Good evening, everybody, and welcome to another Thursday night members webinar. My name is Bruce Stevenson, and I have the honour and privilege of chairing tonight's webinar. We have a well-known speaker to all of us.

Beno is back with us. I'm pleased to be able to say, if you're anything like me, I really enjoy his lectures. And Beno was a graduate of the National Veterinary School of Toulouse in France.

He's also a diplomat of the American College of Veterinary Internal Medicine. And his areas of interest include haematological and immune-mediated disorders, bone marrow diseases, as well as urology and nephrology in companion animals. Beno, welcome back to the webinar vet and over to you.

Thank you very much. Welcome, everybody. Welcome for another talk tonight.

Tonight we are gonna discuss endocrinology for once and look at, . a fairly rare but probably a bit underdiagnosed disease of cats, which is feline hyperaldosterism. So hyperaldosterinism is, a hyperactivity obviously of the adrenal gland with an increased secretion of, .

Aldosterone, in humans, it's called KO's syndrome, and basically it's an excessive autonomous secretion of mineral corticoids, and that leads to a clinical presentation with arterial hypertension, hypokalemia. It was described in humans first, and that was in a Woman in 1955 by Doctor Kons who gave his name to the disease, . And at the time we started to investigate that disease in people with hypertension, and there was a suspicion that this could contribute to about 20% of the population of humans with hypertension.

Then as the diagnosis, improved and you will see through the presentation that the diagnosis of that disease can be sometimes a little bit challenging at first. As the diagnosis improved, they refined the numbers to 10%, . Which would be still something quite significant for a disease prevalence.

And I think nowadays they have finally refined that, to about 6% of, hypertensive patients in humans, that have hyperaldosteronism. And, if you take a subcategory of these patients, which are patients that are refractory, to, hypertensive medication, so therapy resistant, hypertensive patient, about 11% of them have hyperaltosteroidism. In cats, primary hyperaddosteronism is the most common adrenocortical disorder, and it is associated, just like in humans with arterial hypertension.

Cats have been determined to be the pet or the mammal after humans that have the most elevated prevalence of hyperaldosterinism. And it's very rarely described in other species. It's really not something we consider in in dogs, for example, when we investigate, hypertension.

Because we know it's underdiagnosed in humans, we suspect that probably it's also underdiagnosed in veterinary medicine and probably underdiagnosed in cats. And one of the reasons for that might be that the diagnosis is not straightforward and requires not a lot of tests, but some tests that might be a bit finicky to obtain or at least to obtain in general practise. A lot of these cats will have some degree of chronic kidney disease.

The question is, if you see a cat in general practise with hypertension and hypokalemia and he has a mild azotemia, the easy conclusion is to say that this cat has chronic kidney disease and treat that cat as if without pushing further and investigating eventually an adrenal disorder. The other thing is, how often do you measure your blood pressure in your practise? And that's really something that could change our ability to recognise early that disease, because we know that blood pressure is challenging to obtain, and even more so in cats, they are sometimes a bit misunderstood, let's say.

And difficult. So, obtaining your blood pressure is not always the easiest thing to, to do. But by, by skipping that step, and, and we do it too, even in, in order for practise, sometimes you, you just can't.

But by skipping that, you might not recognise hypertension and therefore not investigate a patient with that disease. And some of them can live very well without addressing the disease, although it probably shortens the lifespan in the long run. I want to start with an unusual case that I've seen, back in Canada when I was a resident.

And, it was a very young, Bengal cat, called Baxter. He had about a 1 month history of being inhabitant with a progression prior to his presentation to us, to complete anorexia for about 24 hours. He was very lethargic and the owner actually reported that over the past few days prior to presentation, it was actually very dull, which is something we confirmed upon presentation.

The owners were also very questioning how much that cat was drinking, and they had had a cat before, but, you know, like it's hard to know sometimes exactly how much a cat is expected to drink. It's just they felt like they were seeing the cat going to the water bowl more often than they were expecting to. Despite mirtazapine administered by his referring veterinarian, there was no improvement in his appetite.

Looking at his past medical history, well, obviously it's a young cat who was up to date on vaccine. It was treated against fleas, and he had received all of that 4 days prior to his presentation. Other things in the history included a move to a new house about a month before, as well as a change in diet from his .

Ketten diet to an adult food, about a month prior to the presentation. So this was Baxter. On physical examination at is referring veterinarians, he had administered some fluids because the cat appeared to be a bit dehydrated.

They also had run some bloods and they had seen a mild hypokalemia with hypernatremia, and they decided to refer it to the Ontario vet College. On physical examination, upon presentation, the cat was dehydrated with a dehydration that was estimated between 5 and, 7%. He had a marked cervical ventral flexion and he was looking very dull with like his front legs spread and his head kind of like, pointing towards the, the table, or sometimes even leaning on the table and quite reluctant to move from that position.

His heart rate was 180, his blood pressure was normal with a mean of 135 and a systolic blood pressure of 150, and the rest of his physical examination was otherwise within normal limits. We performed a venous blood gas upon admission to confirm the anomalies that have been described by the referring veterinarians, and we could confirm that there was a mild hyperremia with a sodium of 162, and there was a fairly marked hypokalemia with a potassium of 2.4.

There was also a m hyperkloremia and mild acidosis, associated with that. So Baxter was admitted into our hospital right away because of his dullness and his weakness. We started to aggressively replace his potassium to try to help maybe a little bit with his mobility, his demeanour.

To do that, we administered a CRI of potassium. So we often say that potassium is dangerous and that's true, and it has to be cautiously administered to your patient. But one way to administer it in patient are profoundly hypokalemic is to perform a CRI.

The recommended dose is 0.5 million equivalent per kg per hour over 4 hours, and then you repeat a blood gas. You don't want to do it for too long, obviously at that rate.

You need to make sure that you have fresh and nicely placed IV because it's quite a high concentration of potassium. And we had to repeat that CRI twice because despite the first one, this potassium had not increased significantly from the 2.4 that we were starting from, .

Once you have reached the level of potassium that you want, you can then switch to supplemented fluids to maintain the potassium. This aggressive CRI is really meant to replenish the circulating potassium in the patients. In the meantime, while he was receiving the CRI obviously we gave him fluids with no potassium supplementation.

And we could actually see that he was markedly PUPD. Like, it's rare to see cats drinking, it's even more rare in hospital right away when they are stressed in an environment that they don't know, and that cat was like pitching himself into the water bowl all the time. So if we try to summarise what we have at the moment, we have a young cat that has been presented for one month history of inhabitants, lethargy, all of that associated with dehydration, cervical ventroflexion, PUPD Mar hypokalemia, and mild hypernatremia.

If we start to look at our differentials, what are the differentials for hypokalemia in a cat? Well, as I said in the introduction, chronic renal failure is probably the one that comes first into mind. We also have to consider depression with chronic vomiting and diarrhoea that can be worsened by anorexia.

There can be iatrogenic hypokalemia that are induced by aggressive fluid therapy or diuretic therapy, where potassium is going to be excreted at the level of the kidney, but not replaced. Insulin overdose will lead to a shift of potassium to the intracellular space and therefore hypokalemia resulting from that. Metabolic alkalosis will also operate a shift from the extracellular to the intracellular level of storage of potassium.

Hyperaldosterinism is in the list, shocking. We also have a few infectious diseases, sepsis that can lead to decreasing potassium, renal tubular acidosis, thyrotoxicosis, and in Burmese, there is an idiopathic form of hypokalemia that has been described and associated with some certain type of myopathies. If we look at PUPD now as a differential for a cat, we have to still do the dichotomy between primary polydipsia and primary.

Polyuria. If we look at the differentials for polydipsia, hyperthyroidism, hepatic encephalopathy are both reported to lead to polydipsia. Hyperadrenal corticism, which in a cat would be very, very exceptional, and psychogenic polydipsia.

Looking at polyuria, chronic kidney disease is in the list. Again, diabetes mellituss and acromegaly have been also reported obviously to be associated with polyuria, diabetes incipidus, tubuloatis and Fanconi syndromes. Sorry, post obstructive diuresis, which is quite, common and we see very often in cats when we unblock them, obviously.

And then a medullary washout induced by liver failure, a shunt, hyperthyroidism or hyperadrenal corticism, meaning that there is not enough tonicity between the cortex and the medulla of the kidney, and there is an easy passage of water from the circulation into the urinary tract. Pynephritis pyometra are also associated with PUPD and primary hyperaldosteroneism is also associated with PUPD due to the action of aldosterone, the retention of sodium, and the increasing thirst. So what diagnostic test did we decide to perform with Baxter?

And you can see Baxter and his kind of water bowl here is actually halfway between the litter box and the water bowl. Very, very convenient. We performed a complete blood count that was fairly unremarkable.

We performed a biochemistry profile which confirmed the hypernatremia and the hypokalemia which we had identified on our, blood gas. We also had on that biochemistry panel, phosphorus that was normal, a urea that was barely elevated. There was no elevation in creatinine, and there was an increase in CK activity to 874, for an upper limit of 362, so starting to become a significant elevation in CK.

The urinalysis showed a decreased urine specific gravity. The cat had received fluids at his vet, but that seems to be a bit dramatic for just fluid administration at the vet. We also performed an abdominal ultrasound and we had a myelecttesia at this point.

Again, the cat was on fluid, so difficult to interpret the electteia. So if we want to update our differentials based on these results, we have a cat with hyperkalemia and PUPD. Hyperaldosterinism is really something that has to be considered because it's present in both differentials.

Tubular disease has to be considered, diabetes incipidus has to be considered, and psychogenic polydipsia has to be considered. Other diseases could have been investigated a little bit further. We didn't do proper liver function testing and probably in retrospect it's something that I would have performed, like a bile acid stimulation test or at least an ammonia to confirm that the liver function was normal.

All of the markers, the indirect markers of liver function were normal for this cat. So looking at glucose, urea, bilirubin, albumin, and cholesterol, there was no suspicion of a liver disease there, and there was no indirect signs of a shunt or suspicion for liver disease on imaging either. But that probably would be the other last thing that I would have ruled out in this patient.

Based on the suspicion of hyperaldosteronism, we decided to do some more specific tests. We looked at the cat's urine and we performed what we call a urine biochemistry, which allowed us to measure urine sodium, urine potassium, urine creatinine, and with that we managed to calculate what we call a fractional excretion for potassium, and eventually one for sodium if you want. The fractional expression of an iron is, the ratio roughly between the, the urine concentration of that iron to the plasma concentration of that iron, and this is kind of corrected by the creatinine concentration to try to alleviate the effect, the effect of urine dilution.

It should be fairly low in terms of, the fractional excretion of potassium in a healthy animal below 5%, and it was 46% for Baxter. We're also trying to do a modified water deprivation test to investigate the possibility for diabetes incipidus. However, they are quite challenging to perform if you want, well, they are quite dangerous to perform if you were to do them by the book, so we don't really do them, properly.

We do that modified version where we administer. The DAVP to the patient and we see if there is a response. And if there is a response, you, you have your answer.

There was no response for Baxter, which doesn't completely rule out diabetes insipiddus, but leave the door open for all of the other differentials that we had left in, in our list. And finally we decided to measure aldosterone levels, and they came back very elevated with an aldosterone over 1000 for an upper normal range at 388. So if we dive a little bit further into aldosterone, we have to start with aldosterone physiology first.

As you remember, the adrenal cortex consists of three different layers. The outer area is called the zona glomerullosa. It's a very thin layer, as you can see on the Ito picture in the middle, .

The middle region, which is probably the biggest region, is called the zona fasciulata, and the third layer just before the adrenal medulla is the zona reticularis. The difference in hormones that are produced in these different areas. So the zona glomerullosa is going to produce the mineral corticoid, of which aldosterone is the most known and the most prominent one.

The zona fasciulatta is going to produce more glucocorticoids such as cortisol, corticosterone, and cortisone. And the zona reticularis is gonna produce mostly androgens, . And other sexual hormones, although it's been shown that dona fasciulatta and zona reticularis share a lot of hormones that they produce in common.

But the difference in the hormones that are produced in these different layers lays in different expression of cytochrome P450. And as well as difference in concentration and presence of specific enzyme. So if you remember this diagram from, vet school, and we are not going to go through that in detail, but basically each column represents a different layer and that will depend on the concentration of your cytochrome P450 and of your, 17 alpha hydroxy.

Sorry, 17 alpha hydroxylase enzyme, which is the most important enzyme to process all of this, derivative of cholesterol to produce steroids. So the more concentrated they are, the more transformation you obtain, from your cholesterol, to have your androgens, your cortisol, or your aldosterone as a final product in each of these different layers of the adrenal, cortex. Now if we look at the regulation of aldosterone secretion, you will all recognise this diagram.

It's the diagram of the renin angiotensin and aldosterone . System, and it is well known and well described that the Renin angiotensin aldosterone system, is the main, part of the control for aldosterone secretion, but it's also been shown that potassium concentration is the second most important mechanism to directly control aldosterone secretion. So these two primary mechanisms are coexisting to induce in the adrenal glands the secretion and release of aldosterone in the system.

The RAS system keeps the circulatory blood volume constant, and to do that, it promotes aldosterone secretion because aldosterone will then induce sodium retention and then combat hypovolemia if hypovolemia were to be present. Or it can very, very quickly reduce the secretion of aldosterone and therefore reduce the sodium retention if you were to be overloaded and have an expansion of that circulatory blood volume. Potassium ions will act directly at the level of the adrenal glands.

They are completely independent of the Iranian endiotensin system, and there is a negative feedback loop based on potassium concentration or a negative feedback loop on running angiotensin system, and they are both completely independent. In addition to that, there are other mechanisms that can induce aldosterone secretion. And one of the most common one is ACTH.

ACTH is well known for its relation with the adrenal glands and among all of these effect on adrenal tissue, it will induce the production and secretion of aldosterone. In the in the adrenal cortex. However, it is not a necessary hormone for aldosterone production.

It's a very potent acute aldosterone secretagogue, which means that in moment of stress when we need to release, steroids, all of them will be induced by ACTH including the mineral corticosteroids such as aldosterone, but the action doesn't need to be sustained and it's not sustained because ACTH production is so pulsatile. And the presence of ACTH is not necessary to maintain, a normal glomerulosa cell function and therefore a normal aldosterone, synthesis and, release. So just a quick reminder on the RAS system because it's important, even though it's not directly involved in hyperaldosteroneism, you need to understand it and remind, remember it so that you understand the consequences of the hypersecretion of aldosterone.

So the RAS system is meant to control and tightly regulate the circulating efficient volume within the blood vessels. Therefore, if there is any change in that. Volume there will be changes in renal perfusion, which will stimulate the barrow receptor at the level of the juxtalomerular apparatus and that's a lot of big words that you've heard in lectures many, many times I'm sure.

Basically barrow receptor means that they are all. Going to be able to perceive the change in pressure and the change in that corporeal circulating volume and the juxta glomerular apparatus is just very specialised cells that are sitting just besides the glomeruli in the kidney. These cells Well, the stretch of this receptor will change based on the pressure in the afferent arterial, and that will stimulate the release of renin, directly due to these changes in renal perfusion.

In addition, another factor will be involved, which is the concentration of sodium within the tubules. So that the amount of sodium that is excreted in the urine will also eventually have an effect in the sense that it will be measured by other specialised cells of the kidneys that are called the maculadensa. And that will also eventually induce the production and release of renin by the kidney, which makes sense because if you excrete too much sodium, the body is going to try to keep some of it, and maintain some of it to maintain the, the, the volume that's circulating in the blood vessels.

And you have to remember that all of these mechanisms are very tightly controlled, so, . You know, one minute there is a bit too much sodium, so there is a bit of renin that is released, and then there is a bit not enough sodium, so the renin production is inhibited and it's changing all the time like this to maintain kind of a very steady state of homeostasis. So that's for the synthesis of renin, and then in the meantime, angiotensinogen is produced by the liver and released into circulation.

It's a well-known precursor for all of the angiotensin peptides that we are going to discuss in 2 seconds, . And as it's circulating within the bloodstream, it's cleaved by the renin that has been released by the kidneys, and it's gonna release a new peptide that is called angiotensin one. So all of that happens in this this the bloodstream in circulation.

Then the angiotensin converting enzyme, the famous ACE, which we know quite well because we prescribe quite a lot of ACE inhibitors, will then convert that angiotensin one, which is fairly inactive into an angiotensin 2, which is the really active form that we are interested in today. That angiotensin too. Sorry, that angiotensin too will then stimulate at the level of the adrenal cortex, the production and the release of aldosterone, .

And that is mediated through some specific receptors, which will then lead to also vasoconstriction, cell growth on top of the aldosterone production. So when you inhibit, the angio angiotensin converting enzyme ACE inhibitor, will, will prevent the formation of angiotensin and therefore prevent the formation of aldosterone, and that is to try to regulate the volume of circulating blood, as part of the mechanism of that treatment. Angiotensin 2 will regulate the GFR as well and renal blood flow because it has a direct action on the efferent and afferent glomerular arterioles.

So there will be a direct effect of angiotensin on the kidneys, but the major effect is coming from aldosterone. And aldosterone has two very important physiologic actions. The first one is to regulate that extracellular fluid volume, and the second is that it's a major determinant in potassium and ostasis, but as you will see in the next few seconds, that is an indirect effect of aldosterone.

Aldosterone is binding intracellular receptors, so we'll go through the membrane and bind to receptor in the scitosol of cells, and the cells with the most receptors are obviously in the kidneys, but also colon and salivary gland. So in the distal convoluted tubules of the kidney, aldosterone is going to induce sodium reabsorption. So this is where we are here.

The sodium being reabsorbed is gonna drag water with him and therefore increase the volume of the extracellular fluid. And by that increase the circulating efficient volume in the vessels and increase the blood pressure indirectly. In the meantime, as there is an influx of sodium in these cells at the level of the tubules, there is an activation of potassium transfer, for an equilibrium of, of charges.

So there is such an influx of sodium that there is a passive transfer of potassium from the tubular cells into the urine, to compensate the influx of positively charged sodium. So as you see, the potassium loss, the potassium excretion is not a direct effect of aldosterone. It's not an controlled effect of the aldosterone.

It's just a consequence of that sodium reabsorption, which is really what aldosterone is mainly doing. You can see that there are 2 other arrows from aldosterone going to the heart and the arteries, and there are effects of aldosterone on endothelial cells and on cardiac tissue to contribute to blood pressure homeostasis. So on top of that sodium and water retention, there will also be a direct effect of aldosterone on the muscle heart and on the arteries to promote vasoconstriction and .

And increase the blood pressure with other mechanisms. That was that. So now if you think of hyper aldosterism, what are the pathophysiology and the aetiology behind the disease?

Well there are two pathophysiological mechanisms that we have to consider that will lead to eventually a hypersepression of aldosterone, and a decrease in the effective arterial blood volume. That would be the first one. So if you have a decrease in that effective arterial blood volume, a hypovolemia, if we want to simplify it, you are going to stimulate everything we've just discussed at the level of the kidneys and induce secretion of renin.

You're going to activate that renin angiotensis system, and that is quite common if you have heart failure, for example, you have a decrease in the Sorry, you have a decrease in the effective circulatory blood volume. If you have edoema, third spacing, hypoproteinemia, you are also having alteration of that arterial blood volume, effective arterial blood volume, and therefore an stimulation at the level of the kidney of the release for renin. And that will activate the RAS, which will lead to an increase in aldosterone.

And well, the effect will be the increase in the blood pressure to, you know, correct the hypovolemia that has been detected. That will lead to what we call a secondary hyperaldosterinism. So if you measure the aldosterone in that patient, it's going to be high indeed, but the renin activity in the plasma will also be high.

And so secondary hyperaldosterinism is called hyrein high aldosterone or hyrenin hyperaldosterinism, and it's induced again by a decrease in that effective, circulating blood volume. In contrast, the autonomous and excessive aldosterone secretion is called primary hyperaldosterinism. And that is associated with the primary adrenal disease.

So it can be due to an autonomous secretion because of an adrenal cortical tumour, such as an adenoma or a carcinoma, but there are also hyperplastic zona glomerullosa that have been described in humans, with a bilateral, micro nodular hyperplasia that is reported, in humans, and that has also been described in cats and we, we will get to it in a minute. The number of cats that have been reported with that disease is low. We are probably looking at in total in the literature, something like 30 to 50 cats.

So, you know, we, we, we have a good idea of what's wrong, but we don't have that many numbers to exactly know how many of which category we are supposed to expect when we when we see a patient, . The majority of the cats that have been reported have a unilateral adrenocortical tumour. Both adenomas and carcinomas are, are quite prominent, and that is coming because some of these studies were postmortem studies and so they were based on what do we find on postmortem in cat adrenal glands.

And also some of the cat that don't die and have not a full diagnostic because we don't have the histology are maybe under detected or not considered to have primary hyperaldosterism. So we, we don't have a good feeling of the prevalence of each of the subtype. But these are the three diseases that will lead to an increase in your aldosterone secretion and aldosterone .

Sorry, circulation. The cats with tumours may or may not have metastases. Metastases are fairly rare, but local invasion of the vena cava has been described in both humans and and cats.

And then if we look at the humans, bilateral hyperplasia of the zona glomerulosa, accounts for about 60 to 65%. Of benign cases, versus adenomas being 30 to 35%. So in humans, we know that that hyperplasia is actually fairly common.

When we discussed the diagnostic test in a few slides, you will realise how they, they can be much more certain than we are about what's what's wrong with, with humans versus cats. So in cats that hyperplasia has been described, the the tumour has been described, and then you have that aldosterone and, and what do you think will happen? You have all of the clinical signs that are associated with the high aldosterone, and you have a low renin that is associated with it because there is a feedback that says that there is enough aldosterone in the system, that there is no need for renin to be secreted.

So if you have a primary hyperaldosterism, and that's the big difference between the two types and the The gold standard to try to diagnose them is your primary hyperaldosterinism has low renin high aldosterone, so it's a low renin hyperaldosterinism that we are facing. Just because the image is very pretty, this is a cat with nodular hyperplasia. So, well, these are two cats I should say the left picture, you can see a normal adrenal gland and you can see the C for cortex that is.

Through 3 layers, a thin orange layer at the top, a more clear layer in the middle, and then a slightly more dense pink layer at the bottom before reaching the dark medulla that is indicated by an M. And on the right side you can see that the stain that was so small at the top of the cortex on the left image, that staining that is specific for . Sorry, that staining that is, is specific for the zona glomerulosa is everywhere.

So there is an expansion of nodules, and, and that is compatible with primary hyperaldosterism in, in that cat. Now if we look at the clinical presentation, primary hyperaldosterism occurs mainly in cats that are middle aged to older. And in the studies, cats are often ranging from like 345 to 18.

So Baxter was very unusual because he was very young and and that's kind of maybe threw us off a little bit at the very beginning. If we look at the pathophysiological consequences of excessive aldosterone secretion, obviously there is an increase in that sodium and water retention, and there is that massive potassium excretion or potassium loss through the urinary tract, and that will lead to the clinical signs that we need to know to be able to recognise them. One of them is systemic arterial hypertension.

And the other is a myopathy associated with your low potassium. So the progressive depletion in potassium, and you lose so much that even if you eat, you don't compensate the losses of potassium that that are occurring will lead to hypokalemia and eventually affection of different organ systems, but the neuromuscular system is particularly dependent on potassium and potassium concentration. Because then the polarisation of nerves and muscle membranes is gonna be affected if the potassium is not available.

Therefore, muscle weakness is a very common clinical sign for hyperaldosterism. And if you remember Baxter, he had about the same position as the cat on the picture with, you know, a weak cat with his neck kind of like an extension and flex, ventrally. And that cervical ventroflexion is quite well known to be .

A sign compatible with with hypokalemia, so it, it should ring a bell and if you see cats presenting with this cervical ventral flexion, . You should consider that they might have hypokalemia, but these cats have a general muscle weakness like they are sometimes reluctant to move, sometimes they are very like flaccid, looking almost paralysed, and it worsens as the potassium is the lowest. Potassium is usually around 2.5 in this in this patient.

Some cats will have plantegrity as well, just like if they had diabetes. So you can see all type of manifestation of, a myopathy in this patient. And then in other cats, the presenting kind of signs will be more due to that hypertension.

Due to the retention of sodium and water, and that is usually associated with acute blindness in cats, with retinal detachment or intraocular haemorrhages, and that's really the main, the main one. You can have sometimes behavioural changes, or you know, other more subtle signs of, of hypertension, but unlike us, they can't really complain about headache, so we have to find other ways to suspect that they might have hypertension. When we run our, our first laboratory tests, the most consistent finding is that hyperkalemia, and it's quite pronounced, as you've seen 2.4, 2.5, it's often associated with other laboratory changes, and These are usually mild, like a metabolic acidosis, which was the case for Baxter, a mild hypophosphateemia, which we did not have, hypomagnesmia, we did not measure.

And then the increase in CK activity, which is associated with the myopathy that is reported and the inability of the cats to move. And then azotemia can be present as well in. In bloods, and, that's when the question of CKD comes up.

Is the CKD the cause of the hypokalemia and the hypertension, or is the CKD a consequence of the high mineral corticoid concentration? And as we said, aldosterone can penetrate in many cells and activate a lot of things. And among Things we know that it can be a bit pro-inflammatory and lead to sclerosis, fibrosis, damages in the renal tissue, in the long run.

So therefore, if you identify CKD with a very low potassium, please measure the blood pressure and maybe consider investigating a little bit further because there might be more to it than just a regular CKD. If we want to obtain a diagnosis, we need to measure aldosterone, and it's been shown that with adrenocortical tumours, the plasma aldosterone concentration is usually very high, and, in cats with idiopathic hyperalduosterinism, they are. Sorry, to kind of situation somewhere we have that very high aldosterone, but sometimes it's a bit more mild, like it's just above normal and we know that.

In endocrinology, all of these analytes are sometimes a bit finicky and a bit difficult to measure. So is it really accurate? I think if you have a mild increase in aldosterone in face of a severe hypokalemia, yes, because it should be considered abnormal for a patient that is severely hypokalemic.

To have a high aldosterone because the feedback loop, remember, is directly induced by the concentration of circulating potassium. So you should not have any elevation of aldosterone. So if it, if it's at the high end of normal or just.

Above the end of normal, I would start to become suspicious. And that's probably what we see more with hyperplasia and bilateral hyperplasia versus the tumours where it's like, boom, a massive burden of cells, they just secrete aldosterone and you have a very, very elevated aldosterone. The classic primary hyperaldosterism is that increased plasma aldosterone and decreased plasmare activity, and that duo is that low renin hyperaldosterinism and it's quite pathognomonic for primary hyperaldosterinism.

If you measure both, usually we use a ratio of aldosterone to rein ratio. And that has been shown to be the gold standard in feline, but also human medicine to highly suspect primary hyperaldosterinism. And I say highly suspect because unfortunately, you, you need to know for sure what is wrong with the tissue to to be able to pose a diagnosis, and that's not something we, we would do unless we remove the adrenal glands or we have a postmortem.

There are other tests that have been described to try to confirm the presence of hyperaldosteroneism, and that includes a urinary aldosterone to creatinine ratio. You know, we, we like to measure, adrenal hormones in the urine, a bit like you do, urine cortisol creatine ratio. Here you would do a urine aldosterone to creatinine ratio.

It's easy to obtain. There is less pre pre-analytical challenges than with aldosterone or renin. Rein is quite finicky to obtain like you need probably to have.

Blood and an ice bucket just there to freeze almost right away. Like if you were to do these things, you can do some of it in general practise and, and I'm encouraging you to do so if you suspect that disease, but please contact your lab ahead of time. Before even the cat arrives to your, like, you know, schedule the blood at a specific time and contact the lab to know what they exactly need before the cat arrives and being stuck with like blood in a syringe, the wrong tube, and not knowing what to do anymore.

But most of them can be performed in in general practise. You just need to be, aware of the pre-analytical requirements. For the UACR, there are none.

You just need to obtain urine, can be obtained at home with no absorbent litter. So that's something that's very easy to do. The problem is a bit the same as with the UCCR, .

If you have a very high UACR, it's suspicious for hyperaldosterism, but it's never diagnosis diagnostic because the reference range for that test are very variable and the numbers seems to vary quite a lot from cat to cat. The other thing we like to do in endocrinology is to do a dynamic test. So here, a dynamic test that would use a suppressive agent which would reduce aldosterone secretion in healthy cats, but not in affected cats would be ideal.

And what has been tried is to use fludrocortisone, which is a drug that you know well because it was used for treatment of Addison's disease and it has a strong mineral corticoid balance. To try to suppress the activity of the adrenal glands. The other thing that this, this test has been developed with is to use the urine test to look at the efficacy of the rudrocortisone for practically and, and cost.

And it's been shown that rudrocortisone administered orally for 4 days in healthy cat. Would, would lead to a decrease of the UACR by 40%. So that's good.

It means that if you are a healthy cat and we give you mineral corticoids, you decrease your own production of mineral corticoids. So that's good. That's what we were expecting.

The protocol was 4 days of administration of ferrocortisone and then measurement of the UACR and then. They tried to study it in client owned cats with arterial hypertension and primary hyperaldosterionism. So, they had 9 cats with primary hyperaldosterism and 10 cats with hypertension of other causes.

And they've shown that all of the cats, so 9, all of the cats with primary hyperaldosterism had a basal UACR that was above 7.5. And in the other group, all the cats that had UACR above 7.5 would then have a decrease of more than 50% of that UACR once the ferrocortisone was administered with a decrease that was much less significant in the cats with primary hydrosterinism.

Again, small number but interesting results, and that is maybe a protocol that will be developed in the next few years to to try to diagnose that disease a bit more easily than, than we can at the moment. Teelmisartan, so Telmisartan is an angiotensin 2 receptor blocker, which could eventually help diagnose hyperaldosterinism in cats because it's gonna help with inhibiting the secretion of aldosterone as well at the level of the, of the. Of the cortex, there are discussions about it.

There are a few institutions that I think are trying it, but there is no, publication yet that, kind of test of the efficacy or not, and, and so forth about that test, dynamic test using thermisartan. To continue our investigations and you know, I think we all have in the back of our mind, what if it's just CKD and that's why they are hypertensive and have hyperkalemia, and I think imaging is obviously something that is important for you to have maybe a bit more certainty that there is no. Changes in the kidneys that are compatible with CKD.

It's also gonna help you see if you have a massive adrenal tumour. Well, you know, let's, let's take it reverse. You think the cat at CKD and you do an abdominal ultrasound to stage the CKD and you find a massive adrenal tumour, maybe that will explain his hypertension and his hyperkalemia and maybe that will help you.

Send and initiate more investigation for hyperaldosteronism. So just like with CKD imaging is indicated, and it has a few advantage. One of them is to try to identify a mass versus hyperplasia.

Because obviously if there is a single unilateral mass, then eventually, an adrenalectomy will be, will be recommended and so forth staging prior to surgery is part of this. It's been shown obviously that it's hard to differentiate between tumours and benign process, with, with DI . And in humans and even in in dogs, they have described ultrasound, MRI, CT of the adrenal glands.

They can describe anatomical abnormalities, but they can't really tell you anything about secretion. They can tell us if there are suspicions of metastasis, so that's good, and they can therefore be a great asset for planning of surgery because it's important for your surgeon to know if there is a mass. And an invasion of the vena cava, or just a mass because the surgery, which is already quite a challenging surgery is not gonna be exactly the same if there is already a vascular invasion.

It's also important to realise that we, we, we are dealing with very small patients. And the resolution of our machines are not necessarily the same as in, in humans. In humans they have been trying to find a way to determine if the adrenal glands were secreting, if they were both secreting, one secreting, if, if there was really hyperplasia, they have some humans with what they call micro nodular hyperplasia, where the shape and the thickness of the adrenal gland is actually barely changed.

So what happens is that they have introduced adrenal veins sampling in humans, using a catheter going through the femoral artery, sorry, the femoral vein and up into the vena cava and into the adrenal veins. And so they are actually in humans able to tell you if the excess of aldosterone is coming from your right or your left adrenal and therefore the, the planning for surgery or the diagnosis is . Definitive with that because.

You know, like in dogs, if you scan adrenal glands of all cats, you're gonna have bumps and lumps and then becomes like, OK, which is what are they significant? What do they represent? At least in humans, they can tell you, OK, the right is normal, the left secretes way too much, or both secrete way too much and you have hyperplasia.

So that's why in humans they managed to have like a definitive diagnosis, antemortem or anti-surgery, which we unfortunately can't achieve in cats. So if we go back to Baxter, we measured this aldosterone, as we said, it was above 1000. We measured the plasma in activity, which was a low end of normal, so not as suppressed as we, were hoping, but again, the tests for that are a bit finicky, what can we do with them?

So we decided to go with the ratio and the ratio was very elevated, so we, we decided that Baxter had primary hyper, altosteronism. With his low renin and is very, very high aldosterone. Also, that cat didn't have hypertension, didn't have renal disease.

There was no evidence of a tubuopathy, so we had no other good explanation for his potassium loss. If we think about treatment now, surgical treatment is, the treatment of choice if you have confirmed a unilateral primary hyper aldosterism, and if you have no metastasis at the time of imaging, adrenalectomy can be performed with a variety of technical surgical techniques, more and more often laparoscopic adrenalectomy are available in our referral practises. And I, I'm pretty sure it will eventually become the surgical procedure of choice because the recovery is so much nicer.

In cats, they are smaller, less common, so probably it's gonna be open surgery for a little more while, but there are a lot of places that do laparoscopic adrenalectomy, in dogs at the very least. If there are invasions of the vena cava without any other, visible metastasis, they can remove the tumour amboli with the adrenal vein, the the adrenal gland, and do a venotomy at the same time. So obviously the hyperkalemia has to be corrected before, the surgery.

There is always a risk in cats because we don't do that adrenal vein sampling, that you remove a mass that is a benign mass and the actual mass is a small mass on the other gland that you didn't see, maybe, and that will continue to secrete. So I think I would still tell the owners that there is a chance that we will not be completely curative and at least if the expectations are, You know, not too high, and you succeed, it's great, and if you don't, at least they were aware of of the risk. The survival that is reported is very good, although again, it's just a handful of cats, so hard to know exactly.

And also I think it's a challenging procedure. So some of these retrospective studies are a bit old. The operative mortality surrounding, adrenalectomy has drastically improved and even in dogs, we know that the numbers we have are very old and probably now the survival around the surgeries are much better.

It's important to treat the hypokalemia, as I said, and it's also important to, not overdo it because once you're going to remove the tumour, you don't want the cat to become hyperkalemic because that would be another problem to treat. Some of these cats we also need to receive, fudrocortisone therapy like a disonian patients because if you have a unilateral tumour, most likely the contralateral gland has been completely inhibited. So Main complications are haemorrhage and and canal cavalveotomy if there is an accident at the time of surgery, the vena cava can be affected.

The medical management can be considered in a few cats as well if you're stabilising your patient prior to surgery or if surgery is contraindicated because you've diagnosed your cats with a bilateral hyperplasia of the zona glomerulosa and therefore you can't remove both adrenal glands. Finances obviously will play a role there or comorbidities that may prevent a patient to go to surgery. The treatment is usually mineral corticoid receptor blocker and potassium supplementation to try to counteract the effect of the aldosterone hypersecion.

And then if the patient is hypertensive, a treatment for hypertension is also needed. Often the treatment of choice is spironolactone, because it is an aldosterone receptor blocker, and the initial dose is 2 milligrammes per kilogramme and it's Twice a day, oral medication, very easy to administer, very few side effects. There is one case series that reported that cats taking spironolactone for a variety of diseases, mostly heart disease, had some cervicofacial ruit, but that's the only known, side effects of that drug.

And potassium supplementation, oral supplementation, food is very important. Amlodipine, of course, if there is a persistent hypertension, like spironolactone is a very weak anti antihypertensive, so amlodipine can be added to the mix and try to treat that hypertension, obviously. And eventually thermisartan can be used to treat the hypertension if needed, but it should not have much effect on the aldosterone, .

Because it's, it's, it's doesn't really block directly the aldosterone. Survival times again, we only have very small numbers, so it's difficult to say. If you look just like this, they look.

As good or maybe a bit less good than surgery. I would say it's probably equivalent from the data that we have. However, in theory, if you cure your patient from a unilateral, adrenal tumour, it, it might be cured forever and, and, and deal with the rest of his life very well versus the patient that you treat medically have a good.

Quality of life, but you still never completely suppress the extra extra concentration of these mineral corticoid, and we've mentioned earlier that they have other effects and some of them are to promote inflammation, fibrosis, and probably CKD in this patient. So that might in the long run show that medical management has a less good long term prognosis. So if you go back to Baxter, we initiated the potassium gluconate orally and spironolactone.

We managed to over the course of a few hours and then a few days, increase his potassium and stabilise it. As you can see, it's never very high, it, it's rather in the low end of normal, but there is no clinical signs associated with it and it never go or went below, below 4 except the one time at 3.3.

But he he's been doing, overall very well. We also out of interest, repeated the fractional excretion of potassium, in the urine, and we could see that there was an improvement. But obviously not a complete resolution of the potassium loss and, and that makes sense because as I said, you counteract the action of the hormone, but you don't stop the overproduction so you still have a very high concentration of aldosterone circulating in the, in the body.

Actually, with, Baxter, we tried to see if adding telmisartan would help us, by inhibiting a little bit of the aldosterone, secretion. He also started to develop some proteinuria and some hypertension, after a year, I think, if I remember well. And, it didn't change drastically anything.

It didn't make things worse. So we, we kept it. And I followed him for about 2 years, I think, and, and he was doing fairly well.

He had a low grade chronic kidney disease that was slowly, you know, coming up. So for sure, again, these other effect of the aldosterone couldn't be counteracted by the medications. So the key points of today's presentation, where that it's important to know that hyperaldosterism is the most common feline adrenal disease and it can be secondary to adenocarcinomas, adenomas or bilateral hyperplasia.

The main Clinical signs and the the key points to recognise that disease are either a hypokalemic polyneuropathy or signs compatible with a systemic hypertension and they don't need to be present both at the beginning. And the aldosterone rein ratio is the gold standard for the diagnosis of primary hyperaldosterism. However, as we discussed, there are some pre-analytical cautions that need to be taken, and there are some other tests that are investigated at the moment, but their actual performances are yet to be completely discovered.

Diagnostic imaging, I think, is mandatory in these cases. It's important for you to help you distinguish between a CKD or something else, if it's a unilateral, a bilateral disease, if it's a surgical candidate or not. And then these patients have overall a good prognosis and .

A very good quality of life. If it's a surgical disease, I think surgery is really, really indicated if the patient, the owners can afford it, but medical management seems to provide a good control of the disease and a good quality of life. A few papers and another picture of Baxter.

If you have any questions, I we'd be more than happy to answer them. Thanks, Benoit. That certainly looks like a happier Baxter than what we saw in the beginning.

Yes. Yeah. That's a, a, an incredibly challenging diagnosis, but I'm sure that it's a very rewarding one once you get to it.

Yeah, I think Like that's the case that every resident wants to have because it's so cool. But for me it's not so much to find one, it's just to be aware that it exists and consider it in probably a bit more patient than you would, . Just by being logical and thorough in your approach of a hypokalemic patient or a hypertensive patient, and I, I do think that it is underdiagnosed because we sometimes maybe overlook or we, we brush into concluding it's a CKD and I don't think it's wrong to to.

To think of a CKD as your first differential, but maybe if the evolution of the patient, if the response of the patient to his therapy doesn't, doesn't quite fit what you were expecting, I think it's important that everybody is aware of that disease to maybe start investigating it a little bit more often. Yes. Yes.

That makes complete sense. Well, we don't have any questions for you. I think like myself, you've certainly covered a lot of, of the all the aspects that will lead us to think along those exact lines of, you know, is this CKD and is it responding as I think it should.

So thank you for your time. It is once again very appreciated. Thank you very much.

Have a very good night, everybody. And to everybody who attended, thank you for your time tonight. And I hope you enjoyed it as much as I did.

And we will see you on the next webinar. From myself, Bruce Stevenson, it's good night.