Introduction to Clinical Medicine - Nephrology
I. David Weiner, M.D.
Professor of Medicine and Physiology
University of Florida College of Medicine and NF/SGVHS
Please e-mail me, at weineid@ufl.edu,
with your questions. I'll post the question and my answer, with your
permission, here for others to see.
Questions and Answers from 2007
Questions and answers are posted in reverse chronological order
so that the most recent questions and answers are at the top. I hope this
makes it easier for you to find answers to your questions!
February 20, 2007
Hello Dr. Weiner,
I had two questions with regards to your lectures a few days ago.
On page 5 of the "Assessment of Renal Function" lecture, I understand the
concept that dilute urine may (in the grand scheme of things) have the clinical
presentation of proteinuria. I understand the concept, but if I were given a set
of numbers, I would have no idea (based on specific gravity and urine protein
concentration alone) how to calculate which urine sample has more protein in it.
I may be thinking too deep into this problem. Could you please clarify this for
me?
- There's no direct way to determine the absolute rate of urinary protein
excretion solely from dipstick analysis of urine protein and specific
gravity. Instead, the point is to emphasize that the urine protein
concentration by itself may not accurately predict the absolute daily
urinary protein excretion. For example, a patient with 2+ proteinuria (~100
mg/deciliter) who is excreting a dilute urine with a specific gravity of
1.005 may be excreting 3-4 L of urine per day. Compare this to a patient
with 4+ proteinuria (~300 mg/deciliter) who is excreting a small volume,
approximately one half liter per day, of concentrated urine with a specific
gravity of 1.030. The former patient is probably excreting more more protein
per day in their urine than the latter patient, despite having a "lower
urinary protein" by dipstick. For direct comparison, one needs to
quantitatively measure urine protein to creatinine ratio.
On page 1 of the "Potassium Disorders" lecture, I am confused about how
potassium concentration affects the membrane potential. I see that figure one is
indicating some kind of change with membrane potential, but I don't understand
fully what this figure is indicating. Does a higher extracellular potassium
concentration make cells easier to discharge electrically (or vice versa)?
- Changes in serum potassium effect thrusting membrane potential.
Hyperkalemia results in less membrane polarization, whereas hypokalemia
results in greater membrane polarization. More important is that these
changes in membrane polarization result in changes in electrical conduction
rate and the rate of repolarization through electrically active tissues. It
is these changes that give rise to the electrocardiographic manifestations
that result from changes in extracellular potassium, and result in the
active precipitation of ventricular fibrillation in hyperkalemia and a lower
threshold for development of ventricular fibrillation in hypokalemia. I know
it seems as if both hyper and hypokalemia result in ventricular
fibrillation. Hyperkalemia causes it in the very short term in a predictable
time fashion. That is why bolus infusion of a large volume of potassium is
the active measure that stops the heart in death by lethal injection.
Hypokalemia, by contrast, does not directly cause ventricular fibrillation.
Instead, it increases the susceptibility the myocardium to the development
of ventricular arrhythmias. These arrhythmias may or may not occur, and may
occur either in the short or long term.
- I hope this helps.
I. David Weiner, M.D.
February 20, 2007
Less common causes of prerenal azotemia include
(I'll quote your notes) "the addition of an NSAID to a patient with cardiac
dysfunction or LIVER DISEASE, severe HEPATIC FAILURE and sepsis..." Can you
explain how LIVER DISEASE creates a problem? Can you explain how HEPATIC FAILURE
creates a problem? Thanks,
-
In patients with liver disease with severe
hepatic failure, there is a tendency towards decreased renal perfusion. The
exact mechanism of this decreased renal perfusion is not known -- it could
represent either decreased hepatic production of some unknown compound whose
role is to increase renal perfusion or decreased hepatic clearance of a
compound that causes renal vasoconstriction. In any event, there can be a
stimulus for decreased renal perfusion due to renal artery vasoconstriction.
Prostaglandins produced in the kidney are important component of an
autoregulatory mechanism that helps in maintaining glomerular filtration
rate is close to normal as possible in these conditions. When prostaglandin
formation is blocked, either with nonsteroidal anti-inflammatory drugs or
with Cox-2 inhibitors, there is a resulting decrease in GFR and the
potential development of acute renal failure.
I. David Weiner, M.D.
February 13, 2007
I have a question about the FWD calculation. The Lean Body
weight is total body weight minus fat percentage. Do we have an estimate for the
fat %. Or do we just use the total body weight? Thank you.
- There are a variety of ways to estimate the lean body weight. One, that
I personally prefer, is what I refer to as the "rule of five and six."
In this rule, lean body weight for a female is 100 pounds plus 5 pounds
for each inch over 5 foot tall. The lean body weight for a male is 106
pounds plus 6 pounds for each inch over 5 foot tall.
Of course, one divides by 2.2 to convert pounds to kilograms.
Another way is to look at the person and ask yourself, how much weight
does this person need to lose so that they are no longer overweight? Then
subtract that amount from their actual weight to reach an estimate of their
lean body weight. Obviously, this is subject to much more intrapersonal
variation and is a less quantitative way of predicting lean body weight.
There are a large number of other formulas, most of which in my opinion
are too complicated remember on a routine basis.
I. David Weiner, M.D.
February 13, 2007
Hi Dr. Weiner,
I have two questions regarding the renal lectures notes.
1) In the creatinine clearance formula, why do you include the 1440?
2) When you talked about hypoalbuminemia in the nephrotic syndrome your
handout says that it is not attributed to the mass balance loss (loss>hepatic
excretion). I was wondering what causes the observed hypoalbuminemia if the
liver is still making albumin at a normal or increased rate.
- 1 - The creatinine clearance normally uses a 1 day, or 1440 minute,
urine collection. The 1440 changes the time units from day to minutes.
- 2 - The urinary albumin losses cause the hypoalbuminemia. This is
because albumin is the predominant component of urinary protein in disease
states is albumin. Why the liver doesn't increase albumin synthesis
sufficiently to replace urinary albumin losses is not completely understood,
but it doesn't. The handout is poorly worded, and I apologize for
that.
I. David Weiner, M.D.
Hi Dr. Weiner,
I have one more question:
In pre-renal azotemia the Na concentration is low in the urine but the
osmolality is high. I am confused about this because I thought Na was the major
solute in extracellular fluid and accounted for 95% of osmolality. How can you
have low Na and high osmolalty?
Thanks!
- Sodium is the major component of extracellular osmolality in almost all
places, EXCEPT for the urine. In the urine, the majority of osmolality is
due to urea.
Thus, in pre-renal azotemia, the low BP and/or intra-vascular volume
depletion results in stimulation of ADH release, which stimulates water
reabsorption in the collecting duct. Urinary urea excretion is rather
constant, averaging ~400 mM per day for an average size person. Thus, in a
maximally concentrated urine, where the urine volume is 0.5 - 0.6 L/d, the
urinary urea concentration may reach 7-800 mM/L, and thereby account for
7-800 mOsm/kg H2O.
I hope this helps.
I. David Weiner, M.D.
I have a few questions that I concerning the set of clinical diagnosis
nephrology lectures you presented to use in class.
When you want us to know the clinical situations that predispose and or lead
to chronic hyponatremia, is it sufficient to think of diuretics, kidney disease,
liver cirrhosis, CHF, and SIADH? I assumed you just wanted us to know what
disease processes could cause chronic hyponatremia.
- The things that you've listed are the most common causes of chronic
hyponatremia. However, instead of trying to memorize lists of causes,
try instead to learn the evaluation algorithm that we discussed in class and
is in your handout.
The other question I had was about why the elderly are at risk for the
development of chronic hyponatremia. I think it is due to the increased age,
decrease in body weight which makes them at risk of dehydration when challenged,
higher levels of atrial natriuretic hormone which may promote sodium loss,
diuretics use, and a decrease in plasma renin activity which leads to decrease
in aldosterone secretion which leads to impaired Na+ reabsorption.
- The other major factor that you missed is decreased muscle mass leading
to decreased creatinine production rates that result in the serum creatinine
overestimating the actual GFR. The lower the GFR the less one is able
to deal with fluid loads. So, the elderly person with decreased GFR
who is also on a thiazide diuretic and has a high water intake and low
sodium intake is at high risk of developing hyponatremia.
Also based on the last reason this would mean that due to the decrease
aldosterone secretion the person would also be at risk for hyperkalemia. Is it
common to see Na+ and K+ disorders linked or are there other compensatory
mechanisms that prevent this from occurring?
- Actually, in the great majority of cases suppressed aldosterone
secretion does not contribute to hyponatremia. Hyperkalemia is rather
unusual in hyponatremia, and suggests the presence of adrenal insufficiency,
pharmacologic inhibition of the renin-angiotensin system (ACE-I/ARB) or
chronic kidney disease and dietary increases in K intake.
Lastly, I noticed on the objectives for hyperkalemia that you wanted us to
differentiate between the treatment of hyperkalemia based on whether or not
there were EKG changes. I took this as basically saying that when you see EKG
changes, you want to act quickly and the preferred treatment would be IV calcium
due to the quick onset. Is this accurate?
- Correct, people with EKG changes need emergent treatment, whereas those
without do not.
Thank you in advance for answering all my questions!
I. David Weiner, M.D.
Can you explain the differences between hypo and hypernatremia and sodium
content? How are they exactly different?
- Hypo- and hypernatremia refer to the concentration of sodium in the
blood, whereas sodium content refers to the absolute amount of sodium in the
body. Thus, it is possible to have hyponatremia with an increase in
both total body sodium and water if the relative increase in water is
greater than the increase in sodium.
Why are most cases of hyponatremia associated with total body sodium excess?
- The most common causes of hyponatremia are congestive heart failure,
liver disease and nephrotic syndrome. Each of these is associated with
increased total body sodium and water, but the increase in water exceeds the
increase in sodium, resulting in a decreased sodium CONCENTRATION, i.e.,
hyponatremia.
Why does this happen, you might ask? In each of these cases, the body,
for reasons still not completely understood, "senses" that plasma volume is
low even though plasma volume is actually high. This is called a decreased
"effective arterial blood volume." The decreased EABV stimulates ADH release
which leads to inappropriately high rates of water reabsorption and thereby
results in the total body water increase exceeding changes in total body
sodium.
I hope this helps.
I. David Weiner, M.D.
I have a quick question regarding the treatment of hyperkalemia with EKG
changes versus without EKG changes. Does it have to do with the onset of the
therapy? So faster therapies should be used if EKG changes are present?
I. David Weiner, M.D.
Hi. I've looked at your website regarding the role
hypothyroidism and adrenal insufficiency play in euvolemic hyponatremia. You
talk about thyroid hormone and cortisol being needed for normal DCT function.
The adrenals also produce aldosterone, which normally helps with Na+ and water
retention. If you have adrenal insufficiency, does the decreased aldosterone
come into play with hyponatremia? Thanks,
-
Yes, you are correct. The lack of aldosterone does lead to
lack of sodium reabsorption in the distal convoluted tubule and collecting
duct. This can lead to mild intravascular volume depletion which results in
slight stimulation of ADH release. The combination of sodium wasting in the
urine plus stimulus for water reabsorption further contributes to
hyponatremia. In general, people with adrenal insufficiency do not develop
hyponatremia unless they become ill and can't get access to adequate amounts
of sodium chloride.
I. David Weiner, M.D.
Hi Dr. Weiner,
I have a few questions:
1. What is the role of prostaglandin in autoregulation? In addition, what
is its role in potassium secretion.
- Prostaglandins are critical role in the efferent arteriolar
vasoconstriction response to angiotensin II. thus, the effect of
NSAIDs is similar to that of ace inhibitor or ARB administration in
conditions when renal autoregulation is activated.
- Prostaglandins are also important in collecting duct potassium
secretion. Potassium secretion requires as its last step movement of
potassium from the cell cytoplasm across the apical membrane into the urine
via specific potassium channels. For these channels to be open and
thereby allow potassium transport requires intracellular production of
specific prostaglandins. This process can be inhibited by NSAIDs,
thereby resulting in hyperkalemia.
2. At what stage of chronic kidney disease does the GFR start to
decrease by 12 ml/min per year? Is it from the beginning or around stage 3 when
the GFR noticeably begins to drop?
- Typically GFR begins to decrease at this rate somewhere between stage II
and III CKD. It also depends on the underlying disease process and the
efficacy of treatment of the disease treatment.
3. Microalbuminuria occurs at 30mg/d but in the lecture on glomerular
disorders it says that a normal person can have a urine protein of 150mg/d. How
do you know the microalbuminuria is not just normal?
- Excellent question! The difference is what is being measured.
Microalbuminuria refers to specific assessment only albumin in the urine
whereas urine protein excretion measurements measure all urinary proteins.
There are a number of small molecular weight proteins that can be filtered
at the glomerulus and are normally reabsorbed in the proximal tubule that
may be excreted in very low quantities in the urine. Excretion of
these proteins, which is measured by the quantitative urine protein
assay, does not indicate glomerular disease. However, identification
of microalbuminuria does indicate both glomerular disease and an increased
risk of peripheral vascular disease.
4. Do you use ACE-I or ARB to treat other types of glomerulonephritis or only
IgA nephropathy? And why?
- Ace inhibitors or ARB's are widely used to treat almost every type of
glomerulonephritis. In general, angiotensin II appears to be important
in both development of proteinuria and in the progression of chronic kidney
disease. Inhibition of the renin-angiotensin system with either ace
inhibitors or ARB's reduces proteinuria and slows progression of chronic
kidney disease in almost every type of glomerulonephritis. Moreover,
glomerulonephritis is almost always associated with hypertension and these
classes of medications are effective antihypertensive agents as well.
Finally, they are associated with a very low incidence of side effects, are
relatively inexpensive and are well tolerated by most patients.
I. David Weiner, M.D.
I sifted through the Q&A posted on your website (thank you for
this resource!), but I just wanted to see if I understand prerenal azotemia with
respect to ACE-I and ARBs. Is it that if a patient is already hypotensive, has
renal artery stenosis, or has intravascular volume depletion, they depend on Ang
II for efferent arteriolar vasoconstriction to maintain their GFR -- and that if
you block AngII with ACE-I or ARBs, the patient loses the ability to filter
blood and ARF results?
I. David Weiner, M.D.
3 Renal Pathophysiology questions:
1. Can we use BUN/Creatinine ratios to diagnose patients
with nephrotic and nephritic syndromes, similar to acute renal failure case?
What other lab values would be abnormal in patients with nephrotic and nephritic
syndromes? (other than albumin, LDL-cholest)
-
The BUN to creatinine ratio cannot
be accurately used to diagnose patients with nephrotic and nephritic
syndromes. They really are useful only to differentiate between
prerenal azotemia and acute tubular necrosis. In essence, they only
assess whether renal tubular sodium reabsorption is being stimulated to
reabsorb filtered sodium, as occurs in prerenal azotemia, or is not, as
occurs in acute tubular necrosis. A high fractional excretion of
sodium indicates renal tubules are not maximally reabsorbing sodium, and in
the presence of oliguria (a low urine volume) and acute renal failure
suggest acute tubular necrosis and provide evidence that prerenal azotemia
is not present. Of course, should the patient be receiving medications
that block renal tubular sodium reabsorption, i.e., diuretics, then a high
fractional excretion of sodium may only indicate functional effect of
diuretics on renal tubular sodium transport and therefore cannot be used to
exclude prerenal azotemia. In this case, a high fractional excretion
of sodium is not useful! A low fractional excretion of sodium in the
presence of oliguria and acute renal failure suggests that the renal tubules
are attempting to maximally reabsorb filtered sodium and thereby provide
functional evidence of prerenal azotemia. Unfortunately, there are
other conditions that can give him high and low fractional excretion of
sodium, and therefore these diagnoses are not definitive but instead only
act help exclude specific possibilities.
-
No other laboratory values that
are specifically abnormal in patients with nephrotic or nephrotic syndromes.
If the GFR is impaired due to the glomerulonephritis, the BUN and creatinine
may be elevated. In many cases, particularly in nephrotic conditions,
but also with some nephrotic conditions (such as FSGS), hypertension is
present. Otherwise, the laboratory tests that are abnormal are
generally fairly specific to the underlying disease process.
2. Why will ACE-Is/ARBs cause prerenal ARF in patients
with limited kidney function?
-
Ace inhibitors and ARB's in fact do
not cause acute renal failure in patients with limited kidney function.
You may be thinking of the example that I've discussed of the patient who has
bilateral renal artery stenosis, has a single functioning kidney with renal
artery stenosis or has relative intravascular volume depletion and hypotension.
In theses conditions, renal perfusion pressure is decreased, and glomerular
filtration rate is being maintained by glomerular efferent arteriolar
vasoconstriction. This glomerular efferent arteriolar vasoconstriction is
being stimulated by angiotensin II binding to be AT1 receptor present in the
efferent artery. Either inhibiting angiotensin production, with ace
inhibitors or blocking the angiotensin receptor with a angiotensin receptor
blocker, reverses this efferent arteriole vasoconstriction. This leads to
decreased glomerular hydrostatic pressure, decreased glomerular filtration rate
and acute renal failure.
3.Why is BUN/Creatinine increased in prerenal ARF?
-
The BUN to creatinine ratio is
increased in prerenal azotemia because of stimulated tubular reabsorption of
urea. Many medical schools and renal physiology courses teach that renal
urea transport is passive; this is incorrect. There are number of specific
urea transporters expressed in the kidney. Urea reabsorption is critical
for increasing the medullary interstitial osmolality, and this is critical for a
high enabling water reabsorption in the collecting duct. Remember the
water only moves from areas of low osmolality to hire osmolality. Kidneys
in times when it is necessary to maximally concentrate the urine stimulates urea
reabsorption in specific nephron segments. This raises interstitial
osmolality. The higher interstitial osmotic pressure maximizes the
kidney's ability to reabsorb water in the collecting duct. Thus, in
prerenal azotemia urea excretion rates are less than glomerular filtration rates
due to urea reabsorption. This urea reabsorption raises the blood urea
nitrogen (BUN) and thereby increases the BUN to creatinine ratio.
I. David Weiner, M.D. |
