1 Renal Physiology PART TWO Renal Clearance. Basic Mechanisms of Urine Formation Filtration, secretion, reabsorption and excretion. How do we determine

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Renal Physiology

PART TWORenal Clearance

Basic Mechanisms of Urine Formation

Filtration, secretion, reabsorption and excretion.

How do we determine these rates?

The master equation:Rate of excretion = filtration +

secretion – reabsorption

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TERMS

Urinary output is a flow rate; how much urine are you producing per unit of time, ml/min

This refers to the amount of urine dripping into the urinary bladder, not the amount voided.

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TERMS

Rate of filtration is the flow rate of plasma fluid going into Bowman’s capsule.

This plasma fluid is called “filtrate”. The filtrate is not the same as plasma since

there are no plasma proteins in it (proteins don’t get through the filtration membrane, not just because of their size, but also because of their negative charge).

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TERMS

Glomerular Filtration Rate (GFR) is the amount of fluid going into Bowman’s capsule per unit of time.

Normal GFR is 90 - 125 mL/minDissolved in that filtrate are electrolytes,

glucose, and amino acids. We can also calculate how much of those molecules are entering Bowman’s capsule.

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GFR

Glomerular filtration rate (GFR) can be calculated by measuring any chemical that has a steady level in the blood, and is freely filtered but neither reabsorbed nor secreted in the kidneys.

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GFR

One such substance is creatinine. To determine GFR from creatinine, collect urine

for 24-hours and draw blood before and after the 24-hour period.

Then measure the amount of creatinine that was removed from the blood during that time. Then apply the results to a formula to determine GFR. You do not need to do this for this class. On test questions, I will tell you what the patient’s GFR is.

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TERMS

Filtered Load (or Tubular Load) is the amount of a specific solute (electrolyte, glucose, or amino acid) dissolved in the fluid that enters Bowman’s capsule. There is an equation for this, but you have to know two things:

Patient’s GFR Plasma concentration of that solute.

To determine this, draw blood, place in spectrophotometer.

TL s = Ps x GFR

Filtrate vs. Solute

If I had a cup and I filled it with 125ml of water, and then added one packet of Crystal light, how much fluid entered the cup? 125 ml.

How much fluid (the filtrate) went into the cup is the GFR.

If you know how much solute (Crystal light) went into the cup, you can calculate the filtered load.

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How to calculate Tubular Load

If we want to know how much glucose was filtered into the nephron, we need to know that person’s blood plasma glucose levels, and we would need to calculate their GFR (normal is 90-125mL/min).

Each individual solute will have its own tubular load calculation.

TL sodium = Psodium x GFR

TL chloride = Pchloride x GFR

TL glucose = Pglucose x GFR

Kidney Function and Aging

With age, our filtration membranes deteriorate, and we also lose some of our glomeruli.

With age, the permeability of our kidney membranes also declines, causing a decline in GFR.

Thus, we have a decline of urine production, gradually over our lifetime.

Some people age better than others with our skin, some age better with their GFR.

Older people have to take a lower dosage of medicines that are excreted in the urine.

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Solutes Suck!

Sodium (Na+) is the most numerous of the solutes in our plasma.

Remember, if solutes are being reabsorbed, water will come with it….solutes SUCK water!

When salt is reabsorbed, water will be reabsorbed too. When salt is secreted, water is secreted too.

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Solutes Suck!

Some solutes are being reabsorbed, pulling water with them, but other solutes are not being reabsorbed, so they stay in the kidney tubules and are trying to keep water with them.

If there are more particles being reabsorbed, the water will mostly be reabsorbed also.

What will happen to the concentration of the particles in the tubule that are not being reabsorbed, while water is leaving? Their concentration in the tubule will go up.

Those things that are not reabsorbed will leave the body.

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For any substance,

The rate of = rate of + rate of – rate of excretion filtration secretion reabsorption

Renal Equations

Other terms that are used to express these ideas:

•For “Rate of excretion” we often use the term “urinary output”

•For “Rate of filtration,” when referring to filtered fluid, we often use the term GFR (glomerular filtration rate)

if referring to filtered solute, we use TL (Tubular Load)

(Urinary output) (GFR or TL)

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Calculating Tubular Load of a Substance (any solute, “s”)

At the glomerulus, fluid and solutes (solids that were dissolved in the fluid) are constantly being filtered and enter the kidney tubules.

GFR is the term for the volume of plasma fluid filtered each minute.

Once in the tubule, it is “tubular fluid” and no longer plasma, but not yet urine.

Tubular Load (TLs): the amount of any substance (s) entering the tubule, each minute.

TL depends on two things: the plasma concentration of the solute and the rate of filtration of that solute

TL s = Ps x GFR

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Tubular Filtrate Resembles Plasma

By far, filtered fluid is mainly NaCl and water.

But it also contains other salts and electrolytes, amino acids, small sugars, vitamins and other small molecules, such as wastes.

Na+ and Cl- are present in such large amounts; they are over 99% reabsorbed along the length of the tubule. (Why? We need it to keep our blood pressure up)

At a constant GFR, as plasma concentration of a freely filtered substance rises, the tubular load of the substance rises in direct proportion to plasma concentration

Remember the route the fluid takes:Glomerulus Proximal convoluted tubule (PCT) Descending limb of LOH Ascending limb of LOH Distal Convoluted tubule (DCT) Collecting duct (CD)

Loop of Henle, thick ascending limb

Loop of Henle

descending limb

Collecting duct

Distal convoluted tubule

Proximal convoluted

tubule

Glomerulus

Solutes are reabsorbed into the blood stream

The next photo is of a Proximal Convoluted Tubule (PCT), just beyond the glomerulus. The lumen of the tubule contains the filtrate which leaked out of the capillaries and into the glomerulus, entered Bowman’s capsule, and has now arrived in the PCT.

There are cells (tubular cells) lining the lumen of the PCT. The cells have proteins that allow some solutes to diffuse into the cell, and right back out cell, and into the peritubular capillaries that surround the PCT. In that way, solutes re-enter the blood stream.

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Lumen of PCT

Tubular Cells

Filtrate arriving from Bowman’s Capsule

Peritubular Capillaries

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Peritubular capillaries

Proximal Convoluted Tubule

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PCT

PCT

Proximal Convoluted Tubule Water will follow the solutes. The PCT is the biggest site for reabsorption

of solutes (substances dissolved in water). 100% of glucose and amino acids are

reabsorbed in the PCT. 66% of Na and water are reabsorbed here. If ADH levels are very high, most of the water will

be reabsorbed in the PCT.

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Water reabsorption along the proximal convoluted tubule (PCT) occurs by osmosis resulting primarily from reabsorption of sodium

Proximal Convoluted Tubule In a state of acidosis, the PCT will secrete H+

ions. When the H+ ions are secreted, reabsorption of

bicarbonate ions occurs at the same time. H+ ions are also secreted in the DCT and

collecting duct, but bicarbonate cannot be reabsorbed there.

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Pressures

Because we drop off a lot of fluid (125 ml of filtrate) into Bowman’s capsule every minute, the water pressure in the peritubular capillary beds is low.

Because proteins cannot get through, the osmotic force is very high here (proteins are trying to get in, but cannot).

In the glomerulus, the forces favor fluid to leave the glomerulus and enter Bowman’s capsule.

In the peritubular capillary bed, the forces favor the fluid to enter the capillary bed.

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Solutes without transporters

There are some solutes that cannot get through the tubular cell membranes because they have no protein transporters, so they become more concentrated in the tubular lumen.

The concentration increases until they are forced to diffuse down their concentration gradient and then they can enter the tubular cells and be reabsorbed.

One such solute is chloride (Cl-).26

Active Transport

Active transport, facilitative transport, and simple diffusion are all involved in renal clearance.

It all starts in the membrane of the tubular cells, which have protein transporters that allow Na+, K+, glucose, and other substances to get through. This is called Active transport (it requires ATP, so it uses energy).

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Glucose reabsorption

Glucose and amino acids leave the tubule and enter the peritubular capillaries. That is reabsorption.

When any substance leaves the bloodstream and enters the lumen of the kidney tubules, it is secretion.

By adjusting reabsorption and secretion, your body adjusts its acid-base balance; if too many H+ ions were kept in the plasma, there is too much acid, and the H+ ions will start to be secreted more.

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Transport Maximum

When proteins are shuttling solutes, the rate of this shuttling has a maximum, called a transport max (Tm).

If there are more solutes present than can be transported, the solutes will end up in your urine. There will be a point at which you can saturate these transporters. For instance, when your blood glucose levels are elevated because you have a problem making insulin or responding to insulin, then you will have an increase in glucose load in Bowman’s capsule. This excess filtered load will cause a spill of glucose into the urine.

After the PCT, there are no more glucose transporters to reabsorb it. 220 mg/ml is the max rate to filter glucose. If you filter 125 mg/ml and reabsorbed 125 mg/ml, how much did you excrete? None. If you filter 375 mg/ml but reabsorb 220 mg/ml (transport maximum), 155 mg/ml is excreted 29

Threshold

Transport maximum is the total transport maximum throughout all of the nephrons in the kidney. They do not all have the exact number and type of transporters.

One single nephron might get to maximum and a tiny amount of glucose will appear in the urine. As more nephrons reach their maximum, more glucose will appear in the urine.

That appearance of glucose in the urine before you reach the overall Tm of the kidney is called threshold.

Threshold is the plasma concentration at which a substance begins to appear in the urine

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1

2

3

4

5

=solute= transporter

Transport maximum is reached when carriers are saturated.

5/min

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1

2

3

4

5

=solute= transporter

Transport maximum is reached when carriers are saturated.

5/min

Excretion

Calculate Glucose Excretion

Step 1: Calculate their filtered load: GFR x plasma glucose level 125 ml/min x 2mg/ml = 250 Step 2: Determine reabsorption of glucose

(maximum is 220 mg/min). Step 3: Subtract 220 from 250, and that

tells you their excretion (if any). Filtration – reabsorption = Excretion Answer: 250- 220 = 30 mg/min

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A patient with uncontrolled diabetes has a GFR of 125 ml/min, a plasma glucose of 2mg/ml, and a transport max (Tm) shown in the figure. What is the glucose excretion for this patient?

.

Reabsorbed

Excreted

TransportMaximum(220 mg/min)

Threshold

250

200

150

100

50

0

Glu

cose

(m

g/m

in)

a. 0 mg/minb. 30 mg/minc. 60 mg/mind. 90 mg/mine. 120 mg/min

50 100 150 200 250 300 350Filtered Load of Glucose

(mg/min)Copyright © 2006 by Elsevier, Inc.

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.

Reabsorbed

Excreted

Threshold

250

200

150

100

50

0

Glu

cose

(m

g/m

in)

Filtered Load of Glucose(mg/min)


GFR = 125 ml/min PGlu = 2 mg/mlTmax = 220 mg/min

250 – 220 = 30 mg/min

50 100 150 200 250 300 350


Copyright © 2006 by Elsevier, Inc.

Filtration (GFR x Pglu) – reabsorption (Tmax) = Excretion 125 x 2 = 250

Answer:

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A patient with uncontrolled diabetes has a GFR of 125 ml/min, a plasma glucose of 2.33mg/ml, and a transport max (Tm) shown in the figure. What is the glucose excretion for this patient?

.

Reabsorbed

Excreted


Threshold

250

200

150

100

50

0

Glu

cose

(m

g/m

in)


50 100 150 200 250 300 350Filtered Load of Glucose

(mg/min)Copyright © 2006 by Elsevier, Inc.

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.

Reabsorbed

Excreted

Threshold

250

200

150

100

50

0

Glu

cose

(m

g/m

in)

Filtered Load of Glucose(mg/min)


GFR = 125 ml/min PGlu = 2.33 mg/mlTmax = 220 mg/min

291 – 220 = 71 mg/min

50 100 150 200 250 300 350


Copyright © 2006 by Elsevier, Inc.

Filtration (GFR x Pglu) – reabsorption (Tmax) = Excretion 125 x 2.33 = 291

Answer:

Urea

Urea is also reabsorbed in the PCT. This happens because its concentration in the tubule is

high, so it diffuses down its concentration gradient, which means it will leave the tubule and enter the capillaries.

This is an advantage because it is a particle, and it brings water with it.

But urea is a waste product…how will we get rid of it? We will reabsorb it now and secrete it again further along

in the nephron. By the time the reabsorbed urea travels in the vasa recta to the distal convoluted tubule, its concentration is higher in the bloodstream than it is in the tubule, so it diffuses back out of the capillaries and into the tubule to be excreted. The DCT is impermeable to water, so water does not follow it.

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Salt concentration in the PCT

As you go along the length of the PCT, the amino acids and glucose are reabsorbed, in addition to salt and water.

The salt concentration in the filtrate stays the same as the blood plasma salt concentration.

As we go through the rest of the nephron, the saltiness will diminish as it becomes more watery like urine and less salty like plasma.

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Diuretics in the PCT

Cause diuresis by reducing net water reabsorption from the proximal convoluted tubule

Some diuretics are “Potassium sparing” because they decrease potassium excretion

Mannitol: potassium-sparingLasix: not potassium-sparing

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Diuresis in the PCT

Diuresis means the person is excreting a lot of water. This is what happens in diabetes mellitus (and insipitus). It makes the person thirsty, so they drink a lot of water.

However, that is not why they have diuresis.The reason for the diuresis in diabetes

mellitus is the large amount of glucose in the tubule draws water with it, since glucose is a particle.

Thus, the large filtered load of glucose has an osmotic effect on the tubule

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Summary of PCT functions

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Reabsorbs 2/3 of the salt, water, and potassiumReabsorbs 100% of glucose and amino acidsReabsorbs 50% of ureaRegulates pH in the filtrate Secretes creatinine (waste product after you eat protein) into the filtrate

Now we leave the PCT and enter the Loop of Henle

Our kidneys are responsible for adjusting the urinary output.

They are responsible for determining if you have a lot of urine which is very dilute, or scant, concentrated urine.

If you drink a lot of water, it will make your urine dilute (more water than solutes).

If you are dehydrated, your urine will be concentrated (more solutes than water).

Caffeine and alcohol are dehydrating, so they have the opposite effect of drinking water. They block antidiuretic hormone (ADH) too.

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Before we move onto the Loop of Henle, be mindful of the following:

How can you make a solution more concentrated? Take out water or add more solute.

How can you make a solution less concentrated? Add water or take out more solute.

Your kidneys play that game. To do that, we have to separate solutes and water. But how do we do that, since water follows particles? There are several parts of the nephron that are impermeable to water.

Ascending limbDescending

limb

Loop of Henle

LOOP OF HENLE: Descending Limb

20% of water is reabsorbed Na+ and urea are secreted

What will your filtrate taste like here? We are removing water and adding salt.

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Keep track of the water:

20% of water is reabsorbed in the descending limb, and 66% was reabsorbed in the PCT. That means a total of 86% of our filtered water has now been reabsorbed. The remaining 14% can be tapped into if your body needs it. If you are well hydrated, it will go into the toilet. If you are dehydrated, hormones will be needed farther along in the nephron in order to reabsorb more water.

In the PCT, you have reabsorbed 50% of urea. Although it is a waste product, we use it to create an osmotic gradient to reabsorb glucose and other good solutes. Now, we want to get rid of the urea since we are done reabsorbing all the glucose.

By the time the filtrate is at the tip of the LOH, all of the urea that had gone back into the blood will be secreted back into the lumen, plus some more. The descending limb contains 110% of the urea you initially filtered.

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LOOP OF HENLE: Ascending Limb

Impermeable to water, so no water is reabsorbed or secreted.

Permeable to NaCl and urea:NaCl (or sodium and chloride

separately) diffuses out of tubule (reabsorbed)

Urea diffuses into tubule (secreted)

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Saltiness in the LOH

Now let’s take the LOH together: on the descending limb we have water leaving and salt entering the lumen.

On the ascending limb, we have salt leaving, and no more water leaving the lumen.

As it goes up the ascending limb, it is becoming more and more hypo-osmotic (less and less salty). At the top of the ascending limb, it tastes less salty than blood plasma.

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Now we leave the LOH and enter the distal convoluted tubule (DCT)

Distal convoluted tubule

Late DCT

Early DCT

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Early Distal Convoluted Tubule (DCT)

Thiazide diuretics have their effect in the early distal convoluted tubule.

A thiazide diuretic is one that blocks sodium-chloride channels, so that sodium cannot be reabsorbed, so water cannot be reabsorbed.

This will cause water loss, which will lower blood pressure.

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Distal Convoluted Tubule (DCT)

5% more sodium is reabsorbed The DCT activity can be influenced by

hormones. If there are no hormones around, these cells don’t do anything; whatever is remaining in the lumen will go into the bladder.

If there are no hormones, the last 14% of water and the last 3% of NaCl goes into the toilet.

Anti-diuretic hormone (ADH) and aldosterone will cause more water and salt to be reabsorbed (raises blood pressure).

Distal Convoluted Tubule (DCT)

Special cells in the DCT and collecting duct, called intercalated cells manage your acid-base balance, to secrete more H+.

If you are in a state of acidosis (too much acid in your blood) because you drank alcohol, your intercalated cells will secrete more H+ to bring the pH back to normal.

If you are in a state of alkalosis because you have been hyperventilating (breathing fast), will the intercalated cells increase H+ reabsorption or H+ secretion?

Answer: increase H+ reabsorption.

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We’ve covered filtration and reabsorption….Now, it’s time for Tubular Secretion

Secretion = Excretion – Filtration+ reabsorption

Secretion

Secretion is the opposite of reabsorption. Any time you see a solute going from the peritubular capillaries and into the lumen, it is called secretion. Secreted substances end up in the urinary bladder.

It happens by active transport. We secrete acids, bases, phosphates, excess potassium.

Secretion works this way: solutes diffuse out of the peritubular capillary bed and into the tubular cells, then they enter lumen of the convoluted tubule. From there, they go out the collecting duct, and into the urinary bladder.

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Long-Term Dehydration

Compensations in a dehydrated person who is deprived of water for 36 hours include the following: increased plasma renin increased plasma ADHdecreased plasma concentration of atrial

natriuretic peptide (vasodilator made by the heart; increases diuresis to lower bp)

increased water permeability of the collecting ductdecreased water permeability in the ascending

loop of Henle

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Hormones affecting the kidney Renin: released by kidney when blood pressure is too low, It is an

enzyme, but it also functions as a hormone (secreted by one group of cells and effects the physiology of another group of cells).

ACE: Pulmonary capillary enzyme that responds to renin. When renin is elevated, it cleaves angiotensin I into angiotensin 2.

Angiotensin II: causes blood vessel constriction to increase blood pressure. It also stimulates the release of aldosterone and ADH.

Aldosterone: Secreted from the zona glomerulosa of the adrenal cortex. It increases blood pressure by increasing sodium reabsorption. It is primarily released due to elevated potassium levels.

ADH: Promotes aquaporin insertion in the cell membranes of the tubules Aquaporin is a protein that allows water to pass through the cell

membrane, to be absorbed out of the tubule. Adenosine: Macula densa in the kidney use this to molecule to decrease

the diameter of the afferent arteriole to decrease water loss and prevent lower bp.

Atrial natriuretic peptide (ANP): heart hormone that promotes more diuresis and increases urine production to lower blood pressure. 57

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Summary of What’s Going On

Glomerulus Capillary hydrostatic (water) pressure is very

high here (about 60mmHg). That means water is under pressure to leave the glomerulus capillary and enter the tubule.

Bowman’s capsule colloid (protein) osmotic pressure here is

essentially zero. That means that, since the proteins want to get out but they can’t, there are no proteins in the tubule to suck water. 59


PCT part of the nephron normally reabsorbs the most water Site of sodium-glucose co-transport as well as sodium-

amino acid co-transport Even though reabsorption is occurring, tubular fluid is

isosmotic to plasma throughout the length of this region.

Site of most potassium reabsorption when no aldosterone is present

secretes hydrogen, is rich in carbonic anhydrase, and accounts for most bicarbonate reabsorption

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Descending Limballows secretion of sodium and urea and

is permeable to waterThese are highly permeable to water,

low permeability to solutes, and are considered diluting segments.

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LOHhave the maximally hyperosmotic fluid

(concentrated lemonade) when ADH levels are high

At the Tip of the LOHTubular fluid here is always maximally

hyperosmotic to plasma (filtrate is saltier than plasma) and is not hormone sensitive

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Thick ascending limbhas the Na+/K+/Cl- co-transporteris sensitive to the diuretic furosemide

(lasix). are impermeable to water, reabsorb

solutes, and are considered diluting segments.

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DCTMacula densa is found hereis sensitive to sodium channel blockers like

amiloride and aldosterone inhibitorsSite of hormonally regulated potassium

secretionThe intercalated cells of this region (and also

in the collecting duct) secrete hydrogen, is rich in carbonic anhydrase, and makes “new” bicarbonate.

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Collecting Ducthas the maximally hyperosmotic fluid

when ADH levels are high The intercalated cells of this region (and

also in the DCT) secrete hydrogen, is rich in carbonic anhydrase, and makes “new” bicarbonate.

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NOTE: Print the following slide and write notes on what is going in and what is coming out of each area of the nephron.

66Loop of Henle (tip)

Thick Ascending Limb

Late Distal convoluted tubule

Collecting duct

Descending limb

Bowman’s capsule

Early Distal convoluted

tubule

Glomerulus 1 2

Proximal convoluted

tubule

3

4

5

6

7

8

9

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Bowman’s capsule Glomerulus 1 2

Proximal convoluted

tubule

3

Capillary hydrostatic pressure is very high here.

The filtrate contains water, salt (NaCl), glucose, amino acids, urea, and electrolytes such as potassium (K+), calcium (Ca2+), magnesium (Mg2+), phosphate (PO4), bicarbonate (HCO3

-) and H+

colloid osmotic pressure here is essentially zero

Reabsorbs most of the water, salt, glucose, amino acids, urea, and electrolytes such as potassium (K+), calcium (Ca2+), magnesium (Mg2+), phosphate (PO4

2-).

Secretes creatinine, antibiotics, diuretics, H+ and uric acid.

Loop of Henle (tip)

Thick Ascending Limb

Descending limb 4

5

6

Reabsorbs 1/3 water, 1/3 salt, K+

Secreted into the lumen here is 50% Urea, small amount of salt and water

Reabsorbs Ca2+, Mg2+, Tubular fluid here is hyperosmotic to plasma, and is not hormone sensitive

Reabsorbs salt and bicarbonate.

Is sensitive to the diuretic furosemide (Lasix).

This area is impermeable to water unless a hormone like aldosterone or ADH allows it.

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Late Distal convoluted tubule

Early Distal convoluted

tubule

7

8

Macula densa is found here.

Reabsorbs salt and calcium.This area is acted upon by parathyroid hormone. This area Is sensitive to sodium channel blockers like amiloride and aldosterone inhibitors.

This area is the site of hormonally regulated potassium.

Intercalated cells here secrete hydrogen and make “new” bicarbonate.

•Reabsorbs salt and H2O water if a hormone is present. This area is acted upon by aldosterone and ADH. •Is able to secrete K+, H+, bicarbonate, and urea, as needed.

Collecting duct

9

No water or salt is reabsorbed unless ADH or aldosterone is present.

Reabsorbs bicarbonate and urea Secretes K+

Intercalated cells here secrete H+ or make new bicarbonate.

This area has the maximally hyperosmotic fluid when ADH levels are high.

Imagine It….

• Each of these particles is like a person who works in a factory in Glomerulus City.

• They all leave work at 5pm and have to take the same freeway home (the Tubular Freeway).

• Each of them get off at different freeway exits.

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The People

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THE GOOD NUTRIENTSWaterSalt (NaCl)GlucoseAmino acids

THE WASTE PRODUCTSUreaCreatinineAntibioticsDiureticsUric acid

THE LAW ENFORCEMENT OFFICIALSAldosteroneADHParathyroid hormoneFurosemide (Lasix)Hormones that regulate potassium (aldosterone and insulin)Sodium channel blockers like Amiloride (a potassium sparing diuretic) and aldosterone inhibitors

THE GOOD ELECTROLYTESPotassium (K+)Calcium (Ca2+)Magnesium (Mg2+)Phosphate (PO4)Bicarbonate (HCO3

-) H+

The Freeway Exits• Proximal Convoluted Tubule (PCT)

– Priority City Tunnel (these people are rich and have a Fast Track pass!)

• Descending limb (DL) – Disneyland!

• Loop of Henle, tip (LOHT)– City of Low Hats (and they TIP their hats to you…very polite!)

• Thick Ascending Limb (TAL)– City of TALL TALES (this is where all the movie theaters are)

• Early Distal convoluted tubule (ED)– City of Education (this is where the schools are)

• Late Distal convoluted tubule (LD)– Lucky District (this is where the gambling casinos are)

• Collecting duct (CD)– The criminal district

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The Workers and their exitsTHE GOOD NUTRIENTS–Water (picture a water delivery man)

• PCT

• DL (enters and leaves here)

• TAL (leaves only if aldosterone or ADH present)

• LD (leaves only if aldosterone or ADH present)

• CD (leaves only if aldosterone or ADH present)

–Salt (NaCl) (picture a salt shaker)

• PCT

• DL

• TAL

• ED

• LD

• CD (leaves only if aldosterone is present)

–Glucose (picture a lollipop)

• PCT

–Amino acids (picture a cow)

• PCT

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Leaving the freeway means reabsorption

Entering the freeway means secretion

The Workers and their exitsTHE GOOD ELECTROLYTES–Potassium (K+) allows for muscle contraction (picture a body builder)

• PCT• DL • LD (enters the freeway here)• CD (enters the freeway here)

–Calcium (Ca2+) for strong bones (picture a skeleton)• PCT• LOHT• ED

–Magnesium (Mg2+) for muscle relaxation (picture a massage therapist)• PCT• LOHT

–Phosphate (PO4) for ATP (picture a race car driver)• PCT

–Bicarbonate (HCO3-) (picture a fire extinguisher)

• TAL• ED• LD• CD (enters or leaves here)

–H+ (picture an acid-squirting monster)• PCT (enters the freeway here)• ED (enters the freeway here)• LD (enters the freeway here)• CD (enters or leaves here)

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The Workers and their exitsTHE WASTE PRODUCTS–Urea (a waste product of protein metabolism; picture a Rhea bird, similar to an ostrich)

• PCT

• DL (enters the freeway here)

• LD (enters the freeway here)

–Creatinine (a waste product of protein metabolism)

• PCT (enters the freeway here)

–Antibiotics


–Diuretics


–Uric acid


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The Workers and their exitsHORMONES AND MEDICINES (LAW ENFORCEMENT)–Aldosterone

• TAL (acts on this site)• ED (acts on this site)• LD (acts on this site)• CD (acts on this site)

–ADH• TAL (acts on this site)• ED (acts on this site)• LD (acts on this site)• CD (acts on this site)

–Parathyroid hormone (school milk monitor)• ED (acts at this site to increase calcium reabsorption)

–Hormones that regulate potassium (aldosterone and insulin); (school banana monitor)• ED (acts on this site to cause potassium to either enter or leave)

–Sodium channel blockers like Amiloride (a potassium sparing diuretic) and aldosterone inhibitors;

–(school salt monitor…no more salt allowed to leave)• ED (acts on this site to prevent sodium from being reabsorbed)

–Furosemide (Lasix)• TAL (acts on this site to block water reabsorption)

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Aldosterone/ADH

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Cut out the characters to practice moving them into and out of the tubules. Nutrients are green, electrolytes are yellow, waste is black, hormones and medicines are purple.

Phosphate2/3 water 1/3 water Water Water Water

Salt Salt Salt Salt

1/3 Salt2/3 Salt

Amino Acids Glucose Magnesium

Potassium Potassium Potassium Potassium

Magnesium

Water

Calcium Calcium Calcium

Bicarbonate

Hydrogen ions

Urea

Hormones that regulate K+

Sodium channel blockers

Furosemide (Lasix)

Parathyroid hormone

UreaUrea

Hydrogen ionsHydrogen ions Hydrogen ions

Bicarbonate Bicarbonate Bicarbonate

Proximal convoluted tubule (Priority City Tunnel)

Descending limb(Disneyland)

Loop of Henle (tip) (Low Hat Tipping)

Thick Ascending Limb (Tall Tales movie theater)

Early Distal convoluted tubule(Education Department)

Late Distal convoluted tubule (Lucky District with casinos)

Collecting duct(Criminal district)

Glomerulus

Bowman’s capsule

Capillary hydrostatic pressure is very high here.

colloid osmotic pressure here is essentially zero

Tubular fluid here is hyperosmotic to plasma, and is not hormone sensitive

This area is impermeable to water unless a hormone like aldosterone or ADH allows it.

Macula densa is found here.

This area is the site of hormonally regulated potassium

No water is reabsorbed unless ADH or aldosterone is present. No salt is reabsorbed unless aldosterone is present.

This area has the maximally hyperosmotic fluid when ADH levels are high.

Intercalated cells here secrete hydrogen and make “new” bicarbonate.

Secretes creatinine, antibiotics, diuretics, H+ and uric acid.

Reabsorbs bicarbonate and urea; Secretes K+

Is sensitive to the diuretic furosemide (Lasix).

Reabsorbs salt and H2O water if aldosterone and ADH are present.

Secreted into the lumen here is 50% Urea, small amount of sodium and water

This area Is sensitive to sodium channel blockers like amiloride and aldosterone inhibitors.

This area is acted upon by parathyroid hormone.

This area is acted upon by aldosterone and ADH

Print this page. Add the yellow labels on the previous page first, then run the pictures on the previous page through the tubule and make them exit and enter at the right locations. Then place the white text boxes in the locations where they belong.

Cell Types in the Kidney

• There are many different cell types in the kidney. Like in other organs, cells of the kidney can be divided into cells that make up the functional part of the kidney (called the parenchyma) and cells that make up the connective tissue and supporting structure of the kidney (the stroma).

• In studying an organ's cells, most focus on the parenchymal cells, because it is those cells that are typically unique to a given organ. This is true for the kidney.

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• Parenchymal cells of the kidney are those that make up the nephrons.

• Each nephron segment has several unique cells. The major cell type of the proximal tubule has no particular name, but is responsible for heavy-duty reabsorption of solutes and water from the fluid that's filtered from the blood.

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• The major cell of the thick ascending limb of the loop of Henle is a cell that contains a special transporter called the sodium-potassium-2 chloride cotransporter (NKCC).

• The action of these NKCC-containing cells allows the kidney to produce concentrated urine when an individual has gone without water for a while.

• These same cells are also targeted by a class of drugs (called loop diuretics) that treats high blood pressure.

• A very similar cell occurs in the distal convoluted tubule. This cell uses the same NKCC protein to sense low volume states, such as when an individual has lost a large volume of blood.

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• The major cell of the distal tubule contains a thiazide-sensitive sodium chloride co-transporter (TSC).

• This cell is responsible for reabsorbing about 5% of the sodium filtered by the kidney each day.

• It is targeted by another type of drug (called thiazides) that treats high blood pressure.

• This region also has principal cells and intercalated cells.

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• The collecting duct contains two cell types: principal cells and intercalated cells.

• Principal cells are predominantly responsible for sodium reabsorption and potassium secretion in the kidney.

• This process is stimulated by the action of the hormones aldosterone and ADH.

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• There are two types of intercalated cells in the DCT and collecting duct, but both are responsible for acid-base homeostasis.

• The alpha intercalated cell is responsible for secreting excess acid and reabsorbing base (in the form of bicarbonate).

• The beta intercalated cell is responsible for secreting excess base (bicarbonate) and reabsorbing acid.

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Intercalated Cells • The DCT and collecting duct have two types of cells: principal cells

(respond to aldosterone and ADH) and the intercalated cells. The intercalated cells come in two different varieties: alpha-intercalated cells (which secrete acid) and beta-intercalated cells (which secrete base).

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Intercalated Cells

• The interesting thing is that inducing metabolic acidosis results in the conversion of beta-intercalated cells to alpha-intercalated cells--giving the kidney twice the ability to secrete acids and return pH to the normal range.

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Clinical Correlations

What are the symptoms of severe dehydration?

1. Disoriented2. Falls unconscious3. Measurable loss of weight during strenuous activity (water loss)4. Blood pressure drops

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A marathon runner becomes dehydrated during a race.

1. What will happen to their weight?2. What will happen to blood volume?3. What will happen to blood pressure?4. What will happen to heart rate?5. What will happen to their baroreceptors?6. What will happen to sympathetic outflow?

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1. Weight goes down (water loss)2. Blood volume decreases (water loss)3. Blood pressure decreases (volume loss)4. Heart rate increases (b/c of decreased BP)5. Baroreceptors decrease firing (low BP)6. Sympathetic outflow increases (to

compensate; causes vasoconstriction)92



1. What will happen to their Renal blood flow (RBF)?

2. What will happen to their tubular load of sodium?

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1. Renal blood flow (RBF) will decreaseThe body does not want to lose more

water2. Tubular load of sodium will decrease

Sodium is reabsorbed so water will come with it

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1. What hormones would compensate for this condition?

These would all be elevated:AdenosineReninAngiotensin IIAldosteroneADH

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1. What will be the urinary output?Low volume

2. What will be the urine concentration?High concentration

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A marathon runner becomes dehydrated during a race and falls unconscious.

1. What type of shock is this?Hypovolemic shock

2. What is the treatment?I.V. saline/bicarbonate solution

Giving saline will increase water retentionGiving bicarbonate will reduce acidosis

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Clinical CorrelationsA marathon runner becomes dehydrated

during a race and falls unconscious.1. Why do they have acidosis?

Hypovolemic shock reduces oxygen delivered to tissues.

Muscles without oxygen start to convert to anaerobic metabolism to get their ATP. The waste product of anaerobic metabolism is lactic acid.

The buildup of lactic acid without the kidney excreting it causes metabolic acidosis.

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January 12th, 2007, A 28 year-old mother of three from Sacramento decides to go on a radio program to compete in a contest called, “Hold your Wee for a Wii.”

During this contest, contestants drank great volumes of plain water. She drank 6 liters in 2 hours (3 liters an hour). The maximum the kidneys can filter is 1 liter an hour.

After the contest, she called her co-workers to say she wasn’t coming to work because her head hurt so badly.

Later she is found dead. 99


Drinking too much water changes the extracellular osmolality. When the plasma is too dilute (too much water, too few solutes), water will leave the bloodstream to enter the tissues, where there are more solutes (solutes SUCK!).

Water will enter the tissues (intracellular body fluid compartment), including the brain.

The excess water will cause the brain to swell. 100

Water moves through Compartments

Intracellular water (or other fluid) is the watery substance inside a cell. Interstitial water (or other fluid) is the watery substance between cells. Extracellular water (or other fluid) is the watery substance that is outside

of cells. Some of it may be interstitial, some may be in the blood, joints, CSF, etc.

The concentration of individual solutes (glucose, sodium, potassium, chloride) is different in intracellular fluid than it is in extracellular or interstitial fluid, but the total osmolarity (concentration of all the solutes combined) of the intracellular fluid, extracellular fluid, and interstitial and is the same.

Water can move from one compartment to another. It can be drawn out of the plasma to enter the interstitial compartment first, and then it may enter the cells.

Water can also move from the cells to the interstitial compartment, then into the bloodstream.

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Water/Salt Imbalance Problems

Expansion: the body has retained too much water Contraction: the body has too little water

Hypo-osmotic volume The water in the body has too much water, too few solutes

Hyperosmotic volume The water in the body has too little water, too many solutes

Isosmotic volume The water in the body has the proper balance of water and

solutes.

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Water/Salt Imbalance Problems Hypo-osmotic volume expansion

Excessive water drinking; plasma osmolality is reduced from too much water, not enough solutes (hypo-osmotic) and the extracellular fluid (outside of cells) volume has increased (expansion).

Hypo-osmotic volume contraction Excessive sweating; the person has lost a lot of salt, but has lost

some water, too. They are dehydrated (contraction) and have low salt levels (hypo-osmotic). The water in the body has low osmolality due to loss of the salt.

Hyperosmotic volume expansion High salt intake; there is too many solutes, water is retained, so

the overall volume is increased (expansion), but there is a lot of salt, so osmolality is increased (hyperosmotic).

Hyperosmotic volume contraction Dehydration; the person has lost a lot of water, so overall volume

is decreased (contraction). The salt level has not changed, so that means more salt dissolved in less water (hyperosmotic).

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Isosmotic Volume ContractionDiarrhea or burn victim; loss of water and

solutes. Overall water/salt ratio is maintained (isosmotic), but person loses overall volume (contraction).

Isosmotic Volume ExpansionSalt Infusion; person receives an i.v. of normal

saline (isosmotic), and overall volume of body fluid increases (expansion).

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The same number of proteins remains in the blood, but water may increase or decrease.

These volume changes therefore affect the protein concentrations in the blood.

With more volume (expansion), protein concentrations decrease. With less volume (contraction), the protein concentrations increase.

However, hematocrit is not always affected by blood volume changes. Small changes in volume affect the protein concentrations, but may not affect the hematocrit.

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Hyperosmotic volume contraction

Diabetes insipidus There would be elevated protein

concentration but NO CHANGE in hematocrit with this condition

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Hyperosmotic volume expansion

Conn’s disease (excess aldosterone) would cause this condition

There would be decreased protein concentration and decreased hematocrit

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Hypo-osmotic volume contraction

Addison’s Disease (not enough aldosterone) would cause this condition

There would be increased protein concentration and increased hematocrit

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Hypo-osmotic volume expansion

Syndrome of inappropriate ADH (excessive secretion of ADH) would cause this condition. Since too much ADH is present, water is kept in the body.

There would be decreased protein concentration but NO CHANGE in hematocrit with this

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Iso-osmotic volume expansion

Infusion of a 0.9% saline solution would cause this condition

There would be decreased protein concentration and decreased hematocrit

In these conditions there would be NO CHANGE in the intracellular volume nor osmolality

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Iso-osmotic volume contraction

Diarrhea or burns would cause this condition

There would be increased protein concentration and increased hematocrit

In these conditions there would be NO CHANGE in the intracellular volume nor osmolality

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Water Imbalance category Condition DisorderProtein

s Hct

Hypo-osmotic volume expansion

Excess water, low solutesDrinking too much water or inappropriate ADH Syndrome

Low Normal

Hypo-osmotic volume contraction Loss of water and salt Addison's disease High HighHyperosmotic volume expansion High salt intake Conn's disease Low LowHyperosmotic volume contraction Loss of water, normal salt levels Diabetes insipidis High Normal

Isosmotic volume expansion Increase in normal saline Normal saline iv Low Low

Isosmotic volume contractionLoss of water and solutes, but water/salt is normal Diarrhea High High

Hypernatremia(excess sodium in the blood)

Causes Hypovolemic

Inadequate intake of water, typically in elderly or otherwise disabled patients who are unable to take in water as their thirst dictates. This is the most common cause of hypernatremia.

Euvolemic Excessive excretion of water from the kidneys caused

by diabetes insipidus, which involves either inadequate production of ADH or kidneys not responding to it.

Hypervolemic Intake of a hypertonic fluid such as drinking seawater or

receiving an i.v. of sodium bicarbonate after a vigorous resuscitation. Can also be caused by mineralocorticoid excess due to a disease state such as Conn's syndrome or Cushing's Disease

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Hyponatremia(too little sodium in the blood)

Causesexcessive sweatingpersistent diarrheaoveruse of diuretic drugs

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Hypokalemia(low potassium in the blood)

Mild hypokalemiaOften without symptoms, although it may

cause a small elevation of blood pressure, and can occasionally provoke cardiac arrhythmias.

Moderate hypokalemiaMay cause muscular weakness, myalgia

(muscle pain), and muscle cramps Severe hypokalemia

May cause flaccid paralysis and hyporeflexia

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Hypokalemia(low potassium in the blood)

Causes Inadequate potassium intake (rare)Gastrointestinal loss (vomiting or diarrhea)Urinary loss

Thiazide diuretics Alkalosis in the blood Disease states that cause high aldosterone levels

Conn’s syndrome (hyperaldosteronism) Cushing's syndrome (excess cortisol binds to the

Na+/K+ pumps, so it acts like aldosterone).

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Hyperkalemia(high potassium in the blood)

Extreme hyperkalemia is a medical emergency due to the risk of potentially fatal abnormal heart rhythms (arrhythmia).

Symptoms include malaise (tired), palpitations and muscle weakness; mild hyperventilation may indicate a compensatory response to metabolic acidosis, which is one of the possible causes of hyperkalemia.

Often, however, the problem is detected during screening blood tests for a medical disorder, or it only comes to medical attention after complications have developed, such as cardiac arrhythmia or sudden death.

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Hyperglycemia and Hypoglycemia

Glucose levels vary before and after meals, and at various times of day.

Glucose in fasting adults should be 80 to 110 mg/dl.

Above 126 mg/dl is hyperglycemia. Below 70 mg/dl is hypoglycemia.

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Addison’s DiseaseConn’s DiseaseDiabetes MellitusDiabetes InsipidusCushing’s DiseaseKnow which of these diseases has

hypernatremia, hypokalemia, hypo or hyperglycemia, etc.

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Addison’s Disease

Chronic adrenal insufficiency (low cortisol levels)

HyponatremiaHypoglycemiaHyperkalemiaPossible death at times of extreme stress

Addisonian crisis: low blood pressure coma

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Conn’s Disease

This is hyperaldosteronism. The person releases too much

aldosterone, which increases sodium retention, so water follows, and hypertension results.

Condition associated primarily with hypertension and mild hypernatremia and mild hypokalemia. No diabetogenic (glucose) problems.

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Diabetes Mellitus Condition characterized by polyuria, glucosuria, polydipsia

and ketonuria. Polyuria (frequent urination) Glucosuria (glucose in urine) Polydipsia (thirsty) Ketonuria (ketones in the urine)

When insulin does not pull glucose into the body cells, it stays in high levels in the blood (hyperglycemia) and spills out in the urine (glucosuria). The body is starving, so it breaks down fat into fatty acids for energy, and ketones are the waste product. In small amounts, they are broken down in the liver, but in large amounts, they build up in the blood (ketoacidosis: lowers blood pH) and spill out into the urine (ketonuria). Starvation, fasting, prolonged vomiting, high protein diets, and low carbohydrate diets also cause this condition.

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Diabetes Insipidus

Condition characterized by polyuria and polydipsia, but not glucosuria.

This is more like a disease of water loss (ADH is not produced).

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Cushing’s Disease

HypernatremiaCaused by lack of water in the blood, like

dehydration. Hypokalemia (low potassium) Hyperglycemia (excess glucose) Diabetes mellitus Weight gain, particularly of the trunk and face

with sparing of the limbs (central obesity), moon face, buffalo hump, and females may have growth of facial hair, while males may develop breasts.

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K+ Na+ Glucose BP OtherAddison's High Low Low Low Possible death at times of extreme stress

Conn'sMild low Mild high Normal High

Diabetes Mellitus High Low High Polyuria, glucosuria, polydipsia, ketonuria, ketoacidosisDiabetes Insipidus High High High Polyuria, polydipsia only

Cushing's Low High High Diabetes (Polyuria, glucosuria, polydipsia, ketonuria), central obesity, moon face, buffalo hump, facial hair in women

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Tests to assess kidney function

BUN (Blood Urea Nitrogen or Urea Nitrogen) Creatinine BUN/Creatinine Ratio Calcium Sodium Potassium Chloride CO2

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BUN (Blood Urea Nitrogen or Urea Nitrogen). This is the concentration of nitrogen (within urea) in the serum (but not in red blood cells). A waste product, derived from protein breakdown, produced in the liver and excreted by way of the kidneys. High values may mean that the kidneys are not working as well as they should. BUN is also elevated by blood loss, dehydration, high protein diets and/or strenuous exercise which may temporarily and artificially raise levels. A low BUN level may be the result of liver disease, a low protein diet, pregnancy, or drinking an extreme amount of water.

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Creatinine. A waste product largely from muscle metabolism (breakdown). Concentration of creatinine in the blood depends upon the amount of muscle that you have and the ability of your kidneys to excrete creatinine. High values, especially with high BUN levels, may indicate problems with the kidneys. Low values are generally not considered significant. BUN/Creatinine Ratio - This ratio is sometimes used or diagnostic purposes.

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Calcium. Calcium is one of the most important elements in the body. The parathyroid glands and the kidneys control the amount of calcium in the blood. The parathyroid gland is the main regulator of calcium in the body. Nearly all of the calcium in the body is found in bone (99%). The remaining 1% is very important for proper clotting, nerve, and cell and enzyme activity. An elevated calcium level can be due to medication (such as too much synthetic vitamin D), inherited disorders of calcium handling in the kidneys, bone disease, or excess parathyroid gland activity. Low calcium can be due to malnutrition, drugs and certain metabolic disorders.

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Sodium. An electrolyte regulated by the kidneys and adrenal glands. This element plays an important role in the water/salt balance (and blood pressure) in your body.

Potassium. Potassium is an electrolyte found primarily inside cells and must be controlled very carefully by the kidneys. Its role is to maintain water balance inside the cells and to help in the transmission of nerve impulses. A low potassium level can cause muscle weakness and heart problems. A high potassium level can also cause heart problems and can be caused by kidney disease or by over ingestion of potassium supplements.

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Chloride. Chloride is an electrolyte regulated by the kidneys and adrenal glands. Chloride is important to the function of nerves, muscles, and cells. It is usually associated with a high or low level of sodium or potassium.

Some drugs taken by prostate cancer patients such as estrogens and corticosteriods can cause increased chloride.

CO2. CO2 levels reflects the acid status of your blood. Corticosteriods as well as kidney disease can be involved.

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