Case of Severe Hypertension and Nephrotic Range Proteinuria

Case of Severe Hypertension and Nephrotic Range Proteinuria


Great. Our first case today
will be presented by Dr. Michael Bursztyn and
it is a case of severe hypertension and nephrotic
range protein urea. And we’re ready to start
whenever you’re ready. Dr. Oparil, Dr. Dominiczak, and
Dr. Touyz thank you very much. Thank you very much for
allowing me to present this case, which was taking
place some thirteen years ago. This is an emergency
department perspective. A 37 year old man, referred
by family physician because of severe hypertension. This is not
uncommon where sometimes, primary care physicians panic
and refer patients for having high blood pressure. And usually, these are quickly
dismissed from the emergency room. He’s usually healthy. He, for six months, he’s
treated for hypertension with Athenolol 50mg and
had had headaches, nausea, dizziness,
left flank pains. No diarrhea or constipation. Normally, as
you’ll see in a moment, why it is of interest. He lost some five
kilograms during this period. He has no family history of
hypertension or renal disease. After digging a bit
in his past history, it turns that some
twenty years earlier, he had an appendectomy; but
the appendix wasn’t inflamed. It was some non specific
ilio-cecal inflammation. Crohn’s disease was suspected,
but nothing really followed. He was admitted a decade later
to surgery because of severe abdominal pain. And on CT there was some small
bowel thickening and perhaps peritoneal fat stranding. He was treated with
antibiotics and recovered and this charge had had
nothing to do with it later. However, a few years later,
he showed up in the emergency room with deep
vein thrombosis. A workup for hypercoagulopathy was
recommended but not undertaken. He was treated with
Enoxaparin and Warfarin later, which he
discontinued after a year. On examination, he
was fully conscious, had no distress at all, his
blood pressure was 190 over 126 with a pulse rate of 88
and no asperital distress. He was quite lean. In the eye background,
no alarming findings. He had clear lungs,
normal heart sounds, no abdominal or
flank tenderness, no organomegaly, no
peripheral edema, no peripheral pulses. Calf blood pressure was 232
over 144 culfation of the alta. Had no neurologic deficit
and no other finding: no skin rash, no pulpala. Normal ECG. Voltage criteria for
Left Ventricle Hypertrophy, however, the age of 36,
this if of some questionable meaning, however, his
biochemistry turned severe hyponatremia,
severe hypokalcemia, normal
creatinine, low albumin, 25 grams per liter, high
cholesterol and normal liver function test. This certainly changed the
perception that he’s just one of those patients where we
felt because of physicians panic, which was indeed the
real cause of his referral He had normal CBC and
red blood cell morphology. Urine sediment was
normal, however, stick positive for protein. This was confirmed
also by salicylic acid. At that point,
there’s a dilemma. What would you think? We’re opening this
to the audience. What’s the next step? Yeah. Yeah. I thought, I still think the
severe proteinuria and sever hypertension in the absence of
evident globulin nephritis is somewhat unusual. We need the microphone. Microphone. There’s only one? Two. In very wrong places. Sorry for this. Okay. The camera sees this, yeah? You’ve got significant
proteinuria and significant hypertension to the
degree that they’re linked you probably need to ascertain
what’s going on at the level of the kidney. In our current
practice, I’m in Richmond, Virginia, biopsy probably be
quickly forthcoming soon as the blood pressure has some
measure of control so they don’t bleed out when
you stick the kidney. I’d be attacking it
diagnostically to see if there’s something in the renal
level that may be acting as an approximate cause
of the hypertension. Realizing the hypertension
not been really worked up from neurohumoral point of
view, it’s highly likely that there’s a renal
element to this. I’d go for the jugular earlier
than later in the workup. In usual serologies probably
would be sent off in a diagnostic capacity trying to
ascertain what might be going on at the level of
the kidney as well. The rule-outs would be
there, biopsy would be shortly forthcoming, unless some
miracle happened and sometimes these miracles
happen, but not often. This happened in
the land of miracles. Another comment here. I would also want to work
up his hyponatremia and hypokalemia which
are pretty profound. Urine also allows … the electrolytes
might be useful. Yeah. Thank you, I’m Viknesh
Selvarajah from Cambridge. Interesting case. Putting simply, he’s
got nephrotic syndrome, but he’s not ademptist but
he’s got two interesting things: he’s hypertensive,
which can be associated with secondary FADS, which is
a significant glomeropathy also, he’s
got Crohn’s disease, which is associated
with kidney disease. You can get
intestinal nephritis, which would produce
blood in the urine. There are other renal
pathologies that associate with Crohn’s. It’s not clear due to the
treatment for Crohn’s like five years, or
Crohn’s per say. Renal biopsy would
certainly be important. His electrolytes are interesting,
he’s hyponatremic and hypokalemic with
normal excretory function. Certainly, as mentioned,
checking similarities but checking renal aldosterone
to see if any clear causes of hypokalemic or checking the
magnesium as well would be relevant. Thank you. Of course, but in our place,
the renin and aldosterin take time and as you can see we are still
in the emergency room. The low albumin and high
cholesterol suggest that it is nephrotic syndrome. Nephrotic syndrome is a
hypercoagulable state however, it is usually a state of
the intravascular volume depletion. Therefore, unless there is
a glomerulonephritis most typically, lupus nephritis,
this things don’t go with such a sever hypertension and
that’s time in emergency room, someone thought that a renal
vein thrombosis could somehow link the massive proteinemia
with acute or subacute hypertension. Let me just ask, what
treatment was he on- Atenolol. I’m Dr. Seved Mehrdad Hamrahain
from Jefferson, Philadelphia. I agree with the
majority of the comments made, but I will take a
different approach. The question first is how to
stabilize the patient coming in with such elevated
blood pressure and electrolyte abnormality with
some missing data. Just looking at your EKG and
normal LVH it tells me that despite the diagnosis of
hypertension and being on Atenolol, this advanced or
significantly elevated blood pressure is something, which
most probably is acute on relatively seen stable
hypertension from the past, otherwise he would not have it
relatively seeming normal EKG. The second thing is, what is
the bicarbonate of the patient. What is the ceramnormality
of this patient? We need some urine
protein creatinine ratio, albuminin to creatinine ratio,
that would be the second phase of basically, work
up of this patient, definitely needs a
significant work up. We have to see if the
hypocalcemia is related to hyponitremia versus
two different etiology. Does this patient
have, by chance, a plasma cell dysplasia giving
us a significantly abnormal or pseudohyponatremia. I think there are different
things that we have separate first, but the key thing is
to stabilize the patient. Okay. There is a question here. Czech Republic. I’m a clinical nephrologist
and I would strongly disagree that this patient should first
have renal biopsy and things like that because, first,
you cannot do renal biopsy in someone who has high
blood pressure like this. It would take at least one
week to safely load it down. He has no critical organ
damage at this moment, so his blood pressure should be down
regulated step wise, first thing. The second is that, maybe the
proteinuria can decrease after his blood pressure goes down
and I would say that it’s not sure that he has no
glomerulonephritis. There are no abnormalities
that have no changes in sediment and they have
only nephrotic syndrome. This can still be
glomerulonephritis. But, I will ask whether he was
taking atenolol when his heart rate was at 88 with
such high blood pressure. High blood pressure should
decrease heart rate and when you give atenolol
it should go down. The first thing
is to decrease, somehow, his blood pressure
because this is really dangerous and the
work up should be first. Really, the minerals
and things like that, but not renal biopsy. We also didn’t
think, at that time, a renal biopsy would being
in place and I just want to remind you that you’re
still in the emergency room, however, given the thinking,
the renal vein thrombosis may somehow link the nephrotic
syndrome with severe hypertension. Renal ultrasound with
[inaudible] Doppler was done, didn’t show
any renal thrombosis, however, it shows a
discrepancy between the size of the kidneys. The left kidney was eight
and a half centimeters was hypoallergenic and the right
kidney was twelve point five centimeters with the
resistance index on the left was high and on the
right was normal, suggesting that … It might have been
more progressive. Right. So, there is a queue at this
microphone and they all want to tell you what
they suggest, please. Ana Oliveras from before the
ultrasound results I wondered about this potassium so low. Because, I think that the
patient has a nephrotic syndrome, almost
biological nephrotic syndrome. But, we have no information
about potassium in urine, you must know before
other things I think. If the potassium in urine
is low or is high because, this patient has had two previous
abdominal confusion episodes. This comes first. Maybe, the patient has
something related with this hypokalemia that has nothing
to do with the nephrotic syndrome and we must thought
about the possibility of to link these two things. How was the
potassium in urine? Do you have this data? I think it was not low. Not low. I don’t, unfortunately, I
didn’t write it down and I don’t remember. It was not low. Hi Michael. He’s hypouricemic and he’s
hypokalemic you have to think about a hyperemic state. He probably has high renin. He may have renal
artery stenosis, he may have two
things together. I know he has a pathology
related that we’ll probably find that on biopsy of his
kidney that links together what was happening with
his GI tract for many years. But, this may be a case where
you have two things and he may have renal acarinosis and
he also may have some other glomerulonephropathy. Of course these
things are possible, but we were … how should I say it … rigidly educated to look for
[inaudible] and try to unify the
diagnosis as will turn out, it’s not impossible. Okay. You’ve given a lot away. Please. I’m Alejandro De La
Sierra from Barcelona. I don’t have an explanation
for some of the things that this patient has, but I
was wondering why you were insisting in all this
abdominal previous history? Considering that you are
coming from Israel and the patient was probably Jew, you
know one of the possibilities of all – Actually not. The patient was an Arab. Oh, anyway, let me finish. Considering all these
undiagnosed abdominal events that the patient has and now
it seems that he has also a nephrotic syndrome, I will
consider the possibility of familial mediterranean
fever with complication with [inaudible]
promoting nephrotic syndrome. Anyway, I will need still to
think a little bit more to explain the
apparently, allelopathy or one dysregulation of the severe
hypertension considering that the patient has not a
renal vein thrombosis, which was one of the
original circumstances. This is, of course, very
important and good thinking and certainly
relevant to the area. However, this guy missed
two F’s from the Familial Mediterranean Fever. He had no fever and no history
of fever and no family history so this is not supportive,
let’s put it this way. The other thing
was that usually, when you have a melodotic
nephrotic syndrome you tend to be hypotensive and not, I
think severe hypertension in this context I think
is rarely described. Let’s put it this way. We need to see more. Are we ready to see
more information? At last, the physicians in the
emergency department thought this patient
deserves an admission. Good. Good. In the hospital, an
opportunity arose to see the computer tomography he had
done a few years earlier with his abdominal pain
and on this one, both kidneys were normal
appearing with normal profusion. The blood pressure, when he
had the deep vein thrombosis in the emergency
room was normal. In the hospital,
again, he had, again, normal urine sediment
and the albuminin creatine ration was 11.1. For those who are not used to, this
in grams which is still very high. This is very high. Because of the history of
thrombotic events and the evidence of vascular
compromise of the left kidney, we looked into some
coagulation factors, which were normal with the
exception of prolonged partial thrombotic time. I’d like to … I’m waiting for suggestions. Okay. There is silence. We’ve run out of suggestions. Okay. Prolonged partial thrombosis
time maybe suggestive of presence of
lupus anticoagulant, which was indeed found. Antinuclear antibodies
and ANCA was negative, so this was not
supportive of lupus nephritis, so I don’t know periaortic
or something like that, which is also not associated
with nephrotic syndrome usually. As
antiphospholipid antibodies, were elevated and
confirming the presence of antiphospholipid syndrome,
now what was speculatively possible that part of his
abdominal pain and somewhat evidence of colitis
he might have had, it’s reasonable to speculate it
might have been thrombotic affairs. His supine plasma renin
activity during the atenolol that he was taking
was extremely elevated, 15 nanograms per hour, per milliliter
and aldosterone levels were also elevated. We can say that he as
secondary hyperaldosteronism. This certainly
explains the hypokalemia. Computer tomography confirmed
that the left kidney was small and had nephograph
effect with the large, normal perfused right kidney
and nuclear study suggested that the left kidney’s
contributes less than one percent to the
total renal function. It seems that this patient has
renal vascular hypertension related to what appears to be
occlusion of the left renal artery. I can see, I guess, the
stamp next to the ultra. You can see, again, that the
left kidney is small and it has, I hope you can see, full
radiographic nephographic filling. Treatment was begun with
ramipril and spiranolactone. His blood pressure came down,
his headaches and dizziness dissipated and sodium
was still a bit … he was still hyporeninemic,
potassium normalized, creatinine increased to 124
micromols per liter but came down again to baseline, this is
usual for such a immediate and rapid blood
pressure reduction. Albumin creatinine ratio
decreased dramatically from 11 to 3. He was given Warfarin with
the diagnosis of antiphospholipid syndrome and both venous,
at least one venous and one arterial vein, so he’s doomed
for lifelong anticoagulation. He was discharged and shows
in the hypertension clinic, blood pressure is very high
and ACR was not performed though asked for,
INR was normal, he insisted he
takes his medications. I’m sure one or two of you
have ran into such a situation too, however, we have the
habit of trusting our patients on one hand and suspecting
them at the same time. He was invited to
return and twice, again, he had the same things. Fortunately he was not
taking his Warfarin, that protected him from
cerebral hemorrhage with this horrendous blood pressure. Helplessly, we
had readmitted him. On the second admission, his
blood pressure was very high, he was, again,
hyponephrenic and hypokalemic. After Ramipril was
resumed everything normalized, including a marked reduction of
the Albuminin/creatinine ratio. Albuminin rose from,
I’d like to remind you, 25 grams per liter in a
healthy looking 36-year-old man and rose to 45
grams per liter. If someone had doubts, it is
the urine where his Albuminin was leaking and he had INR4
as should any patient with antiphospholipid
syndrome be treated. So what now? We have the microphone there. I have one question. His kidney was already
shrunken at the time of the first admission, meaning that that
was probably not an acute event. The history of hypertension
was there for six months. It might have been
longer, I can’t tell. Okay. This is a great case. We used to see this kind of
thing more frequently a couple of decades ago when we
were doing renal vascular procedures for unilateral
renal artery stenosis and other causes of this
syndrome, which is a small, shrunken, nonfunctional kidney that
putting out a huge amount of renin. That’s causing a huge
problem both in blood pressure elevation and electrolyte
abnormalities and putting the patient at a higher risk. We had treated many of the
patients after demonstration of noncompliance with
unilateral nephrectomy since the kidney was nonfunctional
we really didn’t think that we were losing very much and that
was highly successful in a number of cases. You’ve still got a
problem, however, that doesn’t take away the
phospholipid syndrome and doesn’t take away the need from
prophylactic anticoagulation. I think to manage this kind
of recurrent hospitalization, I’d bet unilateral nephrectomy
would be a consideration. That’s what we did. He was transferred to surgery
at the time of admission, his blood pressure
was nearly normal. Because of the demonstrated
full compliance and the lifelong need of
anticoagulation and if we entertain the thought
revascularization for the kidney it would be stuck
with Warfarin and if stented, two antiplatelet agents that’s
quite tricky for someone not all that compliant,
to put it mildly. Again, the contribution of
the left kidney to the renal function was
minimal so, by the way, it was difficult to
convince the surgeons. I’ve never run into such a
case where I had difficulty convincing a surgeon
to perform surgery, but that probably deserves
a different discussion. A successful laparoscopic
nephrectomy was done and blood pressure came down and
without antihypertensive therapy. Electrolytes normalized,
Albumin remained normal, and ACR
decreased even further. Now we have the pathology
and some medial hypoplastic changes can be seen in the
artery glumiloising reasonably preserved some
balance space enlargement. However, there is substantial
interstitial inflammation as you can see, almost the
lymphatic follicle forming in the lower part of the figure. You can see it is reasonably
consistent and that, again, the glomeruli are … I missed. Something disappeared. Silver staining showed minimal
periglomerular fibrosis but no capillary thickening. The pathology report
said the kidney was small, we knew that. Unremarkable vasculature
and stump of ureter. The capsule was
easily removed, ruling out a variety of
inflammatory diseases. Parenchymal slices revealed
well demarcated and separable cortex and medulla. On microscopy, there was
interstitial fibrosis, remarkable tubular atrophy. Glomeruli was not sclerotic. There was some thickening of capillary
walls and mesangial abundance. There was no clots within
renal blood vessels and the pathologist concluded it
is consistent with chronic ischemia, which
is what we found. The patient didn’t show up
for hypertension clinic. He claimed, I don’t
know if this was true, that because his blood
pressure was normal, he could not get a referral. I won’t summary here, all the things
that I think are pretty straightforward. However, hypokalemia is readily
explained by hyperaldosteronism. However, the
hypernatremia is not. The hypernatremia was
very repeated finding. There’s no such textbook
feature of renovascular hypertension, however,
angiogensin on one hand promotes cellular absorption
and on the other hand, it is dipsogenic. This could be a possibility
of the similarities did not support a excess of ADH because he
had diluted his urine very well. The sodium and renal
were low, probably, he had the mark pressure
not raising to account for that. However, these things have been
described in several case reports. Hyponatremic
hypertensive syndrome was suggested here and there. I think mostly in pediatric
cases and one of them, that was published in
hypertension almost two decades ago, collected 39 such
patients and please note that the plasma and inactivity
and plasma aldosterone are algorithmic, not
a linear scale. You can see that in the shaded
area were the people who had normal electrolytes
and in the open area, were those who had
hyponatremia and they all had very high plasma
renin activity. Plasma
aldosterone was also high, but if we recollect that in
primary hyperaldosteronism, if anything there’s a tendency
for hypernatremia probably, it’s the secondary effect. However, what the hell has got
nephrotic syndrome to do with neurovascular hypertension? Proteinuria may happen when you
have prolonged hypertension, but is usually mild, certainly
not nephrotic range and certainly not such massive. Usually, when there is heavy
proteinuria it originates from the non-ischemic kidney,
maybe AII dependent and is ameliorated by
either revascularization, ACE inhibition, and
so forth and so on. Blood pressure lowering, per
se, can also do it. I’ll skip and try to tell
you in the Jewish scholarly tradition rabinical
tradition there is a saying that doesn’t
translate very well, but if you give all the
credits or cite properly as if you brought
salvation to the world. Let this be my contribution
to salvation of our world. Doctor Halimi, Ribstein, du Calilar, Mimran
in France have observed such patients with renal vascular
disease and compared … and massive proteinuria,
compared them to those with
glomerular diseases. What they found is that
after a Captopril challenge, those with renovascular
disease have a decrease in the GFR had the decrease in the
renal plasma flow and a marked increase in
plasma renin activity, indicating that, all of
those had occluded arteries. It’s not only renovascular
hypertension if you wanted some more extreme
variety of those. Others also from France,
prompted by the previous publication looked in
their database and found … it’s not very handsome
table, but what they found was predictive massive proteinuria
was not only renal artery occlusion, but also a big
discrepancy between the two
kidneys. In other words, an indication that
the contralateral kidney was normal. This probably allowed for
the massive proteinuria as the contralateral kidney
decreases presumably because of a reduced function. Also, it’s ability to
excrete protein is reduced. I think in the
interest of time … We’re coming to an end. There is a comment from this
microphone and I have one too. Please, first, the
comment on the microphone. I’m Varun Gaur from
Indianapolis, Indiana. Just one comment, there have
case series published with antiphospholipid antibody
syndrome associated with membranous nephropity so,
that should be kept in mind in future if a patient presents
with proteinuria that of nephrotic range and somebody
who has antiphospholipid with antibody syndrome. Absolutely. There was a study published
a few years ago in Current Rheumatology Reports, which
shows a wide range of renal manifestation of
antiphospholipid syndrome. Some of them could have been
relevant but I think there’s no question, what was the
pathophysiology in our case. Yeah. My comment is that of course,
the renal artery stenosis is a disease that progresses. It’s not in one moment. Of course, you
did nephrectomy, but we don’t know what’s going
to happen with this other kidney and I have seen similar
case where everybody was very happy and
everything came through, but then things started going
wrong in another kidney and then, of course, the only
treatment available is renal replacement therapy and things get
much more dramatic. I spotted that he was 37
when he initially presented, there are many, many years
for this other kidney to also be affected. I wonder if a
patient like that, for me, needs to be observed
and followed up in specialist clinic because
things might go wrong. Yes, but it didn’t work out. He didn’t show up
for the clinic. As a matter of fact, ten years
follow up by a phone call everything was
fine, but who knows? Was fine. Especially with a
noncompliant subject. I would like to raise a
question: given the rather benign appearance of the
nephrectomized kidney, maybe with hindsight, would
it have been better to try to revascularize
it, reimplant it? I don’t know? We’ll never know. No. We will never know. But I think there is a
suggestion coming there. Not necessarily a suggestion. But, I do want to go back to the
very beginning of this case. This patient presented with a
history of left flank pain. That should have been a tip
off that or could have been that something was going
on in the left kidney. Acutely. Now this patient presents-
That’s why renal vein thrombosis wasn’t a thing. Yeah. I think what was
happening, actually, was a slowly progressive
shutoff of intrarenal arcuate and interlobular artery flow
as a result of this thrombotic process. That had been going on
for a long time, I think. Probably six months. Now you’re left with a very
small kidney that’s
nonfunctioning. In the highest renin secretion
comes from that kind of kidney. A small kidney, but it still
has to have some perfusion. A lot of times in a patient
with renal vascular disease from a main renal artery, that can
occur by collateral vessels that come into play. You may have actually, a total
shut off of flow by the main renal artery but collateral
circulation is still present so you get these sky high
renin and aldosterone levels. No question about it. Okay. I think we need to
move to the next case. Last quick comment. Just have to ask one question. Do we know anything
about his family history? Yes, there’s no relevant
family history like with any type of history it
depends on the historian. Yes, on this very,
very positive note. Thank you very much. A fascinating case.