death or end-stage renal disease within a year if untreated).
 * If you see hypertensive neuroretinopathy (characteristic messed-up junk on the eye exam), that's malignant hypertension-- it indicates that arterioles are becoming inflamed and completely obstructed and things are starting to necrose. Bad mojo.
 * Messed-up eye junk to look for:
 * Striated hemorrhages
 * Cotton-wool spots
 * Papilledema
 * Note that malignant hypertension is pretty rare (< 1 % of HTN patients).
 * Know the mechanism of action of the different medical treatments for HTN.
 * 4 ways of interfering with RAA axis: ACE inhibitors, angiotensin receptor blockers, aldosterone receptor blockers, direct renin inhibitors. Should know how all of these work already except the direct renin inhibitors, and that's fairly self-explanatory
 * Also diuretics. More on these on Friday.

Pathophysiology of Water Handling Thursday, May 15, 2008 7:59 AM


 * Pathophysiology of Water Handling, 5/15/08:**


 * Understand the implications of serum sodium as a determinant of serum osmolality.
 * Sodium is where it's at. If the total osmolality of ECF is about 285, and the concentration of sodium is about 140 and the concentration of bicarb and chloride are 24 and 110 (bicarb and chloride follow sodium), then you can see that the levels of sodium are the predominant factor in determining serum osmolality. There's some small contribution by BUN and glucose, but are enormously outweighed by the serum sodium concentration.
 * So the sodium concentration is extremely important-- since the serum osmolality dictates cell tonicity. If you chug 10 L of water, your body needs to be able to handle the fact that you're an idiot.
 * Recall that there are two ways of regulating body water: in response to osmolarity and in response to low total volume. Recall also that, once the volume receptors are triggered, they trump the osmolarity receptors.
 * Dr. Berl: "Hypo- and hypernatremia are almost never reflections of too much or too little total sodium in the body. They are reflections of //water// imbalance."
 * [I think the most important thing to be able to do here is to know the decision trees on pages 5, 6, and 9 backwards and forwards. They're both or less recapitulated below.]
 * [Also, it's been made known that we need to know __the formula for calculating serum osmolality__:]
 * **Sosm = 2*[Na+] + [BUN]/2.8 + glucose/18**.
 * This becomes important in diabetics who aren't taking their insulin (glucose way up).
 * Recall that __normal serum osmolality__ should be between **280-295 mOsm/kg**.
 * Differentiate among the causes of hyponatremia.
 * First off, calculate the serum osmolality to see if it's hypertonic, isotonic, or hypotonic from normal serum (280-295 mOsm/kg).
 * **Hypertonic hyponatremia** : When your serum is full of some solute that can't cross cell membranes (not sodium), it sucks the water out of the ICF to compensate, diluting the sodium concentration. The most common cause of this is __hyperglycemia__, particularly in diabetes.
 * __Note for every 100 mg/dL glucose over normal (100) added to the serum, measured (not actual) serum [Na+] falls by about 1.6 mEq/L__.
 * According to our small-group nephrologist, what this means is that if you're looking at a hyperglycemic patient, you need to multiply 1.6 by how many 100's the glucose is off and __add that__ to the measured Na+ level in the serum in order to compensate for the water shift and get the 'real' sodium level.
 * **Isotonic hyponatremia** : If your plasma is at a normal osmolarity, then you're probably looking at a laboratory artifact (not error) resultant from conditions that decrease water volume in the plasma. I'm not really sure how this works.
 * The two conditions cited are __hyperlipidemia__ and __hyperproteinemia__.
 * **Hypotonic hyponatremia** : This is the complex one; generally it's due to altered ADH levels. Remember that hyponatremia means that the amount of sodium divided by the total body fluid is low, which can come about a number of ways. Can break this down by looking at __fluid status__. Remember that fluid status tends to be a clinical diagnosis here (hypervolemia = edema, hypovolemia = diminished skin turgor, etc).
 * **with hypovolemia** : You have a low total body sodium that's lower than the low levels of total body fluid. This seems to be a consequence of the body's fluid-level defense mechanisms overriding its osmolarity defense mechanisms. Effectively you're secreting ADH, __appropriately__, to defend your volume so the point where you're outpacing your sodium retention. This generally occurs in conjunction with a condition in which you're losing sodium quickly (diarrhea replaced with free water, diuretic overuse, aldosterone deficiency).
 * **with hypervolemia** : You have a increased total body sodium that's still lower than the increased level of total body fluid. This frequently occurs in conditions such as __heart failure, cirrhosis, or nephrotic syndrome__ which back up fluid into the venous system, causing a perception of low volume by arterial baroreceptors, causing increased (but __appropriate__ for volume defense) secretion of ADH. It can also occur in renal failure, in which the GFR is low enough that the body can't secrete excess intaken water.
 * **with euvolemia** : You have a fairly normal total body sodium that's dissolved in a clinically normal but somewhat increased level of total body fluid. This seems to occur mainly in __inappropriate__ ADH secretion (ADH secretion in the absence of either high plasma osmolarity or low fluid volume). This happens in:
 * Hypothyroidism
 * Drugs (nicotine, isoproterenol, etc)
 * Adrenal insufficiency
 * Primary polydipsia (patient drinking way, way too much water, generally only in mentally ill patients)
 * SIADH (syndrome of inappropriate ADH secretion) (sometimes caused by cancer, pulmonary diseases, or CNS disorders)
 * Note that SIADH is what you fall back on if you can't figure out what else it is (a 'diagnosis of exclusion').
 * [Notice that if your volume status is altered in hyponatremia, generally you're doing what you're supposed to be doing, which is secreting a lot of ADH in order to increase it-- you're just outpacing your sodium retention. If your volume status is fairly normal, then you're secreting ADH for an abnormal reason.]
 * Understand the physiologic mechanisms by which hyponatremia may be induced.
 * More or less already covered.
 * Know the differential diagnosis of hypernatremia.
 * Note that whenever sodium levels are high, the plasma is hypertonic, unlike in hyponatremia, in which the plasma can be hypo-, iso-, or hypertonic.
 * Hypernatremia occurs only in conditions of low or ineffective ADH levels or inadequate daily water intake.
 * Check total body fluids, as above. Note that this flow chart (p. 9) is, politely, crap; I say this because the clinically important step of how to make these distinctions is missing or confused (he says "What is the ECF volume?", which makes sense, but then seems to ignore his own advice). I think the point is to compare fluid status to sodium levels, as in the algorithm for hyponatremia above. This is my best guess at what he's trying to communicate:
 * You can have a low [Na+] that's still not as much decreased as the really low levels of total body fluid. Tends to be a consequence of excessive water loss (diarrhea, burns, diuretic use without water intake, etc). Check the urine sodium; if it's low (as it should be if you're trying to hold onto sodium), it's probably a loss from somewhere else. If it's high, it's something in the kidneys (eg. diuretic abuse).
 * You can have a really high level of Na in a normal-to-increased amount of body fluid. Rare. Usually occurs if someone gets lots of hypertonic fluid (iatrogenic).
 * You can have a fairly normal level of Na in a decreased amount of body fluid. This is basically because you're not making ADH (central diabetes insipidus) or because you have it but it's not working (nephrogenic diabetes insipidus).
 * __Central diabetes insipidus__: as I said. Often caused by head trauma, neoplasm, or surgery. Should respond to treatment with ADH.
 * __Nephrogenic diabetes insipidus__: as I said. Often caused by lithium use (mental, head-trauma), chronic renal failure, hypercalcemia, or hypokalemia. Doesn't respond to treatment with ADH.
 * Understand the approach to the therapy of both hypo and hypernatremia.
 * Treatment of hyponatremia: be cautious. Try hypertonic saline, maybe with furosemide to drain off excess water. When they become more widely available, maybe can also use ADH inhibitors.
 * For the boards: if you raise the plasma sodium level too quickly, you can get central pontine myelinolysis, which is about as bad as it sounds.
 * Treatment of hypernatremia: correct the hypo/hypervolemia if present; remove sodium as needed.
 * Again, be careful about doing this too quickly. Recall that hypernatremia is going to result in cellular dehydration, which in the brain is compensated for by production of local osmolytes. If you lower the ECF sodium too quickly, the water rushes into the already-compensated brain cells, resulting in cerebral edema. Recall you can treat this with mannitol but a better solution is not to have it happen in the first place.


 * Check volume status if patient is hypo- or hypernatremic. If it's euvolemic, that's an ADH problem, either with too much (hyponatremia) or too little (hypernatremia).**

Pathophysiology of Sodium Handling Thursday, May 15, 2008 8:56 AM


 * Pathophysiology of Sodium Handling, 5/15/08:**


 * Understand the concept of effective arterial blood volume and the hormonal mechanisms involved in its maintenance. Also understand how these systems interact when one (or several) components are diseased.
 * The reason we're talking about "effective arterial blood volume" is that receptors can be in the venous system or the arterial system. Wherever it is, that's what it sees. So if you've got crazy hypervolemia but it's all in the venous system (as in CHF), the arterial sensors are going to think you're volume-depleted, because all they see is the effective arterial blood volume.
 * Recall that sodium regulation (through the RAA axis) is mainly a fluid-level sensitive system-- sodium levels are detected by fluid pressure sensors.
 * This whole system breaks down into sensors and responders ('effectors').
 * **Volume sensors** :
 * __Low-pressure baroreceptors__ (in atria, left ventricle, and pulmonary vessels)
 * Low-pressure baroreceptors detect __venous pressure__ (filling pressures in the heart, for the most part) and regulate renal sympathetic nerve activity to control the RAA axis, as well as controlling the cardiac sympathetic stimulation (contractility, heart rate, etc), to respond appropriately.
 * __High-pressure baroreceptors__ (in carotid and aortic bodies)
 * High-pressure baroreceptors detect __arterial pressure__ and also regulate renal sympathetic nerve activity. They can also stimulate norepinephrine release in severe hypovolemia.
 * __Intrarenal sensors__ (in juxtaglomerular cells)
 * Intrarenal sensors respond to __renal perfusion pressure__ and alter renin release.
 * __Hepatic/CNS sensors__ (effectively 'idiopathic')
 * **Effectors** (things that respond to the sensors):
 * __Glomerular filtration__:
 * Recall this is determined by Starling force balance. Sodium excretion is determined by how much filtration is going on, which is in turn determined by hydrostatic (volume in the capillary and tubule) and oncotic (protein in the capillary and, in some cases, the tubule) forces.
 * Note also that except in pathophysiology, the GFR rate shouldn't change much; it's guarded against significant change by myogenic autoregulation and tubuloglomerular feedback at the macula densa cells. Also recall that glomerulo-tubular balance means that a fixed proportion of the sodium for any given GFR will be reabsorbed in the proximal tubule.
 * __Humoral (blood-borne) mechanisms__:
 * Factors that increase sodium reabsorption in the face of volume contraction: angio II, aldosterone, catecholamines.
 * Factors that decrease sodium reabsorption in the face of volume expansion: natriuretic peptides (ANP), prostaglandins, bradykinin, dopamine.
 * __Renal sympathetic nervous stimulation__: results in increased sodium reabsorption through both increased GFR (differential constriction of efferent arteriole with prostaglandin-mediated dilation of afferent arteriole, peripheral constriction to shunt blood to central organs and kidneys) and increased renin release (aldosterone effect) from JG cells.
 * __Physical factors__ (for our purposes, 'idiopathic').
 * As far as the pathophys is concerned, I'm not sure what he means. The systems respond more or less as you'd expect-- eg., renin secretion goes up in the face of hypovolemia along with increased sympathetic activity to constrict peripheral vessels and create positive inotropy, vasoconstriction of the afferent and efferent arterioles, etc. This seems to be one of those "tell me how the kidneys work" kind of deals.
 * Discuss the forces involved in edema formation and maintenance.
 * These are more or less the Starling forces-- positive hydrostatic pressure in the capillary and the tubule, negative oncotic pressure in the capillary and the tubule, and the rate of lymphatic drainage.
 * Specifically, accumulation of edema is proportional to **(Pgc - Pt) - (** **Π** **gc -** **Π** **t) - lymphatic return**.
 * In __CHF__, you get an increased in the hydrostatic capillary pressure (increased venous buildup). In __nephrotic syndrome__, you get a decrease in oncotic capillary pressure (hypoalbuminemia). In __cirrhosis__ you get the combination platter: increased hydrostatic capillary pressure as well as decreased oncotic capillary pressure (increased venous buildup __and__ hypoalbuminemia).
 * Note you also get edema through overproduction of aldosterone or ADH, or lowered GFR (glomerulonephritis).
 * Understand the nephron site of action as well as potential side effects of diuretics.
 * Quick runthrough of sodium management in the nephron:
 * Proximal tubule: sodium transporters in the apical membrane coupled to transport of other substances (glucose, phosphate, chloride, etc). Also coupled to proton secretion by a Na/H antiporter for bicarbonate reabsorption. The sodium is pumped out of the basolateral membrane by Na/K pump.
 * Thick ascending loop of Henle: Na/K/2Cl transporter in the apical membrane takes in Na, also more Na/H antiporters. Again, Na pumped out the basolateral membrane by the Na/K pump.
 * Loop diuretics (furosemide) block the Na/K/2Cl transporter.
 * Distal tubule: have Na+ channels in apical membranes, Na/Cl co-transporters, and Na/H antiporters. The Na is still pumped by out the Na/K pump.
 * Thiazides block the Na/Cl co-transporters.
 * Amiloride blocks the Na+ channels.
 * Principal cells of the collecting duct (vs. the intercalated cells, which are involved in bicarb): have Na+ channels in apical membranes (enter as potassium is leaking out its own channels).
 * Again, amiloride blocks the Na+ channels.
 * Diuretics and side effects (all this is gone over again in the next lecture):
 * Proximal tubule diuretics: acetazolamide (not used much anymore). Blocks carbonic anhydrase; thus blocks reabsorption of bicarbonate and sodium (can cause __metabolic acidosis__ or can treat metabolic alkalosis). However, distal parts of the nephron can compensate for the diuresis.
 * Loop diuretics: furosemide, bumetanide, torsemide. These block the Na/K/2Cl transporter in the thick ascending limb of the loop of Henle. Side effects: __metabolic alkalosis, hypokalemia, hypocalcemia, hypomagnesia__ (calcium and magnesium are also absorbed in this part of the nephron).
 * Distal tubule diuretics: thiazides. Block the Na/Cl co-transporter. These __increase calcium reabsorption__.
 * Collecting duct diuretics: amiloride and triamterene block the sodium channels, while spironolactone is a competitive antagonist of aldosterone. These cause mild potassium __retention__ (inhibit K secretion).
 * Understand the “fate” of intravenous fluids containing different amounts of colloids, sodium, and glucose.
 * I think what he's talking about here is the correction of ECF volume contraction.
 * So if you give blood, or solutions containing large molecules such as dextran or albumin, they'll preferentially stay in the vascular space (as to correct acute hemorrhage, where the loss is mostly from the vascular compartment).
 * If you give isotonic saline, it'll preferentially expand the ECF, but about 80% will go into the interstitial spaces and only 20% will remain in the vascular space.
 * If you give more or less pure water (5% dextrose, not to be confused with dextran), it'll go preferentially into the ICF and not into the ECF.

Diuretics Friday, May 16, 2008 7:47 AM


 * Diuretics, 5/16/08:**


 * List the major transporters and ion channels involved in renal electrolyte transport. Describe their locations on the nephron and changes that occur when specific diuretic drugs inhibit each one.
 * Not really a transporter: carbonic anhydrase is inhibited by __acetazolamide__. This blocks bicarbonate reabsorption (and thus fair amount of sodium reabsorption as well) in the proximal tubule. Can cause metabolic acidosis, can be used to treat metabolic alkalosis (wastes some of the excess bicarbonate). Its diuretic effect can be partially compensated for by effects in the distal tubule. Note that you can get tolerance to this drug (increased H+ secretion in the distal tubule to compensate for acidosis). Can also use it for high altitude sickness.
 * (acetazolamide is 'bicarbonate-wasting.')
 * Na/K/2Cl transporter in thick ascending loop of Henle: these are blocked by loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid), which leads to excretion of 15-25% of filtered sodium. Since this process is also involved with calcium and magnesium reabsorption, can get hypomagnesia and hypocalcemia. The increased flow and increased sodium content of the luminal fluid increase K+ secretion, particularly in the late distal tubule, leading to hypokalemia. Note that loop diuretics seem to interfere with the body's ability to autoregulate its luminal flow rate. Often used to resolve edema or abused for weight loss.
 * Notice that all of these, but particularly ethacrynic acid, can cause __ototoxicity__.
 * Na/Cl transporter in proximal part of distal tubule: these are blocked by thiazides. Since there's not as much sodium left in the lumen to reabsorb at this point, these are somewhat less potent than loop diuretics (thus often used for hypertension). Note that thiazides actually __increase__ calcium reabsorption, but are potassium-wasting, both because they increase flow rate and also because they increase flow through Na+ channels in the late distal tubule (causing an increased efflux of K+, as well as an efflux of H+, as discussed below).
 * Na+ channels, K+ channels, Na/K pump in collecting duct: stimulated by aldosterone, blocked by spironolactone. Notice that this is potassium-sparing (no potassium secretion in the collecting ducts).
 * Na+ channels in distal tubule: blocked by amiloride, triamterene. These are also potassium-sparing.
 * Note that all the potassium-sparing diuretics produce only a mild diuresis by themselves (occasionally used for mild hypertension), but are often used in conjunction with potassium-wasting diuretics to offset the potential hypokalemia. Note also that potassium-sparing diuretics by themselves can lead to hyperkalemia.
 * Explain the importance of the organic anion transport system to the renal action of diuretics. Provide examples of how other drugs or diseases can interfere with the effects of diuretics through this mechanism.
 * Most diuretics (loop diuretics, thiazides, carbonic anhydrase inhibitors) are organic anions and are secreted into the tubule cells by organic anion transporters. Note that this means that the use of diuretics can take up some of the secretion that normally goes to other organic acids, thereby potentially leading to a buildup of uric acid (therefrom to gout). Conversely, if there's an excess of organic acids (as in gout), diuretics may have less transporters with which to bind.
 * Describe the effects of diuretics on Ca2+ metabolism and, where possible, describe the mechanisms causing these effects.
 * The absorption of calcium in the loop of Henle is dependent on the leakage of K+ back out the apical membrane after being reabsorbed by the Na/K/2Cl transporter-- K+ leaks out, leaving the interstitial fluid with a negative charge, providing a gradient down which calcium (and magnesium) flows between cells through the non-tight tight junctions. Thus loop diuretics, by inhibiting the Na/K/2Cl transporters, inhibit this whole process and lead to hypocalcemia.
 * The mechanism of absorption of calcium in the distal tubule is less clear but seems to be inversely related to the activity of the Na/Cl co-transporter. By inhibiting that co-transporter (which is what thiazides do), the uptake of calcium is increased.
 * Explain the mechanism by which the thiazide and loop diuretics can cause metabolic alkalosis.
 * According to Dr. Hoffman, by retaining a lot of sodium in the filtrate, they increase the sodium reabsorption through sodium channels in the late distal tubule, which results in a concomitant outflow of H+ and thus metabolic alkalosis.
 * Note that she also said you could block this effect with amiloride (which blocks the Na+ channels in question, preventing H+ efflux).
 * Explain how mannitol increases urine flow. Describe its major clinical uses.
 * Mannitol (an osmotic diuretic, no transporter target): non-metabolized sugar that's filtered but not reabsorbed. This increases the osmolarity of the filtrate and forces water retention.
 * Major clinical uses: administered IV to prevent renal failure (increase flow) and to treat glaucoma and elevated intracranial pressure (suck water out of ICF space). Note it's counter-indicated in people with congestive heart failure (already have too much volume in their ECF).
 * Note that urea is an endogenous compound that behaves somewhat similarly.

loop diuretics: calcium-wasting thiazides: calcium-sparing

Both of them waste potassium and cause metabolic alkalosis.

Antihypertensive Drugs Friday, May 16, 2008 9:06 AM


 * Antihypertensive Drugs, 5/16/08:**


 * Understand the factors that regulate blood pressure and know the definition of hypertension
 * Recall delta-P = CO * TPR.
 * Things that affect cardiac output (CO): cardiac inotropy, heart rate, filling pressure.
 * Things that affect peripheral resistance (TPR): vasoconstriction/dilation.
 * Both of these are affected by the para/sympathetic nervous systems. The kidneys also regulate them both with the RAA axis, TPR mainly through angio II, CO mainly through aldosterone.
 * Know the classes of drugs with positive clinical trial outcomes, including prototypes (propranolol, thiazide diuretics, captopril, losartan, diltiazem, nifedipine, verapamil), their mechanism of action, side effects, compelling indications and contraindications
 * (1) Diuretics: more or less covered last lecture. Recall that the decreased CO seems to lead to a decrease in TPR over the long term.
 * (2) Beta-blockers:
 * Decrease sympathetic stimulation, decreasing heart rate and contractility. Should also cause some peripheral vasoconstriction, but clinically they don't (beta-blockers may also prevent sympathetic stimulation of the JG cells and thus inhibit release of renin/angio II).
 * Recall that propranolol blocks both beta-1 and beta-2 receptors, inhibiting airway smooth muscle relaxation and potentially resulting in bronchoconstriction (beta-2s are also responsible for vasodilation).
 * Selective beta-1 blockers (metoprolol, atenolol) are useful for people with asthma or peripheral vascular disease.
 * Labetalol also blocks alpha-1 receptors (thus blocks some vasoconstriction).
 * Also useful to prevent tachycardia resultant from vasodilator (nitrate) administration, also arrhythmias, etc.
 * Recall that some beta-blockers have some intrinsic sympathomimetic activity (some positive inotropy, cause less bradycardia-- useful for CHF). Notable here is pindolol.
 * (3) RAA antagonists:
 * ACE inhibitors (eg. captopril, lysinopril): block ACE from converting angio I (inactive) to angio II (active); thus also blocks aldosterone activity. Recall that most ACE is in the lungs and that ACE breaks down bradykinin, and the bradykinin prompts a cough reflex; thus ACE inhibitor administration can lead to a buildup of bradykinin in the lungs, causing a chronic cough.
 * Used for diabetes, heart failure, post-MI, CAD, chronic kidney disease, stroke prevention. Basically all things cardiac and some renal (increase flow rate to glomeruli).
 * **ACE inhibitors are contraindicated in pregnancy** (can cause renal failure and fetal death).
 * Angiotensin receptor blockers (ARBs, eg. losartan or valsartan): block angio II from vasoconstrictive or aldosterone release activity.
 * **ARBs are contraindicated in pregnancy**.
 * [Also aldosterone inhibitors: spironolactone. Doesn't affect vasoconstriction but stops fluid retention due to sodium reabsorption, also spares potassium.]
 * (4) Calcium channel blockers:
 * Diltiazem, nifedipine, verapamil: block L-type calcium channels with varying degrees of strength. Cause vasodilation, decreasing peripheral vascular resistance, by blocking influx of calcium into smooth muscle.
 * Nifedipine: dihydropyridine compound, little effect on inotropic state, but can cause some reflex tachycardia.
 * Diltiazem and verapamil: negative inotropic effects.
 * Used in CAD, diabetes, also Prinzmetal variant angina.
 * Note also mibefradil: blocks T-, not L-, type calcium channels, specifically targeted to vascular smooth muscle. Very good at dealing with hypertension.
 * Know the alternative classes of drugs (alpha-blockers, vasodilators, CNS active drugs, ganglionic blocking agents, adrenergic neuron blocking agents) and their mechanism of action
 * (1) Alpha-blockers:
 * Prazosin: targets alpha-one receptors, to block sympathetic vasoconstriction in smooth muscle in vasculature. Can cause orthostatic hypotension (can't prompt a good baroreceptor reflex with postural change-- the NE/EPI released binds to beta-2 receptors since they can't bind alpha-1 receptors).
 * Phentolamine/phenoxybenzamine: target both alpha-1 and alpha-2 receptors. Used to treat pheochromocytomas (adrenal gland tumors).
 * (2) Vasodilators:
 * Usually used in conjunction with beta-blockers or diuretics. Tend to increase NO production or open potassium channels.
 * Minoxidil: effective for treating hypertension refractory to other treatment. Watch out for hair growth.
 * Nitroglycerin isn't generally a first-line for hypertension (recall that it is a first-line for angina).
 * (3) Sympathetic blocking agents:
 * Ganglionic blocking agents:
 * Block both sympathetic and parasympathetic pathways by blocking transmission at all autonomic ganglia. Severe side effects, as you'd imagine. Used only in emergency settings where lowering blood pressure takes precedence over other concerns.
 * CNS-active drugs:
 * Alpha-methyldopa: agonist of alpha-2 receptors in the brain, decrease norepinephrine release. Usually used in pregnancy-related hypertension.
 * Clonidine: antagonist of alpha-2 receptors, similar to a-methyldopa.
 * Peripheral agents:
 * Reserpine: blocks vesicular uptake of norepinephrine, dopamine, and serotonin, resulting in decreased vasoconstriction and cardiac output. Well tolerated. Since you're depleting serotonin, watch out for depression and sedation (has some CNS effects).
 * Guanethidine and guanadrel work similarly to reserpine but they don't enter the CNS. Inhibited by tricyclic antidepressant, severe side effects.

Chronic Kidney Disease Monday, May 19, 2008 7:53 AM


 * Chronic Kidney Disease, 5/19/08:**


 * [Most popular causes of CKD:]
 * Diabetes (intrinsic/pre-renal?) (accounts for more than half of CKD)
 * Hypertension (pre-renal)
 * Glomerulonephritis (intrinsic renal)
 * Polycystic kidney disease (intrinsic renal)
 * Interstitial nephritis (intrinsic renal)
 * Obstruction (post-renal)
 * Understand the stages of chronic kidney disease and the utility of this classification system
 * __Stage 1__: Kidney damage (structural/functional abnormalities for more than 3 months) with no impact on GFR.
 * __Stage 2__: Kidney damage as above, mild decrease in GFR (GFR = 60-89).
 * __Stage 3__: Moderate decrease in GFR (GFR = 30-59).
 * __Stage 4__: Severe decrease in GFR (GFR = 15-29)
 * __Stage 5__: "Kidney failure" (GFR < 15, or on dialysis).
 * [Early changes: hypertension, volume overload; when GFR is 50 or so, start to see increased PTH and anemia. When GFR is at 25 or so, start to see acidosis.]
 * Understand how balance is maintained for sodium, water, potassium and protons in chronic kidney disease
 * Evidently, it's with the same mechanisms the organisms use to maintain that balance in response to normal physiological challenges. This section winds up being more about how those mechanisms screw up.
 * [Note that in chronic kidney failure you're still making the same amount of creatinine per day, you just have less nephrons with which to excrete it. So you let the creatinine levels in the serum rise (which will increase the amount of creatinine filtered at the glomerulus) until you reach a new steady-state where you're once again eliminating all the creatinine you make each day. Very passive mechanism, unlike water and sodium adjustments.]
 * __Water__: Recall that the normal spectrum of urine dilution ranges from 50 mOsm/L (about 12+ L/day) to 1200 mOsm/L (0.5 L/day). This range is dramatically lowered in CKD patients (eg. 200-300 mOsm/L). This means they can't respond very well to either suddenly increased or suddenly decreased water loads (can neither adequately concentrate or adequately dilute the urine), thus can get hypo- or hypernatremia with relative ease.
 * __Sodium__: Again, the thing to think about here is the __loss of the extent of flexibility__-- CKD patients can handle a smaller amount of variance than healthy people. Thus they can't respond well to sudden increases or decreases in sodium intake and can develop edema or volume depletion, respectively.
 * __Potassium__: Generally the kidneys can handle a decrease in kidney function by increased K+ secretion until the CKD becomes 'severe' (presumably GFR under 30). At this point the fecal excretion begins to take over to help. Again, sudden potassium loads in dietary intake can cause hyperkalemia. Notice a theme here?
 * __Hydrogen ions__: In CKD, the kidneys kick up their production of NH3 from glutamine, which allows more H+ to be excreted and trapped from the remaining nephrons. This works well up to about a GFR of 20-25 mL/min, at which point you start to dip into your bicarbonate and get a non-anion-gap metabolic acidosis.
 * Understand the definition of the uremic syndrome and the major theories of the pathogenesis of uremia
 * Uremic syndrome: Clinical definition, resulting from the retention of toxic levels of substances normally cleared by the kidney. Note that we're really not sure what those substances are.
 * So there could be two or ten metabolic waste products responsible for this.
 * Alternatively it could be hormones that are released in response to high levels of metabolites (as in secondary hyperparathyroidism, see below).
 * Or damage to the kidney could cause a lack of some normally secreted hormone (like the anemia caused by decreased erythropoietin secretion).
 * Note that it probably has something to do with all of these.
 * [Note also that uremia looks like all kinds of junk. It affects virtually everything under and including your skin. There's a list on pg. 5, but might want to think about it as "weird symptom syndrome" or "bad taste in the mouth syndrome."]
 * Understand the pathogenesis of certain disorders that accompany chronic kidney disease:
 * Anemia: Damaged kidneys can't produce erythropoietin. Also the lifetimes of red cells are shortened, the platelets don't work as well, and you can get marrow fibrosis.
 * Hypertension: Increased fluid retention. Also, decreased GFR causes release of angio II. You can also get baroreceptor dysfunction (so can't tone down sympathetic stimulation with high pressure). Also possibly decreased prostaglandin production by kidney (thus favoring pre-renal constriction, further increasing renin secretion).
 * Mineral and Bone Disease: Complex. My attempt at summing up simply:
 * Older, simpler hypothesis: with increased serum phosphate, the serum calcium binds to the phosphate, thus decreasing serum Ca++, thus prompting release of PTH to liberate more calcium from bones.
 * Complex, newer hypothesis: with decreased clearance of phosphates, the amount of serum phosphorus goes up. This triggers increased production of a protein, FGF-23, which decreases the level of 1,25-OH vitamin D activation by the kidneys. The decreased level of vitamin D causes a decreased uptake of phosphorus by the GI tract, but also decreases the GI uptake of calcium. This leads to a decrease in serum calcium level, prompting release of parathyroid hormone (PTH) to shift calcium from bones to serum and increase phosphorus excretion (called __secondary hyperparathyroidism__). This causes increased bone breakdown and marrow disturbances.
 * It's generally treated by limiting phosphorus intake in the diet and controlling the serum calcium and phosphorus levels, partially by using agents that increase phosphorus excretion.
 * Note that in severe CKD, the metabolic acidosis is partially buffered by bone, which further poses the secondary hyperparathyroidism problems.
 * Note that after a lot of overstimulation, the parathyroid glands can go nuts and start secreting PTH whether or not your serum Ca++ is low (tertiary hyperparathyroidism).

Pharmacology Issues in Renal Failure Monday, May 19, 2008 9:09 AM


 * Pharmacology Issues in Renal Failure, 5/19/08:**


 * [Note that GFR tends to increase with __dilation__ of the afferent arteriole and __constriction__ of the efferent arteriole.]
 * Drugs that promote afferent dilation: prostaglandins, dopamine, caffeine.
 * Drugs that promote efferent constriction: angio II, norepinephrine, ANP.
 * [Note also that if you use drugs that __constrict__ the afferent arteriole and/or __dilate__ the efferent arteriole, you can wind up with acute renal failure in a hurry:]
 * Drugs that promote afferent constriction: __NSAIDs__, norepinephrine, adenosine.
 * Drugs that promote efferent dilation: ACE inhibitors/ARBs (note that these are still indicated to ensure adequate renal perfusion and reduce hypertension).
 * [Watch out for **ATN** caused by aminoglycosides, radiographic contrast media, antineoplastic agents, and amphotericin B.]
 * Describe how the pathophysiological changes that occur in chronic kidney disease (CKD) can alter the pharmacokinetic disposition of, and the pharmacodynamic response to, drugs administered to CKD patients.
 * In stages 1 and 2 of CKD, no dosage adjustments are necessary.
 * In stage 3 and up, need to adjust dosage requirements to account for diminished renal function.
 * __Absorption__: many phosphorus binders also bind to drugs; therefore watch out for drug-induced decreased absorption (decreased bioavailability) of other drugs.
 * __Distribution__: watch out for changes (up or down) in the volume of distribution leading to increased plasma concentrations, leading to increased toxicities. A couple examples:
 * The volume of distribution of digoxin drops like a rock in CKD ('mechanism uncertain'). This means that the effective plasma concentration of digoxin goes up like an anti-gravity rock. This means you can get hyperkalemia much more easily (more inhibition of Na/K ATPase pumps).
 * The volume of distribution of phenytoin (an anti-convulsant) goes up, but it goes up in the plasma (normally bound to albumin), increasing plasma concentration.
 * __Elimination__: can get loss of both hepatic and renal CYP450 enzyme/phase II conjugating activity.
 * [Also have to be careful with drugs that affect potassium:]
 * As mentioned, digoxin plasma concentrations can go up, causing hyperkalemia.
 * Recall that loop diuretics (furosemide) and thiazides (hydrochlorothiazide) waste potassium, as do aldosterone, insulin, and beta-2 agonists. Spironolactone spares potassium, as do ACE inhibitors and ARBs (all three by inhibiting aldosterone).
 * Describe changes in the pharmacotherapeutic regimen that may be necessary to manage changes in plasma drug levels and drug response that occur as a result of these alterations in pharmacokinetics and pharmacodynamics in CKD patients.
 * Here follows a list of Stage 3+ considerations.
 * Oral hypoglycemic agents: Metformin is not recommended (increased risk of lactic acidosis). Half-life of glyburide is prolonged.
 * Diuretics: thiazides may not work well as renal function declines; trade off into more powerful loop diuretics if needed. __Avoid potassium-sparing diuretics__ (easy to get hyperkalemia with the decreased potassium secretion already present).
 * ACE inhibitors and ARBs: used throughout all stages. Watch out for acute renal failure in hypovolemic patients (efferent dilation).
 * Beta-blockers: Half-life of atenolol is prolonged.
 * The recommended fibrate (raises HDL, remember?) in Stage 5 is Gemfibrozil.
 * Relate the pathophysiological changes in CKD that result in anemia, renal osteodystrophy, and hyperkalemia to the pharmacologic strategies that are used in their management.
 * Chronic kidney disease kidneys: have trouble __excreting__ drugs, PO4-, and K+. Have trouble __synthesizing__ 1,25-OH vitamin D or erythropoietin.
 * Can give exogenous EPO without too much trouble to replace the stuff that's not being synthesized by the kidneys.
 * Can give phosphate binders (RenaGel or PhosLo) to take up the excess serum phosphorus.
 * Can give calcitriol (1,25-OH vitamin D) to make up for its decreased production.
 * Hyperkalemia: acutely, treat with IV calcium administration (anti-arrhythmic, depolarizing agent). Chronically can use Kayexelate to bind calcium up.
 * For the drugs listed below, describe their:
 * Mechanism and site of action
 * Pharmacokinetic factors (when clinically relevant)
 * Rational for use in CKD complications
 * Most common and most severe side effects/Significant drug-drug interactions
 * [Ok, this seems silly to me. French didn't mention it and a lot of it is fairly self-explanatory. It's on pages 6 and 7 of his notes and includes EPO, iron supplements, RenaGel and PhosLo, calcitriol, and IV calcium and Kayexalate.]

Development of the Kidney Tuesday, May 20, 2008 8:01 AM


 * Development of the Kidney, 5/20/08:**


 * Describe the early stages of development of the kidney—the position of the urogenital ridge, the nephrogenic cord, the formation of nephrotomes and the origin of the pronephric/ mesonephric duct.
 * The urogenital ridges are notches in the top of the coelom in which the nephrogenic cords sit. These develop into the pronephros and mesonephros.
 * The pronephros is a bunch of cells towards the anterior of the fetus, the mesonephros towards the posterior of the embryo. The pronephros is also more rostral, the mesonephros more caudal. Together, they more or less run down where the spine would be, if the embryo had one.
 * First the pronephros and then the mesonephros start to 'bleb' into distinct masses of cells, like marbles. These are called nephrotomes. This process begins anteriorly and proceeds towards the posterior.
 * Outline the temporal and spatial relationships of the pronephros, the mesonephros, the mesonephric (Wolffian) duct, the paramesonephric (Mullerian) duct, and the metanephros.
 * __3 weeks__: The nephrotomes begin to form vesicles or hollow epithelial sacs (called, appropriately, nephrotomic vesicles). This process also begins anterior and goes posterior.
 * These nephrotomic vesicles start to join together and merge into one long duct. The anterior part of the duct (from the original pronephros) is called the pronephric duct; the posterior part of the duct (from the original mesonephros) is called the mesonephric duct.
 * The mesonephric duct joins into the cloaca (outgoing waste, connected to the hindgut).
 * The pronephric duct (anterior part of the duct) degenerates; by about 5 weeks there's nothing left of the pronephros.
 * From the mesonephros, you get these branches coming off that join up with small capillaries coming off the dorsal aorta-- primitive glomeruli. These go away.
 * Recall that you started out with two mesonephric ducts (also called the Wolffian ducts); there are two additional ducts that parallel its track, called the Mullerian or paramesonephric ducts. These are derived from the coelom and are cytologically unrelated to the mesonephric ducts.
 * One of these two sets of ducts is going to degenerate, depending on gender (women keep paramesonephric, men keep mesonephric ducts). The meso- and paramesonephric ducts are going to be important in the reproductive development of the organism.
 * Be able to describe the development of the collecting system from the ureteric bud through various stages until the appearance of collecting tubules.
 * Around where the mesonephric duct connects to the cloaca, you start to get a bud coming off the duct about __week 5__. This is called the **ureteric bud**.
 * There begins to form a layer of mesoderm surrounding the ureteric bud, called the **metanephric bud**.
 * Both of them start to grow and the ureteric bud begins to branch inside the metanephric bud. Then the branches start to branch, and those branches branch. The ureteric buds are going to eventually form the calyces and renal pelvis.
 * The end point of the ureteric branches begin to send out small processes into the metanephric bud (will become the renal papillae), which branch out into longer strands that infiltrate the metanephric tissue rather extensively (will become the collecting tubules).
 * The renal pyramids will be formed by these ureteric infiltrates.
 * Note that the ureteric bud __stops developing out__ at that point (the collecting tubules don't go on to form convoluted tubules, loops, or glomeruli).
 * Describe the location and development of the metanephric vesicles and their elongation to form metanephric tubules. Be able to detail the relationship of the ends of these tubules with the collecting system and with the glomerulus and to describe the portions of the nephron derived from regions of the metanephric tubules.
 * The ureteric-derived collecting tubules induce the metanephric tissue right next to them to develop into vesicles (metanephric vesicles); predictably, these start to grow and elongate.
 * Note a fairly important detail at this point: the collecting tubule on down is derived from the ureteric tissue, while the distal convoluted tubule on up is derived from the metanephric tissue. This, presumably, is why you only see columnar cells in the nephron when you get to the collecting tubules.
 * The metanephric vesicles begin to form the various parts of the rest of the tubule: convoluted tubules, loop of Henle, Bowman's capsule, and podocytes.
 * The podocytes contact a developing capillary that's grown in to meet it (the vasculature is developing at the same time as all this brouhaha) and the Bowman's (squamous cells) capsule folds over them both to form the Bowman's space. Not to beat a tired metaphor, but the fist-in-a-balloon thing works well here (fist is glomerular capillary network, place where the fist contact balloon is podocytes, rest of balloon is Bowman's capsule).
 * Outline the formation of the urogenital sinus and describe its development to the bladder and urethra. What happens to the allantois and cloaca of the early embryo?
 * Allantois: place where cloaca goes out the umbilicus.
 * The cloaca, recall, is where the mesonephric ducts join the hindgut, which is in turn connected to the allantois.
 * At about 7 weeks, the hindgut separates off to go to the developing anus; the remaining allantois-duct junction is called the __urogenital sinus__ (endodermal tissue).
 * Most of the bladder and urethra is going to form from this urogenital sinus.
 * Recall that the ureteric bud is, at this point, busy differentiating its little heart out. Its site of origin on the mesonephric duct is going to __shuffle down off that duct__ and implant itself in the bladder.
 * Conversely, the rest of the mesonephric duct (minus the ureteric bud) in males is going to connect itself to the prostatic urethra (ductus deferens entry point).
 * It's a sort of mix-up game. The ureter goes off the mesonephric duct and onto the bladder; the mesonephric duct goes off the bladder and onto the urethra.
 * Describe the ascent of the kidney. Know the resultant structures that the Wolffian and Mullerian ducts give rise to in males and females, respectively.
 * Ascent: the surrounding tissue expands below the kidney, pushing it up rostrally.
 * The Mullerian duct forms the uterus and Fallopian tubes, while the mesonephric (or Wolffian) duct forms the ductus deferens and epididymus.
 * Be aware, although the specific molecular mechanisms of inductive processes will not be discussed in class, that kidney development involves a complex series of mutual mesodermal inductive events and that mutations in molecules involved in these processes can have profound effects on kidney development, several effects of which can be observed clinically in neonates.
 * Sure.

Tumors of the Kidney and Urinary Tract Tuesday, May 20, 2008 9:05 AM


 * Tumors of the Kidney and Urinary Tract, 5/20/08:**


 * List the most common benign and malignant tumors of the kidney and describe their most important characteristics:
 * Benign:
 * Renal papillary adenomas (glandular tissue)
 * Renal fibromas/hamartomas (fibrous tissue)
 * Angiomyolipomas (vasculature, smooth muscle, fat; associated with tuberous sclerosis)
 * Oncocytoma (eosinophilic epithelial cells)
 * Metanephric adenomas (derived from glomeruli)
 * Malignant:
 * Clear cell carcinomas:
 * Most common (70-80% of renal cell cancers, mostly in men).
 * Clinical: look for hematuria, can invade renal vein and cause regional lymphadenopathy. Can spread to lungs.
 * Imaging: as mentioned, look for engorged renal vein, possibly with some extension into the inferior vena cava.
 * Pathology: grossly, often looks like a spherical, __single__ tumor; sometimes get cysts. Microscopically, can see three cell types in clear-cell carcinomas: clear cells, granular cells, or spindles. The more clear cells (less nuclear material), the better the prognosis (the lower the 'nuclear grade') is. Granular and spindle cells are associated with poor prognoses.
 * Prognosis: 5-year survival: 45%; 70% without distant metastasis.
 * Papillary carcinomas:
 * 10-15% of renal cancers.
 * Pathology: grossly, often are __multifocal__ within the kidney. Frequently invade through the outer capsule. Microscopically, get a lot of fairly normal tissue stimulated by the growth factors elicited by a small group of cancerous cells. This seems to be good for metastatic prognosis (most of the 'malignant' cells are normal cells that can't seed elsewhere).
 * Prognosis: better than clear-cell.
 * Chromophobe renal carcinomas:
 * 5% of renal cancers.
 * Pathology: microscopically, prominent membranes and eosinophilic cytoplasm. Looks similar to oncocytomas, but can stain for iron; chromophobe renal carcinomas are very heavy in iron, oncocytomas aren't.
 * Prognosis: much better than either clear cell or papillary carcinomas.
 * Collecting duct carcinomas:
 * Less than 1% of renal cancers.
 * Pathology: microscopically, nests of malignant cells in a bunch of fibrotic tissue, usually in medullary region (arise from collecting ducts).
 * Prognosis: poor.
 * Familial renal cell carcinomas:
 * 4% of renal cancers.
 * Can be clear-cell or papillary.
 * Renal medullary carcinoma:
 * Not much detail. Inevitably fatal at present (three weeks to a few months after diagnosis).
 * Understand the basic genetic differences between spontaneous and familial renal tumors.
 * This seems to be basic cancer stuff-- genetic conditions, either inherited or spontaneous, can predispose people to developing tumors.
 * Note that Von Hippel-Lindau (good Lord! It's not a made-up disease after all!) patients are very predisposed to develop renal cysts and clear-cell carcinomas.
 * Various trisomies/lack of chromosome Y are linked to papillary carcinomas (MET gene on chromosome 7)
 * Describe the most important benign and malignant tumors of the urinary tract, calyx, pelvis, ureter, urinary bladder, and urethra.
 * Mainly patients of 50 years or older, mostly men, mostly in smokers.
 * Squamous differentiation is a marker of poorer response to treatment than glandular differentiation.
 * Transitional cell neoplasm:
 * Incidence: more than 90% of urinary tract tumors.
 * Clinical presentation: hematuria, irritated-bladder symptoms (dysuria, frequency, urgency). Can arise pretty much anywhere in the urinary tract system (from urethra to renal calyces). Can invade and metastasize to lungs, bones, liver. Can also cause ureteral obstruction.
 * Pathology: graded by the extent of invasion into other tissues. Papillary lesions look like red, raised 'excrescences.'

Developmental and Cystic Diseases Wednesday, May 21, 2008 8:03 AM


 * Developmental and Cystic Diseases, 5/21/08:**
 * Know the essential facts about congenital mesoblastic nephroma and Wilms tumor including clinical presentation, gross and histologic appearance and underlying genetics.
 * __Congenital mesoblastic nephromas__:
 * Most common kidney tumor from birth-6 months.
 * Detected on prenatal sonogram.
 * Adjective award: "Solitary firm round infiltrating fibrous mass."
 * Microscopically: long, thin spindle cells infiltrating between normal kidney cells.
 * If completely resected, clinical behavior is benign.
 * There's a more aggressive variant associated with a translocation between chromosomes 12 and 15 (activates oncogene).
 * __Wilms tumor, or nephroblastoma__:
 * Most common malignant pediatric kidney tumor (80%- though there's still only 460 cases/year in US).
 * Presents between 4-6 years as a solitary bulging tumor. Soft, mucoid tissue.
 * Microscopically: three cell types (**triphasic** ), stromal, blastemal, and epithelial.
 * If anaplasia is present, unfavorable prognosis (sign of p53 deletion).
 * Note that tumor can make skeletal muscle (rhabdomyoblastic).
 * Treated with resection and either adjuvant or neoadjuvant chemotherapy.
 * Can occur __bilaterally__; this is usually associated with genetic syndromes:
 * Beckwith-Weidemann syndrome: +gigantism, macroglossia (big tongue), pushing out of abdominal contents into the umbilical cord (exomphalos). Due to mutation on 11p15.
 * WAGR syndrome: __W__ilms, __A__niridia (absence of the iris), __G__enitourinary malformation, mental __R__etardation. Due to deletion of 11p13.
 * Know the terminology, embryologic bases and clinical presentation of renal agenesis, renal hypoplasia, renal dysplasia, renal ectopia and horseshoe kidney.
 * Renal agenesis: more commonly the left kidney. The other kidney hypertrophies to compensate. Bilateral renal agenesis is incompatible with fetal life. Unilaterally, see this in about 1/1000 live births. Can be due to failure of metanephros to develop.
 * Look for single umbilical artery in the placenta immediately postpartum.
 * Renal hypoplasia: underdevelopment of kidney, compensatory hypertrophy on the other side.
 * Renal dysplasia: abnormal metanephric tissue differentiation-- get cartilage, cysts, etc developing from pluripotential stem cells.
 * Renal ectopia: failure of the kidney to ascend. Can result in obstruction and/or misform the kidney.
 * Most common: __horseshoe kidney__. Not only failure to ascend, but the kidneys have fused together. Urine flow can stagnate; increased propensity for formation of kidney stones.
 * These tend to get stuck on the root of the inferior mesenteric artery.
 * Know how to classify conditions into of the 3 major etiologies of cystic kidney disease; know ADPKD and ARPKD in terms of phenotype, inheritance and associations; know the characteristics of multicystic dysplastic kidney (MCDK).
 * 3 major etiologies: Acquired, genetic, and developmental. I trust it's reasonably self-evident which conditions will be which.
 * Note that many cysts are benign ('simple cysts').
 * __Autosomal dominant polycystic kidney disease__:
 * 2 genetic loci: mutations in 16p13 and 4q21.
 * Incidence: 1/400 to 1/1000 in Caucasians, frequent new mutation rate (25%), near complete penetrance (if you've got the mutation, you're going to show it).
 * Clinical: bilateral kidney enlargement with multiple fluid-filled (clear or hemorrhagic) cysts, distributed uniformly throughout. Patients classically present with chronic flank pain in their fourth decade or intermittent hematuria. Most of them also have cysts in their liver and diverticulosis, often with mitral valve prolapse; sometimes with cerebral aneurysms and pancreatic cysts.
 * This is another thing to think about with costovertebral angle tenderness.
 * Accounts for 8-10% of end-stage renal disease.
 * __Autosomal recessive polycystic kidney disease__:
 * Due to mutation on chromosome 6p21.
 * Incidence: 1/6000-1/55000 live births, carrier frequency of 1/70.
 * Bilateral kidney enlargement.
 * The cysts are enlarged collecting tubules and are found only from the tips of the renal papilla to the surface of the cortex.
 * Grossly enlarged/fibrotic liver.
 * Shows up as hypertension in first years of life, renal insufficiency.
 * __Multicystic dysplastic kidney__:
 * Most common cause of abdominal mass in a newborn.
 * Incidence of 1 in 1000-2000.
 * Often associated with __ureteral atresia__-- affected kidney is nonfunctional, though usually asymptomatic.
 * The nonfunctional kidney "resembles a bunch of grapes" (numerous, irregularly sized cysts).
 * Seems to result from a problem with metanephric development.

Urinalysis Wednesday, May 21, 2008 9:00 AM


 * Urinalysis, 5/21/08:**


 * Understand the basic principles of urine collection
 * [Note that diabetes insipidus and diabetes mellitus were names based on how the urine of their patients tasted: bland and sweet, respectively.]
 * Need to make sure the urine's not contaminated (wash/clean genital area).
 * Early-morning voiding is usually the most concentrated urine (specific gravity > 1.022).
 * Catheterization can introduce bacteria/trauma.
 * Supra-pubic needle aspiration, done correctly, is the purest technique, "a good method for infants and small children" ("ma'am, I'm going to have to stick a needle in your baby's pelvis now").
 * 24 hour urine collection rules: first morning's voiding wasted; collect everything else that day and the first voiding of the following morning.
 * Note that if the urine is more than an hour old, there's often changes in that urine that make elements of a urinalysis less accurate. Those elements (largely cytology) are best done with fresh urine and not a 24-hour collection.
 * Describe the different types of urinalysis and understand their corresponding clinical-pathological correlation:
 * Macroscopic examination:
 * 1) Check odor: fruity = ketones, sweet = glucose, foul = infection, etc.
 * 2) Check color: yellow-green = bilirubin, red = blood/hemoglobin, brownish-red = acidified blood, etc.
 * 3) Check turbidity: crystals precipitating in urine, cellular elements/bacteria. Nonspecific by itself.
 * Chemical analysis/Use and interpretation of dipstick: Basically you dip a strip in the patient's urine. The strip is covered with binding reagents that semi-quantitatively inform us as to the concentration of various substances in the urine:
 * 1) Glucose. Good test for diabetes mellitus. Doesn't work well with pregnant women (large levels of ascorbic acid in urine screws up electron transfer process).
 * 2) Bilirubin: Pick up hemolysis. Notice it doesn't pick up conjugated (indirect) bilirubin. Also screwed with by high levels of ascorbic acid.
 * 3) Ketones: Look for diabetic ketoacidosis.
 * 4) Specific gravity: should go up after a 12-hour dry fast; if not, indicates inability to concentrate urine.
 * 5) Blood: Pick up rhabdomyolysis, nephritis, etc.
 * 6) pH: Acidic urine (< 4.5): high-protein diet, metabolic acidosis. Alkalotic urine (> 8.0): present in initial stages of some types of renal tubular acidosis.
 * 7) Protein: Look for damaged filtration membrane. Usually developed to pick up albumin; may not pick up Bence-Jones in multiple myeloma or globulins.
 * 8) Urobilinogen: Look for breakdown of conjugated bilirubin (mostly excreted in feces)-- some positive response is normal. Can see hemolytic crisis (too positive) or hepatic dysfunction (negative).
 * 9) Nitrite: Looks for bacteria that reduce nitrate (normal in urine) to nitrite-- like //E. coli// . Correlate with leukocyte esterase test, below.
 * 10) Leukocyte esterase: Indicates the presence of white blood cells in the urine.
 * Microscopic Examination:
 * 1) Sediment about 10 mL of urine, take pellet, resuspend it, scope it.
 * 2) Abnormal findings per high power field:
 * 3) > 3 erythrocytes
 * 4) > 5 leukocytes
 * 5) > 2 renal tubular epithelial cells
 * 6) > 10 bacteria
 * 7) Abnormal findings per low power field:
 * 8) > 3 hyaline casts, > 1 granular cast
 * 9) Any other casts (RBC, WBC)
 * 10) > 10 squamous cells (contamination)
 * Cytology:
 * 1) Don't look for cells in 24-hour or early-morning urine (the cells have been sitting around too long and have degenerated). Can occasionally see dysplasia indicative of malignancy in the urinary tract.
 * Interpret some of the most common chemical and cytological changes in urine samples in the most common inflammatory and neoplastic diseases of the kidney and the urinary tract
 * Hematuria: glomerular damage, kidney-eroding tumors, kidney trauma, stones (especially gross hematuria), infarcts, acute tubular necrosis, UTIs, toxins, physical stress. Watch for contamination in menstruating women.
 * White cells: infection, particularly neutrophils.
 * Epithelial cells: nephrotic syndrome, tubular degeneration as in ATN. Squamous cells tend to represent contamination.
 * Casts: gone through fairly extensively in Dr. Titelbaum's lecture, "Clearance-Based Measurement of Renal Pathology." Granular/waxy casts are caused by casts remaining too long in the tubule before becoming flushed out. WBC casts are often indicative of pyelonephritis.
 * Bacteria: about what you'd expect.
 * Yeast: likewise. Usually //Candida//.
 * Crystals: can be seen in healthy patients; particular kinds of crystals (tyrosine, cysteine, leucine) are rarer and indicative of disease.
 * Other: can sometimes detect schistosomiasis from ova in urine.
 * Cytological changes: look for dysplastic cells (large nucleus, less cytoplasm, irregular nuclear borders, etc), often indicative of transitional cell carcinoma.

Bladder and Micturition Wednesday, May 21, 2008 3:19 PM


 * Bladder and Micturition, 5/22/08:**


 * [pretty sparse here. You guess is as good as mine.]
 * Overview the two primary functions of the urinary bladder
 * He never did say. I'm guessing they're storage and non-reflux release of urine.
 * Detail the parasympathetic and sympathetic innervation to the lower urinary tract
 * Parasympathetic fibers from the hypogastric nerves innervate the detrusor muscle; activation causes contraction and bladder emptying.
 * Sympathetic fibers from the pelvic nerves, when stimulated, inhibit detrusor contraction. They also relax tension in the bladder neck and proximal urethra (preventing voiding).
 * Overview the micturition cycle
 * Storage phase: bladder begins to fill; at some point voiding is begun and detrusor muscle in bladder contracts, building bladder pressure; after voiding finishes, muscle relaxes, pressure lowers again, and filling begins.
 * Categorize the types of urinary incontinence
 * Stress incontinence (physical stress)
 * Urge incontinence
 * Overflow incontinence
 * Unconscious incontinence
 * Continuous leakage
 * Nocturnal enuresis (bed-wetting)
 * Post-void dribble
 * Extra-urethral incontinence
 * Geriatric incontinence
 * Compare/contrast the causes of incontinence in men and women
 * Men: more urge, nighttime, and postvoid incontinences.
 * Women: more stress and mixed-type incontinencies.
 * Both share continuous leakage issues. Women have urge incontinence too, though not to the same degree.
 * Overview the common causes of lower urinary tract obstruction in men and women
 * Men: basically you're either growing the prostate (generally due to benign prostate hyperplasia) or narrowing of the urethra (commonly due to scoping, surgery, or tumors).
 * Women: you've either got a kink in the bladder neck so that it can't compress the urethra (caused by vaginal prolapse or cystocele, which is when the bladder collapses into the vagina), or a kink in the urethra (as due to surgery or cancer).

Pediatric Pathology: Kidney and Urinary Tract Wednesday, May 21, 2008 3:53 PM


 * Pediatric Pathology: Kidney and Urinary Tract, 5/22/08:**


 * Know the definitions for the following terms:
 * 1) hydronephrosis: dilation of the renal pelvis by accumulated urine due to obstruction.
 * 2) In peds patients, most commonly due to ureteropelvic obstruction as a result of incomplete ureteric bud development.
 * 3) hydroureter: dilation of the ureter by accumulated urine due to obstruction.
 * 4) reflux: backflow of urine up the urinary tract when the detrusor muscles contract during micturition.
 * 5) megalocystis: abnormal distention of the bladder by urine due to bladder outlet obstruction.
 * Know the appropriate terminology, embryologic basis, and clinical presentation of the common developmental defects encountered in the urinary tract.
 * As mentioned, __ureteropelvic junction obstruction__ is the most common cause of hydronephosis, particularly in boys, and results from incomplete ureteric development. Evidently you can see a place where the ureter narrows dramatically-- can solve this by cutting the ureter around the narrowing and sewing the ends together.
 * Just in case anyone else was under this misapprehension: the 'pelvis' in 'uteropelvic junction obstruction' refers to the renal pelvis, not an anatomical landmark near the actual pelvis. I, uh, heard that someone got that wrong.
 * __Ureteral duplication__: most common renal abnormality (1% of population, more often in females, more common in kids with chronic UTIs). Two ureters enter the bladder from the same side; one tends to reflux, the other tends to be obstructed. Look for failure to toilet train or continuous drip incontinence.
 * __Ureterocele__: a bulbous dilation of the portion of the ureter within the bladder wall. Can cause ureteral obstruction or reflux, depending on whether it's stenosed. Can prolapse through urethra, causing obstruction.
 * __Urachal remnant__: The urachus is what connects the fetal bladder to the allantois (umbilical outflow tract). It's supposed to go away in utero. If it doesn't, you wind up with a baby that pees a lot into its bellybutton, causing pain, sometimes cysts, irritation, polyps, etc.
 * __Posterior ureteral valves__: abnormal insertion of mesonephric duct into cloaca results in partial obstruction and chronically increased intraluminal pressure-- this in turns results in abnormal development of everything above the ureters. Most common cause of male bladder outlet obstruction.
 * __Hydrospadias__: due to abnormal fusion of the urogenital folds in males, you see a urethral opening on the ventral side of the penis. Often results from androgen insufficiency.
 * __Epispadias__: similar, but the opening is on the dorsal aspect of the penis.
 * __Chordee__: a fibrous band that causes the penis to curve in its direction. Usually associated with epi- or hydrospadias.
 * __Exstrophy__: an absence of the abdominal wall and exposure of the bladder.
 * __Exstrophy-epispadias complex__: caused by failure of the cloaca to divide into the urogenital sinus and the anorectal canal.
 * Know the pathophysiologic events and consequences of urinary tract obstruction in the fetus.
 * [Note: since we're talking pathophys and not physiology, I'm not going to make any babies-are-freaky observations.]
 * In order to develop fetal lungs, the fetus has to inhale its own amniotic fluid/urine. So if it can't excrete urine, it gets decreased amniotic fluid (**oligohydramnios** ), leading to pulmonary hypoplasia, deformation of face and limbs, and nodules on the amnion (membrane surrounding the amniotic fluid).
 * This constellation is called __Potter's syndrome__.
 * Can also get (I am not making this up) __Prune belly syndrome__, in which you see an enormously distended bladder and ureters and an absence of abdominal muscle tone/mass. Boys' testes will not have descended, due to blockage by enormously distended bladder. Can get pulmonary hypoplasia as well.