CPC: Hypertension and its complications in a young man with autoimmune disease

CPC: Hypertension and its complications in a young man with autoimmune disease


– So our next presenters come from Edinburgh again in the UK, and the subject is hypertension
and its complications in a young man with autoimmune disease. The case will be presented
by Eve Miller-Hodges and we’ve got some discussants,
including Dr. Neeraj Dhaun. So thank you very much. – Thank you very much. Good morning, ladies and gentlemen. I’d like to just start
off by apologizing to you for the way I’m dressed. My colleague and I arrived
from Edinburgh late last night and not only was our flight delayed, but my luggage didn’t arrive. So I’m afraid I’m been restricted to having a toothbrush here. So we’re going to phase
shift slightly to hopefully as equally an elegant organ, the kidney. I’m going to hand over to my
colleague Eve Miller-Hodges to start off the case. – So good morning everyone. Many thanks for inviting us
to present our case today. It’s slightly different
from the previous case. Very much more clinical and a lot more audience participation required, so we’re looking forward
to lots of suggestions from everybody here. Our case is entitled “Hypertension
and its complications in a young man with autoimmune disease.” The case is based around
a young man, 30 years old, who’d recently moved to
the UK from Pakistan. He had a recent diagnosis of
systemic lupus erythematosus and was originally presented
through rheumatology clinic with joint pain, skin rash,
and pleuritic chest pain. His immunology at that time is
in keeping with active lupus, he was hypocomplementemic, he had positive anti-double-stranded
DNA and positive ENA. No evidence of antiphospholipid syndrome, immunologically-normal platelets
and he was lymphopenic. He was rapidly referred
to the renal clinic as he had very obvious nephrotic syndrome with a proteinuria of nearly
four grams for 24 hours and a low serum albumin. He was actually found
to have a pre-existent renal vein thrombosis at that time and was subsequently anticoagulated. And this was attributed
to his low serum albumin. His excretory renal function was normal, but he had blood and
protein on urine dip stick, and he obviously went on
to have a renal biopsy which showed both proliferative and membranous forms of lupus nephritis. At this point his blood
pressure was in both American and UK limits, 126 over 88 millimeters of mercury but on no medications, although I would point out he’s only 30 and he has very heavy proteinuria. For your interest, here’s
his renal histology. At the top we’ve got a
lovely normal glomerulus with kind of lacy,
delicate capillary network and just a couple of cells
in the mesangial spaces. This is our patient’s glomerulus. This thickening of the
capillary wall here. And then proliferation in focal areas but not affecting the whole glomerulus. So obviously our prime
concern was treating his underlying disease at this point, and the standard treatment
for lupus nephritis would be anti-inflammatory
with high-dose glucocorticoids and then second line, an
anti-proliferative agent to deplete T-cells and B-cells and reduce auto-antibody production. And he was treated with pulsed
intravenous cyclophosphamide to induce his very active lupus nephritis. But unfortunately his disease proved very difficult to manage. He only tolerated a very short
course of cyclophosphamide because he had an anaphylactoid reaction, probably to the mesna
component which we give to protect the bladder epithelium. We then tried to induce
with mycophenolate mofetil but again he couldn’t tolerate this due to gastrointestinal side effects. Three months of
azathioprine had no effect, and then for the six months
of an enteric preparation of Myfortic also had very little effect. And again he could only
tolerate this at a low dose. We finally treated him with rituximab, which is an anti-CD20 monoclonal antibody, again to deplete B-cells. But as you can see here, we failed to induce remission
of his lupus nephritis and his renal function
deteriorated over the two years. And he was also requiring
high doses of steroids to continue during that time. His proteinuria remained
in the nephrotic range, reaching up to 10 grams a day, and his serum albumin
was usually below 20, which is widely accepted
as being associated with a higher thrombotic risk. Of note in this then, he was maintained on
warfarin during this time, and I’ll just mention now
that his warfarin control was actually very difficult. Despite lots of input from
both his general practitioner and the renal clinic, then
his INR dramatically fell high and low without any
real explanation for it. So, we’ve got a young man with
ongoing nephrotic syndrome. He’s also fluid overloaded and
is now becoming hypertensive. And this is the bit that you’re
probably more interested in. So we’ll go back to the first
six months that we saw him. His renal function was
normal at this point, but his blood pressure rose rapidly, and by month five is 174 over
110 millimeters of mercury on no treatment. His investigations at this time confirm his normal renal function,
normal electrolytes. His inflammatory markers
are in keeping with lupus. He’s still hypoalbuminemic
and his lipids, again, are in keeping with
his nephrotic syndrome. So I’ll just hand over to Bean now. – Okay, so this is the audience bit. We’re gonna start off with some rather
straightforward questions. So this is a young chap
with nephrotic syndrome. So, he’s not very happy, he’s got lupus, and he’s becoming hypertensive, so my questions to you are listed here. Why is he hypertensive? What are the contributing factors here? And how might you manage his hypertension, and finally, what is it
you’re trying to achieve here? Over to you. – This is an easy one to start off with, so there must be some suggestions. – [Anna] Sadly, you need to– – [Garry] Yeah, we have
people leaving the room. (group laughs) – [Anna] That’s always a bad sign. Maybe you need to get
started to get things moving. – Yeah, okay, so why don’t I just tell you that this is a young man. He is recently arrived in the UK and he’s got renal impairment. So the renal impairment will
definitely be contributing to his hypertension. He’s also not Caucasian, which is a risk factor for hypertension, and his lifestyle in terms of what he ate, he had a very high-salt diet. He ate lots of chapatis,
he ate lots of curry to which salt was added,
and so that contributed probably also to his hypertension. Eve, I’m going to hand over to you. – And more specific to his case was his background of autoimmune disease, and this is really the thrust of this case presentation today. So in common with a lot
of auto-immune diseases, he had ongoing systemic inflammation. He was on high-dose corticosteroids and he also had nephrotic syndrome. But more specific to lupus, which is an independent risk
factor for hypertension without any presence of renal disease, and the reasons behind this is that circulating auto-antibodies are thought to contribute directly to immune-complex mediated
endothelial damage. This direct endothelin-1
activation is also activation of the renin-angiotensin system, and that, with his
proteinuric renal disease, these will all be contributing
to his hypertension. In combination, all of
these things lead to premature atherosclerosis
and arterial stiffness. – Based on that, anybody want to suggest some management strategies
for his hypertension? – [Audience Member] RAS blockers. – RAS blockers, okay. So we could give him an ACE inhibitor or an angiotensin receptor blocker. In isolation or combination? – [Anna] Can you come to the microphone? The whole fun is for people
to come to the microphone. – Sorry, yes. – I’d probably start
with an ACE inhibitor. Thirty years ago, that was used for lupus. And then if that didn’t work, I’d probably add an endothelin-blocker. I wouldn’t combine ACEs and ARBs, at least at first. – Okay, so we have the
option of an ACE inhibitor followed by an endothelin-blocker. Those drugs are licensed currently for pulmonary hypertension
and scleroderma, but we’d be using it off-license. Any other suggestions in
terms of how to manage his hypertension? Anything more straightforward
than pharmacotherapy? – We talk a lot about the
renin angiotensin system, but rarely try to use
the markers of activity. You could start by measuring
plasma renin activity, which is very high in a
scleroderma crisis, for instance. We learned from one of the
presentations yesterday that uria angiotensinogen,
which is easily measurable, is increased, and by the way, CellCept appears to down-regulate it, so you could measure angiotensin II. Right, just an idea. – Absolutely, so one thing to mention is that this case is from some years ago. Angiotensinogen in the urine
might not have been available to us then. Certainly, plasma renin,
plasma catecholamines, urinary catecholamines,
might have been available. I don’t know how easy it would
have been to interpret them, given he’s got renal
impairment, proteinuria, he’s fluid-overloaded,
and he’s on a mixture of those steroids and
other immunosuppressives, as you correctly pointed out. – Because of the level of blood pressure, most guidelines say he should be started on two drugs at least, right. – [Neeraj] Sorry, he should be? – Should be started on two drugs. – [Neeraj] Two drugs. – Now, the day before yesterday, I would suggested the second drug and today, I have to
suggest a different one, because of what I learned yesterday. Which is the issue of
calcium channel blockers and impaired auto-regulation. Until now frankly, I have to confess that ACE inhibitors, dihydropyridine calcium channel blockers, and a diuretic were like the
main skeleton of therapy, but I wonder now, in these
people who have already renal disease whether
calcium channel blockers continue being a good idea. And of course, I don’t have the answer, but I wanted to bring this up. – Sir, before you sit down, can I ask you, in terns of
calcium channel blockers, which class of calcium channel blockers? The predominantly afferent
hemodynamic ones, nifedipine, or the predominantly efferent hemodynamic, such as amlodipine? – You know, I wasn’t
surprised by the fact that in the lecture yesterday, there was a mention that the
impairment of auto-regulation was applicable to both dihydropyridines and non-dihydropyridines The effect of
non-dihydropyridines was identical but less powerful, which is
consistent with the hemodynamics being less vasodialator, but the problem was for both. – [Neeraj] I’m going
to take the opportunity of you being there to ask you
one other question, which is, what would you be trying to
achieve here by controlling the blood pressure, in this gentleman? – I’m sorry? – [Neeraj] What is your target? What are you trying to achieve here, apart from a lower blood pressure? What are your goals long-term by controlling the blood pressure? – Are you talking about a number? – No no no, in terms of what
is a longer-term goal here. – The contribution of his blood pressure to the progression of renal disease. – [Neeraj] Renal disease? – Yeah. – Okay, perfect. – So this is what we did. We took four main
elements in managing this, which I think is an appropriate
approach to everybody, but also to really target on treating his underlying disease. Obviously, fluid restrictions and salt restrictions were important, we still needed to induce
remission of his lupus, and actually at this point,
and again I’ll just reiterate, this case was from a few years ago, we wanted to offload him and also blockade his
renin-angiotensin system. As you’ve already mentioned,
then we’re trying both to reduce his proteinuria and
preserve his renal function, but also very importantly,
even in such a young man, well, perhaps particularly
being such a young man, it was to reduce his cardiovascular risk. This is disproportionately
high in lupus anyway. There’s up to a fifty-fold
increased risk of MI in lupus and he also has a number of
extra-traditional risk factors apart from that, so this
was really a very big part of what we were trying to manage here. So this is what happened. At five to six months, we added renin-angiotensin
system blockades. He stopped his own ramipril
because it gave him a headache so he was then started on valsartan, and then a loop diuretic added. As you can see, this really
didn’t make very much effect on his blood pressure. In fact, over the next
months to couple of years, then the addition of two further agents, a calcium channel blocker
and an alpha blocker really made very little difference at all, and actually his blood
pressures at this point are averaging 160-170
millimeters of mercury over about 80 to 90, and this is in a man with five to 10 grams of proteinuria a day and
deteriorating renal functions. That’s someone who you want to prioritize blood pressure control. His investigations at this
time show he’s now anemic, which is in keeping with his
level of renal dysfunction. He’s also got borderline hyperkalemia, and again remains inflamed
and hypoalbuminemic. So I’ll pass over to Bean to see if we can get some more input from the audience about where to go from there. – Over to you again. So his blood pressure is deteriorating, his renal function is deteriorating. Why is his blood pressure
deteriorating, do you think? What factors might be
contributing to this? – [Anna] One problem is
that you haven’t managed to control his lupus. – Absolutely. – [Anna] He still has
an active immune disease that is destroying his
kidneys, whatever you do. And even if his blood pressure
would have been perfect, which is unlikely under the circumstances, you would still have
progression of the disease because the kidney’s being destroyed. – Absolutely, so as Anna
correctly points out, there is the lupus that
is going to be driving, firstly, the renal disease per se, but SLE is by definition
a systemic disease, so it will be contributing to
the hypertension directly. So one target for hypertension management has to be the underlying cause, that is the lupus. And alongside this, he continues
on reasonably high doses of corticosteroids
alongside immunosuppression. Sorry? – Can you go back to the drugs again? – [Neeraj] The drugs? Yeah, sure. Ah, there you go. – Okay, so od means once a day? – [Neeraj] Sorry, yes,
od means once daily. – [Jan] So what was the potassium? – [Eve] 5.8 – [Jan] 5.8? Well, you know, at the risk
of putting myself out there… – [Neeraj] And bearing in mind
we are nephrologists here. – No, I’m not, but go back to the drugs? To me, I know the K is a concern, and I don’t know if you
have the new drugs available to manage the K, but first of all, the furosemide once a day in hypertension, to me is a big mistake, because you’re gonna get
paroxysmal sodium reclamation for a lot of the day. So if you’re gonna use
furosemide for cost concerns, I’d at least use it BID. Valsartan at 160 once a
day, there’s a fire going on and you have a straw to
try to put the fire out, while the fire is raging in the back. The patient’s blood pressure’s elevated. If the patient’s on mycophenolate, and I’m not sure the patient is, why not use diltiazem to reduce the dose of the mycophenolate so
that you can save some money and still get better
blood pressure control. And the biggest problem
I see with diltiazem, and to some extent, verapamil, but that’s the constipatory concern. People underdose for
diltiazem in hypertension. It comes in a 180, a
240, a 300, but really you need good-sized doses of
dilt in this kind of patient. And then as a fourth drug, I’m not sure why you’d
use an alpha blocker before you’d use at least an alpha-beta if you were gonna do it. I know the K’s a concern, and
that might be a reason to use a lower dose of the valsartan, but would you consider
even spironolactone, ’cause I think this patient has a lot of salt-induced hypertension. The other thing is, do
we have any conception of night-time blood pressures? Would you consider giving some
of these medicines at night instead of just in the morning, or split doses, like I
said, of some of them? So, I would have approached the blood pressure control differently. – Those are all excellent points. In response, just broadly, so this chap was managed
in the nephrology unit and so we often tend to focus
on the kidney and the lupus before we tend to focus
on the blood pressure. So for example, this chap is
nephrotic and so our valsartan is very much dedicated towards
trying to reduce proteinuria. The furosemide once a day,
I absolutely agree with you, and that will become apparent later. The furosemide again was
probably more directed at fluid overload than
it was hypertension. And the other thing to
say is that there will be a US/UK divide here, or a
US/European divide here. We tend not to use
diltiazem for hypertension. We tend to use alpha
blockers for hypertension as third- or fourth-line agents. Yeah, so shall I hand over to you? – Mm-hmm. As many of you have identified, the major thing contributing to his worsening renal impairment,
his ongoing proteinuria, and, as you rightly identified,
salt- and water-retention. His disease is still active,
which is a major player here, and he’s also anemic, which is now requiring erythropoietin, which might be contributing. And it’s also worth
mentioning that adherence was a concern at this point. I’d already touched on, his
warfarin control was very poor, and although we never actually
got him to admit to it, and we certainly didn’t
test any drug levels ’cause it really wasn’t
possible at that time, we did worry about whether he
was taking his medications. But it will become
apparent in the future that this was less of a concern. It’s worth mentioning
now the mechanisms behind nephrotic syndrome and hypertension. Obviously you’re all aware of the underfill vs. overfill hypothesis and it’s quite possible
that both these mechanisms were contributing here. He remained very hypoalbuminemic, so had lost oncotic pressure
due to loss of plasma proteins and therefore had
extracellular volume expansion and intravascular volume depletion, so was therefore holding
on to salt and water, as has already been mentioned. However, there’s also
more recent evidence, mainly direct evidence from animal models, that the protein loss itself causes proteolytic activation
of the ENaC channel, therefore directly leading
to renal sodium retention. But again, in combination,
then I think salt and water retention is a big issue here. For those of you who did
ask for more investigations, there wasn’t really any sign
of any other end organ damage, with a normal echo and normal fundoscopy, and we actually didn’t do 24-hour ambulatory blood
pressure measurements. As I said, this is from some years ago, so they weren’t really
available to us then, although it would have been
excellent data to have had. So he’s on an
angiotensin-receptor blocker, a small dose of looped diuretic, a calcium channel blocker, and a small dose of alpha blocker. We’ve already heard from our colleagues, so I think I’ll just move
on in the interest of time. What we did as mentioned is we combined dual renin-angiotensin
system blockade with valsartan and reintroduced ramipril, but this had to be withdrawn
due to hyperkalemia, even though we did try and lower that with correction of his acidosis. We did increase his diuretic to try and offload salt and water, and given the fact that both his lupus and his hypertension
weren’t really behaving as we thought they would, he underwent a repeat renal biopsy, which showed progression
of his underlying disease. As we’ve mentioned before,
then the thrust being trying to manage his inflammatory disease, we underwent a further
trial of cyclophosphamide, this time a low lose and
without the mesna component, to try and get on top of his lupus. Again, his renal biopsy shows, here’s his old one at the top, and then here is the
new one two years later. There’s now proliferation
throughout the glomerulus, with gross thickening of the
capillary basement membranes and virtually no filtration
in that area left at all, so you can see why his kidney
isn’t working very well. At this point, he’s now suffering from the burden of heavy immunosuppression and had a number of hospital admissions with recurrent infections. His renal function
continues to deteriorate, but he’s now unable to
tolerate any of form of renin-angiotensin system blockades, due to hyperkalemia, and
he’s just maintained on loop and thiazide diuretics, a calcium channel blocker,
and an alpha blocker. – So, just before I ask the question, what do you do next here, I just want to raise the point
about the spironolactone. So this gentleman has got
deteriorating renal function, already has a problem
with a tendency towards hyperkalemia on valsartan
at suboptimal doses, and so I don’t think I
would, as a nephrologist, put him on spironolactone, especially because of his
dietary potassium intake. In this gentleman, given his lifestyle, it would have been quite high,
so that would be the reason not for adding in spironolactone. And just going back to the biopsy. When I see this biopsy,
to me, any blood pressure or anything becomes down to the kidney, so I see there is no blood
going through this glomerulus, so the hypertension to
me, rightly or wrongly, is renally driven. So I would then focus on
trying to control his disease, rightly or wrongly. So what would you do
next in this gentleman? Yes, sir. – I like this comment about the plasmin, which is a very new concept, activating the sodium channel, and also because nephrotic syndrome, independent of the ones
that retain sodium, the site of the retention seems to be the cortical collecting
ducts, and ENaC-driven. So that’s why focusing on
downregulating this aspect with either spironolactone or amiloride may work for hypertension, but then you have a worsening
of the hyperkalemia. And that’s where the new
potassium binders may help, right? Here you have patiromer, which already approved
in the United States. You have CS9, the FDA’s studying it. With the old-fashioned kayexalate, perhaps they could be a good… A proteinemia to try the patiromer to try at least to
facilitate the treatment. But I couldn’t agree
more that this mistake of the once a day furosemide is common practice in United States. I see in England it happens too. Thank you. – So the potassium binders
weren’t available to us then. – And they still aren’t. – Yeah we still can’t get them. So actually the diuretics that we used used to be, er, in fact, I can’t remember what we used to use in the old days, but often the diuretic
we used to introduce in people who had a tendency
towards hyperkalemia with renin-angiotensin blockers when we wanted to maintain
the renin-angiotensin blocker, so we used to add in the diuretic to try and increase urinary potassium excretion. But yep, so this is where
we are at the moment. What would you do next
then in this gentleman? We don’t have access to potassium binders. – As he’s stolen back to his seat, I’m going to invent something else. (chuckles) It’s not what I would do next, because there are next things to do, but something that would occurred to me next, next, next, meaning if
you’ve done the three nexts and you’re still stuck. You know, lupus is an
antibody-mediated disease, but you’re really kind of excluded at the current stage of our knowledge participation of T-cell inflammation. Simply it might be the
hypertension, right. Then if I would have failed
all therapies in this patient and even at the risk of going to jail– – [Neeraj] Even renal nerve ablation here. – No, no, no, because
that we have a randomized clinical trial that’s negative. I won’t go to jail for that one. But I would go to jail for abatacept for inhibiting the
costimulation of the T-cells. Because, you know, it’s
the draw of the luck. I don’t know what it
would do to the lupus, I don’t think it would do much because you have a very active process in terms of auto-antibodies, but maybe it reduces the blood pressure. Who knows? – Yes, abatacept is an interesting idea, and the trials for abatacept
in terms of renal disease and hypertension were not there then. I would go back to you
and say, well, to me, lupus, whilst there being a
T-cell mediatory function, it is a B-anti-cell mediated disease and plasma cell mediated disease, so I would come back to you with probably a b-cell costimulatory
blocker, such as blinatumomab. But going back to this, in terms of drugs, what would you do here, any ideas? Yes, sir? – Well, (chuckles). What was his pulse? – [Neeraj] Ah, good question. – [Eve] 90. – Yeah, yeah. So a lot of these drugs work on volume, and to me you have very
little effective blockade of the renin-angiotensin-aldosterone
mechanism. And somehow, I think
we’ve gotta work on that, so clearly if I couldn’t
because of the potassium, which is really tying my hands. You’re saying that because
this is an old case or because where you practice, you don’t have patiromer available? – [Neeraj] It’s both. – [Eve] Yeah, we aren’t allowed to use potassium-binders either. – Okay, okay. So I would at least wanna use an alpha-beta blocker if you feel strongly about the alpha blocker. Or a beta blocker. I would also consider, because of the renal function, I’m not so clear if I could use another loop augmenter. I don’t know how bad the renal function of the GFR is now. I would consider adding
diltiazem to the nifedipine. The nifedipine dose to me, that’s a once-a-day,
long-acting nifedipine? – [Neeraj] Correct. – So once again, that’s
not an industrial dose, and I would feel comfortable
going up on that, or, clearly unusual, but
in these kinds of cases, adding dilt to the dihydropyridine, you can get some
additional blood pressure. It does work on volume as well, so the higher the salt intake, the more the CCBs are
gonna lower blood pressure. That’s why we don’t have
varaparetic and diltiazaretic because when those studies
and cells were done, without controlling
sodium, it was hard to see on a sodium load that you
had an augmented effect of a varapatetic, et cetera. So that’s what I would do next, while you work on the lupus, ’cause I’m not a rheumatologist. – No no, that’s fine. We’re nephrologists, we
manage it much better than rheumatologists actually. (Eve chuckles) And that’s great. I’m going to, in passing,
just make two comments, which actually we didn’t include here. I did try, at the time there
was available aliskiren, it’s a renin-inhibitor, and that was in addition to the valsartan, which we had to stop, and
that drove the potassium up. And then aliskiren was not available. And the other thing we did try was, I tried short-acting nifedipine, which I’m going to say, giving short-acting nifedipine
two, three times a day, I’m going to say, I’ve had
better acute hypertensive effects than long-acting nifedipine, but he suffered really bad headaches with short-acting nifedipine, which is why we had to stop those as well. – However, our hands were tied, because unfortunately,
events got the better of us, and we weren’t able to do anything because then he presented acutely to the Accident & Emergency
Department with a headache, seizures, confusion, and agitation. His blood pressure was very high, 240 over 140 millimeters of mercury, although that doesn’t seem that high in comparison (laughs)
to the previous case. He was tachycardic but afebrile and with a normal blood glucose. He was intubated and sedated, and his seizures were controlled
with intravenous phenytoin. He was still anemic, his CRP was now high, had ongoing impairment
of his renal function was a similar level, electrolytes were normal, and he had an acidosis and
a high lactate in keeping with sustained seizure activity. So what’s the differential diagnosis here? – [Anna] We’ve got some help. (Eve chuckles) – Cheryl Laffer from Vanderbilt. You basically are
questioning whether he has lupus cerebritis versus
what we used to call hypertensive encephalopathy, or now PRES. – I think that’s right. Correct! (Neeraj and Eve chuckle) So I think the question is, is this, well, I suppose there’s
a third possibility here. So is this a complication of his lupus, is it a complication of his hypertension, but I suppose then you also have the two other possibilities, has he had a stroke, is there some sort of
infection going on here. I’ll hand over to you. – And really, the point
that we wanted to make is that actually infection is a really big differential here. He’s very heavily immunosuppressed and there’s been an acute
change in his neurology, so that’s probably the most
important thing to exclude. But then we’re really
trying to differentiate between this being a
primarily vascular event or whether it’s primarily
an autoimmune event, either between the cerebral lupus or PRES, as we’ve discussed. So what’s gonna help us
decide between those things? Do we have any further
investigations or imaging that anyone would like? – [Audience Member] You need an MRI. – Anything else? – [Neeraj] Yes, I’ve just got to say, we’re in the UK, not the US. (Eve chuckles) – [Garry] You might look at his retina. – You said before that you’d like an ECG. I’m joking, I’m joking, I’m joking. – But look at his retina. – Look at his retina and if okay, do lumbar puncture maybe? – These are our UK-type choices. – Yes, membership of the
Royal College of Physicians. (off-mike question) – Well, his GCS at that time was, so he was altered, essentially. His GCS was about 11, so he was kind of moving and
groaning and wriggling around, but not making any sense. – [Audience Member] So
back in the old days, if you didn’t have papilledema, one might want to do an LP. – Yep. – Yep, suggested a minute ago. – And we could actually have
stretched to a CT in the NHS. We put our hands in our
purses and did manage a CT. So we has a non-contrast CT, which is shown here, and although it doesn’t project very well, the more eagle-eyed amongst
you will see that there is some areas of low
attenuation in the posterior occipital regions. He did have a lumbar
puncture, which was acellular. Normal glucose and protein. His viral PCR was negative, and he also had no signs of infection on any other microbiological
investigations. Finally, we did stretch to an MRI, which you can see is very abnormal, with these areas of high signal, again in the posterior occipital regions. So with this in mind, we obviously needed to
control his blood pressure. He still tended with blood
pressures 240 over 110. Any thoughts about how’s
the best to do that? – So essentially the question is, how are you going to reduce
the blood pressure acutely? Again, there might be a UK/US divide here. We don’t use sublingual
nifedipine any more. (off-mike question) – [Anna] Can we get you to the microphone? – [Jan] Yeah, yeah. (panel chuckles) – Sorry to keep making you walk up. – To me, when the brain is involved in an encephalopathic presentation, nitroprusside is the best drug. – Okay, so sodium nitroprusside. Anything else? – [Anna] Nitrates? – Yeah, so intravenous nitrates. Any other class of antihypertensive agent that you might use? Maybe you don’t it in
the US, I don’t know. – And some people also use
labetalol, IV labetalol. – Yeah, so we tend to use labetalol. – Perhaps even earlier in this course, we used to give people minoxidil, and their renal function occasionally got substantially better. I realize, might cause fluid retention, but particularly if you’re only giving furosemide 80 milligrams once a day, but that might be an option. – Yep, I mean, sure. I think minoxidil is
actually used more in the US, isn’t it, than in the UK? ‘Cause we rarely use it. – We use it as a last line. – As a last resort. – [Audience Member] It’s
being used much less. – Is it? – [Audience Member] Yes. – Maybe you have more of an
issue with alopecia here, I don’t know. (audience chuckles) – [Audience Member] We’ve
just got better drugs today. And you have to use a beta blocker and a strong looped diuretic? – Yeah. (off-mike question) – I wanted to remind you
that that improvement in GFR with minoxidil is like
the early improvement of GFR with amlodipine in AASK. – [Neeraj] Nifedipine. – The amlodipine arm of AASK, meaning initially, where
you compare with the– As filtration goes up, and probably you as
nephrologists shouldn’t like it. (panel chuckles) – Also, we don’t like the way
that nifedipine improves GFR as the afferent to efferent dialation, we don’t like that because
it hurts the kidney. – Especially in him. – Especially, yeah, in someone like this or diabetics in particular. Okay, so nitrates, beta blockers, and how much do you want to
reduce the blood pressure? – [Audience Member] A third. – Yeah, we want to go to safe
levels, not normal levels. – And slowly, not too fast. – So we kind of put this in a little bit to catch people out, ’cause although nitroprusside
probably is the best stroke, then we absolutely
cannot use it in this man because of his renal impairments. So the risks of cyanide
toxicity are far greater in patients with pre-existing
renal impairment. Although it will give the
better anti-hypertensive effect, it works very quickly, it’s short acting, sorry, the slide’s been
half-eaten on one side, then we shouldn’t use it in him and intravenous nitrates
or intravenous labetalol are probably the best choice. As we’ve said, slow
reduction in blood pressure is what we’re aiming for, partly dependent on the
rate of blood pressure rise, although he’s presented
from the community, then we don’t really know that. Aiming to prevent further vascular injury but to avoid reducing his blood pressure below the auto-regulatory range and therefore precipitating
secondary ischemia. And so this is what happened. He was put on intravenous
nitrates to start off with and his blood pressure improved
over the first 24 hours exactly as you’d like it to. His conscious level improved, but didn’t get completely back to normal. He was still a bit confused, and even with the addition
of multiple oral agents, some of which he was on already and the red ones, some
of which were added new. Then his blood pressure remained very high over the next few days and in the end we ended up adding in
an adrenergic blockade intravenously as well, still with blood pressures 200 over 100 and without a return to normal neurology. He’s still anemic. His CRP’s still high. His renal function’s a little
bit worse than it was before, and he now has low sodium
and serum potassium. So what further information
would you like here? He’s not behaving as we’d expect him to. (off-mike question) Mm-hmm. Sorry, so yeah, I’ll just
go through the drugs. So he’s on a beta blocker,
he’s on an ACE inhibitor, he’s on loop and thiazide diuretics, a big dose of alpha blocker, full dose calcium channel blocker, and a bigger dose of intravenous
furosemide twice a day. (off-mike question) – I’m calculating. His median pressure went from 200, 100 to 250’s about 200, to 133 on the fourth dot. That’s about a 33% reduction, is that right? My math is not very good, sorry. But what I mean is, he
may be confused because you may have gone below 75%
of his starting pressure. – Yeah, I suppose that’s a good point. This is four, so it did drop,
he’s had four days over this rather than it all happening
in the first 24 hours, which I suppose would go
against that, but yeah. – The safety point, and actually, it’s a relative safety point,
’cause you don’t even know whether that blood pressure
is his blood pressure that determines the range of
the auto-regulatory curves, but I would say if you go below 75% of your starting blood pressure, you start having hyperperfusion. However, because God knew
there were gonna be doctors, there is some increased
extraction of oxygen. You have a little more
safety below that point, but one has to be very careful
with that initial reduction. – We probably were on the
borderline for the first 24 hours, however I do think that we
probably aimed to get it lower in that first four days
and that didn’t happen. I’ve done that. Okay, so anybody else want
any further information at this point? – [Garry] What’s happened
to his creatinine and kidney function? – Sorry, I thought I saw it over there. Yeah this is the one, sorry, we went back two slides. So his renal function’s a bit worse, but his potassium’s now low, his sodium’s low, he’s still inflamed. So this isn’t behaving
as we’d expect it to. – [Anna] Okay, we need help. – At least in our ICU,
nicardipine’s a huge volume when you use it. So he’s becoming overly diluted. I can’t tell you as a nephrologist
what to do about that, but that seems to be part of the problem. Also, is he still on
Cytoxan, because that’s– – [Eve] So he was on
oral cyclophosphamide, which has been stopped. He’s still on some steroids and he in fact was on
hydrocortisone when he came in in a kind of crisis. – In terms of blood-brain barrier, that’s now going to be a problem as well. – Anybody else? Ooh, sorry, wrong way. (off-mike comment) (Eve laughs) – I’ll give a stab at it, but, I mean I’d like to know in some way his volume status. You’ve got him on a dual RAAS blockade. His renal function has
deteriorated from 1.9 to 2.32, so in the risk of being thrown out, at the time this is going on, would a plasma renin and a
plasma aldo in any way help, or a non-invasive
evaluation of cardiac output to peripheral vascular resistance just to get a better handle. I presume the urine output is good? – [Eve] It’s adequate rather than good. – So, you need to know which way to go. I’m concerned that he’s on
the ramipril and the valsartan with renal deterioration at this point. – So the only thing I’m
going to comment on there is that when he presented like this and he had a drop in hemoglobin as well and what we’d known is that for some time he’d had uncontrolled lupus
and once it might have fit in with a hypertensive complication, my worry was with a drop in
hemoglobin and active lupus, that he was developing another
autoimmune complication that was involving the
neurological system. And so whether we should
consider additional treatments for that. And also when we should just give up. That’s the other thing,
whether we should give up on his kidneys because we’ve given him a lot of immunosuppression
over a long time. He’d had a number of
infective complications and so giving up on
his kidneys wouldn’t be the worst case scenario. Because actually, no
matter what we do here, he is going to reach
end-stage renal failure within a relative short amount
of time within his lifetime, whereby we would consider a transplant. It might be better for
him in the long term to cut our losses here,
ditch the immunosuppression ’cause we know we’re gonna
have to immunosuppress him long term for this transplant. – So in my practice, although
I do think plasma renin and plasma aldo has a place
when you’re three drugs in and you’re looking at, you could blindly add spironolactone, this is complicated here, or
I like the relationship there. When you’re on five and six drugs and you’re just adding drugs because the pressure’s not controlled, I think the only time I would
consider plasma renin and aldo is further down the line to try to get an understanding of what you’ve done. Sometimes it’s very hard
to interpret in the setting of RAAS blockade, dual RAAS blockade, but I think it can be
helpful down the line. We did a study published
a number of years ago and Dr. Lerrer was part of
it and he was behind it. The only group we found that
helped know what to add next was that group, far down the line, three drugs in and then
to know that relationship, not when you got it early
as a first-drug decider, but that’s a controversial area. So at the risk of not being thrown out, I think it can be helpful. – Did you want to say something? – Thank you. So we’ve only got a
couple of minutes left, we might wrap this up, but
this comment would be–. – I am Anna Oliveras
from Barcelona, Spain. I was wondering because
for sure this patient the first cause of hypertension must be the radicalization by
the autoimmune disease, but it should be
interesting also to perform an renal ultrasound, doppler, just to
discover renovascular disease in this patient with
such high hypertension and so difficult to treat. – It’s almost as if we
planted that question. (Eve laughs) – So we did do some of these tests. We unfortunately didn’t do
the renin and aldosterone because clinically he was
mildly fluid-overloaded at this time. We didn’t feel that we could
interpret them in the context of all the medications that were done, but I think it’s a very
good point that was raised. His urine catecholamines were normal, he still has immunological
evidence of active lupus, and because we haven’t done these before, then he did have an MRI of his abdomen and it didn’t show any adrenal masses and he didn’t have any
renal artery stenosis. And again, just as you
say, this was precipitated because things were behaving not as we had anticipated them doing. So what’s the diagnosis here? I might skip over this for time reasons. – [Garry] I think if you
keep moving now, we’ll– – With no evidence of infection, his neurology did correspond
to the blood pressure and the radiological appearances
were consistent with PRES, but his blood pressure was
unusually difficult to manage and we’d usually expect it
to recover quite rapidly, and he had ongoing
evidence of active lupus. So we kind of covered both ball parks here by treating both his lupus and then as may of you suggested before, at this point we were in a position to aggressively offload his salt and water and use an aldosterone antagonist. He had high-dose steroid plasma exchange and also was re-treated with MMF, which he’d never had a full dose before, and as you can see, the
diuretic change resulted in an eight-kilogram weight loss and his blood pressure came down. He was discharged about two weeks later. Neurology was back to normal, but he’s still on many, many agents, dual RAAS blockade,
calcium channel blocker, et cetera, et cetera. You can read them all here. But actually, he didn’t
remain on those for very long. His blood pressure came down
to 130, 140 over 80 to 90, and we could rapidly
withdraw his diuretics and some of his more
centrally-acting agents. And by about six weeks, he
wasn’t on very much at all. At the same time as this,
his lupus was melting away, so he had full remission
of his nephrotic syndrome within four weeks of
this acute presentation, with his proteinuria disappearing
to about .5 grams a day. In keeping with this,
his immunology improved and his inflammatory markers went down. He was discharged in the
long-term on dual RAAS blockades, a beta blocker, as was
rightly pointed out earlier, and furosemide twice a day. So we got there in the end. And his renal function stabilized. He still had quite
significant renal impairment, but it certainly wasn’t getting any worse. A repeat MRI at six months
showed resolution of the changes that we saw previously and so
we felt this was a diagnosis of posterior reversible
encephalopathy syndrome within the context of active lupus. His blood pressures improved by diuresis and offloading of salt and water, aldosterone antagonism, and
also the remission of his lupus. That was probably induced
by the combination of plasma exchange and MMF, but also this was eight
months post-rituximab, so there was definitely a B-cell
effect still going on there but it took all of our immunosuppression to get on top of the lupus. I’ll just maybe skip over this bit because we’re short of time. And really just to reiterate that PRES is actually quite a big risk in patients with lupus. They have pre-existent
endothelial dysfunction both because of their
immune complex mediated endothelial damage and also
because of the cytotoxic drugs as have been mentioned, and they’re also hypoperfusing anyway because of their renal impairment, fluid retention and hypertension and that creates a perfect storm. He’s the first of a number of patients that we’ve seen present like this with difficult to control lupus and then end up in a crisis with PRES. So in summary, our patient had posterior
reversible encephalopathy syndrome in the context of active lupus. It was managed with
blood pressure control, diuresis, and treatment
of underlying lupus. We’ve discussed the
treatment of hypertension in the context of an autoimmune disease, management of hypertensive
emergencies, and PRES. Thank you very much. (audience applauds)

Leave a Reply

Your email address will not be published. Required fields are marked *