So even though osmolality is the same b/w two compartments (since water can move freely), the actual

solutes that comprise

the osmoles are different between compartments

How do doctors calculate plasma osmolarity?

1. Plasma Osmolarity = 2 x [Plasma Na+] + [Glucose]/18 + [BUN]/2.8 ≈ 290 mOsm/L
a. Na+ multiplied by 2 because Na+ is balanced by an equal number of anions. (Cl- and HCO3-)
b. Plasma glucose is measured and reported by the clinical lab as “mg/dL,” and is converted to mOsm/L by
dividing by 18 (MW/10)
c. Plasma BUN is measured and reported by the clinical lab as “mg/dL,” and is converted to mOsm/L by
dividing by 2.8 (MW/10)
2. Cells can use Regulatory Volume Increase or Regulatory Volume Decrease to keep the osmolarity at around 290

How do doctors determine a patient’s volume?

1. Abrupt changes in body weight.
2. Necks veins
3. Peripheral edema
4. Symptoms
5. Vital signs

What is the relationship between Extracellular Fluid (ECF) and Effective Circulating Volume (ECV)?
1. Effective Circulating Volume (ECV) is essentially the Cardiac Output
2. If the amount of Extracellular Fluid(ECF) is decreased, Cardiac Output is generally decreased.
a. Because if preload decreasesà Frank Starling Forces decrease
b. Dehydration
3. If the amount of Extracellular Fluid (ECF) is increased, Cardiac Output may be increased or decreased.
a. CO Increased- athletes and pregnant women have more plasma volumeà increase CO
b. CO Decreased- heart failure will cause edema

Challenges to Homeostasis: Understand the impact of the following disturbances on each compartment’s VOLUME
and OSMOLARITY :
Diarrhea
Water deprivation and Insensible Losses
Infusion of “Normal Saline” (aka isotonic NaCl)
Eating a bag of salty potato chips – without drinking anything
 Renal Blood Flow Tuesday
Purpose - and proportion - of renal blood flow (RBF)
1. Purpose
a. Remove toxins
b. Maintain body’s fluid balance
i. Fluid volume
ii. Electrolyte
iii. Acid-base
c. Secrete Hormones
i. Renin
ii. Erythropoietin
iii. 1,25-dihydroxycholecalciferol
2. Proportion of Blood Flow
a. Huge responsibility so needs lots of blood flow
b. RBF is 25% of CO at rest

Anatomy
1. “Afferent” arteriole – feeds into the glomerular capillaries
2. Efferent arteriole – Exits the glomerular capillaries
3. Juxtamedulllary nephron – long looped
4. Cortical nephron – short looped
5. 2 capillary beds in series
a. Glomerular – where ultrafiltrate is formed
i. Only filter blood
b. Peritubular capillary bed –surrounds tubules – where fluids/solutes are resorbed
i. Resorb- opposite of filter
ii. Metabolic purpose too

Autoregulation
1. For a range of MAP, RBF stays constant
2. Controlled by the afferent arteriole
a. High BP can ruin the glomerulusà AA constricts to reduce flow
b. Low BPà AA dilates to let in more flow
3. RBF= MAP / Resistance of AA
a. Resistance= 1/ radius4
b. RBF= MAP x radius4
4. Mechanism is uncertain
a. Not neuronal because transplanted kidneys do it too
b. But there are two hypotheses
i. Myogenic Hypothesis
1. Increased BPà Increased Stretch on AAà opening of stretch-activated cation (Ca)
channelsà Ca enters smooth muscle cellà Contractionà Increased AA resistance
ii. Tubular Glomerular Feedback Hypothesis
1. Increased BPà Increased blood flow and GFRà macula densa cells on thick ascending
limb sense increase in solute (we think it’s Cl) deliveryàMD cells release paracrine
substance (We think it’s adenosine)à acts on AAà Vasoconstriction
2. MD is part of the JG Apparatus
3. This is the only time where adenosine causes vasoconstriction

Capillaries
General
1. Capillary wall separates the ECF into two compartments
a. Interstitial
b. Plasma
2. Osmolarilty of all three compartments is equal since water can move freely
a. AQPNs in cell membrane allow H2O movement
b. Capillary membrane has clefts and fenestrations
 3. Capillary permeability varies from tissue to tissue
4. Oncotic pressure is aka Colloid Pressure
a. In capillary, protein contributes to the effective osmotic pressure between the plasma and interstitial fluid
b. Shown as πC on diagrams

5. 3 Types of Capillaries
a. Continuous- muscle, lung, heart, tight capillary in brain
b. Fenestrated- kidney, gut, joints
i. More permeable to water but not proteins
ii. In places where fluid exchange occurs
c. Sinusoidal- bone marrow, spleen, liver
i. Aka Discontinuous
ii. Allows blood cells and proteins to pass through

6. Permeability to water is hydraulic conductance- not dependent on hydrostatic pressure

7. Depends on
a. Size of clefts between endothelial cells
b. Whether the capillaries are fenestrated
c. NOT aquaporins- which are in cell membrane and determine water movement from ICF to ECF
8. Kidney capillaries have highest hydraulic conductance. Brain has the lowest

Renal
2 capillary beds in series
1. Glomerular capillaries have higher hydrostatic pressure to push fluid out into Bowman’s space
a. very high for a capillary bed. This helps promote filtration
b. very high glomerular pressure is possible since the efferent limb is an arteriole, which maintains the high
c. glomerular pressure.
d. Normally (in non-glomerular capillaries) filtration along capillaries stops around the midpoint, as the
hydrostatic pressure falls. If the hydrostatic pressure remains high, as in the glomerular capillaries, there
will be net filtration for the entire course of the glomerular capillaryà Increasing filtered volume
e. Along the course of the glomerular capillary, the oncotic pressure will increase (fluid is filtered out so the
concentration of the proteins remaining behind is increased)
i. Tends to slow the net filtration towards the distal end of the glomerulus
2. Peritubular has higher oncotic pressure to pull fluid in (resorb)
a. Also more prone to ischemia when BP is low because it has a lower BP to start off with
b. ATN= acute tubular necrosis

Variable Capillaries
Hydrostatic P (favors filtration) Glomerular > Peritubular
Oncotic P (favors resorption) Glomerular < Peritubular
Vulnerability to ischemia (if BP falls) Glomerular < Peritubular

Relationship between RBF and GFR (filtration at renal capillaries)

Dynamics of RBF determines GFR

Can change the relative constriction/dilation of the AA and EAà changes hydrostatic pressure in the capillary bed and the
amount filtered
 1. Afferent Arteriole diameter about equals Efferent Arteriole diameter at steady state
2. If Afferent radius > Efferent radiusà filtrate INCREASES
3. If Efferent radius > Afferent radiusà filtrate DECREASES

A. Baseline relationships
B. Increase afferent arteriole resistance decreases renal
blood flow and the hydrostatic (filtration) pressure so GFR
also falls.
C. Increase efferent arteriole resistance àdecreases renal
blood flow, BUT increases hydrostatic pressure, so GFR is
maintained or even increased.
D. Decrease afferent arteriole resistance increases renal
blood flow and the hydrostatic (filtration ) pressure also is
increased so GFR also increases too.
E. Decrease efferent arteriole resistance, and this increases
renal blood flow, BUT decreases hydrostatic
pressure, so GFR is decreased.

Control of renal blood flow

Sympathetic Nerve Activity
1. More alpha-1 (vasoconstrictor) receptors on afferent arterioles
2. Increased SNA vasoconstricts afferent arterioles
3. If SNA Increasedà AA vasoconstrictà ↓ RBF and ↓ filtrate

Angiotensin II (AG II)

1. Powerful Vasoconstrictor
2. Efferent arteriole is more sensitive than afferent arteriole to AGII
3. At low levels of AGIIà efferent arteriole vasoconstrictsà Increase filtration
4. At high levels of AGIIà both afferent and efferent vasoconstrictà decreased filtration
5. Decreased blood flowà Macula Densa sense a decrease in Clà release Reninà release AG IIà EA constrictsà
Increases filtration

Atrial Natriuretic Peptide (ANP)

1. The “Odd Ball” because it Vasodilates
2. Vasodilates Afferent > > Efferent
3. Increases RBFà Increases Filtration
4. Too much preloadà atrial myocyte stretchesà Releases ANPà travels to Kidneyà Dilate AAà Increase RBF and
Increase filtrateà Get rid of extra fluid

Prostaglandins
1. Protective
2. Help maintain RBF
3. Offset the vasoconstriction in the setting of increased SNA and AGII
4. If somebody with renal issues takes ibuprofenà inhibits prostaglandinsà can’t safeguard the constrictionà RBF is
restricted too muchà kidneys damaged/die

Dopamine
1. Also protective
2. Is a drug (precursor of NE) given IV
3. “Renal dose dopamine”
4. At low levelsà dilates renal arterioles

Review Case Study

Kk
Clearance : Measuring GFR and Overall Renal Function Tuesday
Measure glomerular filtration rate using clearance calculations.
 1. Clinical importance- Early detection of potentially progressive renal disease.
2. Physiological importance- A reference value against which renal handing of specific substances can be compared
3. Requires a substance that is:
a. Freely filtered
b. Not reabsorbed
c. Not secreted
d. Not metabolized by the kidney
e. Not toxic
f. Doesn’t cause hemodynamic changes in the kidney
4. The gold standard is Inulin
a. But it’s hard to test because it’s not very soluble, procedure is time-consuming à so it’s not really used

Excretion rate= Uin x V

Filtration rate = Pin x GFR

Since the rates are equal, you can set the equations equal to each
other: Uin x V = GFR x Pin

And rearrange to: GFR= (Uin x V) / Pin

In healthy, young adults:

Males: 58-125 ml/min/1.73m2
Females: 75-115 ml/min/1.73m2

Discuss the relative merits of the surrogate estimates of GFR (plasma creatinine concentration and BUN).
Creatinine
1. Breakdown product of creatine
2. Produced at a constant rate
a. Ucreatinine x V = constant in steady state= Excretion Rate
3. Freely filtered, little secreted or reabsorbed
a. Pcreatinine x GFR= Filtration Rate

4. Pcreatinine x GFR = Ucreatinine x V à Pcreatinine x GFR = constantà GFR = Constant / Pcreatinine

5. Plasma creatinine concentration varies inversely with GFR

a. Higher Pcreatinine à Lower GFR
6. Normal plasma creatinine= 0.5-1.3 mg/dL

BUN
Approximately proportional to Pcreatinine but affected by other factors like protein intake, hydration status
Understand the basis of clearance calculations and how they can be used to estimate renal blood flow, filtration
fraction, and rates of absorption and secretion of various substances.
1. Clearance= rate at which kidneys excrete a substance in urine normalized by its plasma concentration
a. Units = volume/time
b. The rate is virtual volume of plasma from which substance completely “cleared” per unit time
c. Drug clearance is also expressed this way
2. Equation used to determine GFR can be modified to calculate the clearance of any substance x
a. Cx = (Ux x V) / Px
b. Clearance is the virtual volume of plasma entering the kidney each minute that is completely cleared and
excreted in the urine
3. If a substance is freely filtered and then neither reabsorbed nor secreted, its clearance = GFR
a. example – inulin
4. If its clearance is greater than the GFR, additional amounts must have been added to the nephron by secretion
a. example – penicillin
5. If it is freely filtered and then reabsorbed, its clearance will be less than GFR
a. example – glucose

Analyze glucose reabsorption rates with the help of GFR measurements. Compare analyses of the reabsorption of
urea and the secretion of PAH.
Filtration rate = GFR × Pglucose
Excretion rate = V × Uglucose
Reabsorption rate = filtration rate – excretion rate

(a) The excretion curve plots experimentally determined rates of glucose excretion in
urine.
(b) The filtration curve plots the rates of glucose filtration in mg/min when GFR is 125
ml/min. (You can obtain it by multiplying plasma concentrations by GFR: 100 mg/100
ml × 125 ml/min = 125 mg/min.)
(c) The solid dots are the differences between filtration and excretion rates at different
plasma glucose concentrations. These differences are glucose reabsorption rates as a
function of glucose concentration.
The horizontal dashed line shows that glucose reabsorption becomes saturated at 375
mg/min. This value is called the transport maximum (Tm) for glucose.

Example of active resorption of an organic nutrient

The secretory mechanisms for organic ions can be very avid. So long as [PAH] in the
plasma entering the kidney is ≤ 10 mg/dL all of it is excreted, i.e. [PAH] in the plasma
leaving the kidney is ~0.

Example of an organic anion being secreted by the kidney

At plasma PAH concentrations below 10 mg/dL, the secretion of PAH is so complete that
virtually all the PAH that enters the kidney leaves in the urine and none in the renal vein.
If all the PAH that enters the kidney each minute is “cleared” from the plasma, then the
volume from which it is cleared is the volume of plasma that enters the kidney each
minute. Therefore, CPAH = RPF, the renal plasma flow.
 There is more filtration than Excretion at a given plasma concentration, so
some is being reabsorbed.
It is passive reabsorption

Filtration Fraction= GFR / RPF

Briefly discuss the use of micropuncture and isolated nephron techniques for more precise analysis of renal
function.
Micropuncture samples of single nephrons

Isolated Nephron Segments

Reabsorption and Secretion Wednesday

Costanzo, 5th ed. Ch. 6—pp. 261-267
List the three functions of the kidney.
1. Regulate water, inorganic ion balance and acid-base balance
2. Remove metabolic waste and foreign chemicals from blood and excrete them in urine
3. Endocrine organ
a. Erythropoietin
b. Renin
c. 1,25-dihydroxyvitamin D

List the basic renal processes.

1. A million of these nephrons per kidney are working in unison
2. Each substance in the plasma component of the ECF has a particular combination of (FILTRATION, REABSORPTION
AND SECRETION).
3. For many substances like Na+ and water these processes are under physiological control.
a. So, by altering the rates of FILTRATION, REABSORPTION AND SECRETION whenever the body content of a
substance goes above or below normal homeostatic mechanism regulate the substance's balance.
i. If you drink a lot of water, within hours your body is back to normal hydration through micturition
process.
1. REABSORPTION DECREASED à URINATION INCREASE
 ii. In a desert
1. REABSORPTION INCREASED à URINATION DECREASE

Give examples of substances reabsorbed and secreted.

Reabsorption
1. Any substance that is translocated from the glomerular filtrate to the peritubular capillaries.
a. Water and most solutes (Na+, Cl-, HCO3-, Ca2+, glucose, amino acids, urea).
i. The filter loads are enormous.
ii. Reabsorption of waste product (like urea) are relatively inefficient.
iii. Reabsorption of most useful plasma component substances (like Na+, water and glucose) are
relatively complete.
2. Glucose is valuable energy compound, which is freely filtered at the glomerular capillaries and under normal
circumstance is completely reabsorbed.
a. Glucose and all substance mediated by transporters, although very robust, have a limited capacity know as
transport maximum (Tm)
b. The transporter becomes saturated (at a threshold concentration) and the substance can no longer be
reabsorbed and spills into the urine

Secretion
1. Any substance that in translocated from the peritubular capillaries to the glomerular filtrate.
a. Much fewer substances- Organic acids and bases, K+
2. Para-aminohippuric acid (PAH) is weak acid used for measuring renal blood flow (RBF), which is freely filtered at the
glomerular capillaries and completely secreted.
Diagram normal glucose processing by the nephron.

What are the limitations in glucose processing or any transporter mediated process?
Transporters can become saturated so the solute will spill into urine and get excreted instead of 100% reabsorbed

Diagram normal PAH processing by the nephron.

Diagram normal urea processing by the nephron.

Partial reabsorption?

Proximal Tubule Isotonic Reabsorption Wednesday

List the key transport properties of the proximal tubule.
1. 65-70% of the glomerular filtrate is normally reabsorbed here. The reabsorbate is always isosmotic.
a. Isosmotic Resorption- tight coupling between water and Na resorption
2. Where sugars, amino acids, metabolic intermediates, etc., are nearly 100% reabsorbed, and where organic acids and
bases are secreted.
3. Urea is partially reabsorbed here- passive mechanism.
4. The tight junctions of the epithelium are very leaky to Na+ and Cl–
a. Therefore, the electrochemical gradients of Na+ and Cl– across the junctions significantly affects the
amount of filtrate absorbed.
5. Solute reabsorption in the late proximal tubule uses quite different mechanisms than in early proximal tubule.
a. Reabsorption is rate-limited by uptake of fluid by the peritubular capillaries. Peritubular hemodynamic
forces modulate net reabsorption.
6. The proximal tubule exhibits glomerulotubular balance.