Drug Resistant Hypertension: An Intriguing Case
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Drug Resistant Hypertension: An Intriguing Case

August 31, 2019

– Good afternoon, to everybody. So, there is no conflict
of interest to disclose. Our clinical case is a
very long history that, it has a duration of 51 years. And it started in 1965,
with a right nephrectomy, and it ended 51 years later. So, the patient was a 64 years old lady, with a remote right
nephrectomy, that was referred for resistant hypertension, in 2006. So, the nephrectomy was performed for a massive hydronephrosis
and recurrent infection, when she was 23 years old. Her clinical history, so she
was referred for so-called drug-resistant hypertension while on atenolol and manidipine. She had no symptoms, an
unremarkable medical history, except for iodine contrast medium allergy, and for the nephrectomy. And she had a recent
detection of 50% stenosis of the left renal artery at ultrasound. At physical exam, she had very
high blood pressure values, 211/87 mmHg, and she had
a harsh 3/6 ejection bruit at the base of the heart, so her Erb point and a systo-diastolic
bruit, all over the abdomen. Her blood tests were remarkable. I would like to highlight that
she had normal renal function and she had normal potassium. So, was this really, truly
resistant hypertension? As you know, all of you know, the Major Scientific
Societies’ recommendations for a resistant hypertension
diagnosis, advise to call a resistant hypertension
patient, who is not a target, on three medications. And one of these has to be
a diuretic, or should be a diuretic, based on the
AHA Hypertension Guidelines. And as suggested by the
ESH guidelines, appropriate lifestyle should be implemented. So, going back to the
patient, this was her EKG, that is pretty unremarkable. But her Transthoracic
echocardiography showed a left ventricular mass index increase to left ventricular hypertrophy with a normal end-diastolic
volume, and ejection fraction. And unincreased relative wall thickness, so it was a concentric hypertrophy. She showed also kidney damage. She had an increased urinary albumen excretion
of 325mg/g of creatinine. So, what would you do? What else would you like to know? How would you treat her? So medical therapy? Or left renal artery angioplasty/stenting? – I would maybe try to
check drug adherence. (laughs) – Yes, it’s a very good
suggestion, because it is very important to check for
that, and because we– – And I will not go easily
for angioplasty/stenting, if there’s only a 50% stenosis, also. – I definitely concur. Angioplasty is not warranted in this case. And I concur that nowadays
we should check for adherence in all patients with so-called
resistant hypertension, before giving them,
calling them resistant. – Was this lady a smoker? – [Dr. Giuseppe] No, she was not. – And did she have
peripheral vascular disease? Or signs of peripheral vascular disease? – No, no other signs of
peripheral vascular disease. – That’s it, well if
you put things together, she has a mono, you say
it’s only one kidney. [Dr. Giuseppe] Yes. – She has a deteriorated
renal function, and– – [Dr. Giuseppe] No. – And high blood pressure, so she should have renal
artery stenosis, as probably shown on the echo, but
you have to be sure, by other diagnosis, that that is the case. And probably, her high
blood pressure may be associated with heart failure,
as seen in one kidney, with the stenosis. So, and having said that, I wonder what the cause of
the bruit was, on her heart. You didn’t show it on the echo of the, did you see abnormalities
of her aortic valve? – She did not have stenosis. She had thickened aortic valve, so she had aortic sclerosis. No, no stenosis, and she
had a normal renal function. Her renal function was– – Maybe because we’re
coming from the same clinic, I have a question in the same line. This patient has a one
kidney, one clip situation, and that would lead to
very high blood pressure and deteriorating renal function. Still, she is very hypertensive,
in the face for instance, of using atenolol. Did you consider the
possibility of Pheochromocytoma? – Yes, she was screened
for that, and her urinary, 24 hours urinary
metanephrines were negative. – Did you do a 24 hour
blood pressure monitoring? To confirm that this is not part of it, effect of white coat? – No, this was not a white coat effect. We did an ABP, 24 hours ambulatory blood
pressure monitoring, and it confirmed high blood pressure, systo-diastolic high blood pressure. – What was the size of the left kidney? – Actually, this is a good question. It was, we can show it later. It was normal, though. – [Pr. Bursztyn] It was? – Normal. – Well, you would expect
for someone to have had a single kidney, for 20
years or something like, or 40 years actually, that the kidney will be hypertrophied. Having what you call normal-sized kidney, suggests to me strongly,
that there is a stenosis. A functional stenosis, otherwise, the kidney should have
been well hypertrophied. – This is a possibility,
so we went further with diagnostic and studies. – Did you measure renin and aldosterone under stenodized conditions? – No, because she was
on, so when she was, when we saw her the first
time, she was on atenolol. And she had really very high,
really high blood pressure values, so we thought it was
dangerous, to try to keep her on washout, so on the
channel-blockers and Doxazosin, to screen her. So, our point was that ,
screening a patient with other drugs, like Hydrochlorothiazide,
or ACE inhibitors, or ARBs, which will increase
renin, will not give us reliable information in this case. And, we thought it was dangerous
to keep her on two drugs. [Coordinator] We need to move
on with the case, I’m afraid. So, if we could have very brief comments. This lady has more secrets
to reveal, I think. – Upon physical examination, were there any signs of volume overload, such as edema, or hepatojugular
reflux, for example? – No. – Because presumably, if that
was the case, and you correct the volume overload, her
blood pressure would go down, but, also her kidney
function would deteriorate with the renal artery stenosis. – Yes, that is– – [Dr. van Twist] No signs? – No. – Sharad Ratanjee, Australia. Just two things, this patient
is not yet drug-resistant, because you only got her on two therapies. You don’t have her on a diuretic. Secondly, the best
treatment for her, would be and ACE inhibitor. But, before instituting
that, would you consider doing a Captopril renogram
to look at functional, you know, whether the
stenosis is functional or not? Because with the Captopril
renogram, if you get a reduced perfusion, that will show that the stenosis may be functional. And you may be more careful
about using an ACE inhibitor. – Okay, yes. – [Coordinator] I think it’s
time to find out what you did do, before having what you might do. – Yes, so, well I definitely concur. – So the attending physician increased the anti-hypertension
therapy, adding ramipril. However, he was worried
about her renal function, because she had only one kidney, with a reportedly stenotic renal artery. And therefore, he ordered
careful monitoring of the GFR. And her blood pressure
values were thereafter adequately controlled, and
renal function remained normal, with the medical therapy. And therefore, the lady did
not show up for three years. So, she showed up again in 2009. She verbally reported that
she did an MR angiography, and her left renal artery stenosis was described as unchanged. A CT was unfeasible,
because of the allergy to the contrast medium. And then she did not
present again, until 2011. At that point her blood
pressure was high, very high, while on Ramipril. And she presented with a
renal Doppler ultrasound, that showed an unchanged
level of renal artery stenosis of 50%, with a high resistivity
index of the left kidney, and a fistula, involving
the right renal artery. So, a new MR angiography
was ordered at that point. So the patient actually
did not undergo the actually underwent the MR, but
did not show up for 5 years and her physical exam was unchanged. Still very high blood pressure,
and this time she on very important medical therapy. She was on atenolol, lercanidipine, hydrochlorothiazide, amiloride, and valsartan. And here, you can see
(mumbling) Lancisi’s sign. You can see that the high
pulse pressure of the patient showed here, you can see it here. So you can see the carotid
pulse of the patient. The MR angiography showed,
actually the report of the MR angiography, reported
the right arterial stump, 7mm of diameter, connected through a large arteriovenous fistula, 40mm,
to the inferior vena cava. But the MR angiography images
were still unavailable. So, what would you do? [Coordinator] Any suggestions? – Okay. [Coordinator] Would you like
to, would anybody like to test– (crosstalk) – To bring the cd with the images. – One possibility is to
consider re implantation of the kidney, to the artery. – Re implantation? – Surgery. – I said surgery. – Surgery to re implant
the kidney into the artery – Okay. – To make a bypass, I
think that’s what he means. – Well, I think the
previous discussant meant, to make a bypass of the
left renal artery, but. – Why? – Why, okay. – Oh, so– – That’s not my question. What should I do? It was your question. And I would give her a loop diuretics, because she has a
decreased renal function. You’re using, no – [Dr. Maiolino] No, she did not. – Okay, I seem to have that in my mind, but, well then the issue
is not a loop diuretic. – A few years ago there was
a study on the Rox coupler which was an artificial fistula between the arterial end
vein, resulting in a drop in blood pressure, in fact this is a natural variation of the (mumbling), I guess. So, please explain me, why is
the blood pressure so high? – Not very successful. Not very successful AV
fistula, in this case. – Why is she hypertensive? I don’t understand that. – Well, maybe we will talk
later about fistiopathology. – Can I make just one comment on this? – Yes. – You showed the treatment
was supposed to do, with seven pills a day,
if I counted correctly. My questions I would try
later, in the hospital, and try to give her the
drugs under control, one way or another, because for a patient that does not show up for five
years, does not show up for three years, as in the likelihood
that she takes nothing, or very little of what you
prescribe, I think it’s probably one chance on two. So, I will probably do
that before anything else, since it’s quite a difficult
situation for the kidney, and for we could do any
operations, or whatever. But, be sure that she
takes what you prescribe. – Yes, I concur. As we mentioned before, like a resistant hypertensive patient, 30% of the so-called resistant
hypertension patients are actually not adherent,
very good comment. – [Anna] Okay,
could I make additional, more sort of technological comment? I am surprised that in fantastic
academic center in Italy, you need to bring your MRI on a cd. I thought that we are progressing with precision medicine and digital
radiology across Europe, and that these type of
investigations are accessible to physicians , and we
don’t need to do what’s happening in United States,
where the patient goes with his x-rays, in to the doctor, because insurance company wouldn’t share. So, could Professor
Rossi explain this to me? – Of course, Anna, now we
have all the radiological examinations in the system, so this issue is no longer there. But, as you saw, this
case lasted 51 years, and she had the first MR many
years before, and moreover, she didn’t want to come to
Padua to have the tests, because she lived in the
eastern part of Veneto region, and so she preferred to have
her MR angiography done there. And she didn’t bring the
cd until she was pushed to bring it. – Okay, you’re excused. (laughs) – I didn’t see electrolytes
in the last few visits. Because I thought that in the first time, she had 3.6 potassium,
which is a little bit low. You said it’s normal. What happens to the electrolytes
during the follow-up? – The blood work was unremarkable. It did not change significantly. You have anyway to take
into account that of course, she was on hydrochlorothiazide,
but then we added ARB, and we added amiloride, which is supposed to increase potassium. So, it’s not unexpected her potassium is still within normal range. – Can I make a proposal that
we move to take a look– – [Coordinator] Yes, that’s exactly what I was going to suggest. – To the MR angiography,
because when I saw it, I was shocked. – So, she brought her cd. At that point, she was on
atenolol and lercanidipine, because the valsartan
had been withdrawn by her primary care physician,
for unknown reason. Again, blood pressure very
high, and physical exam that isn’t changed. And so we took a look
at the images of the MR. This is the fistula. It is very, with a very huge
diameter, 4mm , and here, you can see the other part of the fistula. And here you can see
the inferior vena cava. And these are the images,
right renal artery, and this is the fistula. It has two parts, and then it drains into the inferior vena cava. So, the reason why this
happened, is probably, well the Radical
Nephrectomy she underwent, her Radical Nephrectomy
as we said, in 1965. So, at that time, the surgeon
clamped the renal artery and the renal vein
together, with a technique, or (mumbling) technique. And this is the reason
why she developed later, AV fistula. So, at this point, what would you do? Would you schedule a follow-up visit? Would you consult with a vascular surgeon? Or, would you consult with an
interventional radiologist? – [Coordinator] I think the answer is yes. Why don’t we move along? – Okay, so we move forward. We consulted a vascular
surgeon, who gave an unequivocal indication of the AV fistula, because of the high risk of rupture with ensuing fatal hemorrhage. However, I felt the procedure
was a very high risk, so we consulted the
interventional radiologist, who gave an indication to
percutaneous embolization. So, we admitted the patient on April 2016, to proceed with percutaneous
AVF embolization. But, due to contrast
medium allergy, the patient underwent prophylaxis,
according to guidelines, with methylprednisolone, diphenhydramine, ranitidine, because it’s
required in the protocol of our hospital. An anesthesiologist was
present in the CT facility. So after the injection of the
contrast medium for the CT, she underwent an anaphylactic reaction. And the patient was treated
according to guidelines, and she had a swift recovery. And these are the images of the CT scan. And you can see here, is the aorta, her right renal artery, and this is the fistula, here. And you can see the other part, here. So, at this point, what would you do? Would you do a conservative
approach with medical therapy and follow-up? Or an aggressive approach New vascular surgery consult? Or reschedule the patient for
a new percutaneous procedure? [ Coordinator] I don’t think you’re gonna get any help from the audience. So, why don’t you tell
us what you decided? – We rescheduled the
patient for a new procedure. The patient recovered and was
discharged in good health, however, she was very scared,
because she was now aware of the high risk of rupture
of her arterial venous fistula. But also, of the high risk
of the surgical correction. And moreover, she was scared
of the new interventional procedure, because of her
allergy to the contrast medium. Therefore, she was scheduled again, for the percutaneous procedure. However, we decided to exploit the use of carbon dioxide, as a contrast medium. When we admit her again in
October 2016, she had again, high blood pressure on
important medical therapy. The arterial venous emolization procedure was
performed in the angiography suite, with anaesthesiology support, under local anesthesia. These are the images. You can see here the renal artery. This is carbon dioxide, and
you can see here, the fistula. Here, here, and then the
interventional radiologist deployed (mumbling)
device, 14mm vascular plug, (mumbling) device, and you
can see here the angiography at the end of the procedure,
is the (mumbling) device. And the fistula is closed. So, her blood pressure
was this at admission, and at discharge, was 125/75 mmHg. On the same therapy, hydrochlorothiazide, amiloride, lercanidipine, and valsartan. After one month, she was
still normotensive, with lercanidipine and valsartan, only. A few months later we
checked for the occlusion of the AV fistula, was
confirmed in the contrast enhanced ultrasound. And her last follow-up
visit was in January 2018. She was still normotensive
on the same medical therapy. Any comment? – [Coordinator] While you’re
coming to the microphone, this lady was initially diagnosed with left renal artery
stenosis with an ultrasound, and presumably Doppler. I can’t imagine that a fistula like this, could be missed at that time. She didn’t have cardiac
dilatation, at that time, which you’d expect to see in
someone with volume overload, like this. So, what do you think has
happened between her initial presentation many years ago, and now? – What do you mean, like why the blood
pressure was uncontrolled– – Yeah, I think there
are two explanations. One is, it was missed and
it’s gradually progressed. The other is that something’s
happened in the meantime, to create a lesion like this. Anyway, I don’t think we know the answer. Maybe we’ll get some– – Well, it is difficult to
say exactly what happened. Well, probably what happens
is that the fistula is not fixed in time, so it progresses with time, and it increases in fluid, and this affects the
cardiovascular system. Despite we did not see
LV dilatation, later on. – Well, the only explanation
I have to your question, is perhaps the local hemodynamics changes, after the closure. Perhaps maybe, what was
non significant to renal artery stenosis, in retrospect, was a significant renal artery stenosis, because of the flow, that
caused this flow to the remaining kidney. Otherwise, it’s a miracle. Why, after this procedure,
her blood pressure was well-controlled,
instead of seven medication, only two medication. So, maybe local hemodynamic
changes cured her. – In fact, if you look carefully,
at the very first image, that you saw of the fistula,
the aorta downstream at the fistula, was like
tortuous and funneling, consistent with this idea. The other explanation we had, is that she developed nephritic
sclerosis in the remnant kidney, and the 50% renal artery
stenosis hemodynamically was totally irrelevant to that. – Just another hypothesis
in accordance to what Professor Burnier asked earlier. Could it be that the patient
started taking her pills, after she had this intervention? – Well, of course it is a possibility. – And I still don’t
understand why her ROX coupler results and her blood pressure results decreased, and this patient, we do
exactly the opposite. – Well, we can go through
the ROX coupler later, maybe. – Along the same line as this. A lot of data from, especially
the surgical literature, that when you clamp an AV fistula, there is an immediate
rise in blood pressure. So, why, did you see any
changes during the operation, that could provide an extra
argument, that the fistula is responsible? – Well, actually the blood pressure dropped pretty quickly,
after the closure– – But what happened when
the AV fistula was clamped? – With the (mumbling) device? – With the blood pressure. – Yeah, what happened
with the blood pressure, yes as I said, the words are
decrease of blood pressure, basically something like that. – Immediate? – 10 minutes, not immediate, 10 minutes. – How do you explain that
in view of the literature increases in blood pressure,
when you clamp the fistula? – Where did you see that? Like if you clamp a fistula,
you will have an increase in blood pressure. – You have an increase in blood pressure. There’s a lot of data from the surgical literature showing that. – Well, if you can see the data for, okay. – Okay, just one hypothesis
on the current one, you did not do hormonal
examination, and I do not understand how we could not
do it, even if the patient has an important
hypertension, we try to do it. There is something really important. Is there a renin secreting
remnant, that could be related to the vascular, to the vessels that
stayed in the organism. I mean there was a part of the kidney, that was in this, related to this fistula, and that could have been
secreting renin, for a long time. And it could be a
renin-dependent hypertension. This is why after excluding the lesion, her blood pressure dropped rapidly. This could be a hypothesis,
but unfortunately, we don’t have hormones. – Yeah, but unfortunately
if we did the hormones, they will be unreliable, too. – Petramala, from Rome, congratulation. Did you control, or did you remember that the urinary excretion of albumen after treatment of fistula? – No, no. – I’m sorry, but I have
another point which puzzles me. We know from patients with AV fistulas, like patients with beriberi or Paget’s Disease, that they become volume overloaded. Now, you explicitly
stated that this patient had no signs of volume overload. How do you explain this? – Maybe with our, well it
depends what do you mean from volume overload? If you mean that she
did not have left volume increase, she did not
have left volume increase. But, she probably had a volume overload that was subclinical, probably. – But if you have experience in patients with beriberi, for
instances, or other types of Paget’s Disease, you always
find some degree of edema. – Well, I think it depends
Peter, on the stage when you see the patients. And actually, this lady has
a normal systolic function, as Doctor Maiolino pointed out. She had a normal ejection fraction. And it depends also very much,
on the size of the fistula. Obviously, she had a kind
of hyperdynamic circulation, and eventually, she would go
into high blood heart failure. So that was another reason of concern. About the adherence to
treatment, I think she was really adherent. And in fact, we have a clue to that. And that is that in the
EKG, she had bradycardia, because she was on atenolol, okay. And with this type of hemodynamic picture, she should be expected
to have tachycardia. – She certainly had a huge
pulse pressure, consistent with a significant AV stenosis. Yes, final point. – One hypothesis could
be a still of the fistula on the left kidney. When we see the left kidney
on the CT, we observe a very small renal artery. And with probably a schema left kidney, and when you close the fistula, there is a good perfusion on the left. – This is of course a possibility. There is a paper published by Kung, in American Journal of
Physiology, in 2011, on a rodent model of AV fistula. And they demonstrated that basically, if you create a fistula, you will have a decrease, increase in compliance in the rodents that have a fistula. And an increase of blood
flow, you will have a decrease of renal blood flow, with an increase of renal resistance. So, this was published in 2011, in the American Journal of Physiology. And it was a group of Mayo Clinic. So, it actually gives
support to your theory. [Coordinator] Thank you. Would you like to finish
your presentation? – Yes, so our take home messages, are that guidelines do not
always warrant a safe solution. And the use of carbon dioxide
instead of iodine contrast dye is feasible in allergic patients. Secondary forms of hypertension
should always be ruled out, before accepting a diagnosis
of resistant hypertension. And AV fistula can go
overlooked for years, and result in target organ damage. Resistant hypertension can
be due to an AV fistula. And it’s closure can, might
resolve resistant hypertension. And, is this consistent with
data from the literature? And of course, as you
pointed out, it is not. It is not, because as you
pointed out, there is the Rox Control Hypertension study, that was published from Lancet, in 2015. This device is the Rox Coupler. It is the device that creates
AV fistula between the iliac artery and iliac vein. And the conclusion of the others are, that the AV fistula is a associated with a significantly
reduced blood pressure. So, these are the data. Six months data, this
was published on Lancet. You can see here the change
from baseline at office blood pressure, systolic,
diastolic blood pressure, reduced. And reduction also of the systolic and diastolic blood pressure,
at 24 hours ambulatory monitoring, that was not
seen in control patients. And here you can see
the data at 12 months. Again, reduction at 24 hours
ambulatory blood pressure monitoring, of systolic and
diastolic blood pressure. So, there are some words of caution, that we can get from
the Rox Control trials, among others. There was no systematic
screening for secondary hypertension or therapeutic adherence. And it was open label, no blinding, and no sham control group, which we know is pretty important in this intervention trial. And there was not very
low rate of complication, and follow-up is short term. So you have to, all your consideration, that came out in this
discussion, are appropriate, obviously. All your concern are
appropriate, but what we need to take into account,
this Rox Control Trial, has a one year follow-up,
and maybe, maybe not, maybe the difference is that our case is a 40 years old fistula,
the effect of 40 years of having an AV fistula. So, the provocative last question is, I will refer my patient with
drug resistant hypertension for implanting an AV Rox Coupler. Or next time, I will search a high flow arterial venous fistula,
in my patient with resistant hypertension. I thank you for your attention. [ Coordinator] Thank you very much. (audience applauds)

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