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297 Cards in this Set

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What are the 7 major functions of the kidneys?
1) Regulation of water and electrolyte balance
2) Excretion of metabolic waste
3) Excretion of bioactive substances (hormones and many foreign substances, specifically drugs) that affect body function
4) Regulation of arterial blood pressure
5) Regulation of RBC production
6) Regulation of Vitamin D production
7) Gluconeogenesis
What is the “balance concept”?
Our bodies are in balance for any substance when the inputs and outputs of that substance are matched. Any difference between input and output leads to an increase or decrease in the amount of a substance within the body.
Define the gross structures of the kidney and their interrelationships.
• Gross structures: the 2 kidneys lie outside the peritoneal cavity in close apposition to the posterior abdominal wall
o Each is bean-shaped, with the rounded, outer convex surface facing the side of the body and the indented hilum oriented medially
• Calyces are funneled shaped structures that fit over underlying cone-shaped pyramids. The tip of each pyramid is called a papilla and projects into a minor calyx.
• The pyramids constitute the medulla of the kidney. The cortex overlies the medulla, and a thin connective tissue capsule overlies the cortex.
• Tubules and blood vessels are intertwined or arranged in parallel arrays within cortex and medulla; between them lies an interstitium which comprises < 10% of the renal volume
• The medulla is divided into an outer zone and an inner zone
What are the components of the nephron and their interrelationships?
• Each kidney contains 1 million nephrons
• Each nephron consists of a spherical filtering component, called the renal corpuscle, and a tubule extending from the renal corpuscle.
What is the function of the renal corpuscle?
The renal corpuscle is responsible for the initial step in urine formation: the separation of a protein-free filtrate from plasma.
What is the relationship between the glomerulus, Bowman’s capsule, and proximal tubule?
• The renal corpuscle consists of a compact tuft of interconnected capillary loops called the glomerulus, surrounded by a balloon-like hollow capsule, called the Bowman’s capsule
• Blood enters and leaves Bowman’s capsule through arterioles that penetrate the surface of the capsule at the vascular pole
• A fluid-filled space (urinary space/Bowman’s space) exists within the capsule and it is into this space that fluid filters
• Opposite the vascular pole, Bowman’s capsule has an opening that leads into the first portion of the tubule
What are the 3 layers separating the lumen of the glomerular capillaries from Bowman’s space?
• The capillary endothelium of the glomerular capillaries, which is perforated by many large fenestrae, and are permeable to everything in the blood except RBCs and platelets
• A thick basement membrane, which is in the middle and is not a membrane in the sense of a lipid bilayer membrane but is a gel-like cellular meshwork of glycoproteins and proteoglycans
• A single-celled layer of epithelial cells
Define podocytes.
Epithelial cells that rest on the basement membrane and face Bowman’s space; they have an unusual octopus-like structure
Define foot processes.
Also called pedicels; they extend from the podocyte and are embedded in the basement membrane.
o They interdigitate with the pedicels from adjacent podocytes
o Spaces between adjacent pedicels constitute the path through which the filtrate, once through the endothelial cells and basement membrane, travels to enter Bowman’s space
Define slit diaphragms.
They bridge the slits between pedicels and are like miniature ladders; the pedicels form the sides of the ladder, and the slit diaphragms are the rungs.
What is the functional significance of the arrangement of the layers separating the lumen of the glomerular capillaries from Bowman’s space?
It permits the filtration of large volumes of fluid from the capillaries into the Bowman’s space but restricts filtration of large plasma proteins.
What are glomerular mesangial cells? What is their function and location within the glomerulus?
They are found in the central part of the glomerulus between and within capillary loops. They act as phagocytes and remove trapped material from the basement membrane. They also contain large numbers of myofilaments and can contract in response to a variety of stimuli in a manner similar to vascular smooth muscle cells.
What are principal cells and intercalated cells?
• The tubular epithelium has a one-cell thickness throughout
• Before the distal convoluted tubule, the cells in any given segment are homogenous and distinct for that segment
• Beginning in the second half of the distal convoluted tubule, 2 cells types are found in most of the remaining segments
o One type constitutes the majority of cells in the particular segment, is considered specific for that segment – distal convoluted tubule cells, connecting tubule cells, and collecting-duct cells; collecting duct cells are also called principal cells
o The second type is intercalated cells, which are interspersed among the segment-specific cells; there are 2 types, type A and type B
• The last part of the medullary collecting duct contains neither principal nor intercalated cells, but is composed of inner medullary collecting-duct cells
List in order of the vessels through which blood flows from the renal artery to the renal vein.
• Blood enters each kidney via a renal artery, which then divides into progressively smaller branches: interlobar, arcuate, cortical radial arteries
• As each cortical radial a projects toward the outer kidney surface, a series of parallel afferent arterioles branch off at right angles, each leading to a glomerulus
• Unfiltered blood in glomerular capillaries recombines to form another set of arterioles called the efferent arterioles; blood leaves each glomerulus through a single efferent arteriole in the vascular pole of Bowman’s capsule.
• The efferent arteriole soon divides into a second set of capillaries called peritubular capillaries, which are profusely distributed throughout the cortex
• Peritubular capillaries rejoin to form the veins which leave the kidney
Contrast the blood supply to the cortex and the medulla. What are the vasa recta and vascular bundles?
• Arteries and glomeruli are found only in the cortex, never in the medulla.
• The vascular structures supplying the medulla differ from those in the cortex. From many of the juxtamedullary glomeruli (which lie above the corticomedullary border), long efferent arterioles extend downward into the outer medulla, where they divide many times to form bundles of parallel vessles that penetrate deep into the medulla; these are called vasa recta.
• The vasa recta on the outside of the vascular bundles give rise to capillaries that surround Henle’s loops and the collecting ducts in the outer medulla.
• The center-most vasa recta supply capillaries in the inner medulla.
• The capillaries from the inner medulla reform into ascending vasa recta that run in close association with descending vasa recta within vascular bundles.
• The vasa recta also participate in exchanging water and solutes between plasma and interstitium.
What are the differences among superficial cortical, midcortical, and juxtamedullary nephrons?
Nephrons are categorized according to the locations of their renal corpuscles in the cortex.
Describe superficial cortical nephrons.
Renal corpuscles are located within 1 mm of the capsular surface of the kidneys.
All have short loops, which make their hairpin turn above the junction of outer and inner medulla.
Describe midcortical nephrons.
Renal corpuscles are located in the midcortex, deep relative to superficial cortical nephrons but above juxtamedullary nephrons. May be either short or long looped.
Describe juxtamedullary nephrons.
Have renal corpuscles located above the junction between the cortex and the medulla. All have long loops, which extend into the inner medulla often to the tip of the papilla.
What is the juxtaglomerular apparatus?
Macula densa: a portion of the late thick ascending limb at the point where, in all nephrons, this segment abuts the afferent and efferent arterioles at the vascular pole of the renal corpuscle from which the tubule arose.
Juxtaglomerular apparatus: macula densa plus surrounding area, arterioles
What are 3 cell types of the juxtaglomerular apparatus?
• Granular cells (differentiated smooth m cells in walls of afferent arterioles)
• Extraglomerular mesangial cells
• Macula densa cells, specialized thick ascending limb epithelial cells
What is the function of the granular cells?
They secrete the hormone renin, which controls renal function and blood pressure.
What is the function of macula densa cells?
They are detectors of the luminal content of the nephron at the end of the thick ascending limb and contribute to the control of glomerular filtration rate and to the control of renin secretion.
Describe renal innervation.
The kidneys receive a rich supply of sympathetic neurons which are distributed to the afferent and efferent arterioles, the JG apparatus, and many portions of the tubule. There is no significant parasympathetic innervation.
Describe the basic renal processes: glomerular filtration, tubular reabsorption, and tubular secretion.
• Glomerular filtration: the bulk flow of fluid from the glomerular capillaries into Bowman’s capsule. The glomerular filtrate is very much like blood plasma, but contains very little total protein.
o Freely filtered substances are present in the same concentration in the filtrate and plasma; this includes most inorganic ions and low-molecular-weight organic solutes.
• As filtrate flows from Bowman’s capsule through t various portions of the tubule, its composition is altered, mostly by removing material (tubular reabsorption) but also by adding material (tubular secretion).
• Most of tubular transport consists of reabsorption rather than secretion.
What is renal metabolism of a substance? Give examples.
• The tubular cells may extract organic nutrients from the glomerular filtrate or peritubular capillaries and metabolize them as dictated by the cell’s own nutrient requirements
• Other metabolic transformations are directed toward altering the composition of the urine and plasma
o Synthesis of ammonium from glutamine
o Production of bicarbonate
Describe the regulation of renal function.
• Signals regulating the kidney arise from both neural and hormonal input
• Neural signals originate in the sympathetic celiac plexus and exert control over renal blood flow, glomerular filtration, release of vasoactive substances
• Hormonal signals originate in the adrenal gland, pituitary gland, and heart.
o The adrenal cortex secretes steroid hormones aldosterone and cortisol
o The adrenal medulla secretes catecholamines epinephrine and NE
 All adrenal hormones, especially aldosterone, regulate sodium and potassium excretion by the kidney.
o The pituitary secretes ADH, which regulates water excretion and possibly sodium excretion as well
o The heart secretes hormones, natriuretic peptides, that contribute to signaling to increase secretion of sodium by the kidneys.
What is renal blood flow (RBF)?
All the blood that flows through glomeruli in the cortex; about 1.1 L/min, or about 20% of cardiac output. Determined by the mean pressure in the renal a and the contractile state of the smooth muscle of the renal arterioles of the cortex.
What is renal plasma flow (RPF)?
The amount of plasma that enters the glomeruli in the cortex via the afferent arterioles. A normal hematocrit is 0.45, so the amount of plasma in the blood is 0.55. RPF = 0.55*1.1L/min = 605 mL/min.
What is glomerular filtration rate (GFR)?
The amount of fluid filtered by the glomeruli; approximately equal to 125 mL/min.
What is the filtration fraction?
The amount of fluid and freely filtered substances that filters into Bowman’s capsule; equal to GFR/RPF = 125/605 or 20%.
How are flow, pressure, and resistance in an organ related?
Q = ΔP/R, where ΔP = mean pressure in the artery – mean pressure in the vein
Describe the relative resistances of the afferent and efferent arterioles.
Normally, the resistances of the afferent and efferent arterioles are approx. equal and account for most of the total renal vascular resistance.
Describe the vascular pressure in the glomerular capillaries and peritubular capillaries.
• Vascular pressures in the 2 capillary beds are quite different.
• The peritubular capillaries are downstream from the efferent arteriole and have a lower hydraulic pressure.
• Typical glomerular pressure = 60 mm Hg in a normal unstressted individual, and typical peritubular capillary pressure = 20 mm Hg.
• High glomerular pressure necessary for glomerular filtration; low peritubular capillary pressure necessary for tubular reabsorption.
What are the effects of changes in afferent and efferent arteriolar resistance on renal blood flow?
• A change in arteriolar resistance produces the same effect on RBF regardless of whether it occurs in the afferent arteriole or efferent arteriole
• Because the vessels are in series, a change in either one has the same effect on the total.
• When the 2 resistances both change in the same direction, the most common state of affairs, their effects on RBF will be additive
• When they change in different directions, they exert opposing effects on RBF.
How is the glomerular filtrate formed?
Filtrate flows through fenestrae in the glomerular-capillary endothelial layer (fenestrae occupy 10% of the endothelial surface area), through the basement membrane, and finally through slit diaphragms between podocyte foot processes.
How does molecular size determine filterability of plasma solutes?
• The filtration barrier provides no hindrance to the movement of molecules with molecular weights < 7000 d; this includes small ions, glucose, urea, amino acids, and many hormones
• The filtration barrier almost totally excludes plasma albumin (66,000 d)
• For molecules with a molecular weight ranging from 7000 to 70,000 d, the amount filtered becomes progressively smaller as molecules become larger.
How does electrical charge determine filterability of plasma solutes?
• For any given size, negatively charged macromolecules are filtered to a lesser extent, and positively charge macromolecules to a greater extent, than neutral molecules
• This is because the surfaces of all the components of the filtration barrier contain fixed polyanions, which repel negatively charged macromolecules during filtration (note: nearly all plasma proteins bear negative charges)
• Negative charges in the filtration membranes act as a hindrance only to macromolecules, not to mineral ions or low-mw organic solutes (Cl-, HCO3-).
How does protein binding of low-mw substances influence filterability?
Small substances that are partly or mostly bound to large plasma proteins are not free to be filtered even though, when not bound to plasma proteins, they can easily move through the filtration barrier; includes hydrophobic hormones of the steroid and thyroid categories and 40% of blood Ca2+.
What determines the GFR? What equation represents this?
• The GFR is determined by the hydraulic permeability of the capillaries, their surface area, and the net filtration pressure (NFP) acting across them.
Rate of filtration = hydraulic permeability * surface area *NFP
What is the filtration coefficient?
Because it is difficult to estimate the area of a capillary bed, we use a parameter called the filtration coefficient (Kf) which equals hydraulic pressure * surface area.
How might mesangial cells alter the filtration coefficient?
• Contraction of mesangial cells restricts flow through some capillary loops, effectively reducing the area available for filtration, and hence decreases Kf
• Relaxation of mesangial cells increases glomerular surface area and therefore increases Kf.
What are the Starling forces involved in capillary filtration?
• Starling forces: 2 hydrostatic pressures and 2 oncotic pressures
• NFP = (PGC – πGC) – (PBC – πBC)
o PGC = hydraulic pressure in the glomerular capillary
o ΠGC = oncotic pressure in glomerular capillary plasma
o PBC = hydraulic pressure in Bowman’s capsule
o ΠBC = oncotic pressure of fluid in Bowman’s capsule; may be taken as zero because there is normally little protein in Bowman’s capsule?
• So now, we can rewrite our equation: GFR = Kf (PGC – PBC - πGC)
How do pressures change throughout the glomeruli?
• Hydraulic pressure changes only slightly along the glomeruli; this is because the very large total cross-sectional area of the glomeruli collectively provides only a small resistance to flow.
• The oncotic pressure in the glomeruli does change substantially along the length of the glomeruli; water is moving out of the vascular space and leaving protein behind, thereby raising protein concentration and hence oncotic pressure of the unfiltered plasma remaining in the capillaries
• Due to the large increase in oncotic pressure, NFP decreases from the beginning of the glomerular capillaries to the end.
How do changes in each Starling force affect GFR?
• PGC: an increase in renal arterial pressure, an increase in efferent-arteriolar resistance, or a decrease in afferent-arteriolear resistance increases GFR
• ΠGC: An increase in systemic-plasma oncotic pressure or a decrease in renal plasma flow decreases GFR
• PBC: An increase in intratubular pressure because of obstruction of tubule or the extrarenal urinary system decreases GFR
• ΠBC: may be taken as zero because there is normally little protein in Bowman’s capsule
Why is the glomerular filtration rate so large relative to filtration across other capillaries in the body?
The high GFR is due to a high Kf value and the enormous filtration of 180 L/day, as compared to 3 L/day in all other capillary beds combined.
What is “filtered load”?
The amount of substance that is filtered per unit time; it is what is presented to the rest of the nephron to handle. For freely-filtered substances, filtered load = GFR * plasma concentration. A high filtered load means a substantial amount of material to be reabsorbed.
What is autoregulation of renal blood flow and GFR?
• Involves processes that severely blunt changes in GFR and RBF
• Necessary because excretion of blood and water rises and falls with a rise and fall in blood pressure; this effect is so strong that urinary excretion would tend to vary widely with ordinary daily changes in arterial pressure
• With autoregulation, a rise in driving pressure is counteracted by a rise in vascular resistance that almost offsets the rise in pressure.
What is the myogenic mechanism of autoregulation?
• Myogenic response: a direct reaction of the vascular smooth muscle to stretch or relaxation
What is the tubular feedback mechanism of autoregulation?
Tubular feedback: feedback from the tubules back to the glomerulus.
o As the filtration rate in an individual nephron increases or decreases, the amount of sodium that escapes reabsorption in the proximal tubule and loop of Henle also increases or decreases.
o The macula densa cells sense the amount of sodium and chloride in the lumen
o When sodium levels are too high, the macula densa cells release transmitter agents that 1) produce vasoconstriction of the afferent arteriole, thereby reducing hydrostatic pressure, and 2) produce contraction of glomerular mesangial cells, thereby reducing the effective filtration coefficient. Both reduce the single-nephron filtration rate. Low sodium levels increase the single-nephron filtration rate.
Define “clearance” and “metabolic clearance rate".
• Clearance: ridding the body of a substance
• Metabolic clearance rate: the volume of plasma per unit time from which all of substance is removed
o Typically refers to general clearance
o When referring to clearance performed by kidneys, it is called renal clearance.
What is the difference between general clearance and renal clearance?
• General clearance: the removal of a substance from the blood by any of several mechanisms
• Renal clearance: the removal of a substances from the blood and the subsequent excretion of the substance in the urine.
How do you calculate clearance?
• Cx = Ux*V/Px
o Ux = urine concentration of x
o V = urine flow rate
o Px = plasma concentration of x
• We can also say that Cx = excretion rate of x/Px
What criteria must be met for a substance so that its clearance can be used as a measure of GFR?
• It moves into Bowman’s space in the same proportion as the volume filtered
• It cannot move in either direction by the paracellular route around the tubular epithelium
• There are no transport mechanisms either on the apical or basolateral surface of the tubular epithelium to take up inulin.
What substances are used to measure GFR and effective RPF?
• Inulin: gold-standard, but cumbersome because inulin must be infused and infused at a rate sufficient to keep its plasma concentration constant during the period of urine formation and collection.
• Creatine: used for routine assessment of GFR in hospitalized patients
What is inulin?
• Inulin is a polysaccharide starch of about 5-kd molecular weight; it is freely filtered by the glomerulus but is not taken up or transported by the nephron
• All the inulin that is filtered flows through the nephron and appears in the urine, so its renal clearance is relatively large
• It is not taken up by other tissues and the kidneys are the only excretion route.
Be able to predict whether a substance undergoes net reabsorption or net secretion by comparing is clearance with that of inulin or by comparing its rate of filtration with its rate of excretion.
Since the rate of inulin clearance = GFR, substances with a clearance rate higher than inulin undergo net secretion, and substances with a clearance rate lower than inulin undergo net reabsorption.
What is PAH?
• PAH (para-aminohippurate) is a small, water-soluble organic anion that is freely filtered and also avidly secreted by the proximal tubule epithelium.
• It has a clearance rate greater than GFR.
• Its secretion rate is saturable, that is, there is a maximum rate of PAH secretion into the tubule.
• Its clearance is nearly is 90% of the RPF and is used as a measure of RPF, usually called the effective renal plasma flow.
Can a freely filtered substance have a clearance value less than GFR?
• Yes, sodium, chloride, and urea have clearance values less than GFR but greater than zero
• Many freely filtered substances have clearance values of zero, such as insulin and glucose.
What is creatinine?
• Creatinine is the end-product of creatine metabolism and is exported into our blood continuously by skeletal muscle at a rate that is proportional to skeletal muscle mass.
o To the extent that muscle mass is constant in a given individual, creatinine production is constant
• Creatinine is freely filtered and not reabsorbed, but a small amount is secreted by the proximal tubule
• So, creatinine in the urine represents both a filtered component and secreted component; therefore CCr is slightly greater than GFR.
How can you estimate GFR from Ccr?
• The secreted fraction is normally 10-20%, so the measured creatinine clearance overestimates GFR by the same percentage
• For routine assessment of GFR, this degree of error is acceptable
• To measure creatinine clearance, a patient’s urine is collected for 24 hours and a blood sample is taken sometime during the collection period. Blood and urine are assayed for creatinine concentration and we use the clearance formula to yield creatinine clearance.
• Additional errors cloud the issue (e.g., errors in the assays for plasma or urine creatinine concentration or drug-induced alteration of creatinine secretion)
• In patients with very low GFR, creatinine clearance more severely overestimates GFR
Given data, calculate fractional excretion of any substance.
• First, calculate the amount of the substance excreted using the clearance equation
• If the substance is freely filtered, the filtered amount = GFR*PNa
o GFR = Cin
• Compare the amount excreted to the amount that is filtered
Define diffusion.
The frenzied random movement of free molecules in solution
o Net diffusion occurs across a barrier if there is a driving force and if the barrier is permeable
o Channels allow substances to move rapidly across membranes when they would otherwise diffuse slowly or not at all
o Energy source: electrochemical gradient
Define facilitated diffusion.
Movement of a single solute species through a uniporter; the difference between a channel and a uniporter is that a channel is tiny hole, whereas a uniporter requires that the solute bind to a site that is alternatively available on one side and then the other of a membrane. Energy source is the electrochemical gradient.
What are primary active transporters?
Membrane proteins that are capable of moving 1 or more solutes up their electrochemical gradients, using the energy obtained from the hydrolysis of ATP; also called ATPases.
What is secondary active transport?
o Transport that involves energy being provided indirectly from the transport of another solute rather than from the hydrolysis of ATP
o Symporters and antiporters move 2 or more solute species in the same direction or in opposite directions across a membrane.
o At least 1 of the solutes moves down its electrochemical gradient and provides the energy to move 1 or more of the other solutes up its electrochemical gradient.
What is receptor-mediated endocytosis?
A solute, usually a protein, binds to a site on the apical surface of an epithelial cell, and then a patch of membrane with the solute bound to it is internalized as a vesicle in the cytoplasm.
o Subsequent processes then degrade the protein into its constituent amino acids, which are transported across the basolateral membrane and into the blood.
What are the major morphological components of epithelial tissue?
Lumen, serosa, interstitium, apical membrane, basolateral membrane, tight junctions, lateral spaces
What is paracellular transport?
When a substance goes around the cells (ie, through the matrix of the tight junctions that link each epithelial cell to its neighbor).
What is the difference between transcellular and paracellular transport?
• Paracellular route: when the substance goes around the cell (1 step process)
• Transceullar route: when the substance goes through the cell in a 2-step process (across the apical membrane facing the tubular lumen and across the basolateral membrane facing the insterstitium)
Define osmolarity.
The sum of the molar concentrations of all solutes without regard to kind; expressed in units of osmoles per liter.
Define osmolality.
The ability of solutes to lower the concentration of water; it is a function of both the concentration of the solutes and the kind of solutes
o Expressed in units of osmoles per kilogram of water
o Often called osmotic pressure
o Only effective in driving osmosis when the barrier is less permeable to solutes than to water.
Why is osmolarity commonly used to approximate osmolality?
• When osmolality is measured and osmolarity is calculated from solution ingredients, the results are usually within 10% of each other.
• For convenience, physiologists calculate osmolarity and call it osmolality.
What is meant by the expression “water follows the osmoles”?
Given a cell membrane or epithelial layer in which the solutions on the 2 sides have different osmolalities, water will move by osmosis toward the side with the higher osmolality.
What forces determine movement of reabsorbed fluid from the interstitium into peritubular capillaries?
• The Starling forces across the peritubular capillaries favor reabsorption.
• The capillary hydrostatic pressure has fallen and the plasma oncotic pressure has risen, so the net filtration pressure is now a net absorptive pressure, and fluid is reabsorbed back into the peritubular capillaries.
Which Starling forces govern glomerular filtration? Which govern peritubular capillary absorption?
• Hydrostatic pressure drives the volume flux of filtration across the endothelial walls of glomerular capillaries.
• In the endothelial barriers of glomerular capillaries and peritubular capillaries, most of the solutes are as permeable through the fenestrae as water and thus do not influence water movement.
• Large plasma proteins are not permeable and do influence water movement.
• Colloid osmotic pressure or oncotic pressure: the osmotic pressure resulting from proteins only.
Describe tubular maximum-limited systems.
Tubular maximum-limited (Tm) systems reach an upper limit because the transporters moving the substance become saturated; any further increase in solute concentration does not increase the rate at which the substance binds to the transporter and thereafter moves through the membrane.
o Limiting rate is a property of the transporter
Describe gradient-limited systems.
• Gradient-limited systems reach an upper limit because the tight junctions are leaky, and a significant lowering of luminal concentration relative to the interstitium results in a leak back into the lumen as fast as the substance is transported out.
o Limiting rate is a property of the permeability of the epithelial monolayer regardless of the maximal rate of the transport protein.
Contrast “tight” and “leaky” epithelia.
• A tight junction is said to be “leaky” if it is permeable to the substance in question, and the substance will diffuse from the lumen to the interstitium.
• The exact fractions that are reabsorbed depends on the permeability of the tight junctions but are generally in the range of one half to two thirds.
• Ions are driven not only by concentrations gradients but also by voltage gradients, so the transepithelial voltage plays a role here; this voltage enhances paracellular anion reabsorption early and reduces it later.
What are the kidney’s 2 functions in regards to organic substances?
• The kidney keeps or saves organic metabolites that should not be lost
• The kidney excretes waste products and foreign organic substances to prevent their accumulation
What is the normal plasma glucose level? What is it during a meal and in the case of sever diabetes?
Normal plasma glucose level is about 90 mg/dL (5 mmol/L) and rises transiently to well over 100 mg/dL during meals and can reach levels of over 1000 mg/dL (over 55 mmol/L) in severe diabetes.
How much glucose is normally reabsorbed? How is this accomplished?
• Normally, all filtered glucose is reabsorbed in the proximal tubule.
• Glucose is removed from the tubular lumen along with sodium via a sodium-dependent glucose symporter (SGLUT) across the apical membrane of proximal convoluted tubule epithelial cells.
• Then, glucose moves across the basolateral membrane into the interstitium via a GLUT uniporter.
Do tight junctions manifest significant permeability to glucose? What are the consequences of this?
• No; therefore, as glucose is removed from the lumen and the luminal concentration falls, there is no back-leak
• The transport of a solute with no back-leak depends only on the characteristics of the rate-limiting transporter, in this case, the SGLUT symporter, and is a Tm-limited system.
Under what conditions is glucosuria likely to occur?
• Because glucose reabsorption is a Tm system, abnormally high filtered loads overwhelm the reabsorptive capacity; this occurs when plasma glucose rises above 300 mg/dL – a pathological but relatively common situation.
• When the proximal convoluted tubule fails to reabsorb all the filtered glucose, a little glucose begins to spill into the urine.
• Any glucose not reabsorbed is an osmole in the tubule that has consequences for water reabsorption.
Is glomerular filtrate truly protein-free?
No, small and medium-sized proteins are filtered in large quantities, and although large plasma proteins are severely restricted from crossing the glomerular filtration barrier, a small amount does make through.
How does the body prevent filtered protein from being excreted in the urine?
• The proximal tubule is capable of taking up filtered proteins
• We call it “uptake” rather than “reabsorption” because the proteins, although they are transported intact out of the lumen into the epithelial cells, are degraded into their constituent amino acids before being transported into the cortical interstitium.
Describe the process of protein re-uptake by the proximal tubule.
• Larger proteins are taken up via endocytosis at the luminal membrane
o This energy-requiring process is triggered by the binding of filtered protein molecules to specific receptors on the luminal membrane
o Therefore, the rate of endocytosis is increased in proportion to the concentration of protein in the glomerular filtrate until a maximal rate of vesicle formation is reached.
• The pinched-off intracellular vesicles merge with lysosomes, whose enzymes degrade the protein to low-molecular-weight fragments, mainly individual amino acids
• The end products exit the cells across the basolateral membrane to the interstitial fluid, from which they gain entry to peritubular capillaries
• This mechanism is easily saturated, so any large increase in filtered protein resulting from increased glomerular permeability can cause the excretion of large quantities of protein.
What equation is used to determine total filtered protein?
Total filtered protein = GFR * concentration of protein in filtrate
What is a major role of the kidneys in regards to protein?
• Kidneys are major sites of catabolism of many plasma proteins, specifically including polypeptide hormones.
• Decreased rates of degradation occurring in renal disease may result in elevated plasma hormone concentrations.
Describe renal handling of small peptides.
• Small peptides are handled differently than large proteins, but the end result is the same: catabolism of the peptide and preservation of its amino acids
• Very small peptides are completely filterable at the renal corpuscles and are then catabolized mainly into amino acids within the proximal tubular lumen by peptidases located on the luminal plasma membrane.
• Amino acids are reabsorbed by the same transporters that normal reabsorb filtered amino acids.
Describe renal handling of organic anions.
• The proximal tubule actively secretes a large number of different organic anions, both endogenously produced and foreign.
• Many of the organic anions handled by this system are also filterable at the renal corupscles, and so the amount secreted proximally adds to that which gains entry to the tubule via glomerular filtration.
Describe the active secretory pathway for organic anions in the proximal tubule.
• It is the reverse of reabsorption of organic solutes.
• There are active transporters for the anions at the basolateral membrane of tubular epithelial cells that are the rate-limiting step in overall transport.
• Transport out of the cell across the apical membrane into the lumen is via facilitated diffusion on a variety of uniporters or more specific sodium-dependent antiporters.
• Organic anions are not significantly permeable through tight junctions or membranes, so their transport is characterized by Tm.
• The relatively nondiscriminating nature of this collection of transporters accounts for its ability to eliminate from the body so many foreign chemicals.
How does the liver affect excretion of organic anions?
The liver conjugates many foreign substances with either glucuronate or sulfate, which renders the parent molecule far more water soluble.
Describe the secretion of para-aminohippurate.
• At the basolateral membrane, PAH is taken up in exchange for the anion form of dicarboxylic acid. PAH is then extruded into the lumen across the apical membrane via another antiporter.
• PAH is typical of many organic anions secreted proximally in that it undergoes no significant additional transport anywhere along the nephron.
Describe the renal handling of urate.
• Urate is not protein-bound and so is freely filterable at the renal corpuscles.
• Almost all filtered urate is reabsorbed early in the proximal tubule.
• Further on in the proximal tubule, urate undergoes active tubular secretion.
• In the straight portion, urate is once again reabsorbed.
• The total rate of tubular reabsorption is normally much greater than the rate of tubular secretion; the mass excreted is a small fraction of mass filtered.
What are the 3 ways by which altered renal function can lead to decreased urate excretion and hence increased plasma urate (as in gout)?
• Decreased filtration of urate secondary to decreased GFR
• Excessive reabsorption of urate
• Diminished secretion of urate
Describe the secretion of organic cations.
• Transport systems are analogous to those for organic anions: because of the large number of different transporters, a substantial amount of foreign and endogenous substances are transported, the cations compete with one another for transport, and the transporters manifest Tm limitation.
• Organic cations enter across the basolateral membrane via one of several uniporters, members of the OCT family, and exit into the lumen via an antiporter, which exchanges a proton for the organic cation.
What are some examples of endogenous substances and drugs that are organic cations actively secreted by the proximal tubule?
• Endogenous substances: ACh, choline, cretinine, dopamine, epinephrine, guanidine, histamine, serotonin, norepinephrine, thiamine.
• Drugs: atropine, isoproterenol, cimetidine, meperidine, morphine, procaine, quinine, tetraethyl ammonium.
Describe the renal handling of weak acids and bases.
• In general, neutral forms of organic acids and bases are more permeable in lipid membranes than ionized forms.
• The neutral forms can diffuse either into or out of the tubular lumen down the concentration gradient of the neutral form; in contrast, the ionized forms, once in the lumen, cannot diffuse; they are effectively trapped ther.
How does tubular pH affect reabsorption?
• The tubular fluid becomes acidified relative to the plasma with a normal diet.
• For a weak acid in tubular fluid, more will be converted to the neutral free acid form and therefore become more permeable, favoring diffusion out of the lumen.
• So, a highly acidic urine tends to increase passive reabsorption of weak acids
• For many weak bases, the pH dependence is the opposite; at low pH they are protonated cations (trapped in the lumen), whereas at high pH they are converted to neutral free base.
What is special about urea?
• Urea is unique in that it is a waste product that must be excreted to prevent accumulation but also plays a key role in the regulation of water balance.
How is urea produced?
• Urea is produced continuously by the liver as an end product of protein metabolism; the production rate increases on a high-protein diet and decreases during starvation, but production never stops.
What is the normal level of urea in the blood?
• It’s quite variable: 3 mmol/L – 9 mmol/L, reflecting variations in both protein intake and renal handling of urea.
• Over the long term, renal urea excretion must match hepatic production; otherwise, plasma levels would rise into the pathological range, producing a condition called uremia.
• On a shorter term basis, urea excretion rate may not exactly match production rate because urea excretion is also regulated for purposes other than keeping a stable plasma level.
Are sodium, chloride, and water reabsorbed or secreted?.
• All are freely filtered at the renal corpuscle.
• They all undergo considerable tubular reabsorption (usually more than 99%) but normally no tubular secretion.
• Most renal ATP energy is used to accomplish reabsorption of these 3 substances.
What are the 3 generalization that summarize major tubular reabsorption of sodium, chloride, and water?
• The reabsorption of sodium is mainly an active, transcellular process divine by sodium-potassium-adenosine triphosphatase.
• The reabsorption of chloride is both passive (paracellular diffusion) and active (transcellular), but it is directly or indirectly coupled with the reabsorption of sodium, thus explaining why the reabsorption of the 2 ions is usually parallel.
• The reabsorption of water is by osmosis and is secondary to reabsorption of solutes, particularly sodium and substances whose reabsorption is dependent on sodium reabsorption (mostly chloride).
How does sodium enter and leave the body?
• Intake: Food (10.5 g/day)
• Output: Sweat (0.25 g/day), Feces (0.25 g/day), Urine (10.0 g/day)
What is the essential event for active transcellular Na+ reabsorption?
• The primary active transport of sodium from cell to interstitial fluid by the Na-K-ATPase pumps in the basolateral membrane.
• These pumps keep the intracellular [Na+] lower than the surrounding media; because the inside of the cell is negatively charged compared to the lumen, Na+ ions enter the cell passively, down their electrochemical gradient.
What are the 3 types of entry processes for sodium?
• Na-nutrient, Na-phosphate, and Na-sulfate symporters
• Na-hydrogen antiporters * Bring in majority of sodium
• Sodium channels
How can we estimate chloride reabsorption?
• Chloride reabsorption is dependent on sodium reabsorption, so the tubular locations that reabsorb chloride and the percentages of filtered chloride absorbed by these segments are similar to those for sodium.
• Keep in mind that any finite volume of fluid absorbed must contain equal amounts of anion and cation equivalents.
What is critical for active transcellular chloride reabsorption?
• The critical transport step for chloride is from lumen to cell.
• The chloride transport process in the luminal membrane must achieve a high enough intracellular chloride concentration to cause downhill chloride movement out of the cell across the basolateral membrane.
• So, luminal membrane chloride transporters use energy to move chloride uphill from lumen to cell against its electrochemical gradient.
How do chloride ions move from the lumen into the interstitium?
• Paracellular absorption.
• A complicated parallel set of Na-H and CL-base antiporters.
What are the normal routes of water gain and loss in adults?
• Intake: Beverage (1200 ml/day), Food (1000 ml/day), Metabolically produced (350 ml/day).
• Output: Skin and lungs – called “insensible loss” because people are unware of its occurrence (900 ml/day), Sweat (50 ml/day), Feces (100 ml/day), Urine (1500 ml/day). Also, menstrual flow, breast milk, vomiting.
In what ways does water move down an osmotic gradient?
• Simple net diffusion through the lipid bilayer
• Through aquaporins in plasma membranes of tubular cells
• Through tight junctions between cells
What are the 3 general categories into which the segments of the renal tubule fall with regard to water permeability?
• The luminal membranes of the proximal tubule and descending thin limb of Henle’s loop always have a very high water permeability
• The luminal membrane of the ascending limbs of Henle’s loop and the luminal membranes of distal convoluted tubule are always relatively water impermeable, as are the tight junctions
• The water permeability of the luminal membrane of the collecting-duct system is intrinsically low but can be regulated so that its water permeability increases substantially.
What is “obligatory water loss”?
• The minimal amount of water that can be lost per day; 0.43 L/day
• This is the minimum amount required to dissolve urea, sulfate, phosphate, and other waste products and nonwaste ions - about 600 mOsm/day.
• This is not a fixed volume but changes with different physiological states.
What is reabsorbed by the proximal tubule?
• Na+, which enters the cell across the luminal membrane via antiport with protons (which are supplied by carbon dioxide and water).
• The protons cause the secondary active reabsorption of filtered bicarbonate.
• Organic nutrients and phosphate are also absorbed with sodium.
• Chloride reabsorption, via paracellular diffusion.
How does Cl- concentration change throughout the proximal tubule?
• The concentration of chloride in Bowman’s capsule is essentially the same as in plasma (about 110 mEq/L).
• Along the early proximal tubule, reabsorption of water causes chloride concentration in the tubular lumen to increases somewhat above that in the peritubular capillaries.
• As fluid flows through the middle and late proximal tubule, this concentration gradient, maintained by continued water reabsorption, provides the driving force for paracellular chloride reabsoprtion.
Discuss active chloride transport from lumen to cell in the later proximal tubule.
• It uses parallel Na-H and Cl-base antiporters
• Chloride transport into the cell is powered by the downhill antiport of organic bases, which are continuously generated in the cell by dissociation of their respective acids into a proton and the base.
• Simultaneously, the protons generated by the dissociation are actively transported in to the lumen by Na-H antiporters.
• In the lumen, the protons and organic base recombine to form the neutral form of the acid, and this nonpolar neutral acid then diffuses across the luminal membrane back into the cell, where the entire process is repeated.
• Everything is ultimately dependent on the basolateral Na-K-ATPase to establish the gradient for sodium that powers the luminal Na-H antiporter.
Given the tremendous amount of sodium reabsorbed, how can the luminal sodium concentration and osmolality not progressively decrease along the proximal tubule?
• Both remain almost equal to their values in plasma.
• Whereas 65% of the mass of filtered sodium and total solute has been reabsorbed by the end of the proximal tubule, so has almost the same percentage of filtered water.
• This is because the water permeability of the proximal tubule is so great that passive water reabsorption always keeps pace with total solute reabsorption.
What is iso-osmotic volume reabsorption?
Occurs in the proximal tubule; the process by which the concentrations of sodium and total solute (osmolality), as opposed to their masses, remain virtually unchanged during fluid passage through the proximal tubule.
What is osmotic diuresis?
• Diuresis means increased urine flow.
• Osmotic diuresis refers to the situation in which the increased urine flow is due to an abnormally high amount in the glomerular filtrate of any substance that is reabsorbed incompletely or not at all by the proximal tubule.
• Osmotic diuretics inhibit the reabsorption of both water and sodium.
How does reabsorption in Henle’s loop differ from reabsorption in the proximal tubule?
• As a whole, Henle’s loop always reabsorbs proporitionally more sodium and chloride than water.
• The proximal tubule always reabsorbs water and sodium in equal proportions
Describe the anatomic separation of sodium chloride reabsorption and water reabsorption in the loop of Henle.
• The descending limb does not reabsorb sodium or chloride significantly, but is quite permeable to water and reabsorbs it.
• The ascending limbs (both thin and thick) reabsorb sodium and chloride but little water (because they are quite impermeable to water).
What are the mechanisms of sodium and chloride reabsorption by the ascending limbs of the loop of Henle?
• Passive in the thin ascending limb and active in the thick ascending limb.
• Water reabsorption in the descending limb concentrates luminal sodium and creates a favorable gradient for passive sodium reabsorption, probably by the paracellular route.
• In the thick ascending limb, the transport properties of the epithelium change and active processes become dominant; the major luminal entry step is via the Na-K-2Cl symporter.
o There is also an Na-H antiporter in the luminal membrane.
o 50% of sodium reabsorption in the thick limb still occurs by paracellular diffusion.
What does the Na-K-2Cl symporter require?
• It requires that equal amounts of K+ and Na+ be transported
• However, there is far less K+ than Na+ in the lumen, so it seems that K+ would be depleted long before much Na+ is reabsorbed.
• Answer: the luminal membrane has a large number of K+ channels that allow much of the potassium to leak back into the lumen.
What is the “diluting segment”?
It refers to the ascending limb, because it absorbs more solute than water, with the result that the fluid leaving the loop to enter the distal convoluted tubule is hypo-osmotic (more dilute) compared with plasma.
Describe reabsorption in the distal convoluted tubule.
• The major luminal entry step in the active reabsorption of sodium and chloride by the distal convoluted tubule is via the Na-Cl symporter.
• Distal convoluted tubule cells are a major site for the control of calcium homeostasis because they have apical calcium channels that are regulated by parathyroid hormone.
How does the Na-Cl symporter in the distal convoluted tubule differ from the thick ascending loop Na-K-2Cl symporter?
They have different characteristics, so they are sensitive to different drugs.
What is the function of principal cells in the collecting ducts?
• They reabsorb sodium via epithelial sodium channels.
• They reabsorb water, which is subject to physiological control by ADH.
o The inner medullary collecting duct has a finite water permeability even in the absence of ADH, but the outer medullary and cortical regions have a low water permeability without ADH.
• They also play a major role in potassium homeostasis.
How is chloride reabsorbed in the collecting ducts?
Also by active reabsorption by type B intercalated cells.
What are the functions of intercalated cells?
They also play a role in maintaining acid-base homeostasis.
What happens when ADH levels are low?
• When ADH levels are low, and therefore water permeability is very low, the hypo-osmotic fluid entering the collecting-duct system from the distal convoluted tubule remains hypo-osmotic as it flows along the ducts.
• When this fluid reaches the medullary portions of the collecting ducts, there is now a huge osmotic gradient favoring reabsorption, which occurs.
• SO, although there is little cortical water reabsorption without ADH, there is still a finite medullary absorption because of the enormous osmotic gradient.
• However, because there is such a high tubular volume, most of the water entering the medullary collecting duct flows on to the ureter.
• The result is the excretion of a large volume of very hypo-osmotic (dilute) urine or water diuresis.
In water diuresis, what is the last tubular segment to reabsorb large amounts of water?
• The descending limb of the loop of Henle.
• In all later segments, solute reabsorption continues but water reabsorption is minimal; however, reasborption of sodium is not retarded in any way.
• This is possible because these tubular segments are “tight” epithelia, and there is very little back-leak of sodium from interstitium to tubular lumen despite the large electrochemical gradient favoring diffusion.
What happens when the collecting-duct system’s water permeability is very high instead of very low?
• As the hypo-osmotic fluid entering the collecting-duct system from the distal convoluted tubule flows through the cortical collecting ducts, water is rapidly reabsorbed. This is because of the large difference in osmolality between hypo-osmotic luminal fluid and the iso-osmotic interstitial fluid of the cortex.
• Once the osmolality of the luminal fluid approaches that of the interstitial fluid, the cortical collecting duct behaves like the proximal tubule, reabsorbing equal amounts of solute and water.
• In the medullary collecting duct, solute reabsorption continues but water reabsorption is proportionally even greater, so fluid becomes hyperosmotic.
How does ADH convert epithelial water permeability from low to high?
• The tubular response to ADH is not all or none, but shows graded increases as the plasma concentration of ADH increases over a certain range.
• In collecting ducts, renal receptors for ADH are in the basolateral membrane of the principal cells.
• The binding of ADH by its receptors results in the activation of adenylate cyclase, which catalyzes the intracellular production of cAMP.
• cAMP induces, by a sequence of events, the migration of intracellular vesicles to, and their fusion with, the luminal membrane.
• These vesicle contain an isoform of the water channel protein aquaoporin 2, through which water can move.
• In the absence of ADH, aquaporins are withdrawn from the luminal membrane by endocytosis.
How is water permeability of the basolateral membrane of renal epithelial cells different from permeability of the luminal membrane?
• The basolateral membrane is always highly permeable to water because of the constitutive presence of aquaporin isoforms other than aquaporin 2.
• Since the luminal membrane is affected by ADH, it is rate-limiting.
How do the thick ascending limbs help generate a hyperosmotic medullary interstitium?
• At the junction between the inner and outer medulla, the ascending limbs of all loops of Henle turn into thick regions and remain thick until they reach the original Bowman’s capsules from which they arose.
• As they remove solute without water and dilute the luminal fluid, they are simultaneously putting solute without water into surrounding interstitium.
• For portions of the tube in the cortex, reabsorbed solute is immediately reabsorbed by the abundant peritubular capillaries.
• However, since blood flow in the medulla is much lower, solute can accumulate in the medullary interstitium.
How does the physical arrangement of descending and ascending vasa recta help to generate a hyperosmotic medullary interstitium?
• The descending and ascending vasa recta run near each other in parallel.
• Solute and water enter and leave the vasa recta, so that plasma osmolality approaches that of its surroundings, and as plasma flows deep into the medulla, it becomes hyperosmotic.
• If blood vessels were to leave the medulla at the papilla, instead of changing course and returning to the corticomedullary junction, they would remove a very hyperosmotic fluid and tend to wash out or remove the hyperosmolality of the interstitium.
What is a countercurrent exchange system?
• The flow of blood in parallel vessels in opposite direction and the ability of the vessels to at least partially equilibriate with the surrounding interstitium.
• Cannot generate the osmotic gradient, but is crucial in preserving it.
How does the recycling of urea help to generate a hyperosmotic medullary interstitium?
• In the inner medullary collecting ducts, some urea is reabsorbed via specialized urea uniporters; because blood flow in the region is low, the reabsorbed urea raises the interstitial concentration close to that of the lumen – typically half the filtered load remains in the lumen and is excreted.
• Usually, urea constitutes about half the medullary osmolality.
How does ADH affect urea?
• ADH raises urea permeability by stimulating a specific ADH-sensitive isoform of the urea uniporters, but only in the inner medullary collecting ducts.
• When a person is dehydrated, GFR is low and levels of ADH are high, and so both water and urea are reabsorbed.
• During states of overhydration, ADH is low and GRF is high, so little tubular fluid is reabsorbed. The inner medullary collecting duct has a finite water permeability even in the absence of ADH, but not much urea is reabsorbed. The result: the inner medulla is partially washed out (the urea concentration and total osmolality of the medullary interstitium decrease over time).
In regulating Na+ and H2O, what 4 quantities do the kidneys regulate?
Water balance, salt balance, osmolality, and blood pressure
Why is blood pressure crucial in salt and water balance?
It plays an enormous role in generating the signals that alter water and sodium excretion by the kidneys.
What concepts are important for regulation of blood pressure?
• Setpoint: the value that blood pressure should be at any moment.
• To regulate blood pressure near the setpoint requires detectors of blood pressure, which assess the level of blood pressure at any moment.
• Signals generated in response to changes in blood pressure sensed by the detectors communicate with effectors, which change what they do in response to signals in order to raise or lower the blood pressure.
What are the 3 contrasting temporal realms of blood pressure control?
• Short-term, moment-to-moment control (seconds to minutes)
• Intermediate-term control (minutes to hours)
• Long-term control (hours to days)
What controls the blood pressure setpoint?
A set of brainstem nuclei often called the “vasomotor center”
What are the 2 major types of detectors for the control of short-term blood pressure?
• Baroreceptors that mediate the classic baroreceptor reflex. These are afferent nerve cells (mechanoreceptors) with sensory endings located in the carotid arteries and the arch of the aorta. They report arterial blood pressure to the vasomotor center via sensory neural pathways.
• Cardiopulmonary baroreceptors, which are nerve cells with sensory ending located in the cardiac atria and parts of the pulmonary vasculature. They are often called low-pressure baroreceptors because they assess pressures in regions of the vascular tree where pressures are lower than in the arteries. They send afferent neural information to the vasomotor center.
Describe the actions of the vasomotor center.
• Based on inputs from the baroreceptors, the vasomotor center sends regulatory signals to effector systems: the heart, blood vessels, and kidneys via the autonomic nervous system.
• Sympathetic signals directly stimulate vasoconstriction or dilation with consequent changes in peripheral vascular resistance and CVP.
• Sympathetic activity also alters heart rate and cardiac contractility to correct short-term changes in blood pressure.
• Setpoint for MAP is slightly less than 100 mm Hg in most people
How long does it take for short-term control of BP to kick in?
A few seconds (1 or 2 heartbeats)
At what point does the kidney contribute to control of blood pressure?
It does not contribute in the short-term control, but can reinforce the short-term vascular effects of the vasomotor center if a deviation in blood pressure is maintained longer than a few tens of seconds.
What are the major renal detectors involved in intermediate-term regulation of blood pressure?
• Pressure-sensitive cells within the kidney, often called intrarenal baroreceptors, that sense renal afferent arteriolar pressure.
• These are not true baroreceptors but rather are specialization of the cells of the afferent arteriole: granular cells that form part of the JGA
• These are not nerve cells and do not send signals to the vasomotor center; rather, they act entirely within the kidney
• Neural signals originating in the vasomotor center do reach the granular cells via the sympathetic nerve.
What is the function of granular cells in the JGA?
They release the peptide hormone renin in response to changes in afferent arteriolar pressure or signals from renal sympathetic nerves.
What does renin do? What happens after it does what it does?
• It splits circulating angiotensinogen to form angiotensin I.
• Angiotensin-converting enzyme (ACE) in endothelial cells of capillaries further cleaves angiotensin I to produce angiotensin II.
• Angiotensin II is a potent vasoconstrictor and increases TPR and BP.
How is renin production inhibited?
Angiotensin II acts in a negative feedback manner to inhibit renin production by acting directly on granular cells (by interacting with AT1 receptors on granular cells to increase intracellular Ca concentration, which inhibits renin production).
How do the kidneys regulate blood pressure long-term?
• Pressures in the vascular tree require an appropriate volume of blood, and blood volume depends on total ECF volume, which is controlled by kidneys.
Is there a time lag between vascular volume and pressure changes?
• Yes because tendencies to change pressure are buffered by the baroreceptor reflex, and the kidneys change their output of salt and water to match input.
• However, if the kidneys do not match their output to input, and changes in ECF volume are sustained, then pressure gradually creeps toward a new elevated or depressed value.
What is the relationship between osmolarity and volume?
Volume = total osmoles/osmolarity; so, the ECF volume is determined by the total osmotic content of the ECF and regulates its osmolarity.
What makes up the ECF osmotic content?
• 90% of the ECF osmotic content is accounted for by sodium and the equal number of anions that must accompany it; so ECF osmotic content is approximately equal to sodium content x 2.
• 10% of the ECF solute is accounted for by substances such as potassium, glucose, urea, etc. The regulation of solutes other than sodium is unrelated to control of ECF osmolality.
How do kidneys receive information about sodium content?
• Through systemic blood pressure, as sensed through vascular and renal baroreceptor-sensing mechanisms.
• Blood pressure, blood volume, and total body sodium are closely connected.
What is pressure natriuresis and pressure diuresis?
• Pressure natriuresis is the situation in which there is an increased sodium content of the urine as a result of elevated blood pressure.
• Pressure diuresis refers to the situation in which there is an increased volume of urine.
How does the degree of salt and water excretion for a given rise in pressure vary with the volume status of the body?
• If ECF volume is normal or high and pressure rises, pressure natriuresis and diuresis are very effective in increasing excretion of sodium and water and reducing blood volume.
• If ECF volume is low and pressure rises, much less salt and water is lost.
How does GFR affect sodium excretion?
• Sodium excretion represents the difference between filtration and reabsorption, so GFR plays role in the regulation of sodium excretion.
• However, a change in the amount of sodium filtered is also accompanied by a change in the amount of water filtered.
• So, a change in GFR represents a mechanism for altering ECF volume rather than independently regulating salt and water.
Describe the reflex control of GFR.
• It is mediated mainly be changing the resistance of the afferent and efferent arteriolar resistance; these changes in resistance are produced by changes in renal sympathetic nerve activity and circulating levels of angiotensin II.
• A decrease in plasma volume increases activity of sympathetic nerves and angiotensin II, which decrease the GFR.
What is a consequence of changing afferent resistance in order to alter GFR?
• RBF and pressure in the glomerular capillaries are altered, both of which can have deleterious effects.
• Substantial reductions in RBF will severely compromise already oxygen-poor regions of the kidney like the medulla.
• Substantial increases in glomerular capillary pressures can damage glomeruli
• In addition, the ability of the kidney to correct total body electrolyte imbalances depends on keeping tubular flow within a certain limited range.
Describe autoregulation of GFR by the kidney.
• The kidney produces prostaglandins that cause vasodilation of arterioles and relaxation of mesangial cells, and therefore oppose the actions of angiotensin II on the kidneys.
• Increased local angiotensin II concentrations associated with renin release and increased sympathetic input stimulate the production of prostaglandins, which then dampen the effects of these two mechanisms on renal arterioles.
• This maintains RBF and GFR despite systemic vasoconstriction.
Describe tubuloglomerular feedback of GFR and RBF.
• Is associated with the macula densa sodium chloride detector.
• When GFR is high, Na-K-2Cl symporters take up Na/Cl/K, and so cells swell.
• Na-H antiporters are stimulated and depolarize the cell, leading to Ca entry across the basolateral membrane, which causes a release of ATP from the basolateral surface of the cells in close proximity to the glomerular mesangial cells and afferent arteriolar smooth muscle cells. Contraction of mesangial cells decreases the effective filtration area, which decreases GFR. Contraction of the afferent arteriolar smooth muscle cells increases afferent resistance and decreases RBF and GFR.
• The increased Ca also reduces renin secretion.
• The net effect: the pressure natriuretic and diuretic responses are blunted.
Why does a rise in either peritubular capillary pressure or interstitial pressure reduce net reabsorption?
• An increased interstitial pressure causes back-leak of reabsorbed fluid from the interstitial space across the tight junctions into the tubule; this does not alter cellular transport mechanisms, just reduced net reabsorption by those transport mechanism, particularly in the “leaky” proximal tubule.
• An increase in pertiubular-capillary hydraulic pressure (PPC) recues the force favoring movement of interstitial fluid into the capillaries. This causes fluid to accumulate in the interstitium, thereby raising interstitial pressure.
o A decrease in peritubular-capillary oncotic pressure (πPC) does the same thing.
What causes changes in PPC and πPC?
• PPC is set by (1) arterial pressure and (2) the combined vascular resistances of the afferent and efferent arterioles, which determine how much of the arterial pressure is lost by the time the peritubular capillaries are reached.
• ΠPC is set by (1) arterial oncotic pressure and (2) filtration fraction (GFR-RPF), which determine how much the oncotic pressure increases from its original arterial value during passage through the glomeruli.
What happens on a high salt-diet or expansion of the ECF from some other physiological cause occurs?
• Decreased plasma oncotic pressure (results from dilution of plasma proteins)
• Increased arterial pressure
• Renal vasodilation secondary to decreased activity of the renal sympathetic nerves and decreased angiotensin II.
• Simultaneously then, the GFR increases a small amount and so does interstitial pressure, which reduces fluid reabsorption.
Why is the control of tubular sodium reabsorption more important than control of the GFR in the regulation of sodium excretion?
• A change in GFR automatically induces a proportional change in the reabsorption of sodium by the proximal tubules, so that the fraction reabsorbed (but not the total amount) remains relatively constant.
• This is called glomerulotubular balance; when there is aprimary change in GFR, the percentage of filtered sodium reabsorbed proximally remains constant (~65%) and the fraction not reabsorbed remains constant (~35%).
• When the fraction reabsorbed is changed, the change is caused by processes other than changes in GFR.
• The mechanisms responsible for these changes are completely intrarenal.
Are pressure natriuresis and diuresis useful for independently controlling salt or water balance? How is control of salt alone achieved?
• No; sodium balance requires specific hormonal mechanisms.
• Unlike pressure diuresis and natriuresis, most of the processes for independent control of sodium occur in the distal nephron.
What does aldosterone do?
• It increases sodium reabsorption in the cortical connecting tubule and cortical collecting duct, specifically by the principal cells.
• Affects about 2% of the total filtered sodium; this is actually a large amount due to the huge volume of the glomerular filtrate (~552 mmol/day or 30 g of NaCl/day).
Describe the action of aldosterone.
• In the kidney, it acts like many other steroid hormones
• It has enough lipid character to freely cross principal cell membranes, after which it combines with mineralcorticoid receptors in the cytoplasm.
• Aldosterone-bound receptors undergo a change in conformation that reveals a formerly hidden nuclear localization signal.
• After being transported to the nucleus, the receptor acts as a transcription factor that promotes gene expression and synthesis of mRNA, which mediates translation of specific proteins.
• The effect of these proteins is to increase the activity or number of luminal membrane sodium channels and basolateral membrane Na-K-ATPase pumps to exactly what is needed to promote increased reabsorption of sodium.
How are aldosterone levels controlled?
• Increased potassium and angiotensin II stimulates the adrenal cortex to produce aldosterone.
• Atrial natriuretic factors inhibit aldosterone secretion.
Discuss the effects of natriuretic peptides.
• They promote excretion of sodium in the urine.
• Key among them are arterial natriuretic peptide (ANP) and brain natriuretic peptide (BNP); the main source of both is the heart.
• They have both vascular and tubular actions: they relax the afferent arteriole (promoting filtration) and act at several sites in the tubule.
• They inhibit release of renin, inhibit the actions of angiotensin II to promote reabsorption of sodium, and act in the medullary collecting duct to inhibit sodium reabsorption.
What stimulates the secretion of natriuretic peptides?
Distention of the atria, which occurs during plasma volume expansion.
What is the major function of ADH?
• Major function is to increase the permeability of the cortical and medullary collecting ducts to water, thereby decreasing the excretion of water.
• ADH also increases sodium reabsorption by the cortical collecting duct, one of the same segments influenced by aldosterone; this effect is particularly evident when plasma aldosterone is elevated, and ADH’s action seems to synergize with the action of this steroid hormone.
What hormones, aside from ADH and natriuretic peptides, effect the excretion of sodium?
• Cortisol, estrogen, growth hormone, thyroid hormone, and insulin enhance sodium reabsorption.
• Glucagon, progesterone, and parathyroid hormone decrease sodium reabsorption.
• The secretion of these hormones is not reflexively controlled specifically for the homeostatic regulation of sodium balance.
How does the independent control of water differ from the independent control of sodium?
• In both, the major regulated determinant of excretion is not the rate at which it is filtered but rather the rate at which it is reabsorbed.
• In both, excretion consists of 2 major components: a proximal nephron component, in which water is absorbed along with sodium as an isotonic fluid, and a distal nephron component, in which water can be reabsorbed independent of sodium.
What regulates total-body water?
Reflexes that alter the secretion of ADH.
Describe ADH.
• It is a peptide produced by a discrete group of hypothalamic neurons whose cell bodies are located in the supraoptic and paraventricular nuclei and whose axons terminate in the posterior pituitary gland, from which ADH is released into the blood.
• The most important inputs to these neurons are from cardiovascular baroreceptors and hypothalamic osmoreceptors.
Describe baroreceptor control of ADH secretion.
• A decreased extracellular volume reflexively produces an increased aldosterone secretion and induces increased ADH secretion.
• Decreased CV pressures cause less firing by the baroreceptors.
• Via afferent neurons from the baroreceptors and ascending pathways to the hypothalamus, this decreased baroreceptor firing stimulates ADH secretion.
• The adaptive value of these baroreceptors is to help restore ECF volume, and hence, blood pressure.
• Also, high concentrations of ADH (much higher than those needed to produce maximal antidiuresis) directly vasoconstrict arteriolar smooth m; the result is an increased TPR, which helps raise arterial blood pressure independently of the slower restoration of body fluid volumes.
What is the major effect of gaining or losing water without corresponding changes in sodium?
• There is a change in the osmolality of the body fluids.
• This is important because, under conditions of water gain or loss, the receptors that initiate reflexes controlling ADH secretion are osmoreceptors in the hypothalamus (receptors response to changes in osmolality).
Describe the hypothalamus cells that regulate ADH secretion.
They are true integraters that incorporate information from two sources: baroreceptors and osmoreceptors.
What happens when baroreceptor and osmoreceptor inputs oppose each other (eg, if plasma volume and osmolality are both decreased)?
• In general, because of the high sensitivity of the osmoreceptors, the osmoreceptor influence predominates over that of the baroreceptor when changes in osmolality and plasma volume are small to moderate.
• However, a very large change in plasma volume will take precedence over decreased body fluid osmolality in influencing ADH secretion.
• Overall, it is more important for the body to preserve vascular volume and ensure adequate CO than it is to preserve normal osmolality.
What else, beside input to the hypothalamus, effects ADH secretion?
• ADH secretion can be altered by pain, fear, and a variety of other factors, including drugs such as alcohol, which inhibits ADH release.
What causes constant water diuresis in patients with diabetes insipidus?
• They have lost the ability to produce ADH because of damage to the hypothalamus or have lost the ability to respond to ADH because of defects in principal cell ADH receptors.
• Thus, collecting-duct permeability to water is low and unchanging regardless of extracellular osmolality or volume.
Describe thirst.
• The centers that mediate thirst are located in the hypothalamus (very close to those areas that produce ADH).
• The subjective feelings of thirst is stimulated both by reduced plasma volume and by increased body fluid osmolality.
• Angiotensin II stimulates thirst via direct effect on the brain; this constitutes one pathway by which thirst is stimulated when ECF volume is decreased.
• The thirst response is significantly less sensitive than the ADH response.
How is it that, when animals are dehydrated, they rapidly drink just enough water to replace their previous losses and then stop, even though the water has not yet had time to be absorbed from the GI tract?
Some kind of metering system has occurred, but its nature is a mystery.
What are the two components of salt appetite?
• Hedonistic appetite (animals like salt and eat it whenever they can regardless of whether they are salt deficient).
• Regulatory appetite (their drive to obtain salt is markedly increased in the presence of deficiency).
How are CHF and hypertension related to the kidneys?
They involve perturbed renal handling of sodium; the problem seems to stem from inappropriate signaling to the kidneys.
What causes hypertension?
• A blood volume and total body sodium content that is too high for the volume of the vascular tree.
• The reason for excess blood volume may or may not be clear.
• In cases where the defect causing hypertension is more or less obvious, correcting the underlying pathology usually corrects the hypertension.
• When levels of renin, angiotensin II, and aldosterone are normal, the defect in the regulation of sodium absorption must lie subsequent to aldosterone interaction with the cells of the collecting tubule.
Where is potassium found?
• The vast majority is intracellular, with only ~2% extracellular.
• The small EC fraction is crucial for body function and is closely regulated.
• Muscle makes up the largest store of potassium in the body.
How much potassium do we normally find intra- and extracellularly?
• Intracellular potassium concentrations are about 140-150 mEq/L.
• Major elevations (hyperkalemia) an depressions (hypokalemia) from the normal value of 4 meq/L are cause for medical intervention.
• In a clinical setting, only the extracellular concentration can be measured.
What does the EC potassium concentration depend on?
• The total amount of potassium in the body.
• The distribution of this potassium between the ECF and ICF compartments.
• Total-body potassium is determined by intake and excretion.
How is potassium lost from the body?
Normally, via urine. Losses via sweat and the GI tract are small, but large quantities may be lost from the tract during vomiting or diarrhea.
How is the high level of potassium within cells maintained?
• Na-K-ATPase plasma membrane pumps, which actively transport K into cells.
• On a short-term basis, uptake and release of potassium by tissue cells prevent large swings in extracellular potassium concentration.
What is the effect of epinephrine on cellular potassium uptake?
During exercise, K+ moves out of muscle cells that are rapidly firing action potentials. Damaged cells leak K+. In both cases, this raises extracellular K+ concentration. However, at the same time, exercise or trauma increases adrenal secretion of epinephrine, which stimulates K+ uptake by other cells, partially offsetting the outflow from the exercising or damaged cells.
How does insulin affect potassium uptake?
• The rise in plasma insulin concentration after a meal helps move ingesteed and absorbed K into cells, rather than allowing it to accumulate in the ECF.
• This new K then slowly comes out of cells between meals to be excreted.
• A large increase in plasma K concentration facilitates insulin secretion at any time, and additional insulin induces greater uptake by cells, a negative feedback system for opposing acute elevations in plasma K concentration.
How does ECF H+ concentration affect the distribution of potassium?
An increase in ECF H+ concentration is often associated with net K movement out of cells, where as a decrease in ECF H+ concentration causes net potassium movement into them.
Describe filtering and reabsorption of potassium.
• K is freely filtered and the majority is immediately reabsorbed by the proximal tubule.
• Most of the rest is reabsorbed in the loop of Henle, so that under virtually all conditions, only about 10% of the filtered load is presented to the distal nephron. In the collecting ducts, reabsorption is continuous.
What is the nature of K transport in the proximal tubule and thick ascending limb of Henle?
• Proximal tubule: paracellular diffusion, the concentration gradient for which is created by water reabsorption.
• Thick ascending limb: driven by luminal membrane Na-K-2Cl multiporter and partially by paracellular diffusion (so, K reabsorp. depends on Na reabsorp.)
How can the cortical collecting duct manifest either net K+ reabsorption or net K+ secretion?
• K is secreted by principal cells and reabsorbed by type A intercalated cells.
• Under conditions of normal or high potassium intake, principal cell potassium secretion is much greater than potassium reabsorption by Type A intercalated cells; during K depletion, principal cells reduce their secretion.
• So, differences in K excretion over the usual physiological range are due primarily to differences in the amount of K secreted by the cortical collecting duct; there is little homeostatic control of K reabsorption in any segment.
Describe the mechanism of K+ secretion in the cortical collecting duct.
• Critical event: the active transport of potassium from the interstitial fluid across the basolateral membrane into the cell, mediated via Na-K-ATPase pumps, which continuously put potassium into cells.
• K then passively moves across the luminal membrane via numerous luminal K channels.
• Principal cells also express K-Cl symporters in their luminal membranes.
How is K+ secretion by principal cells of the cortical collecting duct regulated to achieve homeostasis of body K+ when K+ levels are high?
• 3 factors: (1) the concentration of K+ in the blood perfusing the kidney, (2) plasma levels of aldosterone, (3) the delivery of Na+ to the distal nephron.
• Principal cells of the cortical collecting duct contain an isoform of Na-K-ATPase that is especially sensitive to increases in the concentration of potassium in the peritubular capillaries and increase their uptake of potassium as the basolateral Na-K-ATP is activated; principal cell intracellular potassium concentration increases.
• Aldosterone enhances potassium secretion by activating apical potassium channels in principal cells (called ROMK) and stimulates the activity of the basolateral membrane Na-K-ATPase pumps.
• Remember: aldosterone increases the activity or number of the luminal membrane sodium channels; potassium secretion is absolutely dependent on sodium reabsorption because potassium cannot be taken up unless sodium is being pumped out by the Na-K-ATPase.
Describe the signaling pathway by which changes in plasma potassium produce changes in circulating levels of aldosterone?
• Aldosterone-secreting cells of the adrenal cortex are sensitive to the potassium concentration of the ECF bathing them; increased intake of potassium leads to increased ECF potassium concentration.
What happens to homeostatic mechanisms when K+ levels are low?
• All the homeostatic processes that function when potassium levels are high are reversed when potassium levels are low.
• Potassium concentration in the interstitium outside the principle cells is lowered, reducing Na-K-ATPase driven entry of potassium into principal cells.
• Decreased K+ also decreases aldosterone production, which reduces K+ and Na+ permeability of principal cell apical membranes, reducing K+ secretion.
• Less potassium is excreted, helping preserve normal ECF K+ concentration.
What happens when decreases or increases in both potassium and plasma volume occur simultaneously?
• There is a conflict because these two changes drive aldosterone production in opposite directions; whether aldosterone increase or decreases depends on the relative magnitudes of the opposing inputs.
• In general, changes in sodium balance and blood pressure have a greater effect on aldosterone secretion than equivalent changes in K+ balance.
If aldosterone secretion is altered due to an altered sodium balance, will the change in plasma aldosterone cause an potassium imbalance?
Usually, no. A high sodium diet will decrease aldosterone secretion (decreasing potassium secretion by cortical collecting ducts) but will also increase GFR and reduce proximal sodium reabsorption, which increases fluid delivery to the cortical collecting ducts (increasing potassium secretion).
Why does an increase in flow increase potassium secretion?
• The movement of potassium across the apical membrane of principal cells is through an ion channel. Ion movement through channels is driven by concentration gradients (and potential).
• Increased luminal flow prevents accumulation of potassium and maintains a very low luminal concentration, thereby promoting secretion.
• This same explanation in reverse applies to sodium-depleted individuals and to those with CHF – such persons have high aldosterone, which will tend to increase K+ secretion, but low fluid delivery, which reduces K+ secretion.
What is the effect of diuretics on potassium?
• Most have the unwanted side effect of increasing the renal excretion of potassium, which may result in sever potassium depletion.
• This is partially due to the fact that potassium rebabsorption in the proximal tubule and Henle’s loop is linked to sodium reabsorption.
• However, most of the increased K+ excretion is due to increased potassium secretion by the cortical collecting duct; this is caused by increased flow and increased delivery of sodium, resulting from upstream inhibition of sodium and water reabsorption.
How are the negative effects of diuretics on K+ avoided?
• Patients given diuretics are also given drugs that block the renal actions of aldosterone; these drugs are weak diuretics because they block aldosterone’s stimulation of sodium reabsorption, but unlike other diuretics they are “potassium sparing” because they simultaneous block aldosterone’s stimulation of potassium channels that promote potassium secretion.
• Blocking sodium absorption upstream from the cortical collecting duct increase potassium secretion; blocking sodium reabsorption in the cortical collecting duct does not.
What pH changes are associated with potassium disturbances?
• Alkalosis is often, but not always, associated with hypokalemia.
• Acidosis is often associated with hyperkalemia.
Why do changes in pH affect potassium levels?
• 1) Elevations and depression in the extracellular concentration of hydrogen ions lead to a de facto exchange of these ions with cellular cations, the most important of which is potassium.
o Ex: a high pH induces cells to take up potassium, causing hypokelmia.
o Ex: a low pH leads cells to dump potassium, causing hyperkalemia.
• 2) Intracellular pH affects cellular Na-K-ATPase and K+ channel activity.
o Low intracellular pH inhibits pumps, allowing K+ to escape from cells to increase plasma potassium; principal cells respond inappropriately and do not effectively secrete excess plasma K+ (paradoxical K+ retention).
o High intracellular pH reverse these effects and relieves inhibition; it promotes potassium loss and contributes to the hypokalemia.
What 2 sets of processes make up acid-base physiology?
• Input and output of acids and bases from the body obey the same principles of balance used in other aspects of renal function.
• The regulation of the components of the main physiological buffer system, carbon dioxide and bicarbonate.
What are the 4 guidelines for studying acid-base biology?
• Acids and bases obey the balance principle.
• Body fluids are buffered.
• Input and output of acids alter bicarbonate but not partial pressure of CO2.
• Excretion of CO2 and bicarbonate are independent of each other.
What are the routes of entry for acids or bases?
• De novo generation of acids and bases from metabolism.
• Activity of the GI tract that adds acids or bases.
• Processing of ingested food, which adds acids or bases.
• Metabolism of stored fat and glycogen can also add acid.
What is an acid-base disturbance?
• Situations in which either there is an unusually high input or output of acid or the plasma pH is abnormal.
• Although the body is sometimes transiently out of balance for acids and bases, acid-base disturbances do not mean there is a persistent imbalance.
• Input and output of hydrogen ion may be in balance during metabolic disorders that produce excess acid, but the balance comes about only after there has been a significant change in blood pH or bicarbonate concentration.
How does a buffered system work?
• A buffered system contains weak acids, which only partially dissociate, and the conjugate base of those weak acids.
• It prevents large changes in pH after the addition or loss of protons.
o Addition: most new H+ binds to conjugate bases
o Loss: H+ are released from existing weak acids.
• They blunt the change in pH and give the kidneys time to alter their excretion and restore balance so that output again equals input.
Where are buffer systems found in the body?
They exist in the ECF, ICF, the matrix of bone, and all these system communicate with each other.
What makes the CO2-bicarbonate system different from other systems?
CO2 is not acid per se (it cannot donate a hydrogen ion by itself), but reacts with water to form carbonic acid, which partially dissociates into a hydrogen ion and a conjugate base.
How much carbonic acid is in our blood?
• The concentration is miniscule (~3 μmol/L), and at first glance appears to have little effective buffering capacity.
• However, because the supply of CO2 is infinite, any carbonic acid consumed in the reaction is replaced from existing CO2.
What does carbonic anhydrase do?
• It greatly speeds the reaction to form bicarbonate and a hydrogen ion from CO2 and water.
• It increases the velocity of the reaction but does not change the equilibrium concentrations of reactants and products.
Why is CO2 often called a volatile acid?
• Because it can escape from solute as a gas.
• Most other acids are fixed acids.
Why is the concentration of CO2 essentially constant?
• Because the partial pressure of arterial CO2 is regulated by our respiratory system to be about 40 mm Hg (a concentration in blood of 1.2 mmol/L).
• Any rise or fall in PCO2 is sensed by the respiratory centers in the brainstem that alter the rate of ventilation to restore the concentration.
• When PCO2 is not 40 mm Hg, this is due to activity of the respiratory system rather than a response to the addition or loss of hydrogen ions.
Adding or removing H+ does not change PCO2; what does it change?
The concentration of bicarbonate; adding H+ drives the reaction to the left and reduces bicarbonate on a nearly mole-for-mole basis. Removing H+ drives the reaction to the right and raises bicarbonate in the same way.
What is another way to look at the problem of maintaining H balance?
• It can also be seen as a problem of maintaining bicarbonate balance.
• For every H+ added, one bicarbonate disappears.
• Generation of new bicarbonate is the responsibility of the kidney.
What is the rate of CO2 production in the body?
9 mmol/min; it is eliminated at the same rate, so there is no net addition.
Are the input/output of CO2 and HCO3- independent of one another?
Yes; one cannot be excreted of the other. Excess CO2 must be balanced by the lungs and excess bicarbonate must be balanced by renal output.
What is produced by the metabolism of dietary protein?
• Protein contains some amino acids that contribute acid or base.
• When sulfur- or phosphorus-containing amino acids and those with cationic side chains are metabolized to CO2, water, and urea, the end result is addition of fixed acid.
• Oxidative metabolism of amino acids with anionic side chains adds base.
• For typical American diets, the input is acidic.
What is produced by the metabolism of dietary weak acids?
• Fruits and vegetables (esp. citrus fruits) contain a lot of weak acids and salts of those acids (conjugate base plus a cation). Metabolism of these acidic substances actually alkalinizes the blood (called the fruit juice paradox)
• The complete oxidation of the protonated form of an organic acid is acid-base neutral, but complete oxidation of the base form adds bicarbonate to the body.
What is produced by GI secretions?
• The GI tract, from salivary glands to the colon, is lined with an epithelium that can secrete hydrogen ions, bicarbonate, or a combination.
• Also, the major exocrine secretions of the pancreas and liver that flow into the duodenum contain large amounts of bicarbonate.
• Normally, the sum of these secretions is nearly acid-base neutral; however, in conditions of vomiting or diarrhea, on kind of secretion may dominate.
• Important: GI secretion of hydrogen ions is accompanied by putting base into the blood and vice versa.
What is produced by anaerobic metabolism of carbs and fats?
• The normal oxidative metabolism of carbs and fat is acid-base neutral; both are oxidized to CO2 and water. Although intermediates are acids or bases, the sum of all reactions is neutral.
• Some conditions lead to the production of fixed acids: the anaerobic metabolism of carbs produces lactic acid; poor tissue perfusion can be a major acidifying factor; metabolism of triglyceride to Beta-hydroxybutyrate and acetoacetate add ketone bodies.
How much bicarbonate is freely filtered per day?
4320 mmol/day, excretion of which would be equivalent to adding more than 4 L of 1N acid to the body – so reabsorption is essential.
Discuss the secretion of hydrogen ions in the nephron.
An enormous amount of hydrogen ion secretion occurs in the proximal tubule, with additional secretion in the thick ascending limb of Henle’s loop and collecting-duct system.
Describe reasborption of bicarbonate.
• Is not accomplished in the conventional manner via an active transporter.
• It is basically the same in all tubular segments, although precise transporters may differ to some extent.
• Within the cells, a hydrogen ion and a bicarbonate are generated from CO2 and water, catalyzed by carbonic anhydrase; the hydrogen ion is actively secreted into the tubular lumen.
• For every H+ secreted, 1 bicarbonate ion is generated within the cell.
• The bicarbonate is transported across the basolateral membrane into the interstitial fluid and then into the peritubular capillary blood.
• Net result: for every H+ secreted into the lumen, a bicarbonate ion enters the blood in the peritubular capillaries.
What is the fate of reabsorbed bicarbonate?
• It is transported across the basolateral membrane via Cl-HCO3 antiporters or Na-HCO3 symporters, depending on the tubular segment.
• In both cases the movement of bicarbonate is down its electrochemical gradient.
How are hydrogen ions transported across the luminal membrane?
Via several distinct luminal membrane transporters: Na-H antiporter, which is the major means of H+ secretion and sodium uptake from the proximal tubule lumen; H-ATPase, which exists in all hydrogen ion-secreting distal subular segments; H-K-ATPase, found in Type A intercalated cells of the collecting-duct system, simultaneously moves hydrogen ions into the lumen and potassium into the cell.
How does the process of hydrogen ion secretion achieve bicarbonate reabsorption?
• Once in the tubular lumen, secreted hydrogen ion combines with a filtered bicarbonate to form water and CO2, which diffuses into the cell.
• Overall result: bicarbonate filtered from the blood at the renal corpuscle has disappeared, but its place in the blood has been taken by the bicarbonate that was produced inside the cell.
• Also, the hydrogen ion that was secreted into the lumen is not excreted in the urine; it has been incorporated into water.
What percentage of filtered bicarbonate is reabsorbed in each tubule segment?
• Through the secretion of H+, the proximal tubule reabsorbs 80-90% of the filtered bicarbonate.
• The thick ascending limb of Henle’s loop reabsorbs another 10%.
• Almost all remaining bicbaronate is normally reabsorbed by the distal convoluted tubule and collecting-duct system.
What catalyzes the intraluminal generation of CO2 and water from the large quantities of secreted H+ ions combining with filtered bicarbonate?
Carbonic anhydrase
What happens when there is an increased filtered load of bicarbonate, caused by increased GFR or increased plasma bicarbonate concentration?
• Proximal tubule reabsorption automatically increases as well; it still reabsorbs 80% of the filtered load, but the filtered load is larger.
• When delivery of bicarbonate is increased, there is a decrease in free hydrogen ion concentration, which provides a natural driving force to incrase the rate of the apical Na-H antiport.
What happens when base is added to the body fluids?
• We excrete some bicarbonate in the urine.
• The kidneys do this in 2 ways: they allow some filtered bicarbonate to pass through to the urine and they secrete HCO3- via Type B intercalated cells.
Describe a Type B intercalated cell.
• They are “flipped-around” Type A intercalated cells.
• Within the cytosol, H+ and bicarbonate are generated via carbonic anhydrase, however, the H-ATPase pump is located in the basolateral membrane, and the Cl-HCO3 antiporter is in the luminal membrane.
• So, bicarbonate moves into the tubular membrane, whereas hydrogen ion is actively transported out of the cell across the basolateral membrane and enters the blood, where it can combine with a bicarbonate ion.
• Overall: bicarbonate is excreted, plasma is acidified, and urine is alkalinized.
How do kidneys excrete an acid load?
• Removal of excess acid: more typical than removal of excess base.
• Adding acid to the body reduces the amount of bicarbonate on an almost mole-for mole basis. The kidney replaces lost bicarbonate by generating new bicarbonate from CO2 and water.
• H+ is secreted and combines with the conjugate base of buffers other than bicarbonate, thereby generating the acid form of the buffer, which is excreted in the urine in an amount equivalent to the renal contribution of new bicarbonate to the blood.
• The process of secreting hydrogen ions generates new bicarbonate the goes into the blood and neutralizes the acid load.
Does filtration of hydrogen ions or excretion of free hydrogen ions make a significant contribution to hydrogen ion excretion?
No; first, the filtered load of free hydrogen ions (when the plasma pH is 7.4) is less than 0.1 mmol/day. Second, there is a minimum urinary pH (approximately 4.4) that can be achieved; this corresponds to a free hydrogen ion concentration of 0.04 mmol/L. With a typical daily urine output of 1.5 L, the excretion of free hydrogen ions is only about 0.06 mmol/day, a tiny fraction of the normal 50-100 mmol ingested or produced every day.
What is the most important buffer than H+ joins with, other than bicarbonate?
• Normally, the most important is phosphate.
• Most free plasma phosphate exists in a mixture of monovalent and divalent forms.
• At the normal pH of plasma (7.4), and therefore of the glomerular filtrate, we find that about 80% of the phosphate is in the base (divalent) form and 20% is in the acid (monovalent) form.
• As the tubular fluid is acidified in the collecting ducts, most of the secreted hydrogen ions combine with the base form.
• By the time the minimum intratubular pH of 4.4 is reached, virtually all of the base has been converted to acid.
How much phosphate is available to buffer H+?
• Amount is quite variable; a typical plasma concentration is about 1 mmol/L, of which about 90% is free (the rest is loosely bound to plasma proteins).
• At a GFR of 180 L/day, the filtered load of phosphate is about 160 mmol/day
• Fraction reabsorbed varies from 75% to 90%.
• So, unreabsorbed divalent phosphate available for buffering is roughly 40 mmol/day. So, the kidneys can excrete H+ at a rate of 40 mmol/day.
What happens in a patient with uncontrolled diabetes mellitus?
• Due to metabolic processes that result from insulin deficiency, the patient may become extremely acidotic because of so much production of acetoacetic acid and beta-hydroxybutyric acid.
• At normal plasma pH, these species completely dissociate to yield the anions beta-hydoxybutyrate and acetoacetate and hydrogen ions.
• These anions are filtered at the renal corpuscle but are only partly reabsorbed because they are present in great enough quantities to exceed the renal reabsorptive Tms for them. So, they are available in the tubular fluid to buffer a portion of the hydrogen ions being secreted by the tubules. However, their usefulness in this role is limited by the fact that their pKs are low (4.5), meaning that only half of these anions will be titrated by secreted hydrogen ions before the limiting urine pH of 4.4 is reached.
Why is a second hydrogen ion excretion system involving the excretion of ammonium necessary?
• Hydrogen ion excretion associated with phosphate is ~40 mmol/day.
• Normal hydrogen ion production is 50-100 mmol/day.
• Quantatively, more H+ can be excreted via NH4+ than via organic buffers.
Discuss catabolism of protein.
• Protein catabolism occurs constantly and, when its constituent amino acids are oxidized, generates CO2, water, urea, and some glutamine.
• After many steps, processing of the carboxyl group of the amino acid produces a bicarbonate and processing of the amino group produces an ammonium ion – which is quite toxic at even miniscule levels.
• Ammonium is further process by the liver to urea or glutamine; in both cases, each ammonium consumed also consumes a bicarbonate. So, the bicarbonate produced from the carboxyl group is just an intermediate and does not contribute to body levels.
• When the urea or glutamine is excreted, the body has completed the catabolism of protein in a manner that is acid-base neutral.
Discuss ammonium as an acid.
It is an extremely weak acid (pk ~9.2) but it is an acid because it does release a hydrogen ion (plus ammonia).
Describe renal handling of glutamine.
• Although the production of glutamine is acid-base neutral, it is important to recognize that glutamine can be though to contain 2 components: a base component (bicarbonate) and an acid component (ammonium).
• Glutamine released by the liver is taken up by proximal tubule cells, both from the lumen (filtered glutamine) and from the renal interstitium.
• The cells of the proximal tubule then convert the glutamine back to bicarbonate and NH4+.
• The NH4+ is secreted by the Na-H antiporter into the lumen of the proximal tubule, and the bicarbonate exits into the interstitium and then into the blood (this is new bicarbonate).
• Further processing of the NH4+ is complex, but NH4+ is eventually excreted.
What 3 questions must be answered in order to calculate the net bicarbonate addition to the body or elimination from it?
• How much bicarbonate is excreted in the urine?
• How much new bicarbonate is contributed to the plasma by secretion of hydrogen ions that combine in the tubular lumen with non-bicarbonate urinary buffers?
• How much new bicarbonate is returned to the plasma by secretion of hydrogen ions that are excreted as ammonium?
How do we measure bicarbonate excreted in urine?
Urine flow rate * urinary bicarbonate concentration.
How do we measure how much new bicarbonate is contributed to the plasma by secretion of H+ that combine with non-bicarbonate buffers?
• Titrate the urine with NaOH to a pH of 7.4; the number of milliequivalents of NaOH need to reach pH 7.4 equals the number of milliequivalents of H+ added to the tubular fluid that combined with non-bicarbonate buffers.
• This value is known as the titratable acid.
How do we measure how much new bicarbonate is returned to the plasma by secretion of H+ that are excreted as ammonium?
• The titratable acid measurement will not titrate hydrogen ions in NH4+ because ammonium is such a weak acid with a pK of the ammonia-ammonium reaction so high (9.2) that titration with alkali to pH 7.4 will not remove hydrogen ions from NH4+.
• Urinary ammonium excretion must be measured separately, remembering that for every ammonium excreted, a new bicarbonate was added to blood.
How can we calculate net HCO3- gain or loss to the body?
Titratable acid excreted + NH4+ excreted – HCO3- excreted
What are the major homeostatic signals that influence tubular hydrogen ion secretion?
• PaCO2 and arterial pH, both of which act directly on the kidneys (no nerves or hormones are involved).
• During respiratory acidosis, PaCO2 increases, causing an increased hydrogen ion secretion. During respiratory alkalosis, PaCO2 decreases, causing a decrease in secretion. These effects are due to the effects of an altered PaCO2 on renal intracellular pH. Because the tubular membranes are quite permeable to CO2, an increased arterial PCO2 causes an equivalent increase in PCO2 within tubular cells. This, in turn, causes elevated intracellular H+ concentration and increases the rate of H+ secretion.
• A decrease in extracellular pH unrelated to PaCO2 acts directly on tubular cells, at least in part by changing intracellular pH, to stimulate H+ secretion; an increased extracellular pH does the opposite.
What are the homeostatic controls over the production and tubular handling of NH4+?
• The generation of glutamine by the liver is increased by low extracellular pH; the liver shifts some of the disposal of ammonium ion from urea to Gln.
• Renal metabolism of glutamine is also subject to physiological control by extracellular pH; a decrease in extracellular pH stimulates renal glutamine oxidation by the proximal tubule; an increase does just the opposite.
How does physiological saline compare with D5W?
• Both are given to hospitalized patients intravenously and neither has any acid-base content.
• Physiological saline is 0.9% NaCl and is iso-osmotic with normal body fluids.
• D5W is 5% dextrose monohydrate and is slightly hypotonic.
What is lactated Ringer’s solution?
• A commonly used intravenous solution, containing a mixture of salts and lactate at a concentration of 28 mEq/L with a pH of 6.5.
• It is an alkalinizing solution for the same reason as the fruit juice paradox.
Describe renal compensation for respiratory acidosis.
• Respiratory acidosis results from low ventilation, which causes an increase PaCO2, in turn causing a decrease in pH.
• The kidneys elevate bicarbonate in response to increased PaCO2.
• It occurs because (1) NH4+ production and excretion are increased by the acidosis and (2) the increase in PaCO2 and drop in extracellular pH both stimulate renal tubular hydrogen ion secretion so that all filtered bicarbonate is reabsorbed, and increased amounts of secreted hydrogen ion are left over for the formation of titratable acid.
How effective is renal compensation?
• It varies; generally, compensation is not complete.
• In well-compensated cases, pH may be normal but the elevated PaCO2 and elevated bicarbonate indicate that something is wrong.
Describe renal compensation for respiratory alkalosis.
• Respiratory alkalosis results from hyperventilation, in which the person transiently eliminates carbon dioxide faster than it is produced, thereby lowering PaCO2 and raising pH. Thereafter, even though ventilation remains high, CO2 production and its excretion are normal.
• Hydrogen ion secretion is reduced (so bicarbonate reabsorption is not complete) and bicarbonate secretion is stimulated.
What is the basis for the decrease in HCO3- in metabolic acidosis?
• The addition to the body of increased amounts of any acid other than CO2 by ingestion, infusion, or production; decreased renal production of bicarbonate (as in renal failure); or direct loss of bicarbonate from body (as in diarrhea).
What is the result of a loss of bicarbonate or addition of H+?
• A lower concentration of bicarbonate and a lower plasma pH.
• Kidneys try to compensate by reabsorbing all filtered bicarbonate and producing new bicarbonate through increased formation and excretion of NH4+ and titratable acid.
Describe respiratory compensation for metabolic disorders.
• A decrease in arterial pH stimulates ventilation, thereby lowering PaCO2.
• A rise in arterial pH retards ventilation, allowing PaCO2 to rise.
How do respiratory and metabolic compensation differ?
• Renal compensation for respiratory acid-base disturbances can be nearly complete, whereas respiratory compensation is usually only partial.
In what situations do otherwise normally functioning kidneys transport H+ inappropriately and thereby either generate or maintain an acid-base disturbance (in this case metabolic acidosis)?
Volume contraction; Chloride depletion; Combination of aldosterone excess and potassium depletion
Describe the influence of extracellular volume contraction.
• Occurs due to salt loss and interferes with kidney’s bicarbonate handling.
• A high HCO3- concentration should cause the kidneys to secrete H+ at a level that falls short of complete HCO3- reabsorption. However, the presence of extracellular volume contraction stimulates not only sodium reabsorption but also H+ secretion due to high circulating levels of aldosterone.
• May also occur when volume is normal or high but the body “thinks” volume is low, such as in CHF and advanced liver cirrhosis.
• Net result: all filtered bicarbonate is reabsorbed, plasma pH remains high, and urine is acidic (instead of alkaline, as it should be).
Describe the influence of chloride depletion.
• The loss of chloride, independent of extracellular volume contraction, helps maintain metabolic alkalosis by stimulating hydrogen ion secretion.
• The most common reasons are chronic vomiting and heavy use of diuretics.
• Result: bicarbonate excretion remains essentially zero and the metabolic alkalosis is not corrected.
Describe the influence of aldosterone excess and simultaneous potassium depletion.
• This combination stimulates hydrogen ion secretion markedly.
• As a result, renal tubules not only reabsorb all filtered bicarbonate but also contribute inappropriately large amounts of new bicarbonate to the body, thereby causing metabolic alkalosis.
• This occurs in a variety of clinical situations, the most common of which is the extensive use of diuretic drugs and can generate metabolic alkalosis.
How is the regulation of calcium different from other substances?
• Its balance is regulated by the GI tract as well as the kidney.
• Like potassium, it is strongly buffered by large amounts of calcium (mostly in bone) that is readily exchangeable with ECF calcium.
What are the 2 time scales of calcium to consider?
• Rapid transfer of calcium between the ECF and other tissue of the body.
• The slow rate of calcium ingestion into and excretion from the body.
Discuss balance for calcium in the ECF.
• Basically, balance is to and from bone, not the outside world.
• The kidneys play an important but indirect role because they excrete some calcium in the urine and are involved in forming the active form of Vit D.
• Dominant regulation is less focused on output and more focused on input from the GI tract, although absorption of dietary calcium is only partial.
What are normal levels of plasma calcium?
10 mg/dL (2.5 mmol/L or 5 mEq/L).
Calcium exists in what 3 general forms?
• Free ionized form (Ca2+): makes up almost half of calcium and is the only fomr that is biologically active in target organs.
• Complexed to anions with relatively low molecular weights, such as citrate and phosphate: about 15% of calcium.
• Reversibly bound to plasma proteins: about 40% of calcium.
What is low-calcium tetany?
Low levels of calcium fool channels into sensing more depolarization than actually exists, leading to spontaneous firing of motor neurons, which in turn triggers inappropriate muscle contraction. If severe enough, it can lead to respiratory arrest because of spasms in the ventilatory muscles.
How does plasma pH affect how much Ca2+ binds to nerve membranes?
• Serum albumin has many anionic sites that reversible bind protons and calcium; these ions compete for occupancy of the binding sites.
• As pH rises, protons dissociate and calcium ions take their place, thereby lowering the concentration of free calcium ions.
• In turn, this tends to cause reduced binding of calcium to cell membranes.
What percentage of plasma calcium is filtrated and reabsorbed?
• 60% of plasma calcium is filtratable; the rest is bound to plasma proteins.
• Most Ca reabsorption occurs in the proximal tubule (~60% of filtered load) and the remainder in the thick AL of Henle’s loop, distal convoluted tubule, and collecting-duct system (overall reabsorption = 97-99%).
Describe calcium reabsorption in the segments of the nephron.
• Proximal tubule and thick ascending limb of Henle’s loop: largely passive and paracellular, and the electrochemical forces driving it are dependent directly or indirectly on sodium reabsorption.
• Distal segments: active and transcelluler; calcium enters across the luminal surface via calcium-specific channels and exits across the basolateral membrane actively by a combination of Ca-adenosine triphosphatase (ATPase) and Na-Ca antiport activity.
Discuss renal excretion of Ca in response to changes in dietary input.
• The response is much less than the equivalent responses to dietary Na, H2O or K; only ~5 % of an increment in dietary Ca appears in the urine, whereas virtually all of the increased ingestion of water or Na appears in the urine.
• The reason: most of the dietary increment never gains entry to the blood because it fails to be absorbed from the GI tract.
• When dietary intake of Ca reduced to extremely low levels, there is a slow reduction of urinary Ca, but some continues to appear in urine for weeks.
How do the renal Ca homeostatic mechanisms operate?
Ca excretion = Ca filtered – Ca reabsorbed (calcium is not secreted)
What happens when a person increases calcium intake?
• Transiently, intake exceed output, positive calcium balance ensues, and plasma calcium concentration may increase.
• A rise in plasma Ca2+ increases both the filtered mass of Ca2+ and excretion. Simultaneously, the increased plasma Ca2+ triggers hormonal changes that cause a diminished reasborption. Net result: increased calcium excretion.
How does sodium, acidosis, and alkalosis influence Ca2+ reabsorption?
• Sodium: an increase or decrease in urinary calcium excretion can be induced simply by administering or withholding salt, respectively. This is because passive reabsorption in the proximal tubule and thick ascending limb of Henle’s loop is dependent on sodium reabsorption.
• Acidosis: the mechanism is not clear, but acidosis markedly inhibits calcium reabsorption and, hence, causes increased calcium excretion.
• Alkalosis does the opposite: enhances reabsorption and reduces excretion.
About how much calcium passes back and forth between bone and the blood plasma each day?
0.5 g of calcium
Describe the structure of bone.
• The majority of bone mass is mad of a tough proteinaceous framework, mostly collagen, on which is deposited hard mineral crystals: hydroxyapatite
• Hydroxyapatite is a complex of calcium, phosphate, and hydroxyl ions.
Define osteocytic osteolysis, remodeling, osteoclasts, and osteoblasts.
• Osteocytic osteolysis involves the movement of calcium across the bone membrane for the purpose of rapid buffering of the plasma.
• Remodeling involves the movement of calcium for the purpose of affecting bone structure in the long term.
• Osteoclasts are giant multinucleated cells involved in remodeling; they erode little pits in the bone matrix.
• Osteoblasts follow the osteoclasts and fill in the pits with new bone matrix.
Describe hormonal control of calcium.
• 2 main hormones: the active form of Vit D (1,25-(OH)2D) and parathyroid hormone (PTH) a peptide hormone produced by the parathyroid glands.
• 1,25-(OH)2D stimulates intestinal reabsorption of calcium and phosphate; in growing children, this ensures a supply of substrate for bone formation and in adults it ensures a supply to replace ongoing dissolution of bone.
• PTH can dissolve bone and move calcium into the blood, via paracellular signals from osteoblasts and by stimulating osteoclasts to resorb bone.
Describe the forms of vitamin D.
D3 (cholecalciferol) is synthesized by the action of UV radiation on 7-dehydrocholesterol in the skin. D2 is ingested in food derived from plants. Both D2 and D3 are referred to as “Vit D” and they act identically.
How is Vitamin D activated metabolically?
• Circulating Vit D is hydroxylated at the 25 position by the liver and then hydroxylated again at the 1 position by proximal tubular cells within the kidneys to yield a cholesterol derivative containing 3 hydroxyl groups.
• The active form of vitamin D3 is called calcitriol.
What are the actions of calcitriol?
• It stimulates active absorption of calcium and phosphate by the intestine.
• Ca probably enters from the intestinal lumen passively through Ca-selective channels, binds reversibly to mobile cytosolic Ca-binding protein that allow Ca to move across the cell without raising the concentration of free calcium, and then is actively transported out of the basolateral side via a Ca-ATPase.
• Calcitriol stimulates synthesis of proteins involved in these steps.
• Calcitriol also stimulates renal-tubular reansorption of Ca and phosphate.
Describe the half-life and secretion of PTH.
• Half life is <10 min and tries to keep free plasma calcium at 5 mg/dL.
• Calcium binds to G-protein-linked receptors whose ligands are divalent cations; the calcium receptors couples via the intracellular G protein to a signaling cascade that inhibits the secretion of PTH. Thus, low extracellular calcium stimulates PTH secretion by removing tonic inhibition.
• Elevated phosphate also stimulates PTH secretion by stimulating the capacity of parathyroid gland to synthesis PTH.
What are the 4 distinct effects of PTH on calcium homeostasis?
• It increases the movement of calcium from bone into ECF by stimulating bone osteocytic osetolysis and the slow resorption by osteoclasts.
• It stimulates the activation of vitamin D; the major control point is the second hydroxylation step, which occurs in the kidneys.
• It increases renal-tubular calcium reabsorption, mainly by an action on the distal convoluted tubule, by increasing apical membrane calcium entry through calcium channels.
• It reduces the proximal tubular reabsorption of phosphate, raising urinary phosphate excretion and lowering extracellular phosphate concentration. This is necessary because the processes that restore calcium to its normal level also tend to raise phosphate above normal; PTH keeps plasma phosphate levels within the normal range.
Describe primary hyperparathyroidism.
• It results from a primary defect in the parathyroid glands.
• The excess PTH causes enhanced bone reasborption, leading to bone thinning and the formation of completely calcium-free areas or cysts.
• Plasma calcium increases and plasma phosphate decreases; the latter is caused by increased urinary phosphate excretion.
• The increased plasma calcium is deposited in various body tissues, including the kidneys, where stones may be formed.
What are the forms of plasma phosphate and how much is filtered?
• 5-10% is protein bound, so 90-95% is filterable at the renal corpuscle.
• Normally, approximately 75% of this filtered phosphate is actively reabsorbed, almost entirely in the proximal tubule (in symport with sodium).