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573 Cards in this Set

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What is the prime function and other functions of the lung?
primary-gas exchange, other include metabolizes some compounds, filters unwanted material from the circulation and acts as a reservoir for blood
What are the blood-gas interface requirements based on properties of diffusion?
O2 and CO2 are exchanged by diffusion or movement of gases from higher pressure to lower, diffusion is proportional to the area of the sheet and inversely proportional to thickness (Fick’s law), efficient gas exchange surface must be both thin and large
What are the surface area and interface thickness parameters of the human lung?
surface area of between 50 and 100 m^2, 0.3 micrometers for the gas exchange interface
What are the layers of the alveoli (from the air -> RBC)?
air -> alveolar epithelium -> interstitium -> capillary endothelium -> capillary -> RBC
How is it possible to obtain such a large SA for diffusion inside the limited thoracic cavity?
capillaries wrap around lots of alveoli, 300 m alveoli, each with about 1/3 mm in diameter, therefore lung generates large diffusion area by being divided into lots of little units, polyhedral in shape
How is the PO2 of inspired air calculated?
PO2 = FO2 * (Pb – water vapor pressure in trachea)
What are the branching components of the airway stating with the trachea and ending with the alveolus?
tubes become narrower, shorter and more numerous as they penetrate deeper into the lung, branching is from trachea -> right and left main bronchi -> lobar bronchi -> segmental bronchi -> terminal bronchioles (smallest airways without alveoli) -> respiratory bronchioles (have occasional alveoli) -> alveolar ducts (completely lined with alveoli), up to 23 branches (first 16 are conduction, last 7 are respiratory)
What are the conducting airways?
from trachea -> terminal bronchioles, function in leading inspired air to the gas exchanging regions of the lung, no gas exchange occurs here, has no alveoli, constitute the anatomic dead space (~150 mL)
What is the respiratory zone?
where gas exchange occurs, has a volume of ~2.5-3 liters, makes up most of the lung, starts with respiratory bronchioles and gets down to alveolar ducts and alveoli
What is an acinus?
portion of lung distal to a terminal bronchiole
What causes the INC in volume of the thoracic cavity during inspiration?
contraction of the diaphragm which causes it to descend, and contraction of the intercostal muscles which raise the ribs
Describe the flow of air through the branches of the lung.
air flows through the trachea to the terminal bronchioles via bulk flow (like water in a hose), past that the cross sectional area gets so big that forward velocity of the gas is slow (so dust accumulates at the terminal bronchioles), diffusion of gas takes over, is so rapid that concentration gradients are abolished within a second, flow is 6L/min, requires about 20 cm water (15 mm Hg) (pulmonary circuit has extremely small resistance)
What are the dimension of pressure and volume during a single breath?
500 mL per breath, requires 3 cm water, balloon requires 30 cm water pressure, pressure required is small, 1 L/sec requires only 2 cm water
Describe the course of the pulmonary system of vessels.
the arteries, veins and bronchi run close together until they are near the periphery where the veins move away to pass between the lobules whereas the arteries and bronchi travel together down the centers of the lobules
What is a downside of having extremely thin capillaries?
they can be easily damaged, INCing the pressure in the capillaries to high levels or inflating the lung to high volumes can raise the wall stresses of the capillaries to the point at which ultrastructural changes can occur, capillaries then leak plasma and even RBCs into the alveolar space
How much time does a RBC spend in the capillary?
about ¾ sec, traverses about two or three alveoli, diameter of capillary is about 10 micrometers (enough for a RBC)
What is the purpose of the bronchial circulation?
supplies the conducting airways down to about he terminal bronchioles, some blood carried away from here by the pulmonary veins while some enters the systemic circulation, only a fraction of blood goes through bronchial circulation and lung can function without it
How is the stability of the alveoli maintained?
there is large surface tension of the liquid lining the alveoli that tend to collapse the alveoli, surfactant is secreted to deal with this, it lowers the surface tension of the alveoli
How are inhaled particles removed from the lung?
large particles removed by the nose, smaller particles in conducting airways are removed by a moving staircase of mucus (propelled by cilia) that continually sweeps debris up to the epiglottis where it is swallowed, alveoli have no cilia so macrophages are present to remove debris here, debris ultimately removed by lympathics or blood vessels
What are the partial pressures of N2, O2, CO2 and H2O gas in the atmosphere, upper airway and alveolar air?
atmosphere-N2 (597), O2 (159), CO2 (0.3), H2O (3.7)
upper airway-N2 (563.4), O2 (149.3), CO2 (0.3), H2O (47)
alveolar air-N2 (569), O2 (104), CO2 (40), H2O (47)
What is tidal volume?
500 mL, how much air enters the lung with each inspiration
What is vital capacity?
amount of air expelled after a maximal inhalation followed by a maximal expiration, a little less than 6 L
What is the residual volume?
gas that remains in the lung after a maximal expiration, about 1.75 L
what is the functional residual capacity (FRC)?
it is the volume of gas in the lung after a normal expiration, about 2.75 L
How can functional residual capacity and residual volume be measured?
these two volumes cannot be measured with a simple spirometer, use a gas dilution technique, subject is connected to a spirometer with a known [He], after some breaths the [He] inside the spirometer = [He] in the lungs (He used bec. it has very low solubility in blood), [He] before equilibration = C1 * V1 and after equilibration = C2 (V1 + V2), therefore V2 = (V1*(C1-C2)) / C2, only measures communicating gas (ventilated lung volume)
How can FRC be measured using the body plethysmograph?
subject is placed in a large airtight tube, at the end of normal expiration, a shutter closes the mouthpiece and subject is asked to make respiratory efforts, as subject tries to inhale, he or she expands the gas in the lungs and lung volume INC, lung P DEC and box pressure rises because its gas volume DEC, measures total volume of gas in lung including any that is trapped behind closed airways
What is Boyle’s Law?
states that pressure X volume is constant (at constant temperature), P1V1 = P2 (V1-changeV), where 1 is the pre-inspiratory effort and 2 is post in the box, also P3V2 = P4 (V2 + change V) where P3 and P4 are the mouth pressures before and after inspiratory effort, V2 is FRC
What is the normal volume for alveolar gas?
3000 mL
What is the normal pulmonary capillary blood volume?
70 mL
What is the normal pulmonary blood flow?
5000 mL/min
What is the alveolar ventilation?
5250 mL/min, total volume of fresh gas entering the respiratory zone, calculated by (volume exhaled/breath – anatomic dead space) * (breath rate)
What is the normal frequency of breathing?
15 breaths / min
What is the total ventilation?
7500 mL/min, is the total volume leaving the lung, measured by volume per breath * breath rate (tidal volume X respiratory freq.)
How is dead space calculated (Vd)?
take expired total ventilation volume/time (Ve)– alveolar ventilation volume/time (Va), also Va = Ve – Vd
What is an alternative method in calculating alveolar ventilation using VCO2?
VCO2 = Va X (%CO2/100), therefore Va = (VCO2 * 100) / (%CO2), Va = (VCO2/PCO2) * constant, note the critical relationship between Va and PCO2, if Va is halved, PaCO2 is doubled
What are the two ways to calculate dead space?
1. Fowler method-intuitive, measures anatomic dead space
2. Bohr’s-not quite as intuitive, measures physiologic dead space
What is Fowler’s method?
subject breathes through a valve box, there is a nitrogen analyzer present, when inspiration brings in 100% O2, the N2 conc. rises as the dead space gas is INCingly washed out by alveolar gas, finally an almost uniform gas concentration is seen representing pure alveolar gas, this phase is often called the alveolar plateau
How is dead space found by using the Fowler method?
plot N2 vs. expired volume and drawing a vertical line such that area A is equal to area B (see fig. 2.6), dead space is volume up to the vertical line
What is Bohr’s method?
Vd/Vt = (PaCo2 – PeCO2) / PaCO2, little a’s can be substituted for big A’s, PeCO2 stands for mixed expired partial pressure (mixture of alveolar and dead space gas), normal range of dead space to tidal volume is in the range of 0.2-0.35, measures physiological dead space (volume of gas that does not eliminate CO2)
Does dead space change or is it constant?
it INC with large inspirations because of the traction or pull exerted on the bronchi by the surrounding lung parenchyma, also depends on size and posture of the subject
Describe the regional differences of ventilation.
lower regions of the lung ventilate better than the upper zones, shown when subject inhales radioactive Xe gas, shows that ventilation per unit volume is greates near the bottom of the lung and becomes progressively smaller toward the top, this difference disappears when patient is supine (but posteriormost now shows greater ventilation than the anteriormost portion)
What is the alveolar gas equation?
used to measure PAO2, PAO2 = PIO2 – (PACO2/R) + F, where R = VCO2/VO2, PAO2 = PIO2 – (PACO2/R) or PAO2 = FIO2 (Pb-47) – 1.2 (PaCO2)
What is the significance of the A-a difference?
take PAO2 (calculated) – PaO2 (measured), used in determining level of ventilation
If a patient has pure alveolar hypoventilation and VA is 50% normal, what would be the expected gas values?
VA halved means PACO2 doubled or PACO2 ~ 80 mm Hg, PAO2 = 54 mm Hg, assuming A-a ~ 10, PaO2 = 44 mm Hg, PACO2 = 80 mm Hg and pH ~7.2
What are some factors that affect the rate of gas diffusion through the respiratory membrane?
thickness (inversely proportional), surface area, diffusion coefficient of gas (which is proportional to the gas solubility but inversely proportional to the square root of its MW), partial pressure difference of the gas, this is all defined by Fick’s law
What diffuses faster through the tissue, CO2 or O2?
CO2 diffuses about 20 times more rapidly than does O2 through tissue sheets because it has a much higher solubility but not a very different MW
What is the partial pressure of different gases in fluid?
partial pressure = [dissolved gas] / solubility coefficient, for O2 (solubility coefficient = 0.024, solubility = 3), CO2 (0.57, 71), CO (0.018, 2.2), N2 (0.012, 1.5), He (0.008, 1)
How is diffusion rate calculated?
diffusion rate = (partial pressure difference * cross-sectional area * solubility) / (distance of diffusion * sq.rt of MW of gas), solubility and sqrt of MW is unique of gas)
What are the diffusion coefficients of different gases?
O2 = 1
CO2 = 20.3
CO = 0.8
N2 = 0.53
He = 0.95
How fast does an RBC in a capillary take up CO, NO2 and O2?
blood partial pressure of NO2 reaches that of alveolar gas very early in the capillary so that the transfer of this gas is perfusion limited, partial pressure of CO is almost unchanged so that its transfer is diffusion limited, O2 transfer can be perfusion limited or partly diffusion limited depending on the conditions
Why is there such a small change in partial pressure for CO when it binds to RBC?
CO has a tight bond with Hb, therefore lots of CO can be taken up with almost no INC in partial pressure, therefore diffusion limited, rate depends on diffusion properties and not on amount of blood available
Why is there such a large change in partial pressure for NO2 when it binds to RBC?
NO2 has no reaction with Hb, partial pressure rises rapidly since it does not bind tightly to the RBC, no NO2 is transferred after a tenth of the way in the capillary, depends on the amount of available blood flow and not at all on the diffusion properties of the blood-gas barrier, is called perfusion limited
Why does the time course line for O2 lie between that for NO2 and CO?
O2 binds to Hb but not as strong as CO does, rise in partial pressure is much higher than for CO, but lower than for NO2, capillary PO2 virtually reaches that of alveolar gas when the red cell is about 1/3 of the way along the capillary, is perfusion limited like NO2, but may also have some diffusion limitations as well (esp. in disease states)
What does exercise do to diffusion properties?
severe exercise reduces the time available for oxygenation of arterial blood, pulmonary blood flow is severely INCd, time spent in capillary is reduced
What does thickening of the blood-gas barrier do to ventilation?
O2 diffusion is impeded, causes the rate of rise of PO2 in the RBC to slow and the PO2 may not reach that of alveolar gas
What happens when alveolar O2 is lowered?
can be due to either going to high altitude or inhaling lower O2 mixture, pressure gradient between alveolus and capillary DEC causing O2 to move more slowly, rate of rise DEC, may lead to a failure of the blood to reach alveolar partial pressures
What is diffusing capacity of the lung and what components contribute to it?
volume of a gas that will diffuse through the membrane each minute for a partial pressure difference of 1 mm Hg, diffusion process itself through the blood-gas barrier and time taken for O2 or CO to react with Hb are the two components that contribute to this, at rest ~21 mL/min/mm Hg (therefore 1/DL = 1/DM + 1/(omega*Vc)) where omega = rate of reaction of O2 w/ Hb, Vc = volume of capillary blood, DM = diffusion capacity of membrane
How is diffusing capacity calculated?
DL = VCO / (P1-P2) or DL = VCO/PACO,
What is the main pressure difference between alveolus and capillary for O2?
PAO2 difference from PaO2 is about 11 mm Hg
What happens to O2 diffusing capacity (DL) with INC during exercise?
INC to ~65 mL/min/mm Hg with strenuous exercise, so 65 X 11, or about 715 mL O2/min
How is diffusing capacity measured?
use CO, add CO to inspired air, CO rapidly combines with Hb so partial pressure in blood is zero, measure alveolar CO concentration in end expiratory gas, this yields the pressure difference across the respiratory membrane, to convert to O2 diffusing capacity, multiply by 1.23 (diffusing coefficient for O2 is 1.23 * CO), average DLCO is 17 mL/min/mmHg
How is DLCO used as a clinical tool?
the risk of O2 desaturation during submaximal exercise is very high in patients with a low DLCO, submaximal exercise tests are safe, even in elderly patients with heart and lung diseases
How long does it take O2 (or CO) to react with Hb when first added to blood?
about 0.2 sec, oxygenation occurs so rapidly in the pulmonary circulation that even this rapid reaction significantly delays the loading of O2 by the red cell
Describe CO2 transfer across the pulmonary circulation.
diffusion of CO2 through tissue is about 20 times faster than that of O2 bec of the much higher solubility of CO2
Describe pulmonary circulation.
high capacity, low-resistance circuit, unlike the circulation to other organs, the pulmonary circulation must accommodate the entire CO, both at rest and during exertion, functions in blood filtering, as a blood reservoir, and metabolizing circulating substances
How does exercise change blood flow through the lungs?
at rest, blood flow through the lungs is not uniform, most is through the lower, dependent regions, with exertion, blood vessel distension and recruitment permit the pulmonary vascular bed to accommodate a large INC in cardiac output with only a slight increment in pulmonary artery pressure
How does pulmonary circulation compare to systemic?
pulmonary circulation is largely a passive vascular bed, lacks elaborate mechanisms for autoregulation of blood pressure, there is small pulmonary vascular resistance (there is a lack of high resistance arterioles) which allows for a low pulmonary artery pressure, vasculature is much thinner and contains less smooth muscle, there is a lack of functional arterioles affects blood flow distribution in the lung as much as it is affected by gravity (minimizes active regulation of lung blood flow)
What is the mean pressure drop between the pulmonary artery and left atrium and what is the mean pulmonary artery pressure?
mean pressure drop between the pulmonary artery and left atrium is 5 to 10 mmHg, mean pulmonary artery pressure is below 30 mm Hg (even during exercise)
What are the two types of circulation in the lung?
1. pulmonary circulation-perfuses alveoli
2. bronchial circulation-provides nutrients and gas exchange from the conducting airways, part of the systemic circulation and receives about 2% of CO from the left heart, pressure is similar to those in other systemic vascular beds
Describe the venous drainage of the bronchial circulation.
1/3 of the venous drainage from the bronchial circulation is to the right atrium, 2/3 drain into pulmonary veins, this adds a small volume of poorly oxygenated bronchial venous blood to the freshly oxygenated blood in the pulmonary vein, this contributes to anatomical shunt
Describe pulmonary circulation as a blood filter.
1. numerous micro-vessels
2. large anatomic and functional reserve available to trap particles w/o disrupting gas exchange
3. if foreign materials were not trapped they might occlude or impede flow in systemic vessels (heart or brain)
Describe the how the left ventricle uses blood from pulmonary circulation as a reservoir.
1. holds about 500 mL of blood in an adult male
2. blood volume serves as a reservoir for the left ventricle particularly during periods when left ventricular output momentarily exceeds venous return
3. CO can be INC rapidly by drawing upon pulmonary blood volume w/o depending on an instantaneous INC in venous return
What are the metabolic functions of the pulmonary circulation?
1. endothelial cells of the vasculature are involved in the uptake or metabolic conversion of several vasoactive substances in the circulation
2. the vascular cells also release biologically active compounds into the circulation that act either locally or in other organs
What is the role of intravascular and extravascular pressures in influencing pulmonary blood flow?
these pressure both influence the distribution of blood flow and vascular resistance, they can affect how well blood flow is matched to ventilation
What is hydrostatic pressure?
it is the actual pressure inside pulmonary vessels relative to atmospheric pressure, is lower than systemic pressure, mean pulmonary arterial pressure is about 15 Torr and is much lower than the average systemic arterial pressure of 90 Torr
What is the driving pressure in the pulmonary circulation?
is the difference between inflow and outflow pressure, difference between pulmonary arterial (Pa) and left atrial pressure (PLA), is about 11 Torr (while the driving pressure in systemic circulation is about 100 Torr, aortic pressure-right atrial pressure), small driving pressure is adequate because of the relatively low resistance to blood flow
What is lung transmural pressure?
the pressure difference between the inside and outside of some walled structure, such as a blood vessel or airway, these are distensible and pressure differences between the inside and outside can affect their diameter and hence the resistance they offer to air or blood flow
What can transmural pressure differences in alveolar vessels affect?
resistance to blood flow, intravascular pressures and blood flow distribution
What happens to intrathoracic (intrapleural pressure) during quiet breathing?
is less than Patm and become INCingly subatmospheric with inspiration, this will cause large vessels and airways to passively dilate with inspiration as the outside intrathoracic pressure DEC, these larger lung vessels, whose outside pressure is intrathoracic are referred to as extra-alveolar vessels
What is alveolar pressure?
the pressure immediately outside the lung capillaries, alveolar vessels are directly affected by alveolar pressure causing a change in the diameter and resistance to blood flow offered by these vessels, varies continuously during the breathing cycle, when alveolar pressures is INC, it tends to narrow the lung capillary and may INC resistance to flow
Where do the values of alveolar pressure lie?
may be above Patm briefly during forced expiration or chonrically dring prositive pressure breathing, as with patients on mechanical ventilation, INC in alveolar pressure are generally reflected by nearly equivalent INC in pulmonary arterial pressure up to about 8 cm H2O
Describe positive pressure breathing.
the INC in alveolar pressure compresses alveolar vessels and INC arterial pressure and resistance to blood flow
How does posture (in the upright position) affect lung pressures and blood flow?
the upright human lung measures about 30 cm from the apex to the base, pulmonary artery enters at the hilum (halfway between the apex and base), right atrium must pump against a column of blood about 15 cm high (11 mmHg) resulting from gravity, therefore at the lung apex intravascular pressure is 11 cm H2O lower than arterial pressure at the hilum and at the base it is about 11 cm H2O higher than pulmonary arterial pressure at the hilum, blood flow is also less at the apex than at the base of the lung
How does being in the supine position affect lung pressure?
pressure differences between the apex and base are less, this results in a more uniform distribution of blood flow and smaller vascular pressure differences
How does alveolar hypoxia affect lung pressure?
alveolar hypoxemia will cause pulmonary vasoconstriction (hypoxic vasoconstriction, HPV), mechanism is not known
What does hypoxic vasoconstriction to blood flow?
redirects blood flow away from poorly oxygenated alveoli towards alveoli that have higher PO2 levels, HPV is a mechanism that operates to help optimize gas exchange by DECing blood flow to poorly oxygenated alveoli
How is pulmonary vascular resistance (PVR) calculated?
PRV = driving pressure / blood flow, can also be obtained by using a pulmonary artery catheter
Describe the use of a pulmonary artery catheter.
this specialized catheter is a multi-lumend, balloon-tipped catheter that is inserted into a systemic vein (jugular) and advanced through the right heart into the pulmonary artery, can be used to measure pulmonary arterial pressure and estimate left atrial pressure (PLA) and determine blood flow (i.e. CO), thus PVR can be computed
Where is the PVR distributed?
uncertain as the lung lacks the high resistance arterioles, in man it has been estimated that as much as 50-60% of the total PVR may reside in the capillaries, the distribution of PVR likely varies widely with changes in blood flow, left atrial pressure, alveolar pressure and body position
What role does sympathetic stimulation have on PVR?
can either INC or DEC PVR depending on the pre-existing vascular tone, role of ANS in regulating PVR is not well understood in humans
When is gas exchange optimal in the alveoli?
when alveolar ventilation (VA) is matched to the cardiac output (CO) perfusing that alveolus, the ideal whole lung Va/Qc is between 0.8 to 1.0, for a typical adult male, V ~4.5 L/min while CO is ~5.0 L/min
Why does V/Q vary from the apex to the base?
because of disparities in the distribution in of ventilation and blood flow to these regions
How can the distribution of ventilation in an upright human lung be measured?
can be evaluated by inhaling a small amount of radioactive Xe133 gas, after the radioactivity is counted from each level the findings show that alveoli at the base receive more ventilation than those at the apex of the lung, lower zone receives more ventilation than upper zone
Why is there a difference in the distrubtion of ventilation between the apex and base of the lung?
there are differences in the transmural pressures between the lung apex and base, the upright lung is influenced by gravity pulling the lung downward in the direction of gravity leading to a more subatmospheric intrapleural pressure at the apex than base, base receives about two times more ventilation
What is the transmural pressure in the apex and base?
apex is a greater transmural pressure (more negative outside) or distending pressure than those at the base so they are more inflated before inspiration begins, because of this greater initial volume, alveoli at the apex are less compliant than those at the base
Where does the greater amount of air volume go to? base or apex?
greater air volume goes to alveoli at the base than apex because alveoli at the base are more compliant and they expand more for a given change in transmural pressure, alveoli at the base receive about twice as much ventilation per unit lung volume than as those at apex
What is the distribution of blood flow in the upright lung?
a greater portion of blood flow goes to dependent (below heart level, base) rather than nondependent (above heart level, apex) lung regions, largely because of the influence of gravity on blood flow distribution, base receives about 4 times more perfusion per unit lung volume
Why is there a difference in the distribution of blood flow in the lung?
gravity causes blood to preferentially flow to lower lung regions, these differences in blood flow distribution are minimized in the supine position
What happens to V/Q between the apex and the base?
at the base the lung receives an excess of perfusion relative to ventilation so the V/Q is less than 1, at the apex there is an excess of ventilation relative to perfusion so the V/Q is greater than 1, V/Q DEC from apex to base
What does this variation in V/Q mean for PO2 and PCO2 in the apex and base?
in the apex there is over-ventilation which leads to a PO2 that is greater than 100 Torr and a PCO2 of less than 40 Torr, alveoli near the base are slightly over perfused relative to ventilation and results in an alveolar PO2 of less than 100 and a PCO2 in excess of 40 Torr, so PO2 is highest at the apex and diminished towards the base whereas PCO2 is lowest at the apex and INC near the base
What are the three ventilation-perfusion zones of the lung?
1. zone 1-near the top of the lung, PA > Pa > Pv, so no blood flow occurs (and therefore no gas exchange) and V/Q > 1
2. zone 2-Pa > PA >> Pv, so the difference between Pa and PA is a main factor in determining the resistance to blood flow, out-flow pressure is alveolar pressure and the driving gradient for flow is the pulmonary arterial-alveolar pressure difference, flow through zone 2 can be intermittent, when pulmonary venous pressure exceeds alveolar pressure, blood flows, when PA > Pv there is no flow
3. zone 3-Pa >> Pv > PA, optimal gas exchange with a V/Q = 0.8-1.0
What happens to gas exchange when there is an accumulation of fluid between the alveoli and pulmonary capillary blood?
this causes an INC in diffusion distance and impedes gas exchange
What is the Starling’s Law?
shows the relationship between filtration and reabsorptive forces, disturbances in on eor more of these forces can result in the accumulation of fluid in the interstitial or alveolar space (pulmonary edema)
What is the Starling Equation?
Jv = Kf [(Pc – Pis) – delta (pi c - pi s)], Jv = net fluid flux across the alveolar capillary membrane, Kf = filtration coefficient (measure of the ease of fluid movement across the alveolar carpillary membrane), Pc = alveolar capillary hydrostatic pressure, Pis = interstitial pressure, delta = reflection coefficient with a value from 0-1 (normally 0.7 to 0.8), pi c = capillary oncotic pressure, pi s = interstitial oncotic pressure
What are the two types of edema?
1. hydrostatic-principally related to an INC in capillary pressure (Pc), an INC Pc (filtration pressure) causes an INC in fluid flux (Jv) often without any change in the Kf
2. permeability-results from an INC in the permeability of the barrier (vessel wall) that separates blood from the tissue, vascular fluid (plasma) exits the vascular space (capillary) simply because the barrier function of the membrane is compromised or incompetent, more fluid is filtered from the vascular to interstitial space that can be reabsorbed by plasma oncotic forces or the lymphatic system
when clinically is hydrostatic edema seen?
common with left heart failure where pulmonary vascular pressures are elevated, resulting in more fluid filtration form the vascular space than can be returned by plasma oncotic forces or the lymphatic system, referred to as cardiogenic pulmonary edema
When clinically is permeability pulmonary edema seen?
AKA non-cardiogenic edema, is the principal disorder in adult respiratory distress syndrome (ARDS), with permeability edema, the Pc is not necessarily elevated as with hydrostatic edema
How much of the output of the right heart does the pulmonary circulation receive?
the pulmonary circulation receives the entire output of the right heart, but vascular pressures are considerably lower than in systemic vessels
In what forms is blood carried in the blood?
is carried in two forms (dissolved and combined with Hgb)
What is Henry’s Law?
states that the amount of dissolved O2 is proportional to its partial pressure, fro each mmHg of PO2, there is a 0.003 mL O2 * 100 mL^-1 of blood, normal arterial blood with a PO2 of 100 mm Hg contains 0.3 mL O2 * 100 mL^-1 (3 mL O2/L of blood)
What is the cardiac output and how much O2 is consumed during vigorous exercise?
CO may reach 30 L/min and 3000 mL of O2 consumed, but only 30 L (3 mL/L) = 90 mL of O2 delivered to tissues
Describe the structure of hemoglobin.
heme is attached to a protein globin with four polypeptide chains (of alpha and beta types), binds with O2 (O2 + Hb (tense state) <-> HbO2 (relaxed state))
What are the different types of hemoglobin?
normal adult hemoglobin is A, fetal hemoglobin is F (makes up part of the hemoglobin of the newborn infant and is gradually placed over the first year of postnatal life), sickle cell has hemoglobin S which has valine instead of glutamic acid in the beta chains (shift O2 dissociation curve to the right, the deoxygenated form is poorly soluble and crystallizes within the red cell, sickle shape gives it INC fragility and tendency to thrombus formation), methemoglobin has ferrous ion oxidized to ferric form (binds H2O)
What are the various PO2 and PCO2 during different times of gas exchange in the arterial and venous end of the capillary?
PO2 in the arterial end is 95 mmHg, in the venous end 40 mmHg, 23 mmHg in the cell and 40 mmHg in the interstitial space, PCO2 in the arterial end is 40 mmHg, 45 mmHg in the interstitial space, and 46 mmHg in the cell
How does O2 bind to Hb?
the amount of O2 carried by the Hb INC rapidly up to a PO2 of about 50 mm Hg but above the curve becomes much flatter
What is O2 capacity?
the max amount of O2 that can be combined with Hb, can be measured by saturating blood with a very high PO2 (600 mm Hg), 1 g Hb can bind 1.39 mL of O2, normal blood has about 15 g of Hb/L of blood, O2 capacity of blood is 21 mL O2/100 mL of blood
What is O2 saturation of Hb?
percent of the available binding sites that have O2 attached, given by O2 combined with Hb/O2 capacity X 100%, PaO2 = 100 mm Hg and has an Hb saturation of 97.5%, PO2 of mixed venous blood is 40 mm Hg and has an Hb saturation of 75%
How do PO2, O2 saturation, O2 concentration and [Hb] all relate?
as [Hb] DEC, the O2 dissociation curve moves down, less O2 is needed to get full HbO2 saturation, as [O2] INC, the HbO2 saturation INC, PO2 INC
How is the total O2 concentration of blood calculated?
(1.39 X [Hb] X Sat/100) + 0.003 PO2 (dissolved O2)
What is the significance of the shape of the O2 dissociation curve?
flat upper portion means that even if the PO2 in alveolar gas falls somewhat loading of O2 will be little affected, the steep lower part of the dissociation curve means that the peripheral tissues can withdraw large amounts of O2 for only a small drop in capillary PO2 (assists the diffusion of O2 into the tissue cells)
What can cause a rightward shift in the O2 dissociation curve?
causes O2 to be bound less tightly to Hb (reduced affinity for O2, INC in unloading), can be caused by an INC in [H+] (Bohr effect), INC in PCO2 [Haldane effect], INC in temperature, and INC in 2,3 BPG (occurs in chronic hypoxia at high altitude or in the presence of chronic lung disease)
What can cause a leftward shift in the O2 dissociation curve?
opposite changes to pH, pCO2, temperature and 2,3 BPG as well as a small addition of CO to blood
How does CO affect Hb?
CO interferes with O2 transport by binding to Hb and forming carboxyhemoglobin, CO has about 240 times the affinity of O2 for Hb, if have even small amounts of CO, can have normal [Hb] and PO2 but have reduced O2Hb
What is P50?
it is the PO2 for 50% O2 saturation, normal value for human blood is 27 mm Hg, used in determining the position of the O2 dissociation curve
How is CO2 carried in the blood?
dissolved as gas (obeys Henry’s law, CO2 is 20 times more soluble than O2, about 10% of CO2 entering alveolus is form dissolved form), bicarbonate, carbamino compounds
What are the proportions of how CO2 is carried in arterial blood and in venous-arterial difference?
in arterial blood, 5% is dissolved, 90% is bicarb and 5% is carbamino, in venous-arterial difference, dissolved is 10%, bicarb is 60% and carbamino is 30%
What is the equation that shows bicarb formation?
CO2 + H2O <-> H2CO3 <-> HCO3- + H+, when using carbonic anhydrase (in RBC) it is a fast step to HCO3- + H+, when non-enzymatic (in plasma), it is slow when making H2CO3 but fast when making HCO3- + H+
What is the scheme of the uptake of CO2 and liberation of O2 in systemic capillaries (when O2 is delivered to cells?
CO2 is dissolved across the capillary wall into the RBC, either reacts with H2O and makes bicarb and H+ or reacts with Hb to make carbamino Hb, bicarb can diffuse out but H+ cannot, Cl- enters the RBC (via the chloride shift) to maintain charge since H+ is accumulating in the RBC, H+ reacts with HbO2 to form O2 and HHb, O2 can then diffuse to the tissue through the capillary wall, H2O enters the cell to counteract osmolarity content INCing its volume, opposite events occur in the lung capillaries
Describe how carbamino compounds are made.
formed by the combination of CO2 with terminal amine groups in blood proteins, follows the equation HbNH2 + CO2 <-> Hb-NH-COOH (carbaminoHb), occurs rapidly without an enzyme, reduced Hb can bind more CO2 as carbamino-Hb than HbO2
Describe the CO2 dissociation curve.
CO2 dissociation curve is more linear than the O2 dissociation curve, the lower the saturation of Hb with O2, the larger the CO2 concentration for a given PCO2 (moves the curve up, due to Haldane effect since reduced Hb has the ability to mop up H+ ions and form carbamino-Hb), CO2 curve is also steeper
What is the Henderson-Hasselbalch equation?
pH = pKa + log [bicarb] / (0.03*PCO2), as long as ratio of bicarb to 0.03*PCO2 remains equal to 20, pH is 7.4
What is a Davenport Diagram?
shows the relationship between pH, PCO2 and HCO3-, graph is plasma bicarb vs. pH, buffer line is displaced if alter bicarb concentration by kidney, if INC [bicarb] then buffer line is shifted upwardcan cause displacement of the PCO2 line when changing PCO2 levels
What are the four types of acid-base disturbances and what are their primary and compensatory actions?
1. respiratory acidosis-has an INC in PCO2 which is compensated by an INC in HCO3-
2. metabolic acidosis-has a DEC in HCO3- and is compensated by a DEC in PCO2
3. respiratory alkalosis-has a DEC in PCO2 and is compensated by DEC in HCO3-
4. metabolic alkalosis-has an INC in HCO3- and often no compensation for it
Describe respiratory acidosis.
caused by INC in PCO2, CO2 retention can be caused by hypoventilation or ventilation-perfusion inequality, if respiratory acidosis persists, the kidney responds by conserving HCO3- and secreting a more acid urine (with an INC in [H+])
Describe respiratory alkalosis.
caused by a DEC in PCO2, caused by hyperventilation (such as in high altitudes), renal compensation occurs by an INC excretion of bicarb
Describe metabolic acidosis.
caused by a DEC in HCO3-, can be due to an accumulation of acids in the blood (as in diabetes mellitus or after tissue hypoxia which releases lactic acid), respiratory compensation occurs by an INC in ventilation that lowers the PCO2, stimulus to raise ventilation is chiefly the action of H+ ions on the peripheral chemoreceptors
Describe metabolic alkalosis.
caused by an INC in HCO3-, caused by excessive ingestion of alkalis and loss of acid gastric secretion by vomiting, some respiratory compensation sometimes occurs by a reduction in alveolar ventilation that raises the PCO2 (though often small and may be absent)
What happens to O2 consumption by muscles during exercise?
during exercise the O2 consumption of the muscle INC, additional capillaries open up, thus reducing the diffusion distance and INCing the area for diffusion, as O2 diffuses away from the capillary it is consumed by tissue and PO2 falls
What is a critical situation in PO2 levels between adjacent open capillaries?
occurs when the intercapillary distance or the O2 consumption has been INCed until the PO2 at one point in the tissue falls to zero, different from an anoxic region where aerobic metabolism is impossible (zero for a period of time)
How low can the tissue PO2 fall before O2 utilization ceases?
O2 consumjption continues at the same rate until the PO2 falls to the region of 3 mm Hg, the purpose of the much higher PO2 in the capillary blood is to ensure an adequate pressure for diffusion of O2 to the mito and that at the sites of O2 utilization the PO2 may be very low
What is tissue hypoxia?
it is abnormally low levels of PO2, caused by low O2 delivery, expressed as the cardiac ouput multiplied by the arterial O2 concentration
What are some causes of tissue hypoxia?
1. low PO2 in arterial blood caused by pulmonary disease (hypoxic hypoxia)
2. a reduced ability of blood to carry O2 as in anemia or CO poisonining (anemic hypoxia)
3. a reduction in tissue blood flow as in shock or because of local obstruction (circulatory hypoxia)
How much of the 50-100 m^2 of total alveolar SA available for gas is actually employed for gas exchange?
at rest, ~30-40 m^2 is employed for gas exchange, with as few as 1/3 of lung capillaries being perfused
Why is the respiratory epithelium internalized?
deals with dehydration, the lungs are enclosed within the thoracic cavity to control their contact with the outside environment, internalization creates a humid environment for exchange of gasses with the blood and also protects the exchange surface from damage
What does airflow in humans require?
a muscular pump to create pressure gradients to move the air in and out of the body, thus in humans the respiratory system can be through of as two separate components, a muscle driven pump provided by the musculoskeletal structure of the thorax and an internalized exchange epithelium associated with blood vessels
How much air and blood does the lung take in at rest?
takes 4 L/min of air and 5 L/min of blood and directs them within 2 microns of each other and then return them to their prospective pools
What is the maximum ventilation and cardiac output of the lung during maximal exertion?
ventilation may INC to 100 L/min and CO to 25 L/min
How does the chest create a pressure gradient between the atmosphere and the alveoli?
alveolar pressure is made lower than atmospheric pressure, contraction of the inspiratory muscles lowers alveolar pressure and in turn then INC alveolar volume
What purpose do the respiratory muscles have?
perform a certain amount of work that must be done on the respiratory system in order to produce airflow
What is the most important muscle of inspiration?
the diaphragm, supplied by phrenic nerve (C3,4,5), when it contracts the abdominal contents are forced downward and forward and the vertical dimension of the chest cavity is INC, rib margins are also lifted and moved out INCing the transverse diameter of the thorax, inspiration is active during quiet breathing, contraction of the diaphragm contributes to 60-70% of inspiratory volume during quiet breathing
How much does the diaphragm move during normal breathing and forced inspiration?
diaphragm moves about 1 cm in normal breathing and up to 10 cm in forced inspiration
What happens when the diaphragm is paralyzed?
it moves up rather than down with inspiration because the intrathoracic pressure falls (paradoxical movements), creates a negative intra-thoracic pressure
What is the geometry of the diaphragm and what does Laplace’s law have to do with it?
diaphragm is a curved muscle, Laplace’s law describes the relationship between pressure, tension and radius of the curvature (P = 2T/r), as the diaphragm flattens, the radius INC and pressure DEC (as seen in patients with DEC diaphragm strength in patients with hyperinflation due to COPD)
Describe the generation of trans-diaphragmatic pressure.
as intra-thoracic pressure (pleural pressure) falls, abdominal pressure rises, because downward motion of the diaphragm compresses the abdominal contents, trans-diaphragmatic pressure (Pdi, pressure across diaphragm during inspiration) = Pab (abdominal) – Ppl (pleural) (+ values with active contraction of the diaphragm)
What do the external intercostal muscles do?
slope downward and forward, pull ribs upward and forward when they contract causing an INC in the lateral (bucket-handle movement) and AP diameters (pump-handle movement) of the thorax, movement of the rib cage creates the remaining 25-40% of the inspiratory volume
What are the accessory muscles of inspiration?
include the scalene muscles which elevate the first two ribs and the sternomastoids which raise the sternum, little activity of these muscles during quiet breathing, called into play during exercise or coughing or sneezing, SCM elevates the sternum and helps INC the A-P and transverse dimensions of the chest
Do the inspiratory muscles contract simultaneously?
YES, if the diaphragm contracted alone, the rib cage muscles would be pulled inward (retraction), if the inspiratory muscles of the rib cage contracted alone, the diaphragm would be pulled upward into the thorax
What are the most important muscles of expiration?
abdominal muscles (rectus abdominis, internal and external oblique muscles and transversus abdominis), expiration is passive during quiet breathing (and no respiratory muscles contract, INC elastic recoil of the distended alveoli DEC alveolar volume and raises alveolar pressure above Patm, pressure gradient is made that allows for airflow out of the lungs) but can be active, when these muscles contract intra-abdominal pressure is raised and the diaphragm is pushed upward, contract during coughing, vomiting and defecation
What doe the internal intercostal muscles do?
assist active expiration by pulling the ribs downward and inward DECing the thoracic volume
Describe the relationship between force and length in limb skeletal muscles.
force is a function of its length, for a constant level of stimulation, maximal tension is generated at the muscles resting length, shortening or stretching of the muscle before stimulation results in generation of sub-maximal tension
Describe the relationsihip between force and length in the diaphragm.
the diaphragm generates peak force at approx. 130% of its resting length, there is a decline in the force generated with DECing muscle length, this corresponds to an INC in resting lung volume
Describe the relationship between the force of contraction and the freq. of muscle fiber simtulation and the vileocity of fiber shortening.
up to a point, force generation INC with INCing-stimulation freq. thereafter, force remains constant, despite further INC in stimulus freq., less tension is generated with higher velocities of muscle shortening or higher airflow rates (which = greater velocities of muscle shortening)
How is the amount of work of breathing calculated?
the work performed by the respiratory muscles is determined by the change in thoracic volume that occurs with each breath and the pressures generated, W = changeP * changeV
What is Boyle’s Law?
it describe the pressure-volume relationship of gases, states that pressure is exerted by a gas when the molecules collide with each other and with the wall of the container in which they are located, if the size of the container is reduced the collisions become more freq. and the pressure rises
How is Boyle’s Law represented mathematically?
P1V1 = P2V2, DECing volume INC collisions and INC pressure
Describe the pleural sac.
it forms a double membrane surrounding the outer surface of the lung and the inner surface of the thoracic cavity, similar to a fluid-filled balloon surrounding an air-filled balloon, has pleural fluid in between the double membrane that hold the opposing layers of the pleura together (has a total V of only a few millimeters)
What is the purpose of the pleural fluid?
1. provides a slick surface that allows the lung and chest wall to slide across each other
2. holds the lung tight against the chest wall
3. holds the lung to chest wall helps keep the lungs stretched even in the resting state
What is normal intra-pleural pressure during rest?
is normally sub-atmospheric (~3 mm Hg), this is created during development when the thoracic cage and parietal pleura grows more rapidly than the lung and visceral pleura, the elastic lungs are forced to conform to the large volume of the thoracic cavity, the elastic recoil of the lung creates an inward directed force that attempts to pull the lung away from the chest wall while the elastic recoil of the chest wall tries to pull the chest wall outward
What happens to the intrapleural pressure during normal breathing (inspiration)?
intrapleural pressure is made even more negative than atmospheric pressure by contraction of the muscles of inspiration generating an outward force expanding the lungs (Boyle’s Law, INCing volume DEC pressure), this negative intrapleural pressure creates a transmural (transpulmonary) pressure gradient that causes the volume of the alveoli to INC and lowers the alveolar pressure according to Boyle’s Law, alveolar pressure DEC causing air to enter the lung, there is also an inward recoil of the alveoli
What is transmural pressure and how is transmural pressure (PL) calculated?
PL = PA (alveolar pressure) – Ppl (intrapleural pressure), PL is responsible for maintaining alveolar inflation and is sometimes referred to as the alveolar distending pressure
What is atmospheric pressure in mechanics of breathing?
0 cm H2O, so lowering pressure below atmospheric pressure is known as negative pressure breathing
What happens to intrapulmonary pressure during inspiration and expiration?
starts from 0 (atmospheric pressure) and becomes negative during inspiration and begins to head back towards positive, when expiration starts, intrapleural pressure starts at 0 and becomes +, intrapulmonary pressure is always greater than intrapleural pressure (is always negative)
What happens to intrapleural pressure during inspiration and expiration?
the start of inspiration marks the its greatest pressure (least negative), when inspiration ends and expiration begins, intrapleural pressure is at its most negative and becomes less negative with expiration
What happens during a pneumothorax?
air flows into the intraplueral space and its pressure equalizes with that of the atmosphere, lung collapses to unstretched size, rib cage expands slightly, when draining air and fluid from the chest want the tube as near the top of the pleural cavity as possible
What are the series of events in inspiration?
1. CNS intiates inspiration
2. PNS carries the impulse to the inspiratory muscles
3. the inspiratory muscles contract
4. thoracic cavity volume INC as the chest expands
5. the intra-pleural pressure becomes more negative
6. the alveolar transmural pressure gradient then INC
7. the alveoli expand in respone to the INC transmural pressure gradient
8. this expansion INC alveolar elastic recoil
9. alveolar pressure falls below atmospheric pressure as the alveolar volume INC
10. this establishes a pressure gradient for airflow
11. air flows into the alveoli until alveolar pressure equilibrates with atmospheric pressure
What are the series of events in expiration?
1. CNS stops inspiratory command
2. inspiratory muscles relax
3. thoracic volume DEC, this causes the intrapleural pressure to become less negative and DEC the alveolar transmural pressure gradient
4. the DECd alveolar transmural pressure gradient lets the INC alveolar elastic recoil return the alveoli to their pre-inspiratory volume
5. DECd alveolar volume INC alveolar pressure above atmospheric pressure and this establishes a gradient for airflow
6. the air flows out of the alveoli until alveolar pressure equilibrates with atmospheric pressure
What are two forces that oppose the inflation of the lungs?
1. elastic forces-due to elastic properties of the lungs and thorax
2. frictional forces-due to either the resistance of the tissues and organs as they move and become displaced during breathing or the resistance to gas flow through the airways
What is Hooke’s Law in terms of the elastic properties of the lung?
the lung can be analogous to a spring, when the spring is stretched energy is put in and V INC, change in V proportional to change in P
What is the compliance of the lung and how is it calculated?
C = changeV / changeP, the compliance of any structure is the relative ease with which the structure distends, a balloon that is easy to inflate is very compliant, one that is hard to inflate is noncompliant
What is elastance of the lung and how does it relate to compliance?
compliance is the inverse of elastance (C = 1/e), elastance is the tendency of a structure to return to its original form after being stretched
What are some factors that determnine the elastic recoil of the lung?
1. elastic tissue content-elastin and collagen are present in alveolar walls and around bronchi and blood vessels
2. surface tension is another important factor in determining pressure-volume relationships in the lung
How does the pressure on expiration compare to that on inspiration?
for any particular volume, the pressure on the expiratory curve is less than that on the inspiratory one, this is because the elastic recoil on expiration is always less than the distending transmural pressure gradient requited to inflate the lung
What is hysteresis?
the manifestation of loss of energy seen in the fact that the pressure on expiration is less than on inspiration, it is a property that is common to all bodies that obey Hooke’s Law
What is harder to inflate, air-filled or saline-filled lungs?
air-filled lungs are much harder to inflate, there is a larger difference in the pressure difference between expiration and inspiration
What is surface tension and what creates it?
surface tension is created by the thin fluid layer between the alveolar cells and the air, surface tension arises when cohesive forces between molecules in the liquid phase exceed adhesive forces between molecules in the liquid and gas phases, surface molecules are attracted to other water molecules beside and between them but not to air, so at any air-fluid interface, the surface of a liquid behaves as if it is under tension like a thin membrane being stretched. LaPlace’s law also refers to bubbles
What are the physiologic roles of surfactant?
1. lower suface tension thus INCing lung compliance
2. stabilizes lung units through two effects-(1) lower surface tension to a greater degree at low lung volumes than at high volumes, thereby minimizing collapse of atelectasis or (2) prevents emptying of smaller alveoli into larger ones as a result of lowering surface tension to a greater extend in the smaller units, this offsets the effect of a smaller radius of curvature and an INC pressure
How is flow rate of gas through a tube calculated?
v = P/R, where P is driving pressure (difference between alveolar pressure and pressure at the airway opening), and R = airway resistance (determined by the diameter of the tracheobronchial tree)
What are the three types of airflow?
laminar (straight), turbulent (multiple directions), transitional (occurs at a junction)
Describe laminar flow.
is characterized by streamlines of gas flowing parallel to one another and the sides of the tube, laminar flow prevails at low flow rates and is described by Poiseuille’s Law
What is Poiseuille’s Law?
P = (8*viscosity*length*velocity) / (pi*r^4)
Describe turbulent flow.
is a more random movement of gas along the tube prevails at high flow rates, gas density is important in determining turbulent flow rates, an INC in density results in a DEC in flow rate
What are the levels of airway resistance in the nose, pharynx and larynx and larger airways?
1. nose-50%
2. pharynx and larynx-25%
3. larger airways-80% of the remaining resistance
4. smaller airways-~20% (because of the total cross-sectional area)
What are some additional factors that determine airway resistance?
airway length, airway smooth muscle tone, and the physical properties of the gases flowing through the airways such as gas density and viscosity
How is the density dependence of resistance taken advantage of in patients?
patients with obstructing lesions of the upper airways breathe a mixture of 80% He and 20% O2, this gas mixture is less dense than air, the resistance offered by obstructing lesion is less
What is the role of the integrator in respiratory control?
it is the neuronal network that breathing in man depends on, it is located in the brain stem that receives and analyzes information from various body sensors, the integrator then transmits an appropriate signal to INC or diminish the activity of the appropriate effector, these three work together to adjust breathing rate and depth to meet the need for O2 uptake and CO2 removal, involuntary reflexes
What happens to breathing rate or depth when the cerebral cortex and cerebellum were removed?
it had little or no effect upon these two
What happens to breathing rate or depth when the vagus is cut (either before or after the cerebral cortex and cerebellum transaction)?
resulted in a slower breathing rate and an INC in tidal volume (VT), suggests that some sensors send signals via vagal afferent nerves to influence breathing rate and depth, these vagal afferents innervate the brain below midbrain level
What happens to breathing rate or depth when a cut between the lower midbrain and upper pons was made?
had no affect upon breathing rate or depth
What happens to rate and VT when a transaction is made along the upper 1/3 of the pons and the vagus is still intact?
resp. rate is slowed and VT is INC, similar to that of cutting the vagus alone, but if the vagus is severed with this then an apnuestic breathing pattern results (breathing stops, just one big, prolonged upstroke that plateaus)
What is apnuestic breathing?
defined as the termination of breathing at end-inspiration, often manifested by inspiratory spasms and gasps
What role does the lower 2/3s of the pons have in regulating breathing?
it encourages inspiration because without input from vagal afferents or the upper pons, apneustic breathing was observed, therefore the upper 1/3 is the pneumotaxic center and the lower 2/3 is the apneustic center
How does the apneustic center work? where does it get its innervation from?
believed that both the pneumotaxic center and vagal afferent nerves innervate the apneustic center to diminish inspiratory drive, some suggest that the apneustic center continuously promotes inspiration and requires periodic inhibition form the pneumotaxic center and vagal afferents for expiration to occur (acts as a cut-off switch)
What is the role of the medullary center in breathing?
if the medullary center is transected leads to irregular breathing characterized by a variable tidal volume and rate, cutting the vagi after this transaction has little influence on the normal breathing pattern, this suggests that vagal afferent likely innervate the pons as opposed to the medullary region
What is the role of the lower medulla in breathing?
a transaction across the lower border of the medulla results in apnea (termination of breathing at end expiration), indicates that the minimal neuronal pools necessary for spontaneous breathing reside in the medullary portion of the brain stem
Overall, what are the different parts of the midbrain that contribute to breathing?
although neuronal pools of the medullary center alone appear sufficient to initiate and maintain sequences of inspiration and expiration, input form the pontine pneumotaxic and apneustic centers appear to be essential for rhythmic and coordinated breathing
Where are sensors for neurogenic reflexes located?
lungs, CV system, skeletal muscles and the muscles and tendons of respiratory muscles, at least 8 different sensor reflexes have been identified according to the receptor location, structure or afferent pathway
Describe the Hering-Breuer Initiation Reflex.
also called the inhibito-inspiratory reflex, initiated by stretch receptors (sensors) located in the smooth muscles surrounding both large and small airways
What does the Herin-Breuer Reflex do during lung inflation?
stretch receptors are stimulated and send neural signals via vagal afferents that appear to be inhibitory to the pontine apneustic center, function to facilitate termination of inspiration
Describe the Hering-Breuer Deflation Reflex.
AKA excito-inspiratory reflex, initiated either by DEC activity in the same airway stretch receptors involved in the inflation reflex or by stimulation of other proprioceptros that are activated by lung deflation, this info is also conveyed via vagal afferents to the brain stem respiratory centers to encourage inspiration
Are the Hering Breuer reflexes easily detectable?
readily demonstrated in anesthetized animals, they are more difficult to demonstrate in humans, except at large tidal volumes, are detectable in infants and are probably important in regulating the work of breathing
Where and what are the pulmonary J(uxtapulmonary-capillary)-receptors?
located in or near the walls of pulmonary microvessels, they appear to be stimulated by vascular emboli, interstitial edema, and certain chemicals, info from these receptors are delivered via vagal afferents to the brainstem, stimulation results in rapid shallow breathing (tachypnea)
What is dyspnea?
psychological sensation of air hunger, J-receptors are responsible for this, dyspnea is characterized by the sensation of labored breathing and shortness of breath
Describe the role of chemoreceptors in the lung.
specialized cells capable of detecting changes in the concentration of dissolved O2, CO2 or H+, divided into the peripheral and central chemoreceptors, function to regulate ventilation so CO2 is maintained nearly constant and at a level consistent with CO2 production and O2 consumption by the tissues of the body
Where are chemoreceptors found?
1. peripheral chemoreceptors-located in discrete structures known as the carotid and aortic bodies, only ones capable of detecting a fall in the PaO2, INC ventilation caused by hypoxemia, only detect levels of physically dissolved O2 and not the O2 that is chemically attached to hemoglobin
2. central chemoreceptors-located physiologically and not anatomically, located along the ventrolateral surface of the medulla near the cerebral spinal fluid of the 4th ventricle of the brain, at least three areas of the brain stem appear capable of chemodetection, more sensitive to changes in [H+] rather than CO2 but not sensitive to changes in BLOOD [H+] bec. entry of H+ into the CSF is limited by the BBB
Describe the carotid body.
a small nodule located on the bifurcation of the common carotid artery just above the carotid sinus baroreceptors, appear to be more important than the aortic bodies (but this may relate to their greater
Describe the aortic bodies.
located above and below the aortic arch
What do the carotid and aortic bodies monitor?
monitor the physically dissolved O2 and CO2 and the H+ concentration of arterial blood, these chemoreceptors are stimulated by a decline in the PO2, especially when it falls below 60 Torr, also stimulated by a DEC pH or an INC in the PaCO2
What do the central chemoreceptors measure?
like the arterial chemoreceptors, the central chemoreceptors are stimulated by an INC in the PCO2 or [H+], but not O2, appear to be more sensitive to changes in the H+ or PCO2 of CSF than of cerebral blood
What role does the BBB have on central chemoreceptors?
BBB separates blood from CSF, limits access of certain ions such as HCO3- and H+ to the CSF, the central chemoreceptors are not sensitive to changes in the PO2 of cerebral blood of CSF
What molecules are freely permeable and impermeable through the BBB?
O2, CO2, but largely impermeable to charged ions such as H+ or HCO3-
What happens when CO2 diffuses through the BBB into the CSF?
in the presence of carbonic anhydrase, CO2 can undergo hydration to form H+ and HCO3-
What is the most potent stimulus to ventilation?
an INC in CO2, PCO2 of arterial blood is closely maintained around 40 Torr by the medullary center via chemoreceptor input
What monitors PO2?
monitored only by the peripheral arterial chemorecetpros, has to decline markedly (from 100 Torr to 60 Torr) before ventilation is noticeably INC, this would correspond to a DEC in the inspired O2 from 21% to about 8%
What is the medullary integrator?
takes sensory input from the central and peripheral chemoreceptors that responds to changes in PCO2 of CSF and arterial blood, respectively, is the most important component in regulating respiration on a breath-to-breath basis
Which chemoreceptors responde to abrut changes in PCO2? in long-term changes in PCO2?
peripheral receptors are more proficient in responding to abrupt changes in the PCO2, whereas the central receptors respond to changes in PCO2 over longer periods
What happens when the neural afferent from the peripheral receptors are severed?
the ventilatory response to CO2 is only slightly dimished (10% to 20%), thus central chemoreceptors appear to account for a sizable portion of the ventilatory response to CO2, the INC ventilation that accompanies an elevation in arterial H+ concentration or a decline in PO2 are largely mediated via the peripheral receptors
How is the size of the body fluid compartments measured?
add a tracer to body which uniformly distributes itself throughout the fluid filled compartments, V = quantity of tracer/concentration of tracer
How is total body water measured?
use D2O (2H2O) or THO (3H2O) as a tracer, V = quantity of tracer (amount administered – amount lost) / concentration of tracer, remember that 1000 mL H2O = 1 Kg of H2O, water is 55.4% of total body weight
How is plasma level measured?
measured using a single tracer (Evan’s blue), blood volume = plasma volume/(1-hct)
What is hematocrit?
is packed red cell volume, fraction of the blood which is composed of RBCs, 0.40 in average adult man, 0.36 in average adult woman, may be as low as 0.1 in anemia or as high as 0.65
What tracers are used in measuring ECF?
inulin, mannitol, S45-O4 2-, sucrose, thiosulfate, radiochloride, , radiosodium, radiobromide, thiocyanate, these do not enter the cells
What are the two types of ECF?
1. fast ECF-is the readily accessible ECF, includes interstitial fluid proper as well as lymph and plasma, measured with inulin or thiosulfate, constitutes about 16.5% of total body weight
2. slow ECF-includes fast space plus an additional slowly accessible component, due to dense CT, bone, joint and intraocular cavities, cerebral ventricles
How is total ECf measured?
with dyes such as thiocyanate or radiobromide since these dyes penetrate the slow spaces, constitutes appox. 27% of total body weight
How is instertial fluid measured?
it is not measured directly, determined by interstitial fluid = extracellular – plasma, need to use two markers (one for ECF and one for plasma)
How is ICF measured?
not measured directly, use two dyes, ICF = total body water – ECF
What is the distribution of water among the various compartments in a 70 kg man?
extracellular water = 17 kg (for 70 kg man = 24.3% total body weight, of extracellular water, 3L (or 4%) is plasma and 2L (1-3%) is transcellular water
intracellular water = 25 kg (for 70 kg man = 35.7% total body weight
total body water is 60% of total body weight (20-40-60 rule)
What are average values for total body water in normal man as a % of total body weight?
0-1 month-75.7%
1 to 12 months-64.5%
1 to 10 years-61.7%
17-39 years (male)-60.6%
over 60 (male)-51.5%
17-39 years (female)-50.2%
over 60 years (female)-45.5%
What is the distribution of water in various tissues of a 70 kg man?
Tissue % Water % Body weight Liters H2O/ 70 kg
Skin 72 18.0 9.07
Muscle 75.6 41.7 22.10
Skeleton 22 15.9 2.45
Brain 74.8 2.0 1.05
Liver 68.3 2.3 1.03
Heart 79.2 0.5 0.28
Lungs 79.0 0.7 0.39
Kidneys 82.7 0.4 0.25
Spleen 75.8 0.2 0.10
Blood 83.0 8.0 4.65
Intestine 74.5 1.8 0.94
Adipose tissue 10.0 10.0 0.70
What is the relationship of total body water to total body weight?
water is about 73% of total lean body weight, solids is about 27% total lean body weight, fat is the biggest variable in the relationship and varies
What are the different classifications for different % fats?
Classification Women (% fat) Men (% fat)
Essential Fat 10-12% 2-4%
Athletes 14-20% 6-13%
Fitness 21-24% 14-17%
Acceptable 25-31% 18-25%
Obese 32%+ 25%+
What are equivalents?
refers to the moles of particles times the number of charges on each particle (referred to as either moles or Osm), moles refers to number of particles while osmoles takes into account how effective the molecule is as an independent osmotically active particle, each mole of particles does not exert exactly one osmole of osmotic activity
What is the normal range plasma osmolality?
280-295 mOsm/L H2O
What are the different mEq/L H2O for the various charged species in plasma, interstitial fluid and intracellular fluid?
intracellular fluid (~200 mEq/L H2O) is of greater amplitude than plasma (~160) and interstitial fluid (~150) because there are more multicharged species in this compartment, pluses = minuses (macroscopic electroneutrality is maintained)
What are the different osmolal distributions in the plasma, interstitial fluid and intracellular fluid?
the osmolality of plasma (~280) is significantly greater than that of interstitial fluid (~270) and intracellular fluid (~265) due to the presence of impermeant plasma proteins, this results in a greater osmotic pressure on the plasma side of the capillary
Why is there a net flow of water out of capillaries if the osmotic pressure is greater on the plasma side?
the osmolality of interstitial and intracellular fluids is the same, this occurs because the sodium pump continually pumps sodium out of cells and K+ back in, thus maintenance of osmotic equilibrium between the insteritial and intracellular compartments requires energy and is lost when the pump is blocked
What are three simplifying assumptions that are made for the purposes of analyzing clinical water shifts?
1. Na+ is considered as essentially an extracellular ion (when added remains largely extracellular
2. K+ is considered as essentially an intracellular ion (when added most shift into cells)
3. the intracellular compartment as a whole is considered to be a perfect osmometer (its solute content is assumed to be constant so that volume swells or shrinks according to the pressures exerted by extracellular osmolality)
What are some additional considerations in volemic disturbances?
1. Most body fluid disturbances originate in the extracellular compartment.
2. Loss or gain of fluid in the extracellular compartment affects primarily the cardiovascular system. Over hydration is associated with edema, dehydration with circulatory collapse.
3. Osmolality changes on the order of +/ 25% are life threatening and changes as small as +/ 5% frequently cause symptoms. In both intracellular overhydration and dehydration (water and salt intoxication, respectively), nervous system symptoms predominate, progressing ultimately to coma and death.
Describe the Darrow plot.
diagram that plots osmolality on the ordinate (y-axis) and volumes of the extracellular and intracellular compartments to the left and right abscissa (X-axis)
What are normal values of volume and osmolality for ECF and ICF?
ECF-V = 17 L and osmolality = 300 mOsm
ICF-B = 25 L and osmlality = 300 mOsm
How is total number of solute particles?
osmolality * volume = total number of solute particles in each compartment, area of each compartment equals its solute content
What is overhydration? dehydration?
overhydration-refers to a pathological INC in the volume of the extracellular compartment
dehydration (hypovolemia)-refers to a pathological DEC in volume of the extracellular compartment
What is cellular overyhydration? cellular dehydration?
overhydration and dehydration alone does not specify if cellular hydration has changed, likewise cellular overhydration or cellular dehydration does not specify the state of the ECF compartment
Describe isotonic overhydration.
is an accumulation of EC solutes with water in isotonic properties (e.g. careless parenteral administration of saline, edema through loss of plasma proteins or elevation of capillary hydrostatic pressure (usually progresses to hyponatremia)) ECF gets larger
Describe hypotonic overhydration (dilutional hyponatremia, water intoxication).
accumulation of water in excess salt (e.g. compulsive water drinking, IV therapy with isotonic glucose in patient with poor renal function), ECF and ICF INC but osmolality DEC for both
Describe hypertonic overhydration (salt intoxication).
accumulation of EC solutes in excess of water, the paradox of edema, dry tongue and intense thrist, drinking sea water, excessive water restriction in edematous patients, ECF INC, ICF DEC, osmolality INC
Describe isotonic dehydration.
loss of EC water and solutes in isotonic proportions, e.g. hemorrhage, losses from GI tract (vomiting, diarrhea), exudation accompanying excessive burns, not initial isotonic losses may easily convert into hypotonic or hypertonic losses, ECF DEC
Describe hypotonic dehydration (hypovolemic hyponatremia).
loss of extracellular solute in excess of water, e.g. adrenal cortical insufficiency (Addison’s disease), ECF DEC, ICF INC, osmolality DEC for both
Describe hypertonic dehydration.
loss of water in excess of extracellular wolute, e.g. water deprivation, excessive sweating, diabetes insipdus (lack of ADH), DEC in ECF and ICF, INC in osmolality
Can serious hydration defects exist in the face of normal Na+ concentration?
yes, think isotonic dehydration or isotonic overhydration
Do Na+ levels give an indication of whether the disturbance is dehydration or overhydration?
Na+ gives no indication whether the disturbance is over- or de-hydration, overhydration can be expected to lower hematocrit and plasma protein concentration and dehydration to raise them, these changes are not infalliable though, it is important to consider all aspects of the patients condition including plasma values as well as history
How many nephrons are in each human kidney?
there are ~1 million nephrons/human kidney
What is the basic functional unit of the kidney?
nephron, composed of the glomerulus (consists of a tuft of 20-40 capillary loops and Bowman’s capsule) with its associated afferent and efferent arterioles and a renal tubule
What is the course of the renal tubule and what is its purpose?
begins at Bowman’s capsule which is an expanded, invaginated bulb surrounding the glomerulus, consists of Bowman’s capsule, the proximal convoluted tubule, the loop of Henle, the distanl convoluted tubule and the collecting duct that carries the final urine to the renal pelvis and ureter
What are the two different types of Nephrons?
1. cortical nephrons-comprise about 85% of the nephrons in the kidney and have glomeruli located in the renal cortex, these nephrons have short loops of Henle which descend only as far as the outer layer of the renal medulla
2. juxtamedullary nephrons-located at the junction of the cortex and the medulla of the kidney, juxtamedullary nephrons have long loops of Henle which penetrate deep into the medulla and sometimes reach the tip of the renal papillae, these nephrons are important in the countercurrent system by which the kidneys concentrate urine
Where does the blood supply to the kidney come from?
each kidney receives a renal artery, a major branch from the aorta, which divides to form interlobular arteries, 90% of the blood flow goes to the cortex and only 10% to the remainder of the kidney
What do the renal arteries branch into and what do these branches form?
each renal artery subdivides into progressively smaller branches and the smallest branches give off a series of afferent arterioles, each afferent arteriole forms a tuft of capillaries which protrudes into a Bowman’s capsule, these capillaries come together and form a second arteriole (efferent) which divides shortly after to form the peritubular capillaries that surround the various portions of the renal tubule
What are the different type of efferent arterioles?
1. efferent arterioles of cortical nephrons-divide into peritubular capillaries that connect with capillaries surrounding other nephrons forming a rich meshwork of microvessels (functions to remove water and solutes)
2. efferent arterioles of juxtamedullary nephrons-form peritubular capillaries but has a second portion called the vasa recta, the vasa recta descend with the long loops of Henle into the renal medulla and return to the area of the glomerulus
What is the venous drainage of the kidney?
renal veins are formed from the confluence of the peritubular capillaries and exit the kidney at the hilus to return blood to the vena cava
What is the epithelial lining of the different portions of the nephron?
1. PCT-large [mito], marked basal membrane in-foldings, well developed brush border, juncions between cells and more open than those of the distal tubule
2. descending loop of Henle-flat cells, few mito, sparse brush border
3. thick ascending limb, loop of Henle-fewer mito and sparser brush border than PCT but more than thin segment, very tight junctions
4. DCT-similar to thick ascending limb
5. connecting tubule and collecting duct-composed of principal cells (Na+ reabsorption) and intercalated cells (acid secreting), very tight junctions between cells
6. glomerulus-consists of capillaries (composed of endothelial cells) and Bowman’s capsule (epithelial cells), separated by a thin (200 nm) basement membrane
What are the layers of the basement membrane between the capillaries and Bowman’s capsule?
lamina rara externa (which is closest to the epithelium), lamina densa (in the middle) and the lamina rara interna (which is closest to the endothelium)
What is the order of the different portions of the nephron in terms of the relative tightness of their tight junctions?
descending < proximal < thick ascending = distal convoluted = collecting duct
What role does ADH have on the DCT and collecting duct?
give the two segments variable water permeability depending upon the levels of circulating ADH, the water permeability change does not involve a modification of the tightness of the junction but rather ADH directly affects membrane permeability to water
What is the proposed mechanism of the filtration barrier?
the endothelium acts as a valve that screens out cells and controls access to the main filter which is the basement membrane, epithelium monitors this main filtration barrier, mesangial cells close capillary loops and recondition and unclog the filter and to influence the size and number of fenestrations through contractile properties
What factors contribute to the fact that there is higher transmural filtration rate of glomerular as opposed to extrarenal capillaries?
1. a much greater permability for water and crystalloids per unit of SA
2. a larger capillary SA per volume of tissue
3. a slightly higher mean net ultrafiltration pressure
Describe the composition of the juxtaglomerular apparatus (JGA).
includes cells located in both the glomerulus and the intial portion of the distal tubule, has specialized macula densa cells and mesangial cells, contains specialized secretory or granular cells located in the afferent and efferent arterioles which are called juxtaglomerular cells (JG cells), innervated by sympathetic nerves
What releases renin?
renin is released from JG cells located predominantly in the afferent arteriole and this leads to formation of angiotensin II
How is the release of renin controlled?
1. flow past the macula densa cells in distal tubule-senses [NaCl], initates a poorly understaood sereies of events which feeds back onto the glomerulus leading to an INC in GFR and release of renin
2. [NaCl]-i.e. when flow in the ascending limb of the loop of Henle DEC a greater fraction of the NaCl is reabsorbed leading to a DEC in NaCl concentration in the fluid entering the distal tubule
What is the pathway involved when a DEC of arterial pressure causes an INC in efferent arteriolar resistance and a DEC in afferent arteriolar resistance?
DEC in arterial pressure -> a DEC in glomerular hydrostatic pressure -> DEC in GFR (glomerular filtration rate) -> DEC in macula densa NaCl, this causes three things:
1. INC in proximal NaCl reabsorption
2. DEC in afferent arteriolar resistance which INC glomerular hydrostatic pressure
3. INC in renin -> INC in angiotensin II -> INC in efferent arteriolar resistance which INC glomerular hydrostatic pressure
What else contributes to TGF?
changes in capillary permeability produced by the mesangial cells (when GFR goes down, additional feedback mechanisms appear to cause relaxation of mesangial cells which INC capillary permeability, this in turn will INC GFR
How are the capillary beds arranged in renal circulation and how does that affect pressure?
contins capillary beds in series as wells as in parallel, this causes the pressure to drop in the kidney circulation are different from elsewhere (renal circulation has pressure drops then stops then drops then stops in steps while in other vascular beds there is an almost sigmoidal DEC in pressure from artery to vein)
What are the pressure levels in the glomerular capillaries and peritubular capillaries?
glomerular capillary is a high pressure bed while the peritubular capillaries are low pressure capillaries, because of this difference in hydrostatic pressure, only net filtration takes place at the gloermular capillary wheras only net reabsorption takes place at the peritubular capillaries, this is different from other non-renal capillary beds where both of these functions take place along the same capillary bed
How is renal blood flow calculated?
renal blood flow = change in P / (afferent arteriole resistance + efferent arteriole resistance)
How is GFR changed?
depends upon the pressure in the capillary like filtration in all capillaries, pressure in capillary in turn depends upon both the afferent and efferent arteriolar resistances, if Ra INC, the pressure in the glomerular capillary DEC and thus GFR DEC whereas if Re INC, the pressure in the glomerulus INC and GFR INC, a simultaneous INC in Ra and Re will produce a small change in capillary hydrostatic pressure and thus GFR
What is the importance of the changes in RBF and GFR?
allows for renal blood flow to be integrated into overall circulatory homeostasis while maintaining a farily constant level of glomerular filtration, the limitation of this independence is the amount that plasma oncotic pressure changes (i.e. oncotic pressure rises more steeply with distance into the glomerular capillary bed if a larger fraction of the plasma is being removed (as occurs when flow is reduced), this in turn tends to limit GRF
What is filtration fraction and how is it calculated?
the percentage of plasma which actually enters the tubule (i.e. the GFR), filtration fraction = GFR (mL/min) / renal plasma flow (mL/min)
How is renal plasma flow measured?
renal plasma flow = RBF * (1-hct)
How does contraction or dilation of the efferent arteriole affect filtration fraction?
when the efferent arteriole contracts less plasma flows through the kidney but a greater proportion of the plasma gets filtered, when the efferent arteriole dilates more plasma flows through the kidney but a smaller proportion of the plasma gets filtered, changes in afferent arteriolar resistance will have much smaller effects on filtration fraction since GFR and RPF either both go up or both go down
Describe autoregulation of the kidneys.
refers to the capcity of the kidneys to maintain a relatively constant flow of blood as perfusion pressure is changed, an intrinsic property of the kidney and of the smooth muscle cells (inhibition of vascular smooth muscle with papaverine abolishes autoregulation), believed to be due to two mechanisms
How does renal blood flow affected by prefusion pressure?
RBF is relatively independent of perfusion pressure from 80 mm Hg to 180 mm Hg, demonstrated in the denervated kidney and in a kidney which is removed from the animal and artificially perfused
What are the two mechanisms though to be responsible for autoregulation?
1. myogenic mechanisms-INC in perfusion pressure -> INC transmural wall pressure -> INC RAa (myogenic response) -> maintanence of capillary pressure and blood flow
2. TGF-when prefusion pressure INC there is a transient INC in GFR, sensed in distal tubule and macula densa cells then feedback to cause constriction of the afferent arterioles
What is the neurogenic control of RBF?
renal vasculature is richly innervated with sympathetic fibers, found on arterial segments before the glomerulus, little resting sympathetic activity to the renal vasculature thus cutting the sympathetic nerve does not lead to vasodilation, sympathetic nerves can lead to renal vasoconstrictoion under some circumstances
What are the circumstances that lead to renal vasoconstriction?
1. anesthesia, pain, changes in posture, emotional responses, physical activity, these lead to an INC in sympathetic activity to the kidney
2. hemorrhage, even small loses of blood can lead to striking DEC in RBF, this occurs primarily by reduction in flow to the superificial cortex, the vasoconstriction is probably due to sympathetic nerve stimulation
What stimulates renin release?
1. reduced stretch of JUG cells (during DEC BP)
2. reflex activation of renal sympathetic nerves (beta adrenergic receptors stimulated on the JG cells)
3. DEC delivery of NaCl (DEC flow) to the macula densa
serves to stabilize BP and extracellular fluid volume, angiotensin II negatively feeds back to inhibit further renin release
What does renin do?
renin (stored in JG cells) causes the conversion of alpha2-globulin (angiotensinogen) present in the blood to angiotensin I, ACE (located on the endothelial cells of the lungs and kidney) split angiotensin I (decapeptide) to angiotensin II (octapeptide)
What does angiotensin II do?
1. constricts systemic arterioles
2. release ADH and INC thirst
3. release NE from sympathetic nerves
4. release aldosterone from the adrenal cortex that INC sodium retention, also release NE and E
5. INC filtration fraction by contracting the efferent and to some extent the afferent arterioles
What do prostaglandins do?
modulate renal arteriolar resistance relaxing renal arterioles, released when sympathetic activity and angiotensin II INC to dampen the arteriolar contraction, protects the kidneys from an excessive reduction in blood flow during DEC MAP
What do NSAIDs do to prostaglandin release?
can upset the balance between excitatory and inhibitory influences on renal arterioles, blocks prostaglandin synthesis, if given to someone with CHF (so they have DEC MAP) can result in acute renal failure because of the large reduction in renal blood flow which follows the blockade of prostaglandin synthesis
How does renal artery stenosis affect renin release?
renal artery stenosis reduces afferent arteriolar pressure, will enhance renin release, INC angiotensin II and aldosterone levels and can result in hypertension since renin levels are inappropriately high
What happens if ACE is administered to an individual with renal artery stenosis to deal with their hypertension?
can lead to acute renal failure, this is because the actions of angiotensin II on GFR, in the individual with renal artery stenosis, GFR is maintained by angiotensin II, this aids in maintaining glomerular capillary and hence GFR, blockade of ACE will diminish angiotensin II production leading to reduction in GFR, acute renal failure can develop if GFR reduced enough
What is the O2 consumption of the kidney?
1. O2 consumption per weight of renal tissue is greater than that of any other organ except the heart
2. renal a-v difference in O2 is only about 15% of that observed in the heart
3. despite this low a-v difference the kidneys behave like flow limited organs
What is O2 consumption of the kidney dependent on?
dependent upon glomerular filtration rate, as filtration takes place Na+ enters the nephron, since almost all filtered Na+ is resorbed (at the expense of O2 and energy) the true independent variable that determines renal O2 consumption is the amount of Na+ that must be reabsorbed
What is ultrafiltration and where does it occur?
occurs at the glomeruli, filtration under pressure through the permselective glomerular capillary wall, separates plasma water and its nonprotein constituents (cyrstalloids) which enter Bowman’s space, from the blood cells and protein macromolecules (colloids) which stay in the blood
What is starling’s hypothesis and what does it measure?
filtration (GRF) = K ((Pc + pi t) – (Pt + pi c)) = mL/min, K = filtration coefficient (mL/min/mmHg), Pc = glomerular capillary hydrostatic pressure, Pt = proximal tubule hydrostatic pressure, pi c = glomerular capillary oncotic pressure, pi t = proximal tubule oncotic pressure
What determines the value of K?
dependent on area of capillary wall, distance across wall, viscosity of filtrate and permeability of capillaries, not fixed and may change due to the area available for filtration (mesangial cell contraction or relaxation, caused by angiotensin II or ADH, contraction DEC K)
What is a normal value for K in renal capillaries of humans?
12 mL/min/mmHg
What is the normal value for pi t?
is usually 0 since very little plasma protein passes into the tubule
What is the normal value for Pt?
18-20 mmHg, not physiologically regulated but if nephron is blocked then pressure goes up
How is Pc regulated?
regulated by arteriolar contractile state, the fall in pressure in the glomerular capillaries is much less than in extrarenal capillary beds since the blood exiting from the glomerulus enters a second set of arterioles
Compare the forces occurring in glomerular capillaries and extrarenal capillaries.
hydrostatic pressure (both glomerular and tubular) remains relatively constant when moving down the glomerular capillaries but declines considerably along the length of extrarenal capillaries
1) Glomerular capillaries are less permeable to proteins therefore oncotic pressure in Bowman's space is considered to be 0 whereas in the interstitial space of extrarenal capillaries oncotic pressure is approximately 8 mmHg.
2) Plasma oncotic pressure rises along the glomerular capillary (due to the volume of fluid which is filtered) whereas oncotic pressure is relatively constant in extrarenal capillaries.
3) Hydrostatic pressure in Bowman's capsule (i.e., 20 mmHg) is considerably higher than the pressure in the interstitial space surrounding extrarenal capillaries (i.e., -3 mmHg.).
4) Total capillary surface area and permeability/surface area (i.e., K) is greater for glomerular capillaries than for either extrarenal capillaries or renal peritubular capillaries.
5) In systemic capillaries net ultrafiltration declines because capillary hydrostatic pressure decreases. In glomerular capillaries, net ultrafiltration declines mainly because plasma oncotic pressure increases.
6) In glomerular capillaries net filtration occurs whereas in peritubular capillaries net reabsorption occurs.
7) In extrarenal capillaries both filtration and reabsorption occur within the same capillary bed (i.e., filtration in the initial portion of the capillary and reabsorption in the later portion.)
What is the mean value for GFR?
120 mL/min, each minute 120 mL of plasma is filtered into Bowman’s space, for one day this individual filters 172 L/day, our total body volume is only 5 L so it is obvious that most of the fluid which is filtered must be reabsorbed
When does net filtration occur?
net filtration will take place until the capillary hydrostatic pressure equals the tubular hydrostatic plus oncotic pressure (Pc = Pt + pi c), this gives filtration equilibrium
What and where are mesangial cells?
cells located between capillaries and are mechanically coupled to them, contraction of these cells can lower K, when they contract they DEC the permeability of the surrounding capillaries and GFR DEC, under basal conditions they are contracted to some degree so that their relaxation can lead to an INC in K
What types of molecules do the glomerular capillaries permit free passage to?
small molecules such as water (2A), urea, sodium, Cl- and glucose (7A) but they do not permit free passage of larger particles such as erythrocytes or large plasma proteins, Hb (65A) and small plasma proteins (36-150A) get through the membrane but not freely
What other factors about a molecule determine if it passes through the glomerular capillaries?
shape, flexibility and deformability and even its charge, seen with dextrans which have various sizes, weights and charges, + charge dextrans pass more readily than neutral, and negative encounter even greater hindrance, this is because there are negatively charge glycoproteins on the surface of the glomerular capillary wall, lamina rara interna and externa and podocyte foot processes
What molecule can be used to measure GFR?
inulin, it is a small (30 A), uncharged, freely filtered molecule that is not bound to plasma proteins nor is it metabolized within the tubule and it is neither reabsorbed nor secreted by renal tubules, inulin serves as a convenient marker for plasma which has passed into the proximal tubule (GFR), inulin infused intravenously
How is the clearance of inulin calculated and what does it tell us?
clearance of inulin allows us to calculate GFR, if is a measure of the volume of plasma which is completely freed of a given substance per minute by the kidneys, Cin = (Uin X V) / Pin, where C in is ml/min, Uin = concentration of inulin in urine, V = rate of urine flow, P in = concentration of inulin in blood plasma and Cin = inulin clearance
How is creatinine used in measuring GFR?
a good estimate of GFR can be obtained by measuring creatinine in the blood, it is freely filtered but is somewhat secreted as well, therefore the creatinine clearance (Ccr) will be somewhat greater than GFR (Ccr/Cin) ~= 1.2, Ccr is a reasonably accurate estimate of the GFR
What does GFR allow us to calculate and what does it tell us?
knowing the GFR allows us to determine how much of a particular substance the kidney must handle per minute (filtered load)
What is filtered load and how is it calculated?
is how much of a freely filtered substance the kidney must handl per minute, filtered load = GFR * Px (plasma concentration of substance X)
How is fractional excretion calculated?
fractional excretion = excretion rate/filtered load, it is a term used to describe the renal handling of a substance
What is the purpose of the kidney?
it filters blood, as it passes through the kidneys the nephrons clear the plasma of unwanted substances (urea) while simultaneously retaining other, essential substances (water), unwanted substances are removed by glomerular filtration and renal tubular secretion and are passes along to the urine, substances that the body needs are retained by renal tubular reabsorption and returned to the blood
How much of the filtered Na+ and water are returned to the body?
What are the different steps in solute movement into or out of the nephron?
filtration (from glomerular capillaries into Bowman’s capsule), reabsorption (from tubular lumen to the peritubular capillaries of the efferent arteriole (where it enters the renal vein back to systemic circulation), facilitates the conservation of substances essential to normal function), secretion (from peritubular capillaries back to tubules (leaves the systemic circulation and enters the ultrafiltrate for excretion through urine)) and secretion (urination)
What is Tm and what are some substances that exhibit it?
Tm is the maximum rate at which a carrier can transport (reabsorb or secrete) a substance, is known as maximum tubular reabsorptive capacity, seen in glucose, phosphate, sulfate, amino acids, urate, lactate and plasma protein
Describe the reabsorption of glucose.
glucose is a small molecule (7A) which is not bound to plasma proteins, freely filtered and normally there is no glucose in the urine therefore it must all be reabsorbed, transport of glucose can saturate through at high plasma concentrations due to Tm, transported via a secondary active transport system in the proximal tubule
How do secondary active transport systems work in reabsorption or secretion?
energy from transport comes from the sodium gradient established by the Na+/K+ ATPase, leaves the [Na+] in the tubular lumen to be very low (from the actions of the Na+/K+ ATPase) so that glucose can be brought in with Na+ from the lumen into the tubular lumen, from there [glucose] INC and it diffuses (through a transporter) form the tubular lumen to the peritubular capillary
What is renal threshold (threshold concentration)?
refers to the plasma concentration of a solute at which it begins to appear in the urine and is characteristic of that substance
How is reabsorption rate calculated?
reabsorption rate = filtered load – excretion rate = (GFR * Px) – (Ux * V), where Px is concentration of substance X in blood, Ux is concentration of substance X in urine and V is rate of urine flow
When is it best to calculate the maximum tubular reabsorption rate?
when a significant concentration of glucose has appeared in the urine (rather than when the first detectable quantity appears), in this way one avoids the splay which occurs at the renal threshold
What is the splay and why does it occur?
splay is a period that occurs when excretion rate is 0 for early levels of plasma concentration, it occurs because of inhomogeneity of nephrons and the fact that the transport molecules must be surrounded by a small excess of solute before the maximum rate of transport is attained, thus some solute spills out of the urine before a concentration of solute is reached at which all transport molecules are working at a maximum rate (Tm)
What does filtration rate vs. plasma concentration graph show?
shows that a constant rise in plasma concentration causes a constant rise in filtration rate
What does excretion rate vs. plasma concentration graph show?
after the initial splay, there is a constant INC in excretion rate with INC in plasma concentration
What does reabsorption rate vs. plasma concentration graph show?
reabsorption rate initially goes up with INCs in plasma concentration but reaches a threshold point where reabsorption rate stays constant with INCs in plasma concentration
What is phlorizin and what does it do to the excretion curve?
phlorizin is a glucose transport inhibitor, if the reabsorption of glucose is blocked then all glucose filtered will be excreted (the excretion curve will look like that for inulin), gets rid of splay
What is associated uncontrolled diabetes mellitus?
associated with large INC in blood glucose levels as well as INC renal blood flow and GFR, leads to an INC in Na+ reabsorption with glucose, this DEC the delivery of NaCl to the macula densa cells, activating TGF-mediated dilation of the afferent arterioles and subsequent INC in rengal blood flow and GFR, this INC urine flow rate
What happens if Pglu INC to the point that Tm is exceeded and significant amounts of glucose remain in the urine?
glucose can act as an osmotic particle keeping additional water in the tubules, this results in enhanced urine flow rate (osmotic diuresis)
What information is given to us if Cx < Cin?
1. there is hindered filtration, if X is a large molecule it will not pass through the filtration barrier, this is apparent with dextrans which can be made different lengths
2. or there is reabsorption (either by active transport or passive diffusion) from the tubule to the plasma, this conclusion can be made if X has a molecular weight less than 4000
What information is given to us if Cx > Cin?
then there must be secretion of that substance
How does the clearance of glucose compare to the clearance of inulin?
Cg is always less than Cin, as the reabsorption rate of glucose becomes small compared to the plasma concentration of glucose, Cg approaches Cin
Describe the secretion of organic anions and cations.
proximal tubule actively secretes a large number of different organic anions and cations (both foreign and endogenously produced), many of these molecules are also filterable at the glomerulus while others are bound to plasma proteins and so undergo only limited glomerular filtration, the active secretory pathways for organic molecules have relatively low specificity
Describe the secretion of paraaminohippurate (PAH).
PAH enters the renal tubule by secretion and by filtration, once it is present in the tubule it is not reabsorbed since it is a polar molecule and hardly soluble in lipid, thus all PAH is excreted in urine, transported across both the basolateral (rate-limiting, determines Tm) and apical membranes, almost complete removal of PAH from the blood can take place with a single cycle through the kidney
How is secretion rate calculated?
secretion rate = excretion rate – filtered load = (Ux * V) – (GFR * Px)
What substancecs secreted by the kidneys have a Tm?
penicillin, certain diuretics, salicylate, PAH and vitamin B1
How does the clearance of PAH compare to the clearance of Cin?
the greatest clearance of PAH occurs below the Tm for PAH, above the Tm a percentage of the PAH remains in the peritubular capillaries and fails to get secreted, as the plasma concentration of PAH becomes large compared to the secretion rate, Cpah approaches Cin, the clearance of PAH is greater than Cin because PAH enters the tubule via both filtration and secretion
What is renal plasma flow (RPF) and how is it calculated?
RPF = (Upah * V) / Upah = Cpah, referred to as the effective renal plasma flow since a small percent of the plasma never gets near a PCT and hence can’t be secreted
How is filtration fraction calculated in terms of GFR and RPF and what are normal values?
FF = GFR/RPF = Cin/Cpah, FF is approx. 20% (20% of plasma gets filtered into the tubule at the glomerulus and 80% stay sin the blood vessels and advances to the peritubular capillary
How is renal blood flow (RBF) calculated?
RBF = RPF / (1-hct)
Describe the movement of water through the kidney.
is always a passive process resulting from the establishment of osmotic gradients, however there are several important active transport processes which allow for the reabsorption of ions
How much NaCl is normally consumed in a day and how is it excreted?
normally take in 150 mEq/day, 140 will be eliminated in the urine while an additional 5 mEq is lost in the stool and 5 mEq in sweat
What are some general considerations concerning renal handling of Na+?
1. movement of Na+ from lumen into the epithelium is down its electrochemical gradient
2. Na+ is subsequently transported out of epithelial cells into the interstitial space by Na+/K+ ATPase
3. renal excretion of Na+ is controlled by how much Na+ reabsorption takes place
What is the role of the proximal tubule in renal handling of Na+?
1. most Na+ is reabsorbed in the PCT (around 67%)
2. the favorable Na+ gradient from lumen to epithelial cell interior is utilized in the transport of other molecules such as glucose, amino acids (e.g. Na+/Glu cotransport)
3. the entry of Na+ into epithelial cells may also be coupled to H+ secretion in the proximal tubules (Na+/H+ exchanger)
What is the role of the thick ascending limb in renal handling of Na+?
1. Na+ reabsorption in thick ascending affects Na+ delivery to distal tubule and hense renin and TGF
2. Na+ moves into epithelial cells via a carrier which transports Na+/2Cl-/K+
3. loop diuretics (furosemide) often work by blocking the Na/2Cl/K carrier
What are the two most important cell types in the distal tubule?
1. principal cells-reside in the cortical collecting tubule, the terminal portion of the DCT and the outer stripe of the outer medullary collecting tubule, they have a high resting sodium conductance (Gna) and are the site of K+ secretion
2. alpha-intercalated cells-reside in the same areas of the nephron as the principal cells but are not as abundant, are involved in the secretion of H+ and contain both a H+ ATPase and a H+/K+ ATPase at the luminal membrane
What is the role fo the distal tubule in renal handling of Na+?
1. contains a unique Na+/Cl- cotransporter (blocked by thiazed diuretics)
2. in late DCT/cortical collecting duct, Na conductance in principal cells is very high, variable and controlled in part by aldosterone (aldosterone INC Gna)
What is the role of the collecting duct in renal handling of Na+?
1. Gna is very high and variable in cortical collecting duct principal cells, lwer in inner medullary collecting duct
2. Na+ is reabsorbed throughout the collecting duct with the inner medullary collecting duct reabsorbing approx. 2% of the filtered Na+ load
3. the cortical collecting duct is the primary site of action of aldosterone
4. amiloride si a diuretic which blocks Gna in principal cells, spironolactone blocks the action of aldosterone (the “anti-aldosterone”)
What are some general considerations involving renal handling of Cl-?
1. net movement of Cl- from the tubular fluid to the epithelial cell interior is up an electrochemical gradient and therefore requires some form of transport (i.e. either Na+/Cl- cotransport, Na+/K+/Cl- cotransport or Cl-/HCO3- exchange)
2. net movement of Cl- from epithelial cells interior to the peritubular space is down its electrochemical gradient and is typically (but not always) passive
3. the majority of Cl- is reabsorbed passively via a paracellular route
4. luminal negativity enhances Cl- reabsorption
What is the proximal tubules role in renal handling of Cl-?
active Na+ reabsorption leads to passive H2O reabsorption which in turn INC the tubular concentration of Cl-, this in turn provides a favorable gradient for the passive reabsorption of Cl-, although Cl- concentration in the PCT rises, Cl- content falls
What is the role of the thick ascending loop in renal handling of Cl-?
1. secondary active transport via Na/2Cl/K carrier at luminal membrane
2. Cl- either passively diffuses into peritubular space or is transported via a K+/Cl- cotransporter at the basolateral membrane
What is the role of the DCT in renal handling of Cl-?
1. secondary active transport of Cl- with Na+ at luminal membrane (blocked by thiazide diuretics)
2. passive diffusion of Cl- from cell interior to peritubular space
3. some passive reabsorption occurs via paracellular route
What is the role of the cortical collecting duct in renal handling of Cl-?
1. paracellular reabsorption enhanced by negative luminal potential
2. some Cl- movement into cells involves Cl-/HCO3- exhcnager at luminal membrane of beta-intercalated cells
What is the average consumption of K+
around 80 mEq K+/day, ~70 mEq will be eliminated in the urine while an additional 9 mEq is lost in the stool and 1 mEq is lost in sweat, hence the kidneys are central to the control of K+ balance in the body
What are some general considerations of renal handling of K_?
1. movement of K+ form lumen into epithelial cell interior is up an electrochemical gradient and therefore requires some form of transport (e.g. K+ ATPase, Na/2Cl/K cotransporter, K+/H+ ATPase
2. secretion of K+ is due in large part to passive leak out of cells down its electrochemical gradient
3. movement of K+ from epithelial interior to interstitial space can occur passively
What is the role of the proximal tubule in renal handling of K+?
1. about 50% of the filtered K+ is reabsorbed in the proximal tubule
2. most K+ reabsorption in the PCT occurs via a paracellular route, some K+ may be transported into cells via a K+ ATPase, once inside the cell K+ passively moves into peritubular space across the basolateral membrane or is transported with Cl-
What is the role of the thick ascending limb in renal handling of K+?
1. some net reabsorption of K+ occurs here (K+ reabsorption is less efficient than Na+ because of back leak
2. K+ is trlansported into epithelial cells via Na+/2Cl/K carrier, some passively leaks from cells into peritubular space or moves via K/Cl cotransport
What is the role of the DCT in renal handling of K+?
1. very little net K+ movement in the eearly distal tubule
2. secretion or reabsorption occurs in the late distal tubule depending upon K+ status of individual and other factors, secretion in late DCT and cortical collecting duct is due to principal cells, on the other hand, alpha-intercalated cells reabsorb K+, usually secretion predominates over reabsorption
3. K+ secretion is stimulated by the high Na+ conductance (Gna) present in the principal cells, aldosterone affects both Na+ reabsorption and K+ secretion
What is the role of the collecting duct in renal handling of K+?
1. usually secretion in cortical collecting duct (although net reabsorption can occur with hypokalemia), reabsorption only in medullary collecting duct
2. secretion dependent upon aldosterone and intracellular K+ levels
3. the cortical collecting duct (principal cells) is the predominant site for K+ secretion
Describe renal excretion of K+.
K+ is the only plasma electrolye which is both reabsorbed and secreted into the renal tubules, reabsorption of K+ in the proximal tubule and loops of Henle is 90-95% complete regardless of whether the body is K+ loaded or depleted
What does the amount of K+ excretion depend upon?
1. K+ secretion in late distal tubule/early collecting duct
2. K+ reabsorption by medullary collecting ducts
range of excretion is 1-200% of the filtered load, normally 10-20%
What are the most important physiological regulators of K+ secretion?
1. intracellular K+ concentration
2. aldosterone
What happens in an individual who consumes large quantities of K+?
it will first lead to an INC plasma K+ levels, K+ will eventually move into cells, an INC in intracellular K+ concentration will enhance K+ secretion because a larger K+ gradient exists from epithelial cell interior to tubular lumen, rises plasma K+ that stimulates release of aldosterone from the adrenal gland, this enhances K+ secretion from principal cells
What is the role of diuretics in K+ secretion?
ex: include furosemide (loop diuretic) and thiazide (distal tubule action), these enhance both distal tubular flow and the concentration of sodium in the DCT INCing K+ secretion, creates a large gradient that favors K+ secretion, Na+ also INC K+ secretion since an INC in Na concentration will tend to depolarizes principal cells and thus enhance K+ secretion
What do diuretics such as amiloride are called K+ sparring diuretics?
amiloride blocks the sodium channels present on the luminal membrane of the principal cells and hence the luminal membrane hyperpolarizes, this hyperpolarization in turn reduces the driving force for K+ secretion and thus K+ is spared
How many mEq of K+ will have to be consumed per day to balance the level of excretion of K+?
filtered load = GFR * Pk, if there is 10% excretion multiply 0.1 by filtered load then multiply by 60 min/hr * 24 hr/day to get the amount of excretion/day
What is urea?
it is a low molecular weight, uncharged molecule produced by the metabolism of amino acids which are not used for protein synthesis, body makes excess urea and is eliminated from the body by the kidneys, more osmoles of urea in the urine than any other particle, there is also a sizable proportion of the urea that is passively reabsorbed
What does reabsorption of urea depend on?
1. permeability of the tubule
2. tubular area
3. urea concentration gradient
4. time available for the movement of urea
What is reabsorbed first, water or urea?
water, urea reabsorption is not as rapid as that of water, this INC concentration of urea and develops a gradient for passive reabsorption of urea
Is urea clearance diuresis dependent?
the higher the velocity of tubular flow the less time available for reabsorption of urea leading to INC urea excretion so it urea clearance is diuresis dependent
What are some typical values which one might measure form an individual nephron was modulated by drinking behavior?
1. while drinking ad labium: Uurea = 480 mg/100mL, Curea = 48 mL/min and % reabsorbed is 62%
2. after 12 hours of thirsting:Uurea = 720 mg/100mL, Curea = 36 mL/min and % reabsorbed is 71%
while urea clearance goes down following a period of thirsting (and consequently reduced distal nephron flow rate) the concentration of urea in the urine goes up, these two changes can occur simultaneously because the volume of urine being produced is less following the period of thirsting
Describe the reabsorption and secretion of weak organic acids and bases.
many weak organic acids and bases have fluctuating rates of excretion or clearance, transtubular transport of such substances is brought about by non-ionic diffusion and the non-uniform excretion may be caused by variations in urine pH
What are some characteristics of non-ionic diffusion?
1. occurs with weak acids and bases
2. high lipid solubility in the uncharged state, much less in the charged state
3. if the charged molecule is present in the tubular lumen it is diffusion trapped wherease the uncharged moiety will cross membranes according to concentration gradients via non-ionic diffusion
When is non-ionic diffusion employed?
may be employed to rid the body of poisoning levels of weak acids or bases, for example Phenobarbital or acetylsalicylic acid overdoses can be treated by infusion of a NaHCO3 solution whereas amphetamine overdoses can be treated by infusion of arginine-hydrochloride
How is 99% of the fluid which is filtered returned to the blood when a reverse hydrostatic pressure can not be invoked?
the energy for transport of fluid back into the body is generated by active ion pumping and predominantly from the Na+/K+ pump of the peritubular membrane, urine is normally hypertonic and this causes problems for the assumption that there is an active water pump
Describe the counter-current mechanism.
generates an interstitial osmotic gradient from outer to inner medulla which is equivalent to that present in the lumen of the descending limb of the loop of Henle
What special features of the loop of Henle allow for the counter-current mechanism?
1. the ascending limb has very low water permeability
2. actibe reabsorption of salts occurs in the ascending limb
3. the descending limb of salts occurs in the ascending limb
4. since the loop of Henle is a loop, osmotic gradients established by the ascending limb of the loop can affect the osmolality of the descending limb
5. flow occurs in the loop so that tubular fluid can be sequentially modified by different portions of the loop
Describe the role of the loops of Henle of juxtamedullary nephrons in the osmotic gradient.
it generates an osmolar gradient in the kidney from cortex to the inner papillary segment, this gradient does not approach the 1200 mOsm observed during antidiuresis if vasa recta did not work in concert with the loops to maintain the gradients
What is the role of the vasa recta in stabilizing the osmotic gradient?
are long capillary loops that follow the loops of Henle into the medullary region of the kidney, share same interstitial space as the loops of Henle and collecting ducts, help maintain the gradient
What are the significant features of the vasa recta that allow it to help in the stabilization of the osmotic gradient?
1. the permeability of the capillaries on both the descending and ascending limb is high so that ions and water flow according to the concentration gradients which exist between the lumen of the capillaries and the interstitial space
2. flow is slow enough to allow equilibration to take place between plasma and the surrounding interstitial fluid
What is the significance of the features of the vasa recta?
plasma of vasa recta becomes very hypertonic with respect to normal plasma by the time it reaches the end of the descending limb of the loop, almost completely reverses this process on the ascending limb, a small excess of solute is removed as the blood exits from the vasa recta
What would happen if the hair pin configuration of the vasa recta were absent?
tubular fluid would exit instead from the papillary region of the kidney and much larger amounts of salt would be lost, there would be a continual washing out of the gradients created by the loop of Henle
What are the reasons for blood flow to the medullary regions?
1. nutritive/oxygen delivery
2. water and solutes which are conserved by the loop of Henle and collecting duct must be returned to the venous blood, flow of blood exiting form the vasa recta is twice as great as the flow entering the vasa recta
What are the two predominant factos which insure that net reabsorption of fluid occurs in the vasa recta?
1. the hydrostatic pressure in these capillaries is low
2. the oncotic pressure in these capillary is high
both 1 and 2 result from the anatomical location of the vasa recta (downstream from two arteriolar beds and the glomerular capillaries
Describe the filtering of urea by the glomerulus
urea is freely filtered by the glomerulus and reabsorbed to some extent in a flow dependent manner, handling of urea can greatly affect the medullary interstitial osmolality
What is the role of urea in the development of an osmotic gradient?
1. during antidiuresis (water retention) when ADH levels are high the water permeability of the late distal tubule and collecting duct is INC, however the DCT and cortical collecting ducts are relatively impermeable to urea, in contrast, the inner portion of the medullary collecting duct has a much greater permeability to urea and it can be further increased by the actions of ADH on urea transporters (see figure).
2. Urea becomes concentrated in the late distal tubule and collecting duct as water leaves. This leads to an increase in urea gradient across the collecting duct.
3. Urea leaves at the medullary collecting duct where its permeability is higher. This movement continues until the concentration of urea in the medulla approaches that in the collecting duct.
4. Urea constitutes about 40% 50% of the total medullary and papillary osmoles during antidiuresis, whereas it contributes less than 10% during water diuresis. Thus the fluctuation in medullary interstitial osmolality is mostly a consequence of the quantity of urea present.
What factors enhance the ability urea to contribute to the establishment of an osmolar gradient?
1. with low urine flow rates proportionately more urea is reabsorbed
2. urea is recycled
3. the vasa recta serves to keep interstitial urea in the medullary portions of the kidney (in the same way that it maintains the NaCl osmolality)
Why is urea recycled?
it allows the kidneys to excrete high concentrations of urea without brining with it large quantites of water, this is accomplished by matching the tubular urea concentration with the interstitial urea concentration, urea no longer represents a major osmotic stimulus and can exit without large volumes of water
What is the half-life of ADH?
16-20 minutes
How is ADH important in the counter current multiplication system?
the counter current multiplication system is of little value without the ability to regulate the water permeability of the late distal tubule and collecting duct, only in the presence of ADH can a hypertonic urine be formed
How is ADH formed?
ADH contains 9 aa, formed in cell bodies of the supraoptic and paraventricular nuclei of the hypothalamus
After ADH is formed, what is the course of travel to storage?
transported in small packets down the nerve axons of the supraoptic hypophyseal tract to nerve terminals located in the posterior pituitary where it is stored until release, during transport is bound to carrier protein
How is ADH released?
changes in the osmolality of the plasma (as little as 2 to 3 mOsm) are sensed by osmoreceptors in the hypothalamus, this stimulates the hypothalamic neurons to produce an AP which is propagated down to the nerve terminals in the posterior pituitary, results in release of ADH (while still bound to carrier protein) into the capillary blood of the posterior pituitary, once it enters the plasma but before it reaches the kidney the carrier protein is cleaved
What is the receptor for ADH?
ADH (AKA arginie vasopressin or AVP) binds to V2 receptors in the basolateral membrane of the principal cells from the cortical collecting duct to the end of the nephron
What is the molecular bio of ADH?
binding to V2 activates Gs stimulating adenyl cyclase which activates PKA, PKA phosphorylates unknown proteins that play a role in the trafficking of intracellular vesticles containing aqua-porin2 proteins and the fusion of these vesicles with the apical membrane in clusters to form water channels, when ADH levels decline these proteins are shuttled back to the cytoplasmic vesicle pool
What is diuresis?
urine flow that is greater than normal (in excess of aobut 1 mL per minute in an adult human being
What is osmotic diuresis?
INC urine flow that is due to extra amount of nonreabsorbed solute within the tubular lumen, common example is mannitol diuresis
What is water diuresis?
INC urine flow that is due to DEC reabsorption of free water, this type of diuresis is seen in persons who have durnk large amounts of dilue fluid and in patients with diabetes insipidus who have some abnormality of ADH
What is antidiuresis?
urine flow that is less than normal, usually below about 0.5 mL per minute in an adult human, the term is also frequently used to connote the excretion of urine that is hyperosmotic to plasma
How does antidiuresis cause a formation of hyperosmotic urine?
With high concentrations of ADH in the blood, the membranes lining the late distal tubules and collecting ducts are highly permeable to water. Thus, water flows down the osmotic gradient between the intratubular fluid and interstitium. As water leaves the tubule the osmolality of the tubular fluid increases and consequently the urea gradient increases. Urea exits at the medullary collecting duct contributing approximately 40 to 50% to the osmolality of the medullary interstitium.
How does water diuresis cause a formation of hypoosmotic urine?
In water diuresis the blood concentration of ADH is low or zero, so that the membranes lining the late distal tubules and collecting ducts are relatively impermeable to water. Hence, very little water is reabsorbed even though an osmotic gradient between intratubular fluid and interstitium exists. Some NaCl continues to be reabsorbed by active transport mechanisms, which accounts for the further dilution of tubular fluid from approximately 150 mOsm/kg H2O at the beginning of the distal tubule to approximately 75 mOsm/kg H2O in the urine.
What are the levels of input and output in a steady state?
input = output, water turnover rate averages between 1.5 and 3 L/day
What constitutes our water input?
water in food (60-97% of weight in food), metabolic water (1 g carb = 0.6 g H2O, 1 g fat = 0.1 g H2O, 1 g protein = 0.4 g H2O), water in drinks makes up the remainder
What constitutes our water output?
1. insensible (skin and lungs, ~350 mL at rest and 350 and 650 mL during exercise, respectively)
2. sensible-urine = 1500 mL at rest, 500 during exercise, sweat = 100 mL at rest and 5000 mL during exercise, feces = 200 at rest and exercise
3. output at rest = 2500 mL and output during exercise is 6700 mL
How does water balance control body fluid osmolality constant during normal circumstances?
1. the kidney-the actions of ADH on the kidney have been discussed before
2. drinking behavior-the thirst mechanism is not so well developed in humans as in certain other vertebrates, nonetheless, drinking behavior is equally as important as renal function, severe kidney disease can be masked and adequate water balance maintained by appropriate drinking behavior
What is osmolar clearance and how is it calculated?
reflects the rate at which the plasma is being cleared of osmotically active particles, does not indicate water balance of the subject itself, Cosm = (Usom * V) / Posm
What are the values for the Cosm equation for isotonic urine?
Uosm = 300 mOsm/L, V = 2 mL/min, Posm = 300 mOsm/L, Cosm = 2 mL/min, therefore 2 mL/min of plasma is cleared of osmotically active particles, in the case of an isotonic urine the water int eh plasma which was cleared of particles actually accompanied the particles into the urine (V = Cosm)
What are the values for the Cosm equation for a maximally dilute urine?
Uosm = 60 mOsm/L, V = 10 mL/min, Posm = 300 mOsm/L, Cosm = 60 * 10/300 = 2 mL/min, in the case of a dilute urine the volume of plasma cleared of osmotically active particles is significantly less than the total volume flow of the urine
What are the values for the Cosm equation for a maximally concentrated urine?
Uosm = 1200 mOsm/L, V = 0.5 mL/min, Posm = 300 mOsm/L, Cosm = 2 mL/min, the volume of plasma cleared of osmotically active particles is significantly greater than the total volume flow of the urine (this is typical of what one sees for substances such as inulin and PAH)
What does the fact that the Cosm for the three urine cases above show?
shows that very different circumstances can produce the same osmolar clearance
What is free water clearance and how is it calculated?
free water clearance helps in determing what is happening with water balance (if the kidney is excreting excess water or excess solute), v (urine flow) = Cosm (osmotic clearance) + C H2O (free water clearance), free water clearance is the amount of distilled water which must be subtracted from or added to the urine in order to render that urine isosmotic with plasma (it is not a classic renal clearance)
Where is the majority of free water generated?
in the thick ascending limb of Henle’s loop, if C H2O is positive, then that is how much free water is being generated, if it is negative then there is additional water that is removed from the collecting duct to conserve the water (referred to not as a negative free water clearance but a positive TcH2O)
What is C H2O for isotonic urine?
C H2O = 0, therefore V = Cosm
How does furosemide act as a diuretic?
blocks the Na/2Cl/K cotransporter on the luminal membrane of the thick ascending limb of Henle’s loop (K+ losing), leads to urine which contains less free water
How does thiazide diuretics act as a diuretic?
blocks the Na/Cl cotransporter in the early DCT (K+ losing)
How does amiloride work as a diuretic?
blocks Na+ conductance (permeability) of principal cells primarily in the cortical collecting duct (K+ sparring)
How do changes in volume affect ADH and thirst?
DEC plasma volume -> DEC venous, atrial and arterial pressures -> reflexes mediated by cardiovascular baroreceptors -> INC ADH secretion -> INC plasma ADH -> INC tubular permeability to H2O -> INC H2O reabsorption
What does a hemorrhage do to levels of ADH?
it can acutely produce levels of ADH up to 100 X higher than produced by an osmotic stimulus as well as profound thirst, high enough [ADH] to directly stimulate blood vessels to contract which also aids in restoring BP, ADH alone is not able to regulate both osmolality and volume
What is the bodies response to an acute INC in water load
when distilled water is consumed, osmolality is reduced and the body responds by DECing production of ADH leading to a hypotonic urine (water diuresis)
What is the body’s response to an actue INC in Na+ load
with a Na+ load the INC in ECF volume will lead to an initial DEC in the level of ADH so that water is excreted, but this will not continue for long since the loss of water will INC fluid osmolality leading to the reverse stimulus to ADH secretion, deals with volume overload by regulating salt
How is extracellular volume regulated?
extracellular volume is regulated primarily through regulation of sodium balance, the matintenance of a normal extracellul volume requires the precise balance between the amount of NaCl ingested and that excreted from the body
Describe sodium balance.
the amount of NaCl in the urine reflects dietary intake, the kidneys response to variations in dietary NaCl usually takes several days, during the transition period excretion does not match intake and the individual is in either positive or negative sodium balance
What is the normal intake of NaCl?
is between 2 and 10g NaCl/day, if NaCl intake is reduced to about 200 mg/day or raised to about 30 g/day the body responds by losing or gaining several kg in weight, then stabilizes, this represents about the limits with normal renal function
How does the kidney control sodium balance?
kidney is a very important volume sensor, regulation of Na+ excretion by the kidneys dependus ultimately on the relationship between the filtered load of Na+ and the tubular reabsorption of Na+, when at an ideal volume this stimulates the controller to release neural and intrarenal elements (GFR, aldosterone, natriuretic hormone, peritubular pressure) that tell the kidney to retain sodium, this causes a change in the blood volume which talks with volume sensorys (venous stretch receptors, baroreceptors, intrarenal elements)
What are the 4 factors that affect Na+ retention?
GFR, aldosterone, angiotensin II, atrial natriuretic hormone
How does GFR remain constant in humans?
due to autoregulation and feedback control mechanisms
What happens when GFR INC?
the filtered load of Na+ also INC, if GFR INC by 2% the additional filtered load of Na+ would be on the order of 504 meq/day, this Na+ is not lost because of glomerulotubular balance
What is the importance of glomerulotubular balance?
glomerular tubular balance insures that under steady state conditions a constant fraction of filtered Na+ is reabsorbed in the proximal tubule in spite of changes in GFR, excess Na+ is reabsorbed in the loops of Henle, distal tubules and the collecting duct so that almost all the additional Na+ load encountered with an INC GFR is returned to the body
What is the ultimate regulator of urinary Na+ excretion?
the collecting ducts (and to a lesser extend the late distal tubule) are the ultimate regulateor of urinary Na+ excretion even thought they process a small fraction of the glomerular filtrate
What is the proposed mechanism for GTB?
relates to peritublar factors and to the fact that sodium participates in the co-transport of various other molecules, GTB appears to be influenced by the level of Na+ consumed and consequently ECF volume, Na+ reabsorption becomes greater than 67% when ECF volume is depleted (low Na+ intake) and DEC below 67% with an expanded ECF volume (high Na+ intake)
How does INC Na+ consumption result in an INC in ECF volume?
INC Na+ intake -> INC plasma [Na+] -> INC Posm -> fluid shift from IC to EC compartment and an INC in ADH and thirst -> INC in ADH and thirst leads to an INC in water reabsorption and water consumption -> INC ECF volume
How much of an effect does aldosterone have on renal handling of Na+?
modulates the reabsorption of the last few percentr of filtered Na+ which amounts to around 30 grams of NaCl per day which aldosterone can influence
How does aldosterone work?
it is through to act primarily on the cortical collecting ducts and late distal tubule and exerts its effect by combining with intracellular receptors, stimulation of receptors in the nucleus leads to synthesis of mRNA which then mediates translation of specific proteins, one of these opens previously closed Na+ channels in the luminal membrane
What does opening Na+ channels in the luminal membrane do?
allows greater entry of Na+ into the cell, INC cell Na+ concentration, and INC pumping of Na+ across the basolateral membrane by Na+/K+ ATPase pumps, thus the INC pumping of Na+ across the basolateral membrane is driven simply by the INC intracellular Na+ concentration
What does aldosterone do to production of ATP and what effect does this have on renal handling of Na+?
it enhances ATP production, this ATP works on the Na+/K+ ATPase which over a longer span of time will have an INCed synthtesis (there will also be INC in Na+ channels), all the effects of aldosterone in enhancing Na+ reabsorption also leads to an INC in secretion of K+
What is aldosterone’s affect on H+ secretion?
aldosterone’s third action on Na+ reabsorption involves stimulation of H+ secretion in the distal nephron
What is the time requirement for sdioum reabsorption actions by aldosterone?
enhancement of sodium reabsorption requires time (at least 45 minutes) for protein synthesis, DEC in sodium excretion that occur within minutes are not caused by INC aldosterone
What is primary adrenal insufficiency?
Addison’s disease, involves degeneration of the adrenal cortex and is most commonly due to autoimmune destruction, causes reduction in aldosterone which leads to (1) urinary retention of K+ resulting in hyperkalemia, (2) retention of H+ ions resulting in acidosis and (3) sodium wasting associated with hypotension, hypovolemia and in some cases hyponatremia, treatment involves replacing cortisol and aldosterone
What does hyperkalemia cause?
usually asymptomatic, can cause muscle weakness and life-threatening cardiac arrhythmias, treatment involves replacing cortisol and aldosterone
What is primary hyperaldosteronemia?
elevated secretion of aldosterone by the adrenal gland due to an adrenal lesion (adenoma), renin levels are low
What is secondary hyperaldosteronemia?
high aldosterone secretion is due to a non-adrenal lesion (CHF, renal artery stenosis), renin levels are high
What are some associated problems with hyperaldosteronemia?
hypokalemia and metabolic alkalosis, Na+ reabsorption is enhanced, patients do not typically exhitibe hypernatremia since there are other mechanisms which can regulate sodium excretion, usually manifested as hypertension
What role does angiotensin II have on renal handling of Na+ reabsorption?
has indirect (release of aldosteron) and direction actions on the nephron, includes contraction of the efferent arterioles and direct stimulation of Na+ reabsorption
What does contraction of the efferent arterioles do?
aides in INCing Na+ reabsorption, contracting the efferent arteriole reduces pressure in the peritubular capillaries (Pc) and INC colloid oncotic pressure (INC Tc) both of which enhance tubular reabsoprtion
What does direct stimulation of Na+ reabsorption by angiotensin II do?
it directly stimulates the Na+/K+ ATPase activity on the basolateral membrane of proximal tubular cells, this will also enhance Na+ reabsorption
What role does atiral natriuretic hormone (ANF) have on Na+ reabsorption?
28 aa pepetide which is released from the atria in response to expansion of ECF volume and by Na+ loading, it inhibits NaCl and water reabsorption across the medullary portion of the collecting duct, there is a new 32 aa peptide found (urodilatin) that acts in a similar manner that is released by the distal tubule and collecting duct
Describe volume regulation and the releationship between ECF volume and Na+ balance in CHF patients.
in CHF the hearts contractility is too low to maintain the CO required for the body’s metabolic requirements, manifestations include a DEC GFR and INC activities of the renin-angiotensin-aldosterone system and renal sympathetic nerves, leads to complete reabsorption of Na+
Why does the CHF patient have completely reabsorption of Na+ when the CHF patient exhitibts markedly positive and progressively INCing Na+ balance?
total ECF volume itself is not measured but rather cardiovascular pressure is, in heart failure there is a discontinuity between changes in plasma volume, EC volume and total body sodium vs. cardiovascular pressure (which normally have no discreprencies in healthy patients), the reflexes of the body are responding to the DEC BP signals as though the individual was undergoing hemorrhage or diarrhea while in fact overexpansion of ECF and formation of edema are occurring
Is the kidney able to maintain Na+ balance under exteme changes in nephron loss?
the kidneys are capable of maintaining Na+ balance under fairly extreme changes in nephron loss and associated changes in GFR, this occurs due to an INCingly greater fractional excretion of Na+ compared to the reduced GFR
What happens with INCing nephron loss?
the ability of the kidneys to respond to INC in Na+ intake become progressively more impaired, this is not surprising, given the fact that each remaining nephron functions closer and closer to its maximum capcity as nephrons are progressively lost to disease
What happens when the nephrons are challenged beyond their capacity?
patient experiences + Na+ balance with expansion of the extracellular circulating volume, results in generalized and pulmonary edema, as the number of functioning nephrons is reduced the capacity to conserve Na+ DEC, the osmotic diuresis that develops in the remaining functioning nephrons necessitates the loss of INCingly larger quantities of Na+, patients with renal failure can develop – Na+ balance with a DEC in effective circulating volume if Na+ intake is restricted
How does metabolic acidosis develop in patient’s with progressive nephron loss?
develops in these patients when GFR falls below approx. 50-70%, due to the inability of the kidney’s to keep up with the fixed acids which are produced through metabolism
How do plasma creatinine INCes develop in patient’s with progressive nephron loss?
it INCes since the main mechanism by which creatinine enters the nephron for excretion is through filtration, when less creatinine enters neprons less can be excreted leading to a build-up of creatinine in the plasma, this + creatinine balance only persists until the plasma creatinine rises to a level at which the filtered load of creatinine returns to the value which occurred when all nephrons were intact
How does plasma BUN INCes develop in patient’s with progressive nephron loss?
similar to creatinine, this is not a tubular flow related issue since the single nephron flow rate of the remaining nephrons is quite high
How does plasma osmolality INCes develop in patient’s with progressive nephron loss?
INC as urea, creatinine and other molecules accumulate in the plasma, as nephrons are lost, the ability to regulate water balance and there fore plasma osmolality is impaired
How does the range in max and min urine osmolality change in patient’s with progressive nephron loss?
as GFR DEC, range becomes narrower, leading to the production of urin with an osmolality near that of plasma, The production of smaller volumes of urine with an osmolality similar to plasma results from the osmotic diuresis that develops in the remaining functioning nephrons. With the increased tubular flow induced by the osmotic diuresis, there is almost no change in the composition of the tubular fluid as it flows through the remaining functioning nephrons. In addition, disease-induced structural changes in the kidney, especially the renal medulla, can impair the countercurrent multiplication process. Without countercurrent multiplication the medullary interstitial osmotic gradient cannot be established, and water reabsorption from the collecting duct in the presence of ADH is therefore impaired
What is normal arterial pH?
7.4 +/- 0.05, venous pH is slightly lower, limits of pH compatible with life are about 7.0 to 7.8, most serious effects are on CNS function, we are capable of tolerating a greater acid load than a base load
How is volatile acid produced?
normal oxidative metabolism produces about 13,000 mmol of CO2/day, CO2 + H2O -> H2CO3 (carbonic acid)
How is non-volatile acid produced?
this form of acid cannot be readily converted to gas thus it must be eliminated by the kidneys, protein intake produces about 40-100 mmol/day of non-volatile acid, includes sulfuric acid, phosphoric acid, lactic acid, ketone bodies
Describe sulfuric acid as a non-volatile acid and its production.
75% of non-volatile acid production is sulfuric acid, comes from metabolism of sulfur containing aa (cystine, cysteine and methionine), ex: 2 Met + 15 O2 -> 4H+ + 2 SO42- + urea + 7 H2O + 9 CO2, for 100 g of protein you get 10 mmoles of H2SO4
Describe phosphoric acid as a non-volatile acid and its production.
quantity of phosphoric acid produced is not an important consideration within the plasma however it is very important for the renal handling of acid-base balance, phosphoric acid is formed from nucleic acids and phospholipid metabolism
Describe lactic acid as a non-volatile acid and its production.
is formed during intermediary metabolism, usually then completely oxidized, normally eliminated by destruction vs. renal excretion, builds up during heavy exercise, exists predominantly as lactate within the body, kidneys reabsorb any lactate that is filtered, serious lactic acidosis can occur accompanying the anoxia of circulatory insufficiency: lactic acid + Na+ -> H+ + Na-lactate
Describe ketone bodies as a non-volatile acid and its production.
acetoacetic (pK = 3.8) and beta-hydroxybutyric (pK = 4.8) acids are normally produced in fat metabolism but their plasma concentrations are low and they are quickly further metabolized, accumulate in DM and starvation, almost all their H+ is buffered in the body fluids, accumulation may lead to coma and death
where does most of the base produced in the body come from?
base is produced from the intake of milk and certain types of fruits and vegetables, what we take in is the salts of weak acids (Na-lactate, Na-citrate, Na-isocitrate) that consume acid (Na-lactate + H+ -> 3CO2 + 3H2O), vegans may have a net production of alkyl
What is the first line of defense the body has in defending its mild alkaline pH from acid loads?
chemical buffering, adding a strong acid to a weak acid buffer causes a smaller DEC in pH than just adding the strong acid itself, buffer is most effective when [salt of acid] = [weak acid]
What is a buffer?
a solution which minimizes the change in pH which occurs when you add a strong acid or base to it, buffer solutions contain a weak acid or a weak base and the salt of that weak acid or base
Describe blood as a chemical buffer.
exchange across the RBC membrane is so fast that we can consider blood as a single buffering compartment, the principal buffers are bicarb and Hb, with plasma proteins and phosphate making quite minor contributions
What is the buffering capacity of the whole blood for bicarb and non bicarb buffers?
plasma bicarb (35%), RBC bicarb (18%), Hb and O2-Hb (35%), plasma proteins (7%), organic phosphate (3%) and inorganic phosphate (2%)
Describe interstitial fluid as a chemical buffer.
principal buffer in this compartment is bicarb, interstitial volume is much greater than plasma volume so this compartment is at least equal in importance to blood for buffering metabolic acid
Describe intracellular fluid as a chemical buffer.
contains approx. half of the body’s total buffer capcity for metabolic acids, most of the cell’s impermeable anions form weak acids thus phosphates, proteins and organic anions do the lion’s share of the buffering
What are the major buffer anions in the intracellular fluid and what are their concentrations?
HPO4 2-/H2PO4 – (6 mM/L), protein-/H-protein (6 mM/L), organic anions (84 mM/L), HCO3- (12 mM/L)
How long does it take for cellular buffers to come into play?
somewhat more slowly that EC buffers, hours or even days may be required for an acute acid load to be handled completely, CO2 presumably crosses the membrane rapidly, H+ as such crosses more slowly, cellular buffering is probably slowed by the attendant shifts out of the cell of Na+ and K+, finally we should note that virtually all buffering of CO2 is intracellular
Describe bone as a chemical buffer.
bone salts are buffers since they are almost completely composed of phosphates and carbonates, after several days of an INC in acid load, buffering of acid was almost entirely bone, this accords well with the observation that the bones of patients with chronic acidosis are freq. very rarefied
What is the second line of defense the body has in protecting its slightly alkaline pH from acid insults?
respiration, it helps control extracellular fluid CO2 concentration by the lungs, ability of the body to blow off or conserve CO2 makes the carbonic acid-bicarb buffer system an effective buffer system, for example, as the pH DEC the reponse of the body is to INC respiration to blow off CO2
What is the corrected Henderson-Hasselbalch equation for PCO2?
pH = pK + log [HCO3-] / (0.03 * pCO2), normal levels include: pK = 6.1, [HCO3-] = 24 and pCO2 = 40 mm Hg
What is a consequence of respiration returning pH near normal?
bicarb is loss and hyperventilation occurs, in order to render our buffer system effective, bicarb must be replenished (through the rid of non-volatile acid via a renal response)
What is the third line of defense the body has in protecting its slightly alkaline pH from acid insults?
the renal response, gets rid of the strong acid which was introduced into the body and regenerates the lost bicarb, this part of defense can take days, bicarb is regulated by kidneys while CO2 is regulated by the lungs
What can the kidneys do to regulate acid-base balance?
1. the kidneys conserve filtered bicarb
2. kidneys can make new bicarb
3. the kidneys can excrete excess bicarb
4. kidneys can excrete excess H+
2 and 4 occur together (H2CO3 -> H+ + HCO3-
What happens to [HCO3-]/[CO2] during acidosis?
ratio is reduced, kidneys therefore work to conserve all filtered bicarb, in addition they excrete acid into the urine, at the same time the kidneys also make new bicarb which is added back to the blood, this slowly INC bicarb returning the ratio back to the normal 20/1 ratio, almost all acid excreted is bound to urinary buffers and carried as titratable or ammonium forms
What happens to the [HCO3-]/[CO2] ratio during alkalosis?
ratio is abnormally high, kidneys excrete excess HCO3- and do not make new bicarb, returns ratio to 20/1
Where is most bicarb reabsorbed?
occurs in a number of sites but about 80-90% is reabsorbed in the proximal tubules, ~15% is thick ascending loop and 5% in collecting tubule
How does the proximal tubule reabsorb bicarb?
In the early tubular segments H+ ions are secreted by secondary active transport (i.e., Na+ /H+ antiporter). This mechanism does not establish a very high hydrogen ion concentration in the tubular fluid (i.e., pH falls to about 6.0). Carbonic anhydrase is present both within proximal tubule cells and on the luminal membrane of cells. No acid excretion occurs in the process of bicarbonate reabsorption because the secreted acid becomes re-incorporated into CO2. Once CO2 diffuses from the tubular lumen into the cell carbonic anhydrase aids in re-forming H+ and HCO3.
How does the distal nephron reabsorb HCO3-?
The reabsorption of bicarbonate in the distal nephron differs in that primary active secretion of hydrogen ions occurs at intercalated cells. It also differs in that the pH of the tubular fluid can go as low as pH 4.4. This can occur because: 1) a primary energy driven transporter is involved, 2) the permeability of the luminal membrane to hydrogen is very low. Another difference between HCO3 reabsorption in the distal nephron is that there is no carbonic anhydrase on the luminal membrane. The forward reaction HCO3 + H+ → H2CO3 occurs because of the low luminal pH.
How is total HCO3- reabsorption calculated?
HCO3- reabsorption = filtered load – excretion rate
What form is phosphoric acid found in at pH 7.4?
most of the acid is present as HPO4 2-, pK = 6.8 for H2PO4 - <-> H+ + HPO4 2-, very little of the acid is present as H3PO4 (pK = 2.2) or PO4 3- (pK = 9.7) since the pK of these equilibrai are so far away from 7.4
What is the bicarb regeneration mechanism using TA?
as flow of filtrate moves down the tubule there is an INC in phosphate, CO2 diffuses into the tubule cell, reacts with H2O and makes bicarb and HCO3-, HCO3- is actively transported out and makes new HCO3-, H+ is actively transported back to the filtrate where it reacts with the excess phosphate there to form H2PO4- which is excreted in urine (as titratable acide)
Describe the formation of titratable acid and bicarb formation.
When hydrogen is secreted into the tubular lumen it can combined with HPO42- to become H2PO4-. In this way hydrogen becomes buffered. Most T.A. is formed in the proximal tubule since the pK of the buffer pair H2PO4-/HPO42- is 6.8 and the tubular lumen falls to 6.0 in the proximal tubule (i.e., at a pH below 6.8 most phosphate is in the form H2PO4-). The amount of T.A. formed is exactly equal to the amount of new HCO3 added to the body, i.e., the tubular cells do this (CO2 + H2O -> H2CO3 -> H+ (excreted as T.A) + HCO3- (new buffer base for body))
What are some factors affecting the amount of titratable acid formed?
affected by the acid-base status of the individual because this dictates how much acid is secreted, when lots of acid is secreted the tubular fluid pH DEC and all HPO4 becomes H2PO4, things which reduce H+ secretion (reduced CO2 levels) will DEC T.A. formation
What happens to the concentration of beta hydroxyl-butyrate in diabetic acidosis?
has a pK = 4.8, during diabetic acidosis, there is lots of this substance around and urine pH becomes very acidic so that a significant portion of the beta-hydroxybutyrate will bind H+ and carry them out in the urine
Describe the excretion of ammonium.
there is very little ammonia present in the blood since following the formation of ammonia via the breakdown of aa it is usually convereted into urea (2 NH3 + CO2 -> urea + H2O), at pH 7.3, most NH3 is actually NH4+ since the pK is 9.3
What is the bicarb regeneration mechanism via ammonium production?
glutamine is taken up by the tubule cell, it is turned into AKG2- + 2 NH4+, NH4+ is actively excreted from the tubule cell into the urine, AKG2- combines with H+ to form CO2 and glucose, H+ comes from the formation of HCO3- from CO2 and H2O, HCO3- is then actively transported out of the tubule cell and regenerates one new HCO3-
How is bicarb formed in conjunction with the formation of ammonium?
in the presence of acid loads, kidney tubules synthesize ammonia in the epithelial cells in the proximal and distal nephron, glutamine is transported into the tubular cell, glutamine gives rise to both ammonium (which is excreted into the tubular lumen via a Na+/NH4+ exchanger) and alpha-ketoglutarate which is further converted to glucose or CO2, this takes H+ ions from H2CO3 leaving behind a bicarb molecule
What happens to NH4+ when in the tubular lumen?
once in the tubule it is trapped because it is a charged species, then excreted, by excreting NH4+ the kidneys rid the body of excess H+ at the same time new HCO3- is created and added to the body
What is a general rule of thumb for H+ excretion and HCO3- generation?
for each H+ ion excreted a new HCO3- molecule is added to the body
How is total bicarb reabsorption calculated?
bicarb reabsorption = bicarb filtered – bicarb excreted
How is the new bicarb generated calculated?
neb bicarb generation = TA + NH4+
How is the amount of H+ excretion calculated?
H+ excretion = TA + NH4+
How is the total H+ secreted calculated?
total H+ secreted = H+ excrete + reabsorbed HCO3-
How is the total bicarb delivered to plasma calculated?
total bicarb delivered to plasma = New HCO3- + reabsorbed HCO3- = total H+ secreted
Under normal conditions what are the relative excretion rates of ammonia and TA?
more H+ is normally excreted as NH4+ than as TA, H+ combined with NH3 (30-50 mEq/day), H+ as TA (10-30 mEq/day)
Under uncontrolled DM what are the relative excretion rates of ammonia and TA
1. Over production of nonvolatile acids (mainly beta hydroxybutyric acid).
2. Chronic acidosis
3. Increased production of NH3 by tubular cells in response to acidosis.
4. Increased excretion of NH4+
5. Acid urine
6. Beta hydroxybutyric acid concentration in urine high. Becomes a significant portion of total T.A. in the presence of acid urine.
H+ combined with NH3 (300-500 mEq/day), H+ as TA (75-250 mEq/day)
Under chronic renal disease what are the relative excretion rates of ammonia and TA?
1. DEC functioning renal tissue
2. both TA and NH4+ reduced
3. TA falls less than NH4+ because TA is dependent upon filtration wherease NH3 involves tubular metabolic prcocesses
H+ combined with NH3 (0.5-15 mEq/day), H+ as TA (2-20 mEq/day)
What is normal pH levels?
normal pH range = 7.35-7.45
What is acidemia?
blood pH outside the normal range, pH < 7.35
What is alkalemia?
blood pH outside the normal range, pH > 7.45
What is acidosis and alkalosis?
disease or pathological process or condition that causes pH to change, acidosis causes acidemia, alkalosis causes alkalemia
What is respiratory acidosis or alkalosis?
caused by pathological change in PaCO2, often caused by abnormal function of the lung, but not always, for example, patient with CO2 poisoning, respiratory acidosis (INC PaCO2, retaining CO2) but lungs are normal
What is metabolic acidosis or alkalosis?
caused by pathological change in [HCO3-]
What is an alternate form of the H-H equation in terms of acid-base disturbances?
pH = pKa + log (metabolic/respiratory)
What is the effect of changing PaCO2 in acid-base behavior of blood?
equivalent experiments can and have been done with patients, results are similar, want to measure pH and [HCO3-] as PaCO2 is changed, if INC PaCO2 to 60 mm Hg get [HCO3-] of 25 mM and pH ~7.24, [HCO3-] slightly changed, pH dropped lots, if repeat the experiment at various partial pressures get buffer line of blood
Why did the pH drop so much but the bicarb went up only slightly when PaCO2 changed to 60 mm Hg?
INC in PaCO2 pushed equation to the right, bicarb went up slightly due to a simple buffering reaction or a simple readjustment in the equilibrium, HCO3- did not go up b/c exogenous HCO3- was added to the system by the kidneys
What does the buffer line show?
shows how a patient would respond if their PaCO2 was altered, small changes in HCO3-, remember pH = [HCO3-]/PaCO2, INCing PaCO2 causes a drop in pH, not a large change in [HCO3-], DECing PaCO2 causes an INC in pH, small DEC in bicarb., has a very slight slope, would be much greater if there was no Hb or plasma protein to act as non-volatile buffer, binds to H+
What is a Davenport diagram?
graph that compares [HCO3-] vs. pH, normal [HCO3-] of 24 mm Hg at pH of 7.4
What are some common clinical causes of respiratory acidosis?
1. CNS depression-drug overdose or anesthesia
2. severe asthma attack
4. severe pneumonia
5. upper airway obstruction
6. severe pulmonary edema
What are some common clinical causes of respiratory alkalosis?
1. voluntary hyperventilation
2. hypoxemia
3. liver failure
4. anxiety hyperventilation syndrome
5. sepsis
6. any acute pulmonary problem-acute PE, pneumonia, mild asthma attack, mild pulmonary edema
What is the effect of changing [HCO3-] in acid-base behavior of blood?
equivalent experiments can and have been done with patients, results are similar, want to measure pH and [HCO3-] as [HCO3-] is changed, titrate in strong acid into the blood, bicarb is consumed (it buffers some of the added acid but not all of it), pH will go down but dissolved CO2 will remain at 40 mm Hg (no changes in PaCO2) b/c any generated CO2 will equilibrate with a large chamber of CO2 held at 40 mm Hg, again pH = [HCO3-]/PaCO2, line on Davenport diagram for changing [HCO3-] is line with constant PaCO2 (called an isopleft (?)),
What happens if titrate in strong base to system?
bicarbonate is generated, CO2 is consumed, CO2 buffers some of the added acid but not all of it, pH will go up but dissolved CO2 will remain at 40 mm Hg b/c any CO2 that was consumed is replaced by other CO2 in the large chamber of CO2 held at 40 mm Hg
What happens if perform acid-base titration (by changing [HCO3-]) at various PaCO2?
get numerous isopleft lines at different pH, proceeding along an isopleft results in changing the HCO3- but not the PaCO2
What happens when adding strong base or acid?
adding strong base = metabolic alkalosis, adding strong acid = metabolic acidosis, there is no change in the PaCO2 when the patient went from normal pH to either acidic or basic
What causes metabolic acidosis (hypobicarbonatemia)?
1. INC in EAP-derangements in gut function, derangements in metabolism, due to exogenous intoxicants
2. reduced net acid excretion due to renal defects
What are some GI causes of metabolic acidosis?
diahrrhea or laxative abuse, can lead to INC in stool volume, INC in secretion by lower gut, loss of HCO3- in the stool, concomitant INC in H+ delivered to the blood, INC in blood H+ are buffered by HCO3- = loss of HCO3-
What are some metabolic causes of metabolic acidosis?
1. imbalance between organic acid production and consumption-normal incomplete metabolism of carbos and lipids (carbos and lipids <-> organic acid <-> A- + H+) or to complete the metabolism (A- + H+ <-> CO2 + H2O (requires O2))
2. therefore during hypoxia (DEC perfusion or DEC O2 carriage) organic acids will build up along with the protons-will lead to metabolic acidosis
What are some examples of metabolic acidosis?
1. lactic acidosis-strenuous exercise with volume depletion
2. ketoacidosis-diabetes
What are some exogenous causes of metabolic acidosis?
alcohols that get metabolized to acids-including methanol (CH3-OH -> CH2O (formaldehyde) -> HCOOH (formic acid)) and ethylene glycol (HO-CH2-CH2-OH -> glycolic acid -> oxalic acid)
What are pH, HCO3- and PCO2 levels for different clinical states of metabolic acidosis?
1. metabolic acidosis with acute buffering-pH of 7.22, HCO3- of 16 and PCO2 of 40
2. actue respiratory compensation-pH of 7.32, HCO3- of 15 and PCO2 of 30
3. chronic condition-pH of 7.22, HCO3- of 12 and PCO2 of 30
What are some clinical causes of metabolic alkalosis?
vomiting or nasogastric drainage-leads to loss of H+, upper GI must generate more H+, which dumps more HCO3- into the blood
What are pH, HCO3- and PCO2 levels for different clinical states of metabolic alkalosis?
1. metabolic alkalosis with acute buffering-pH of 7.60, HCO3- of 38 and PCO2 of 40
2. actue respiratory compensation-pH of 7.53, HCO3- of 40 and PCO2 of 50
Instead of making more H+ and dumping more HCO3- into the blood, why not just spill the HCO3- into the urine and keep pH normal?
metabolic alkalosis requires both a generation mechanism (vomiting) and a maintenance mechanism (INC in the renal threshold for HCO3- spillage), there are three main factors responsible for maintenance (volume deplection, hypokalemia, aldosterone excess)
What are confidence bands on the Davenport diagram?
show how 95% of the patients in a give situation would react, adds width to the buffer line
What must be met for a disturbance to be classified as an acute respiratory acidosis?
pH must go down by 0.07 and [HCO3-] must go up slightly (~1 mM) for every 10 mm Hg change in PaCO2, then acute and has not been compensated
What causes of respiratory acidosis?
1. insufficient neural drive for ventilation
2. inadequate movements of the respiratory muscles or thoracic cage
3. airway obstruction
4. pulmonary disease
What are the pH, HCO3- and PCO2 for different clinical states of respiratory acidosis?
1. baseline-pH of 7.4, HCO3- of 24 and PCO2 of 40
2. respiratory acidosis not compensated-pH of 7.10, HCO3- of 24 and PCO2 of 80
3. acute buffering of respiratory acidosis-pH of 7.17, HCO3- of 28 and PCO2 of 80
4. chronic respiratory acidosis-pH of 7.30, HCO3- of 38 and PCO2 of 80
What must be met for a disturbance to be classified as an acute respiratory alkalsosi?
pH must go up by 0.08 and [HCO3-] must do down slightly (~2 mM) for every 10 mm Hg change in PaCO2, then acute and has not been compensated
What are the pH, HCO3- and PCO2 for different clinical states of respiratory alkalosis?
1. respiratory alkalosis not compensated-pH of 7.70, HCO3- of 24 and PCO2 of 20
2. acute buffering of respiratory alkalosis-pH of 7.63, HCO3- of 20 and PCO2 of 20
3. chronic respiratory alkalosis-pH of 7.47, HCO3- of 14 and PCO2 of 20
What is a chronic respiratory acid-base disturbance?
it is a compensated disturbance, has been in the body for a while, patient values are not along the buffer line of blood and does not meet the rule of acute respiratory acidosis, for example, the renal system may have had time to compensate by INCing plama bicarbonate which returned the pH back toward normal
What is compensation?
is a change in [HCO3-] or PaCO2 that occurs as a result of the primary event (acute event), change in PaCo2 in the metabolic disorders represents the lung’s role in compensation, the change in bicarb represents the kidney’s attempt to compensate for the respiratory acidosis or alkalosis
What is the purpose of compensation?
it is to return the blood pH to normal, in the example given in the ppt., the change in the bicarb level represents the kidney’s attempt to compensate for the respiratory acidosis or alkalosis
What happens in chronic respiratory acidosis?
there is an INC in PaCO2, just like in chronic, but pH will DEC only a slight amount and [HCO3-] will INC to help compensate for the severe INC in PaCO2, try to return pH toward normal values
What is the timeline of chronic respiratory acidosis?
1. DEC alveolar ventilation (which controls PaCO2)-acute acid-base disturbance not yet compensated from #1->3
2. DEC CO2 excretion
3. INC PaCO2
4. equilibration of body buffers (10 min after initial disturbance), DEC pH = [HCO3-] / INC PaCO2
5. chronic adaptation (renal)-occurs in 4 days, INC H+ excretion (new bicarb regeneration via titratable acid and NH4+, INC [HCO3-] reabsorption, occurs for #5->6
6. INC new [HCO3-], INC plasma level
7. pH returns toward normal-small DEC in pH = small INC [HCO3-] / INC PaCO2
Why does the acid-base Davenport map not include an acute and chronic respiratory alkalosis category?
the respiratory system is very quick to respond, so patient would already have compensated assuming that respiratory system is intact
What is a rule of thumb for metabolic acidosis?
1. primary change-fall in [HCO3-]
2. compensatory change-fall in PaCO2
3. expected value of compensation-PaCO2 = 1.5 X [HCO3-] + 8 +/- 2
What is a rule of thumb for metabolic alkalosis?
primary change-rise in [HCO3-]
compensatory change-rise in PaCO2
expected value of compensation-PaCO2 bup by 0.5-1 mm Hg for each 1 mM rise in [HCO3-]
How to evaluate blood gas step-by-step?
1. check pH, if less than 7.35 (acidosis) or greater than 7.45 (alkalosis)
2. for acidosis, if [HCO3-] < 24 then metabolic acidosis, if PaCO2 > 24 respiratory acidosis, if both/neither then mixed
3. for alkalosis, if [HCO3-] > 24 then metabolic alkalosis, if PaCo2 < 40 then respiratory alkalosis, if both/neither then mixed
Describe the reciprocal movements of H+ and K+.
when extracellular pH is DEC by processes involving an INC in organic acid, there is a small shift of K+ ions out of cells, can lead to hyperkalemia, mechanism for this involves the activity of both the Na+/K+ pump as well as the Na+/H+ transporter (K+ and H+ move in opposite directions), treating a patient to reverse the acidosis can cause a rapid uptake of K+ into cells and result in hypokalemia
What is hypokalmic alkalosis?
When [K]o is reduced, there is a shift of K+ ions out of cells as well as a shift of H+ ions into cells (see right side of previous diagram). This situation differs somewhat from that discussed above for acid base disturbances in that changes in [K]o led to a consequent shift in H+ rather than the reverse. Under these circumstances some degree of intracellular acidosis and extracellular alkalosis develops. The acidification of the intracellular compartment has a significant effect on the renal excretion of acid, i.e., the tubular cells will respond to the intracellular acidosis by secreting H+ and conserving and creating new HCO3 . This leads to the paradox of an acid urine with metabolic alkalosis.
Describe the clinical relevance of continued vomiting.
With vomiting lots of acid can be lost from the stomach as well as Na+ and Cl . With a short period of vomiting the kidney will simply lose HCO3 and excrete less H+ to compensate. Extra K+ goes out with the HCO3-. Some respiratory compensation can also occur by decreasing respiration rate to increase CO2 however this mechanism is rather limited since we need O2 to function. If acid is continually lost for days more severe problems develop.
What is the affect of continued vomiting on plasma [Na]?
Plasma [Na] hasn't changed much. Since there is vomiting, food and water intake are likely minimal. With decreasing blood volume those factors which lead to enhanced Na+ retention will be maximized (e.g., aldosterone release).
What is the affect of continued vomiting on plasma [K+]?
Plasma [K] concentration is down. When vomiting occurs the body loses acid leading to a metabolic alkalosis. The kidneys will therefore secrete little H+ to begin with and a significant amount of HCO3- is lost to compensate for the alkalosis. Aldosterone levels are up in response to the decrease in extracellular fluid volume and this serves to stimulate the secretion of K+ as well as the reabsorption of Na+. The secreted K+ accompanies the HCO3- out in the urine. K+ excretion is therefore taking place at a greater rate than the replenishment of K+ through food. These events lead to K+ depletion from the body.
What is the affect of continued vomiting on plasma [Cl]?
Plasma [Cl] is down since Cl- was lost by vomiting. Cl- and HCO3- are the major extracellular anions in the body. As a result, often times as the concentration of one of these anion goes down (in this case Cl-) the concentration of the other goes up (in this case HCO3-).
What is the affect of continued vomiting on urine pH?
Urine pH is low. This is a situation which develops with sustained periods of vomiting. In the earlier stages of vomiting the reabsorption of Na+ was countered by the secretion of K+, however as K+ continues to be secreted it eventually can become depleted. If K+ loss is sufficient to reduce body stores of K+, H+ secretion will increase. Thus the paradox of an alkaline plasma pH and an acid urine! The defense of extracellular fluid osmolality has a higher priority than acid base balance, i.e., pH will go up before plasma [Na] goes down. Several factors lead to this situation: 1) hypokalemia will lead to a shift of K+ out of cells and a shift of H+ into cells thus as hypokalemia develops the pH inside cells will become more acidic even though the individual is alkalotic (as discussed earlier), 2) aldosterone itself increases the activity of the H+ pump. As volume depletion continues and aldosterone levels rise the H+ pump is stimulated, 3) the absence of K+ secretion means that another cation must counter the reabsorption of Na+, in the absence of K+ secretion, H+ secretion fulfills this role to some extent.
What is the affect of continued vomiting on plasma [HCO3-]?
Plasma [HCO3-] is up due to several factors. 1) loss of acid from the digestive tract shifts HCO3/H2CO3 ratio, 2) increased H+ ion secretion leads to increased HCO3- reabsorption and new HCO3- formation, 3) decreased H+ delivery into small intestine will inhibit HCO3- secretion into G-I tract.
What is the affect of continued vomiting on PCO2?
PCO2 is slightly high to provide partial compensation for the metabolic alkalosis (i.e., respiration is decreased).
What is the affect of continued vomiting on BUN and plasma creatinine?
BUN is high due to the low urine flow rate which will be present with volume depletion (i.e., a large proportion of urea will be reabsorbed and therefore the plasma urea concentration will increase).
Plasma [creatinine] is somewhat high due to the loss of extracellular fluid volume.
What is the affect of continued vomiting on urine Na, K and Cl?
Urine [Na] is low. The excretion of Na+ is low due to the volume depletion (i.e., Na+ is being avidly conserved).
Urine [K] is low. K secretion has gone down as the body becomes K+ depleted.
Urine [Cl] is low because Cl- followed Na+ back into the body. Also low since PCl is low.
What is contraction alkalosis?
Contraction alkalosis occurs when NaCl and H2O are lost but not HCO3 . In this setting, which is most commonly due to diuretics, extracellular volume is diminished but the quantity of extracellular HCO3 is initially unchanged. As a result plasma [HCO3 ] rises,
How is anion gap calculated?
anion gap = ([Na+] – ([Cl-] + [HCO3-]), normal anion gap is approximately 12  4 mEq/L plasma (cations greater than anions) since uncounted anions (i.e., ketoacids, lactate and protein) are present in the plasma. Determining the anion gap is often helpful in the differential diagnosis of metabolic acidosis since it allows one to evaluate whether a foreign anion is involved in the acidosis.
What are some examples of metabolic acidosis with a normal anion gap?
a. G.I. loss of HCO3 (diarrhea)
b. Renal HCO3 loss (proximal renal tubular acidosis)
c. Ingesting NH4Cl
What are some examples of metabolic acidosis with a high anion gap?
a. Ketoacidosis (uncontrolled diabetes mellitus)
b. Lactic acidosis (altered redox state during shock)
c. Ingestion of substances which produce organic anions
(e.g., methanol → formic acid)
d. Salicylate ingestion
What is the relationship between plasma HCO3- and Cl-?
HCO3- and Cl- represent the major extracellular anions and are the only ones measured in determining the anion gap. As may be apparent from the examples above when metabolic acidosis does not involve the addition of a foreign anion a reduction in HCO3- will always be associated with an increase in Cl-. This is not surprising if one considers that there must always be a balance between cations and anions in solution (i.e., macroscopic electroneutrality must be maintained). In the example sited above in which HCO3- is inappropriately lost in the urine due to a defect in the proximal tubule (proximal renal tubular acidosis) the reabsorption of Na+ will be associated with an enhanced reabsorption of Cl-. Thus, plasma Cl- levels go up as plasma HCO3- levels go down. Conversely, in the case of vomiting when Cl- is lost from the body as a part of the stomach contents, plasma HCO3- levels will rise as plasma Cl- levels fall (see previous laboratory data for continued vomiting).
What role does diarrhea have on acid-base disturbances?
Severe diarrhea is probably the most frequent cause of metabolic acidosis. This form of metabolic acidosis is particularly serious and can be a cause of death, especially in young children. Intestinal, pancreatic and biliary secretions are relatively alkaline with high HCO3 concentration. Diarrhea also leads to hypokalemia since K+ is present in these secretions (note: the effect of HCO3- loss on acid-base balance is greater than the effect of the hypokalemia). Diarrheal fluid is roughly isosmotic to plasma therefore loss of this fluid doesn't alter Posm or PNa. The loss of HCO3 leads to a decrease in the [HCO3 ]/H2CO3 ratio. The respiratory system compensates initially by blowing off CO2. Ultimately bicarbonate must be regenerated by the kidneys with the excretion of titratable acid and ammonium.
What is the role of chronic renal failure on acid-base disturbances?
When kidney function declines markedly, acid end products of metabolism are not excreted at a normal rate and hence accumulate in the body. In addition, impaired synthesis of ammonium contributes to the decreased ability of the kidneys to excrete hyrdogen ions.
What is renal tubular acidosis (RTA)?
This type of acidosis results from a defect in renal excretion of hydrogen ion or in reabsorption of bicarbonate or both. Two types of RTA will be considered here
What is distal (type 1) RTA?
This type is characterized by an inability to lower the final urine pH below 5.5, even in the face of severe acidosis. Distal RTA may be the result of an inherited defect, antoimmune disease, treatment with lithium or the antibiotic amphotericin B, or the result of diseases of the kidney medulla. The fundamental defect may be impaired secretion by the collecting duct H-ATPase or abnormal leakiness of the collecting ducts to hydrogen. The acidosis may lead to buffering of acid by bone leading to bone rarification. Diagnosis can be confirmed by an acid load test, i.e., ingestion of NH4Cl. If urine pH does not fall below 5.5 after several hours of NH4Cl treatment then distal RTA may be present.
What is proximal type II RTA?
In this type of RTA the capacity of the proximal tubules to reabsorb filtered bicarbonate is impaired, leading to loss of this base in the urine. Proximal RTA often occurs in the setting of a generalized disorder of proximal tubule function and is seen in several inherited diseases, after renal transplantation or intoxication with heavy metals, or after treatment with carbonic anhydrase inhibitors or certain antibiotics. If an acid load test is administered urine pH will fall below 5.5.
What changes might one predict to occur shortly after the distal H+ ATPase stopped working?
A. Urine
1) The 5 to 10 % of HCO3 in the distal nephron will not be reabsorbed.
2) As the kidneys conserve Na+, K+ will be lost along with the HCO3
3) The urine pH will be less acidic
4) There will be less T.A.
5) Ammonium excretion will be lower
6) Less "new" HCO3 will be formed

B. Plasma
1) Plasma HCO3 will decrease
2) [Cl ] up to maintain electroneutrality (i.e., less will be lost urine)
3) Plasma pH will go down
4) Plasma [K+] will go down leading to muscle weakness
5) Not much Na+ will be lost compared to total [Na]o

Treat by administering bicarbonate and K+.
What are mixed acid-base disorders?
In some cases more than one disturbance of acid-base balance occurs simultaneously. Under these circumstances it may be useful to consult an acid-base nomogram. In this diagram pH, bicarbonate concentration and PCO2 levels are plotted according to the Henderson-Hasselbalch equation. The various labeled areas of the diagram show the 95% confidence limits for the normal compensations to simple metabolic and respiratory disorders. 6-12 hours is required for the ventilatory compensation in primary metabolic disorders and 3-5 days for the metabolic compensations to primary respiratory disorders. If a value is within the shaded area, it suggests that there is a simple acid-base disorder. Note however that it is possible for a mixed disorder to have values which fall within the shaded area (i.e., the chart is useful but not infallible).
Don’t forget as well our rule of thumb for assessing whether an acid base disturbance is mixed, i.e., IF THE CHANGES IN HCO3 and CO2 ARE OPPOSITE TO ONE ANOTHER (e.g., HCO3 is elevated and CO2 is reduced) THEN A MIXED DISORDER MUST BE INVOLVED .