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, unless you ask
me not to do so, here for others to see.
Questions and Answers from 2009
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!
March 22, 2009
Dear Dr. Weiner,
I had a question regarding the sodium lecture. I was wondering
how thiazide diuretics block the formation of free water and inhibit dilute
urine formation.
Thank you for your help!
- In order to generate dilute urine, that is urine with an osmolality less
than blood, you have to start with luminal fluid with an osmolality similar
to blood and then reabsorb sodium and chloride without allowing water
transport.
The only place in the kidney where that occurs is in the distal
convoluted tubule. Here, the starting luminal osmolality is ~300 mOsm/kg
H2O, and NaCl is absorbed by an apical Na-Cl cotransporter. Aquaporins are
not present and there is no ability to reabsorb water. Accordingly, at the
end of the distal convoluted tubule the luminal osmolality can be as low as
50 mOsm/kg H2O. Thus, this is the segment, and the only segment, that
generates dilute urine.
Thiazide diuretics work by blocking the Na-Cl cotransporter in the DCT.
As a result, they inhibit the kidney's ability to generate a dilute urine.
I. David Weiner, M.D.
March 21, 2009
Hi Dr. Weiner, on the assessment of renal function lecture you showed the
graph of serum Cr and GFR. As an example question you asked "Which of the
following changes in Cr will lead to a larger change in renal function?" And
options were 2-4, 4-6, or 6-8. If Cr goes from 2-4, the GFR change is 60-30 (so
50%dec in renal function) If 4-6, GFR change is 30-15=15; which is 50% decrease
of renal function If 6-8, I'm assuming the GFR change will be down to 15/2 so it
is again 50%
However, the wording of the question seems to ask a quantitative change, not
a percent change, of renal function. These would be different answer choices on
an exam (2-4 has a higher change in renal function, all have same change in
percent of renal function). Is the exam appropriately worded so as to know which
difference you are looking for? Or am I confused about something that I don't
realize?
Thanks so much for your help!
- Your calculations are a little off. If the creatinine changes from 4 to
6, the GFR decreases from ~30 to ~20. The decrease is ~33%, not 50%. If the
creatinine changes from 6 to 8, the GFR decreases from ~20 to ~15, only a
25% decrease. Both the percent changes and the absolute changes differ in
the different examples.
The approximate formula for the percent decreases
is: (final creatinine - initial creatinine) / final creatinine.
In general, if a test question asks when is the change bigger or
smaller, they are probably referring to absolute changes, not relative
changes, unless the question specifically states the relative change.
I. David Weiner, M.D.
March 21, 2009
Hi Dr Weiner,
Thanks for replying, it helped a lot! SO renal failure is always
measured by GFR and in cases of renal failure, the GFR is always low. I am
getting confused with the situation where the urine output can be high even
though the GFR is low. How is this possible? Can you please give me an example
of a situation where there is renal failure and decreased GFR but the urine
output is high?
THanks
- Remember that "renal failure" does not necessarily mean "complete" renal
failure, i.e., GFR = 0. If the GFR is decreased from 120 to 20, that is also
renal failure.
Some medications can cause renal failure associated with normal or even
high urine volumes. One example is the class of antibiotics called
aminoglycosides. Their biggest side-effect is renal damage leading to renal
failure, and it is typically associated with normal or even increased urine
output. A second example is partial urinary tract obstruction. This, if
partial, can cause progressive renal failure even though the obstruction is
not complete, and urine volume is maintained normal. Finally, the person
given high doses of diuretics can develop renal failure because of
intravascular volume depletion and pre-renal azotemia. Their urine volume
remains high because of the diuretics that caused the renal failure.
I hope this helps.
I. David Weiner, M.D.
March 20, 2009
Hi Dr Weiner,
I also had another question. In terms of renal failure, is it
more accurate to define renal failure when we see high serum BUN and Creatinine
or Decreased urine output. I guess my question is that if you have renal
failure, is it almost always manifested by decreased urine output, or can it
have other presentations as well.
Please let me know, thanks
- Renal failure is defined as a decreased in GFR.
It can manifest either with increased BUN and creatinine or with
decreased urine output. The reason to also assess the urine output is that
the BUN and creatinine lag several days behind the actual GFR. For example,
ten minutes after having both kidneys removed in surgery, such as for
bilateral renal cell cancer, the GFR is zero, but the BUN and creatinine
have not had sufficient time to increase to reflect the change in GFR.
However, the rate of urine formation is zero (no kidneys, no urine!). Thus,
in early stages of renal failure one can have decreased urine output, but
the BUN and creatinine have not had time to rise to reflect the decreased
GFR.
One also needs to know that not all patients with renal failure have a
low urine output. Many patients with renal failure, whether acute or
chronic, have normal or high urine outputs. The urine volume depends on many
factors, including severity of renal failure and the originating cause.
I. David Weiner, M.D.
March 20, 2009
Hi Dr Weiner,
I had a question about the BUN:Cr ratio in parenchymal disease,
specifically glomerulonephritis. Since the renal tubules are not damaged here,
the urea can be reabsorbed. So shouldnt the Urea concentration be high as in
prerenal azotemia? Versus in intrinsic kidney disease such as acute tubular
necrosis where the tubules are damaged so urea cant be reabsorbed?
Please let me know, thanks!
- It could be, if there were a need to concentrate the urine. However, the
originating problem is decreased glomerular filtration, which would tend to
decrease the kidney's ability to excrete sodium and water. As a result, most
patients with glomerulonephritis tend to be slightly volume overloaded, not
volume depleted. If they are not volume depleted, there is no specific need
for the kidneys to retain sodium and water, so there is no need to activate
urea excretion. This results in a normal BUN:Cr ratio.
I hope this helps.
I. David Weiner, M.D.
March 17, 2009
Dr. Weiner, This is --- from Clinical Diagnosis again. I had a
couple more questions.
1. Could you explain the difference between SLE causing
secondary nephritic syndrome versus SLE causing rapidly progressive
glomerulonephritis versus SLE causing chronic glomerulonephritis? How does it
cause all three? Are the five classes of SLE nephritis only with respect to
chronic nephritis and acute SLE nephritis has a different presentation?
-
Glomerulonephritis from lupus is always a secondary form of
disease because it is a component of a systemic disease. This is just the "definition" of secondary disease. You are correct that lupus can cause
either chronic or rapidly progressive glomerulonephritis. The difference is
that the progression of the disease differs in different patients. Why the
progression is mild and only very slowly progressive in some patients and
rapid and aggressive in others is not known, but is an important area of
investigation. Typically, class IV lupus nephritis has a much more
aggressive presentation and it is the most common diagnosis in patient with
lupus who have a rapidly progressive glomerulonephritis. Classes I, II and V
typically present much more slowly as a form of chronic glomerulonephritis.
Class III lupus nephritis can either be slowly progressive or rapidly
progressive. Nevertheless, the associations are generalities. Renal biopsy
is necessary to define the exact histologic type of lupus nephritis in order
to guide appropriate therapy.
2. I also didn't understand how high phosphate could cause an
increase in parathyroid hormone production (this was in your CKD lecture on page
5). I thought that parathyroid hormone is regulated by a calcium sensing
receptor. Is there also a phosphate sensing receptor on the parathyroid gland?
All I could find online was information about how a high extracellular phosphate
concentration prevents the normal inhibition of PTH secretion by high calcium,
so with renal failure and hypocalcemia the calcium would be low, thus
stimulating PTH release, while the phosphate would be high, thus preventing the
feedback of hi calcium inhibiting PTH release (which should not be going on in
kidney failure because calcium is low to begin with). So I'm confused about how hyperphosphatemia can stimulate PTH release in the context of kidney failure
since there is hypocalcemia. (http://www.nature.com/ki/journal/v63/n85s/full/4493810a.html#ack)
-
The are several mechanisms by which hyperphosphatemia
stimulates parathyroid hormone release. First, mild hyperphosphatemia can
decrease serum calcium, which then stimulates PTH secretion. Second,
phosphate retention inhibits 1, 25-dihydroxy-vitamin D3 production by the
kidney, which decreases in intestinal calcium absorption, leading to mild hypocalcemia, which then stimulates PTH
secretion. Third, 1,25-dihydroxy-vitamin D3 itself inhibits parathyroid hormone secretion.
Thus, the decreased levels of 1,25-dihydroxy-vitamin D3 in response to hyperphosphatemia stimulate PTH release.
Phosphate has direct
effects on the parathyroid gland that both stimulate PTH secretion through
mechanisms that are independent of
calcium and vitamin D. Finally, hyperphosphatemia stimulates
parathyroid gland hyperplasia, which, by increasing parathyroid gland mass,
leads to long-term increases in PTH secretion.
-
From a teleologic perspective, phosphate's stimulation of
PTH has some beneficial effects in that PTH stimulates renal phosphate
excretion, thereby helping to maintain serum phosphate as close to normal as
possible. The tradeoff is that chronic hyperparathyroidism has
long-term adverse effects on bones, cardiac and cardiovascular tissues, and
many other organs.
-
I
know this is complicated. Sorry.
Thank you!
I. David Weiner, M.D.
March 16, 2009
Dr. Weiner, My name is ----, I'm a second year in the Clinical
Diagnosis class and I had a couple of questions from lecture today.
1. In class today you mentioned that hemoglobinuria on dipstick
can indicate urine positive for hemoglobin or myoglobin, and that you have to
see red cells in the urine to determine if the positive dipstick shows
hemoglobin in the urine as opposed to myoglobin (because with myoglobin in the
urine no red cells would be seen). My question is, are there situations where
hemoglobin spills over into urine without red cells coming into urine? In other
words, do my "holes" have to be diseased enough to let red cells through in
order to have a positive dipstick hemoglobin? What about intravascular hemolysis
and excess hemoglobin in the blood getting out via urine with intact glomerular
function? In that case the urine dipstick would be positive for hemoglobin, but
there would be no red cells on microscopy, and you wouldn't be able to say that
the dipstick was positive because of myoglobin, right?
-
In general, intravascular hemolysis does not result in
hemoglobinuria. This is because hemoglobin molecules are too large to be
filtered across glomerular capillary loops. In contrast, the size of
myoglobin is smaller and it is able to be filtered.
2. I don't understand the cause behind non- allergic acute
interstitial nephritis. You said in class that the prototype for this is NSAID
use because they alter prostaglandin metabolism and cause production of
leukotriene metabolites, which are toxic to the renal tubules and result in
proteinuria because they affect the glomerulus at the same time. I tried to
Google it and all I could find was allergic NSAID induced acute interstitial
nephritis. Is the non-allergic type caused by NSAIDS because once cyclooxygenase
is blocked it forces the arachidonic acid into the lipooxygenase pathway to
produce leukotrienes which then damage the tubules/glomerulus which then causes
proteinuria? And by the same token in allergic acute interstitial nephritis
since the eosiophils are like hand grenades and damage tubules why is there no
proteinuria?
-
There is some controversy in the literature as to whether
nonsteroidals cause interstitial nephritis through a toxic metabolites'
mechanism or whether it is through an allergic mechanism. I believe the
majority of evidence favors the former possibility. Allergic interstitial
nephritis can cause proteinuria, but is typically very low grade. There is a
small amount of albumin and other proteins that are filtered across the
glomerular capillary loops that are typically retort by the proximal tubule.
Damage to proximal tubule in allergic interstitial nephritis decreases
absorption of these proteins, resulting in mild proteinuria. There is not
substantial damage to the glomerulus in allergic interstitial nephritis
because the allergic response takes place in the interstitium, typically
surrounding peritubular capillaries, and therefore relatively spares the
glomerulus.
Thank you for your help,
I. David Weiner, M.D.
March 16, 2009
Hi Dr. Weiner,
I was a little confused about the Scr and its usefulness. You
mentioned that Scr. is a measure of GFR and that GFR correlates with all renal
functions. However, you also said that Scr. does not correlate with renal
function.. However, based on the first statement I thought that one could get an
idea of the renal function from Scr. because its a measure of GFR. I was
wondering if you could resolve my confusion in understanding these points.
Thank you.
The point that I was trying to make is that the serum
creatinine is an important indicator of glomerular filtration rate, but that
it is an imperfect indicator. Its limitations include that it lacks 2-3 days
behind actual renal function, and that patients with altered muscle mass
have serum creatinine values that may be either inappropriately normal or
abnormal and thus not accurately reflect true renal function.
Nevertheless, it is currently the best routinely available
laboratory test that we have to measure renal function. It is important that
the astute clinician remembers that the eGFR value, which is calculated from
the serum creatinine, age, gender and race, provides a more accurate
assessment of renal function than solely relying on the serum creatinine.
I hope this helps.
I. David Weiner, M.D. |
