CPC ESH2019 | Case 1: Resistant Hypertension in a Dialysis Patient


– Today we will present a
case of resistant hypertension in a patient with chronic kidney disease. The patient is a 41-year-old woman who first presented to
her GP almost 20 years ago with peripheral edema and lethargy. She is a lifelong smoker and is obese. Her past medical history is noted here. The reason for referral to the renal team was dipstick positive proteinuria in the context of a low serum albumin. Now as this case is from Scotland, the vast majority of
results we report today will be in SI units. In the context of a 24-hour
urinary protein excretion of almost four grams per 24 hours, hypoalbuminemia of 24 grams per liter, and clinical evidence of peripheral edema bilaterally to her knees, a diagnosis of nephrotic
syndrome was made. Her renal function and blood pressure were normal at this stage. Here are some of her
initial blood results. She is not anemic and has
a normal white cell count and inflammatory markers. However, her serum
cholesterol and triglycerides are markedly elevated. Immunology screen was negative as was blood-borne virus serology. Here we have some pictures of
this patient’s renal biopsy, from which she was diagnosed with primary membranous nephropathy. For your interest, on the
left there is evidence of glomerular basement
membrane thickening. On the right there is evidence
of granular IgG deposition, also typical for this disease. Membranous nephropathy is a cause of nephrotic syndrome in adults. And over 4/5 of cases are associated with phospholipase A2 receptor antibodies. Of relevance to this audience, hypertension is present in up to half of patients at the time of diagnosis. As I said before, this patient presented to our team around 20 years ago. At this time, management
of membranous nephropathy largely revolved around the treatment of blood pressure and proteinuria. In keeping with this,
this patient was commenced on an ACE inhibitor and loop diuretic. Here is a graph of the patient’s blood pressure readings
over the first six months. On the y axis is blood pressure
in millimeters of mercury and on the x axis is time
in months since diagnosis. The blue and red dots represent systolic and diastolic blood pressure
readings, respectively. The patient’s blood pressure rose over the first six months from
diagnosis despite a doubling in both the dose of ACE
inhibitor and loop diuretic. Although no longer routinely
practiced in the UK, the patient was also commenced on an angiotensin receptor blocker at four months to provide dual blockade of the renin-angiotensin system. The patient’s excretory function, represented here in red and on the y axis, remained within the reference range for the first six months. Despite this treatment, the patient remained heavily proteinuric. In keeping with this, and as can be seen from
the graph on the right, the patient was also hypoalbuminemic. So, to summarize, we have a
patient with clinical features of ongoing nephrotic syndrome with escalating clinic
blood pressure readings. For our first discussion point, is there any additional information you would like to know at this stage? What are the key factors driving this patient’s blood pressure? And are there any suggestions
for ways in which we can manage this patient’s
blood pressure at this stage? – Question, I have a first question. Why would you combine ACE inhibitor and angiotensin receptor blockers? All guidelines say no in
red, in very big letters. Why? – So, that is
an excellent question, Anna. So, this is, as we said, as Peter said, this case is from around 20 years ago, and it was managed by nephrology. At that time management of proteinuria, especially in the context
of nephrotic syndrome, was targeted at reducing proteinuria. And as you are all aware, if you, the best drugs to use for proteinuria in patients with renal
disease are ACE inhibitors or blockers of the
renin-angiotensin system. Now with an ACE inhibitor or an angiotensin receptor blocker alone you can reduce proteinuria
by around 30 to 50%. There is then an additional effect of adding in an angiotensin
receptor blocker of around 10, 20% on top of that. And that is partly due
to maximally blocking the renin-angiotensin system, although I appreciate it’s only then blocked with dual
blockade up to about 90%. But there is an additive
anti-proteinuric effect. I appreciate now we wouldn’t do these, we wouldn’t use dual
RAS blockade routinely, although you might use it in some patients. But this is a case from some time ago. So, I’m going to ask open
questions to you now. So, Peter asked what any
other information you’d like. So, you’ve got a lady in her
early 40s, nephrotic syndrome. – [Prof. Dominiczak] Microphone. – [Prof. Touyz] And please
remember to state your name. – I’m Dr Nademi from Iran,
interventional cardiologist. I want to know imaging data. Her kidneys. Sonographies, CT, angiography. – Sure, so you’d like some
imaging of the kidneys. So, this lady underwent a renal biopsy, so, she would have had ultrasound
scanning at that time, and the ultrasound scan was unremarkable. So, it did not show of relevance
any cysts, for example. And because we do Doppler ultrasonography we didn’t see any obvious signs of compromise in renal blood flow. At that time we didn’t
progress to a CT scan. – Yes please, sorry.
– Excuse me, what about, what about
renal arteries in evaluation including scan or angiography? – Yes sure, so we did an ultrasound scan with the Doppler ultrasound scan, and so, with that we could see that there was intact flow to the kidneys, although we didn’t progress
to formal angiography. So, any other information you’d like? – Marcin Adamczak (voice muffled) Poland. I’ve got one remark,
so, you used furosemide. Patient has got normal kidney
function at this stage. So, from the antihypertensive properties, first of all you should use thiazide or thiazide like diuretics. – Torsemide, did you say?
– Thiazide or thiazide.
– Thiazide, sorry. – Furosemide or torsemide,
but also, always also in combination because the antihypertensive
effect would be better. Furosemide is not very good
on the hypertensive drugs, even in this patient. If you have good kidney
function you should start with the thiazide or the
thiazide-like diuretics. – So, in– – Sorry, go on.
– First remark. And second question, what are the treatment
of underlying diseases? What is the treatment? Steroids, tacrolimus
(voice muffled) started or you are just waiting? There was a question and
solution about treatment. – Okay, so in response
to your first question about the choice of antihypertensive, so, this patient had nephrotic syndrome. So, certainly in the renal community, and I accept there may well be differences between what’s practiced
in the UK and the US and even in other parts
of Europe, Australasia, but in the setting of nephrotic syndrome we would probably choose a blocker of the renin-angiotensin system first, so probably an ACE inhibitor. In terms of management alongside
this of peripheral edema and fluid overload in the
context of nephrotic syndrome, we would probably choose a
loop diuretic first of all just by virtue of the
percentage of sodium blocked, sodium channels blocked. So high ceiling diuretic, loop diuretic would be our first choice. And then we may well go on to
additional thiazide blockade on top of loop diuretic treatment. In relation to your second question about the treatment of underlying
membranous nephropathy, so, this case was from 20 years ago, and at that time, I think,
even nowadays I suspect, for membranous nephropathy,
the kind of standard of care is you probably give
them a six months’ wait to see nonspecific treatment. So, we’re still within
that six-month period. I accept that you may use other agents, which we shall come onto, and– (voice muffled) Sorry? – [Prof. Touyz] I’m just asking if
there was another question. – I’d like to have 24 hours
profile in the patient. And the, so the first thing. And then why you don’t add
calcium channel blocker. – So, I think those are
excellent suggestions, and I didn’t show you
the slides beforehand, but with that I’m going to
hand back to Peter. – Can I just ask you–
– Oh yes, of course. – One question before you move on to the next part of the case report? So, it was interesting that
as you added more drugs the blood pressure went up. I’m going to ask you about the doses of the drugs that you used and particularly with
respect to candesartan, because in the late 1990s
there was this concept about us probably using
doses that weren’t optimal. And there were some large studies that were done by Ellen
Burgess, actually from Calgary, particularly with candesartan where I think she went up to 32 milligrams and found really very significant effect, especially in renal patients. So, I’d be curious to know if you would have considered that at this point. – So, actually super therapeutic doses of angiotensin receptor blockers
were in vogue at that time. And actually, I think, I
still think in the UK the top licensed dose of
candesartan is 64, I think. I might be wrong about that. I think in this patient we
went to 32, 64 milligrams, but we didn’t, there
was some data suggesting you could actually go as
high as 128 milligrams, which we didn’t in this patient. I think some people feel
nervous about combining an ACE, an ARB in renal
patients in particular, because when you have nephrotic syndrome you have a state of
intravascular volume depletion. So, when you have duel RAS
blockade of that degree, all you need is a hit
like diarrhea or vomiting and that can precipitate
acute kidney injury. – Thank you. – [Prof. Dominiczak] There was another question. – Sorry.
– We didn’t talk about the second point, what factors are contributing to her hypertension. Yeah but we didn’t talk about her obesity. This patient is obese. She has a renal disease. She has a protein, a major proteinuria, and nephrotic syndrome,
so, she has three factors that are impending the
(voice muffled) of her blood pressure. So, these, all of these factors should be treated in this patient. Moreover, for strategies, we have data. We have data comparing the RAS blockade versus nephron blockade. And we know that patients
with chronic kidney disease, blocking the nephron by–
– Sequential blockade– – Sequential blockade
with different diuretics, as my colleague say, could be more, have more potential to
decrease blood pressure in this patient compared to RAS blockade. But combining both of them
would be also suitable, I think. – So, I’m just going to
agree with all of that and say that we’re only
at six months so far, so, we will get to some of, cover those points in just a minute. – Perhaps we’ll progress the case and then we can bring up more
discussion in a little while. – So, thank you for your comments. So as was suggested, 24-hour
blood pressure monitoring was conducted and
confirmed that the patient did indeed have sustained hypertension throughout the 24-hour period without the expected 10%
dip in overnight readings. The patient’s 24-hour
urinary sodium excretion also suggested that her dietary
salt intake was very high. Both ECG and echocardiogram
were normal at this stage, and there were no
abnormalities on fundoscopy. Serum and urinary
cortisol were also normal as were urinary metabolites. Broadly, general factors contributing to this patient’s hypertension include underlying essential hypertension, her adherence to her
antihypertensive medications, but lifestyle as has been pointed out, is also very relevant, especially given we’re from Scotland. For example, we know the
patient was overweight, did not exercise, and consumed a diet relatively high in salt. In terms of factors specific to the underlying membranous nephropathy, her persisting nephrotic syndrome will also lead to ongoing
salt and fluid retention through activation of the
renin-angiotensin system. There are also the effects of
inflammation and autoimmunity. And all of these factors combine to contribute to vascular stiffening, accelerated atherosclerosis, and so worsened hypertension. And there were some excellent suggestions regarding a treatment strategy. What we actually did in the first instance was maximize the
angiotensin-receptor blocker, and thereafter, attempt to
introduce a fourth agent, namely amlodipine. Unfortunately, full dose
amlodipine was not tolerated by the patient due to
worsening of her leg swelling. Whilst atenolol was contraindicated due to the history of asthma. Consequently, the patient was
commenced on the rate limiting calcium channel antagonist verapamil. However, as can be
appreciated from this graph, it made little impact on the patient’s clinic blood pressure readings, which continued to average
between 160 and 170 systolic and 90 to 100 diastolic. The patient’s excretory function started to decline after about six months after her initial diagnosis with the estimated
glomerular filtration rate dropping from around 45 to 25 in one year. Perhaps unsurprisingly the patient continued to have heavy proteinuria and remains hypoalbuminemic
with an albumin mostly in the range of 15 to 20. Bloods at one year also
demonstrate a new anemia, most likely as a consequence of the declining renal function. Here is a summary of
the patient’s treatment and investigations at 12 months. Are there any suggestions
regarding a management strategy for the patient’s
hypertension at this stage? – Yes, please. – You mentioned in your earlier
slide about the salt intake, which is very important factor there because if patient, I mean if you’re doing all this treatment and patient is on a high-salt diet, you’re not going to
accomplish much progress. And it kind of leads me to the question, I mean, is clinically patient also (voice muffled) nephrotic, she’s very edematous, and
maybe the diuretic dose is not sufficient yet. I mean, if she’s volume overload you can throw six, seven blood pressure and you’re not going to
make much progress there. – So, I, I mean I absolutely
agree with your comments. And as I’m sure this audience is aware, reducing salt intake, per se, actually has an excellent
antihypertensive effect, it has a significant
antiproteinuric effect. So, if you reduce salt intake to less than, if achievable, less than
three to four grams per day, you can reduce proteinuria by about 25%. But I absolutely agree
that trying to target these general lifestyle
factors is very important. In terms of the diuretic
dose, I also agree. I mean, certainly in renal circles we’re not scared to
give doses of furosemide up to 500 milligrams a day and to them that we think about
adding sequential blockade of sodium output. – You said, you showed that she
was a non-dipper, no dipper. – [Dr. Dhaun] She was a
non-dipper, that’s right, yes. – What about sleep apnea? – Sorry–
– Polysomnography, sleep apnea.
– Oh, sleep apnea, sorry. So that’s a very good question, actually. Now I remember this patient very well, and she was of the clinical phenotype that would, yes, she’s, so, she had, for example,
she had a big neck. There was no doubt… I mean, she snored at night. I remember this. She came in, she was tired. And I suspected a lot of these factors, I mean, although we never
diagnosed sleep apnea I’m sure she did have sleep apnea. If we did the Epworth Scale she would have a number greater than four. I’m sure that it did contribute to, I’m sure that did
contribute to some of her adherence we have not talked about, but her dietary and her lifestyle. And indeed, hypertension. – So, the patient has (voice
muffled) progression. First of all because of
the concerning salt intake, what kind of advice was
given to the patient? – What kind of advice did we give? Yeah, okay. So, that’s a very good question. So, in renal clinics,
as I’m sure many of you who have these clinics,
we have dietary inputs into our renal clinics. So, we will give them advice
on how to reduce salt intake, how to use alternatives to salt, not adding salts, not eating white bread, not eating processed meats. So, a lot of these patients will get specific dietary input. The problem we have in Scotland, which I’m sure is not
peculiar to Scotland, is that many of these
patients will not adhere to the diets prescribed. – I mean, it is not
enough to say to patient to eat less salt but is necessary
to avoid processed food. So, which is the most important, 85% in diet is from the processed food. So that’s why this instruction
would be more complex. Not just (voice muffled)
don’t use salt additives. Just reduce and replace
this, so this first point. Second, this progression of
this patient is still ongoing, so, would necessary to urgently
reduce blood pressure. What we can do, we can
give calcium blocker, but maybe another one, (voice muffled) which doesn’t give peripheral edema. We can give something of doxazosin, especially in this patient–
– Excellent, excellent, yes. – With the non-dipper will be perfect because we can start in the evening. The dose in the evening to mimic this physiological dipping pattern. So, my suggestion is, on every visit discuss about salt intake, start doxazosin from the small
doses and then escalate this, and maybe try another
calcium channel blocker. – So, those are all excellent suggestions. In just some brief comments
before you will see what actually happened, doxazosin, I think it’s a great drug, it works well. Chronotherapy, so this case
is still about 20 years ago, so, the kind of, the importance of diurnal blood pressure variation
and its links to outcome, I don’t think were as well known then. So, the concept of chronotherapy, that is giving some of the
blood pressure tablets, even one at night where
you can then enforce a nocturnal dip in blood pressure, improving outcomes probably
wasn’t as well known, certainly not in renal
circles at that time, and reinforcements at each clinic visit about not eating processed food, one of the things, perhaps,
we’ve not brought out is that attendance at clinic
wasn’t necessarily perfect. – [Prof. Touyz] Please, yes. – Marielle Krekels from the Netherlands. Maybe I missed it because
everybody talks very fast, but what did happen to her weight when you installed the furosemide, because I think if she didn’t lose weight the first thing I should do is rise the loop diuretic. – Yes, so I think that’s
an excellent point. So, her weight, so, the weight, as I’m sure you appreciate so that the assessment
of fluid balance is done, weight is an excellent example provided. You do it on the same scale, same time of day, same clothing. I mean, at the renal clinic she came to the same renal clinic so
weights were probably reliable, weight was rising alongside
the clinical assessment of increasing peripheral edema, hence the rising dose of furosemide. And also, as renal excretory
function was declining the likelihood of the
similar dose of loop diuretic in isolation working
and actually getting rid of that fluid would be less likely. So, you’ll see what happens in just a bit. – So, could I ask two additional questions? First of all, you’re now
giving her lots of drugs… Don’t go away. You’re giving her lots of
drugs, lots of everything, and you’re not having effect. Have we checked the adherence? Because if the patient is
not coming to the clinic and takes so much salt
despite your advice, I am getting suspicious,
that’s number one. And number two, the six months, the magic six months of
nephrology have now passed. Is the process in the kidney
getting very, very severe? Are we now not just idle
membranous nephritis? Is that becoming some
rapidly progressive story? – So, in response to the adherence issue, I think we all thought about
adherence being an issue, as reflected by a lack of
100% clinic attendances, weight going up, and
actually, drugs not working when these drugs work for
the majority of people. So, she did have one or two admissions where we had to bring her in
for intravenous diuretics, trying to get the weight down, and we were then giving her the tablets. So, we knew we were giving her the tablets, unless she was hiding
them and putting them beneath her tongue and not taking them, but we knew she was taking
tablets in hospital, we were giving them, and
so, on observed dosing the blood pressure remained high. And in response to the
second question about are we now reaching a point
where the renal function decline reflects underlying worsening
of intrarenal disease, in this case membranous
nephropathy, absolutely. And we shall see what happens in a second. – For treatment, I think
that now the next step would be not to increase, my colleague suggested
to increase furosemide, but I think we should add now a thiazide and after an (voice muffled) blocker, why? Because we have this less nephrons for treating the same salt load. So, using one site blockade would not be sufficient in this patient. The second thing, I think in 2019, I would add rapidly a GLP-1 antagonist to help her to lose weight and to improve her renal function. We have data now. And it is usually in this
patient to lose rapidly weight and to control her blood pressure just to save her kidneys. This would be the ideal
strategy for me. – I mean, I think the
temporal nature of this case from being such a long time ago, I think management now would
probably would be different, you’re right. – So, I just want to add, so, I agree with some of the suggestion. However, this patient has
been on a lot of medication, and still seeing about
the primary process. So, we know that she has a
severe nephrotic syndrome. She has significant
proteinuria, low albumin, and so, by definition her
blood pressure is driven by heavy salt intake and all the edema. So, should really you have to think about primarily controlling the volume. Second is controlling the
underlying condition and disease and how do we treat the
underlying membranous nephropathy. And as a nephrology, I
failed to mention that because we have different specialists here, but as a nephrologist, as the kidney function
has declined very quickly, and you have to think about is there, with a severe nephrotic syndrome could it be some renal vein thrombosis contributing to her picture as well? – So, I think just in, I mean, I think those are all excellent points. The one I’ll comment on
in the interest in time is the last one about
renal vein thrombosis. So, at that time we didn’t
routinely anticoagulate for membranous patients. Nowadays, I suspect people would
probably anticoagulate. And the decline in renal
function was probably of, clinically there wasn’t a sudden increase in peripheral edema, the decline in renal function
was quite gradual. However, we did exclude
a renal vein thrombosis, although the tempo of the
disease was probably slightly, it was probably a bit slower than you might expect for
renal vein thrombosis. I agree with you about
treating underlying disease, and I’m, from what
we’re about to show you, you must bear in mind, this was in the pre-rituximab, well, pre-PLA2R era. – Is it possible that she was
taking some other medications? I missed the age, but certainly NSAIDs and contraceptive, too. I don’t know the age.
– No, no, sure. No, no, that’s okay. She’s 41. – So, I mean, you know, unlikely, but the additional medications which she might have been taking. – No, no, I think that’s
a very good point. I mean, she was 41. There were no hormonal
treatments that she was taking that would be prescribed in the UK In terms of nonsteroidals, I think that’s an excellent point, especially given the fluid resistance. But as far as we could
tell, there was nothing, when we explained to her what over-the-counter nonsteroidals were like, she didn’t take any of those. – [Prof. Touyz] Perfect, I think we’ll move on in the interest of time. We’ll have time in the next little series
talk588
00:24:14,770 –>00:24:16,240
to ask further questions, but let’s see how the patient progresses. – Well thank you for
your participation there. So, what we did was, first
of all, as has been suggested, we increased the dose
of the loop diuretic, and that was predominantly due to issues with persistent peripheral edema. And an attempt was also
made to introduce a fifth antihypertensive agent, and it was namely an alpha blocker. But unfortunately, the patient
failed to tolerate this due to headache. As a result, the centrally
acting antihypertensive, moxonidine, was introduced around 12 months after the diagnosis. Additionally, we thought
the blood pressure was being driven by the
underlying active renal disease. As nephrologists we love
to give immunosuppression. And so, we started the
patient on immunosuppression during this period. At that time, around 20 years ago, there was no consensus on the optimal immunosuppressive regimen for primary membranous nephropathy, meaning the patient received
numerous different agents during the course of her treatment. Despite the immunosuppression the patient’s excretory
function declined further before stabilizing around a GFR of 15. And the patient continued to have nephrotic range proteinuria, and an albumin of less than 20. Just over two years after her diagnosis, the patient was admitted to hospital with a fluctuating GCS and
brief observed episodes of left lateral gaze deviation, involuntary eyelid
twitching, and nystagmus. The patient was markedly
hypertensive on admission with a blood pressure of 225/130. In addition to the
antihypertensives listed, the patient was also
prescribed erythropoietin and oral steroid. There were some secondary changes evident on both ECG and echocardiogram, although fundoscopy was normal. The patient’s CT brain
here shown on the left, and MRI brain here shown on the right, were also both normal. Given the patient’s presenting features and marked hypertension, a diagnosis of hypertensive encephalopathy was felt most likely. This diagnosis will not
be covered any further during this presentation as it
has been discussed previously during a CPC conference in 2015. However, following this admission, we elected to stop all immunosuppression. Our team also reviewed
the patient’s lifestyle and adherence to treatment before commencing the
thiazide-like diuretic, metolazone. Over the subsequent years the patient’s blood pressure
remained problematic. The patient’s admission with
hypertensive encephalopathy unfortunately precipitated
a significant deterioration in the patient’s excretory function. And she, therefore, received
a preemptive renal transplant at six years after her initial diagnosis. Here you can appreciate that the patient’s renal function improved modestly during the four years
following the transplant. However, her residual function
was still relatively poor with a GFR of around 20. She remained hypertensive, and at one year some further
investigations were conducted. The patient underwent repeat 24-hour blood pressure measurements in addition to 24-hour pulse
wave velocity monitoring. Again, the patient was hypertensive without the expected nocturnal dip in either blood pressure
or arterial stiffness. Here is a summary of the
patient’s medication at this time, including her immunosuppressive regimen at one-year post transplant. Why do you think the
patient’s blood pressure is proving so difficult to
control post-transplant? – Can I just ask one question before we go on to the
question from the floor? So, we have seen for the past
20 years before she came, or when she first presented, that slowly the blood pressure
medication has been increased in dosage and we’ve added a number of new antihypertensive drugs. All of them seemed to be at maximal or super maximal concentrations, at what point do you think we
should say, hang on a minute, how can we rationalize this
and actually start removing some of these antihypertensive drugs because it seems most likely that the added benefit
of all these extra drugs are probably not doing
anything and maybe some harm. – So, I think that’s a
very, very good point. And I think partly we probably suffer from when this case was actually undertaken, I think, and probably
where it was undertaken, so, I think in nephrology
we, by this point, will have been focusing, I think, when we started the immunosuppression we would have been focusing
on immunosuppression and on the side effects
of immunosuppression, we would then be focusing in
the post-transplant period about immunological
factors such as rejection. And actually I think we are
not as good as we might be or think we might be at
managing hypertension and rationalizing antihypertensive
medication in this patient. There will be in some time to come, I think in this presentation, about some rationalization, but I think that’s a very fair point that probably wasn’t addressed adequately. – Please. – Okay, so, I have one or two, one comment and one question. So obviously it’s not the case here, but one thing we (voice
muffled) discuss is a woman of reproductive age when
she has hypertension or underlying kidney
disease, have to think, was she pregnant around that time, because pregnancy can worsen obviously the hypertension and vice versa. So, my other question is
that we know, clearly, based on pathology she has underlying membranous
nephropathy, although, and we assumed this is primary, but we didn’t think
could that be something else, could it be a lupus with
a membranous presentation, and that’s something we didn’t talk about, systemic symptoms or rash or joint issues or any immunological testing. Maybe you mentioned and I missed that. – No, no, I mean, that’s
a very fair point. I think, and I’ve
forgotten your first point. Your first point about pregnancy. So, she wasn’t pregnant, and the reason that we
know she wasn’t pregnant, certainly, in the UK before giving any of the immunosuppression
we actually give pregnancy test as routine. In terms of your second point about could this be a secondary
membranous nephropathy, from a renal perspective,
so, her renal biopsy showed it was IgG4 positive. Her immunology for double
stranded DNA ANA was negative. There was, we don’t do this routinely, but prior to giving immunosuppression for membranous in the UK, it’s many centers, ours included, would do a CT chest, abdomen, and pelvis, trying to exclude malignancy
as a driver for this, but I think the features
on histology largely, and the way the patient progressed, would be in keeping with a
primary membranous nephropathy. – Swapnil Hiremath from Ottawa. A couple of comments which don’t address the overall
course, of course, but given that she’s on tacrolimus and the erythropoietin beta, so, with tacrolimus we
think the hypertension caused by tacrolimus,
calcineurin inhibitors, is a, the vasoconstriction, which could be antagonized
by calcium channel blockers, which you know, she’s on verapamil, but she’s not on the dihydropyridine throughout the course. And the second one is that they also act on the thiazide sensitive sodium channels, so, she’s not on a thiazide diuretic, so, whether those agents would be helpful. And the second, of course, is the role of erythropoietin
in hypertension. – Brilliant, so in terms of,
as you very eloquently put, one of the contributors
to the hypertension is likely to be the tacrolimus. So CNI inhibitors, calcineurin inhibitors, vasoconstrict the afferent
arteriole in particular, and you can compensate this
by giving a general afferent, a more specific afferent arteriole dilator such as nifedipine, for example. And this is why nifedipine improves GFR in the post-transplant period. As you say, you put erythropoietin, especially chronic EPO
use, more short-acting EPO rather than the long-acting EPO
contributes to hypertension. And the thiazide component
I hadn’t thought of. – What was the tacrolimus
blood concentration? Because the patient is, this is crucial, not dose but the blood concentration, so, it should be adjusted dose
to the blood concentration. Because otherwise we have
hypertension due to tacrolimus. And second, verapamil increased the tacrolimus blood concentration, so maybe they changed it into another calcium channel blocker, and third remark, even in this patient, this blood pressure
was generally not very, just not very good control. In this patient it’s necessary to check about renal artery stenosis
of transplanted kidney. – Sorry–
– renal artery stenosis of transplanted kidney,
ultrasound of the kidney and ultrasound, as a screening, and ultrasound of the, Doppler ultrasound. – Absolutely, so you’ve made quite a lot of very good points there, which I’m going to try and remember. Tacrolimus trough levels. So, we’ve not included this information. She had a DCD kidney, it
was a reasonably good match. Tacrolimus level in the first six months we tend to keep it about
eight, eight to 10, after that five to eight. So, it’s, from an
immunological point of view, appropriate tacro concentrations. Renal artery stenosis in
the transplanted kidney, so, it is not unusual to
see that, as you say. We performed Doppler. We have resistive indices,
which were not in keeping with renal artery stenosis
of the transplanted kidney, and also, this lady was
on an ACE inhibitor. So, it would be more in keeping if you had an ACE inhibitor
with a transplanted kidney with renal artery stenosis
that you would get a consistent and worsening
decline in renal function. – Okay.
– Excuse me. I want to know about the inflammatory parameters of this patient. For example, ESR, CRP, ANA. And also, in these years, does she develop something more in other
organs like a lung, eye, and others? – So, to answer your last question first, because I remember it, she
already has evidence of hypertensive end-organ damage. So, we have an echo from
an admission recently which showed, well
recently in this timeline, that she concentric left
ventricular hypertrophy. She has poor renal function, so that, I suppose with associated proteinuria, which is partly, I suppose,
well it is hypertension related. I’m going to your first question, I’ve now forgotten it. – About lung? Any new problem in lung?
– In the lung? – Something like sarcoidosis
and a new problem? – So, no I don’t think, well no there was no obvious new problem that required us to, that
would have triggered us to investigate or image the lungs. In terms of the other
question about immunology and inflammatory cascade, so CRP, the problem with CRP in these patients is you often will see a low-grade CRP response post-transplant. So, I mean, if you check CRP, you will often see it between about 10 and 20 milligrams per liter. But the immunology remained negative, and that was relevant
in what’s to come. – It’s general dictum that
there’s usually one disease, but did you look at renins and aldos? I mean, there might
have been primary simple hyperaldosteronism which might be hiding? Micronodule or something. – That’s a very fair point. When she was admitted with her episode of hypertensive encephalopathy
she underwent CT scanning. And that didn’t show any
obvious macronodules, I suppose. She’d also had the 24-hour
urinary (voice muffled) sometime ago, I think at presentation, those were not repeated. I think we, because she was
looked after by nephrology, we tend to focus on, and
now she has a transplant, we would focus more on non-endocrine renal causes for her underlying disease. – Okay, let’s see how
the patient progresses. – So, in addition to the factors
we’ve discussed previously, we have the immediate
effects of immunosuppression including calcineurin inhibitors, as well as the alloimmune response towards the transplanted kidney. There are changes in vascular
structure and function that predate the transplant. They improved somewhat
following transplantation, but nevertheless, remain significant. Finally, chronic EPO administration is associated with increases
in arterial blood pressure. This may be related to
changes in the production or sensitivity of endogenous vasopressors or as a direct result of vasoconstrictive effect of EPO itself. Unfortunately, around four years after she received her transplant the patient experienced recurrence
of membranous nephropathy in her graft, confirmed
by repeat renal biopsy. This occurs in around
1/3 of such patients. Within 24 months she had
reached end-stage renal failure and had commenced hemodialysis. Blood pressure remained
as much of a problem for this patient even after
commencing hemodialysis, with readings averaging around 150 systolic and 90 diastolic. Metolazone was stopped shortly
after commencing hemodialysis because the patient had started to lose her native urine output. So, for our next discussion point, why does this patient remain hypertensive? And how would you manage her
hypertension at this stage? – So, this lady’s now on hemodialysis. She’s in her early 50s, I think. – So, I don’t know why is she hypertensive? I think we have never managed
to control her hypertension. But in hemodialysis,
especially given the data, which has come out recently, so, there was the Italian
study a few years ago on the carvedilol, but then the small (voice muffled) she’s not on a beta blocker. I often use beta blockers as first line or second line on hemodialysis patients. And there’s some
observational studies showing that for end-organ damage,
beta blockers are perhaps superior to other agents
in hemodialysis patients. – I think that’s an excellent point. I think beta blockers probably should be or are the first line
antihypertensive agent in dialysis, partly because dialysis,
per se, is arrhythmogenic, and it reduces part of the arrhythmias associated with dialysis and some of the cardiovascular morbidity. And the comment of why she wasn’t on a, sorry, why she wasn’t on a beta blocker, we tried previously atenolol. Now I think she has asthma. That doesn’t, I mean, you could argue why did we not try cardio specific beta blocker, and that’s a very reasonable point. – During the dialysis
the most important cause of the hypertension is overhydration. So, we should go intensify diuresis with achieving so-called dry
weight as much as possible. And second important point is a sodium concentration and dialyzed. What was the current
natremia in this patient? And if the natremia in
this patient is higher than sodium concentration dialyzed. When you dialyze the sodium
is transferred to the patient. So that’s increase overhydration, and that’s the one of the concepts is (voice muffled) make
an individual decision about the sodium
concentration and dialyzed. – I think those are excellent points. And without getting too renal and going to the biophysics of dialysis, I think, as you very, very articulate, as you articulated, in dialysis patients, especially in those who’ve lost
their native urine outputs, then hypertension is largely
dictated by dry weight, and that is the interdialytic weight gain. And you manage that by reducing, essentially advising the patient to limit their fluid intake, often to a liter or so, and then you take off the
corresponding amount of fluid that’s been accrued
between dialysis sessions. As maybe you’ve realized, this patient wasn’t the
most compliant of patients or adherent of patients. And so, trying to restrict patients, especially where they
have a high-salt diet, to a half a liter or a
liter of fluid is difficult. And the second thing you
pointed out about sodium, so, this time, so this
is now 10, 15 years ago, hemodiafiltration wasn’t the kind of standard type of dialysis we used. It is now. But sodium profiling was generally done in all these patients, trying to improve
hypertension, as you say. – [Prof. Touyz] Yes please. – Beata Naumnik (voice muffled) Poland, my question is about what
has happened to this graft. Could you perform a kidney biopsy? Maybe this patient got
relapse of the membranous, let’s say, nephropathy, or
maybe it was a rejection? And the second question is
what about immunosuppressors? Immunosuppressive therapy. It was withdrawal immediately? – Yes, that’s very good question. So, she lost her transplant
due to recurrence of membranous nephropathy. So, we performed a biopsy to show that. And the biopsy didn’t show any
evidence of that rejection. So, as she then eventually
progressed to hemodialysis, and the graft was left in situ, now we can debate from an
immunological point of view what happens to immunosuppression, but actually what happens in many patients is that we remove, we leave a bit of immunosuppression just because we want to prevent
formation of new antibodies which might prevent a
further transplant in future. – (voice muffled) important. – In this patient, so what we tend to, I would probably remove tacrolimus, I would remove the antiproliferative, and I might just leave a small dose of prednisolone, for example, this patient, I think, was
again not brought out here, probably we weren’t going to
consider for another transplant in the near future for
a number of reasons, and in that setting we did
leave the prednisolone low dose whether she was taking it
or not was a separate issue. Can I just ask one question,
regarding the diuretics that you’ve used and
you’ve used quite a number, I haven’t seen anywhere the mineralocorticoid receptor
blockers, the spironolactone, and I’m just curious
because we know aldosterone is very profibrotic, and in terms of the
accelerated vascular aging and target organ damage, and I’m just wondering
what your thoughts are. – So, I think that’s an excellent point. And I think, in relation to spironolactone, I think we all know now that
spironolactone is excellent, especially in renal disease for the cardiovascular
benefits associated with it. I think the problem at this time was that we had somebody with, well gradually worsening renal impairment with or without a transplant, who is already on an ACE and/or an ARB. And her potassium pretransplant, even in transplant ran in mid fives. So, all you needed was the ACE, potassium of mid fives and an episode of acute kidney injury, for whatever reason, whether she took a
nonsteroidal for a headache or volume depletion that I think would just precipitate some
sort of catastrophe for us. In terms of diuretics, so, she pretty much lost her urine output by the time she was
established on hemodialysis, and actually then you could argue why you leave her on the furosemide. And I think some nephrologists
tend to use furosemide largely for his vasodilator effect as opposed to its diuretic effect. – So, a quick additional point, so, if we assume she took every
tablet you ever prescribe, and this is an assumption, was there, as colleague said before,
another condition somewhere? Some tubular defect, very rare, that was reabsorbing sodium
that shouldn’t be reabsorbed. Maybe some syndrome we don’t know yet. Help us. – So, I think that’s a very fair point. I think the problem is that if you have an underlying
glomerular disease and trying to work out what’s going and trying to do studies
of tubular function, I think was very difficult, especially when you’re on a RAS blocker, diuretics, trying to
interpret these studies would be very difficult, I think, so urinary studies are not going to help you. I think nowadays we might be
helped by genetic profiling, which I don’t think was
really available to us then. And I know you’re giving a talk about this tomorrow in the morning. But I think what’s likely is that she had primary membranous nephropathy that we just couldn’t control. And some patients just have diseases that we are not able to treat, and despite all the
treatments we give them. – Right, let’s carry on with the case and see how things progress. – [Prof. Dominiczak] We’re running out of time. – So, again, some excellent
suggestions from the audience, and certainly, an important
factor at this stage, which we’ve slightly covered
is dialysis adequacy. The patient was troubled
by persistent uremia, volume overload, and difficulties in removing fluid during dialysis, all of which will have contributed to her high blood pressure readings. There’ll also be contributory effects from her previous transplant, as well as renovascular changes and disordered bone metabolism
already highlighted. Finally, two factors
that have been relevant throughout this patient’s journey are her adherence to
antihypertensive medication and her excessive
dietary salt consumption. We felt there were four
main management options at this stage for her
ongoing hypertension, or five if you’re from
other parts of Europe such as Glasgow. And we firstly opted to
increase the amount of fluid removed during each dialysis session, and secondly to optimize dialysis efficacy through a combination of longer sessions, greater use of biocompatible membranes, and a trial of hemodiafiltration to remove more middle size molecules. So, in summary, resistant hypertension is an important diagnosis, especially in patients with
chronic kidney disease. And as this graph demonstrates, it is a problem that’s attracting
increasing recognition. It’s important to consider
terminology used in this area. So, whilst resistant hypertension is defined as suboptimal
blood pressure control, despite treatment with three
or more antihypertensive agents of different classes but
including a diuretic. Refractory hypertension is, in fact, used to describe patients whose blood pressure remains uncontrolled despite maximal
antihypertensive treatments. But another important concept is that of pseudo-resistant hypertension, which is resistant hypertension that is in fact caused by something else, such as the white coat effect,
poor medication adherence, inaccurate blood pressure measurements, or even undertreatment. Observational studies
report a highly variable prevalence for resistant hypertension, ranging between two and 30%, depending entirely on how it’s defined. However, regardless,
resistant hypertension is significantly more common in patients with chronic kidney disease and in patients with
cardiovascular disease. Perhaps unsurprisingly,
resistant hypertension is also associated with an increased risk of cardiovascular events. Patients with resistant hypertension have an approximately
threefold higher risk of cardiovascular events
compared to patients with treated hypertension. Resistant hypertension is also associated with poorer renal outcomes. A sub-analysis of the
ALLHAT Trial demonstrated that progression to end-stage renal failure is almost twofold higher in patients with resistant hypertension,
compared to normotensive patients. But finally, a word regarding our patient. There was no improvement
in her blood pressure over the following years. She remained on hemodialysis, but unfortunately suffered a fatal stroke, age 56, just 15 years after
her initial diagnosis. Thank you very much for listening. (audience applauding)