Hello guys and welcome to this evening's webinar on the problem of persistent proteinuria. So during this webinar, we're going to talk through how we screen for, diagnose and treat various different patients with proteinuria, in primary care practise. So let's get started.
First question we need to ask ourselves, why is proteinuria important? Well, I think . First and foremost, we know that proteinuria is associated with the progression of chronic kidney disease, OK, and I think everybody is fully aware of that.
Proteinuria is proven to reduce survival in azotemic animals, but also interestingly enough, in non-azotemic animals as well. And that the treatment of proteinuria has also been associated with delayed progression of chronic kidney disease and or increased survival. So with regards to our kidneys themselves, there's quite a lot of evidence to say that proteinuria is linked with the severity or progression of disease and that the treatment of it can help limit progression of disease and improve outcome.
There's also other things that we have to bear in mind as well. If proteinuria becomes severe enough, it can lead to hypoalbuminemia, which unto itself can obviously cause quite a few problems, which we'll touch on a bit later on when we mention nephrotic syndrome. But it can also lead to alterations in coagulation factors.
And this in particular can put our patients at increased risk of thromboembolic disease, because of a hypercoagulable state. So that can be quite important too. Proteinuria can also affect cellular immunity and hormonal status as well, and lead to abnormalities of mine, mineral and electrolyte levels as well.
And proteinuria can lead to hyperlipidemia, which again, we touch on a little bit later when we talk about nephrotic syndrome. So lots of reasons already why proteinuria is important. So which patients should we look at screening for evidence of proteinuria?
Well, there is quite a long list, and some of these I'm sure everybody is already screening for proteinuria, such as those patients with primary kidney disease. So those that have got a chronic kidney disease, an acute kidney injury, or evidence of a glomulopathy. But there's lots of other potential patients as well that we should be screening for proteinuria.
Patients who have a breed pre dispicion, for protein losing nephropathy, are one group. And an example of a breed, would be the soft-coated Wheaton terrier who do have a familial, form of proteinuria. So we might screen those guys at regular intervals long term for proteinuria.
Patients who have infectious disease, so these are generally, the systemic infectious diseases, such as Lyme's disease, leptospirosis, leishmaniasis, and heartworm. All of these can can potentially lead to protein urine and are worth screening those guys for proteinuria. And systemic hypertension as well, which is really quite common in older patients, particularly our cats, or in patients who already have pre-existing renal disease, that can lead to significant proteinuria too.
A neoplastic disease is a category where we're primarily looking at patients with either multiple myeloma, which again we touch on a bit later on as a cause of pre-renal proteinuria, but also there's some evidence that patients with other neoplastic diseases as well, such as lymphoma can have quite significant proteinuria, requiring therapy. Any inflammatory disease as well potentially can lead to proteinuria, so patients who have chronic pancreatitis, infection of the heart valves, which is endocarditis, patients with chronic hepatitis, and even patients with inflammatory bowel disease as well. Several endocrine diseases have been associated with it, and in dogs, hyperadrenal corticism, would be probably the most important one.
We do also see it in cats with hyperthyroidism and as well in dogs with diabetes mellitus. Patients who have generalised immune-mediated disease as well. Will be at risk.
So we think about our patients with immune-mediated hemolytic anaemia, patients with systemic, lupus, and patients with immune-mediated polyarthritis as well. Drugs can also lead to proteinuria and probably the most important one to be aware of is is prednisolone, OK? Much in the same way, that, endogenous glucocorticoids can cause proteinuria and hyperadrenal corticism, exogenous glucocorticoids can cause that as well on chronic prednisolone therapy.
So lots of different patients here, that we might want to screen for proteinuria to see if it's present, if it's particularly severe, and if we need to, intervene with treatment and, and organise ongoing monitoring. So we're just gonna go over a little bit of, anatomy, physiology, pathophysiology. It is gonna be pretty brief.
And I think the first thing just to quickly remind ourselves of is, the glomeulus itself, because we're gonna be talking quite a lot about glomerular disease. So the glomeulus is this whole unit here, and it's essentially made up of the afferent arterio, going into the glomeulus. And then that forms the glomerular capillaries within the glomeulus itself, which, you know, is, is sort of comprised of the Bowman's capsule, and then, that then leads on to the proximal tubule.
Of the nephron, and then the blood supply that leaves the glomerular capillaries is the efferent arterioles. OK. So essentially blood enters the afferent arterial, it is filtered, through the, glomerular capillaries, into the glomus, and then that ultrafiltrate, or glomerular filtrate moves down into the proximal tubule.
OK. So pathophysiology, let's define proteinuria. So proteinuria quite simply is the excess of protein in the urine, very straightforward, easy to remember.
The capillary tuft that I showed you in the previous diagram of the glomeulus is quite high pressure. And when our blood enters the capillary tuft, and the ultrafiltrate is is pushed through the walls of the capillary, and into the, the bowman's capsule, what we tend to have is that smaller, so less than 200,000. Daltons in size, proteins, and generally these are proteins as well that are non-negatively charged, and they are able to pass across the membrane, into the ultrafiltrate.
So small proteins do cross, The, the, the wall of the capillary, and that's very normal for them to enter the ultrafiltrate, OK, whereas larger proteins or negatively charged proteins such as albumin are unable to pass through that barrier in healthy patients. And the smaller proteins, are then reabsorbed generally in the proximal tubules, so they're filtered and then reabsorbed quite early. However, patients who have tubulo interstitial disease will have abnormalities of reabsorption of those proteins.
So those guys can develop protein urea because of a, a lack of reabsorption of the sort of normal, proteins that are filtered across the glomulus. Patients, who have glomeular disease, it's a little bit different. So the glomeular wall itself comprises of fenestrated endothelial cells, a glomeular basement membrane, and then the podocyte cells.
And between the podocytes, they have a thing called a slit diaphragm, which are little spaces that are made up, between the cells, in these regions of interdigitating foot processes. And basically, diseases, can affect the permeability of this slit diaphragm, OK, increasing filtration of protein through that diaphragm and allowing larger proteins such as albumin into the ultrafiltrate. And that can occur for a few different reasons, the most common of which are increased blood pressure within the glomulus, so glomerular hypertension.
Endothelial cell dysfunction or primary glomerular disease itself. So the increased permeability of the glomeulus as I say, allows albumin and other larger proteins into the ultrafiltrate and Albumin certainly in patients with glomerular disease is the most prominent protein that is lost. And when we're thinking about, as I say, different causes of glomerular disease, we've typically said previously that, glomeulone nephritis, has been, the most common cause of glomeular protein loss, but we'll come back to that a little bit later on.
OK, fantastic. So, we're now going to think about how we can easily remember our causes of proteinuria, and this is probably the best way. So we think about pre-renal causes of proteinuria, so abnormalities within the bloodstream.
OK, that will cause, increased levels of protein within the bloodstream that will be lost in the urine. We've then got renal causes of protein urea, so diseases of the kidney itself, and we break down, those diseases in a few more slides, a bit more specifically. And then we've got post renal causes of proteinuria.
So abnormalities or disease within the lower urinary tract that can lead to increased levels of protein in the urine. So just to start off with pre-renal proteinuria, this can be caused generally by one of three situations. So you can have hemoglobinuria, which is due to obviously increased haemoglobin levels in the bloodstream.
And that haemoglobin is then filtered across the glomulus into the urine, producing high levels of haemoglobin within the urine. So that's something that we would see in patients with primarily hemolytic disease, so immune mediated hemolytic anaemia. So those ones are quite, quite easy to spot, obviously.
Myoglobin urea very similarly is due to increased levels of myoglobin within the blood because of damage to skeletal muscle. And that can lead to high levels of myoglobin in the urine. We've then got patients who have got Ben Jones proteinuria.
So this is something that really is most commonly associated with multiple myeloma. So, multiple myeloma is, is obviously a cancer. Of dogs, and it is a cancer of the plasma cells, and these plasma cells produce high numbers of small proteins, OK, which are not normally present in the plasma.
And these high numbers of small proteins, pass through the filtration barrier and into the urine, causing what we call Bentz Jones protein urea. And these, Bentz Jones molecules are actually the light chains of, the antibodies. So this is a whole sort of, you know, antibody immunoglobulin, as it were, and it's made up of light and heavy chains, and it's primarily the light chain.
Which is found in high numbers in the bloodstream and then obviously, within the urine. So, it's an important one, to be aware of when we're thinking about causes of pre-renal proteinuria. But actually pre-renal proteinuria is pretty uncommon in general, OK, but those are the diseases that we do need to be made aware of.
We then move on to renal proteinuria. So with renal proteinuria, it's intrinsic, you know, loss of protein because of, disease or or abnormalities within the kidney, or a failure to reabsorb, the smaller protein molecules because of disease within the kidney. And within the causes of renal proteinuria, we have those that are functional or physiologic, and then those that are pathologic.
So the functional causes, these are often quite mild and actually transient. So we don't get worried about them. If we detect one of these.
Situations as a cause of the proteinuria, you know, we can monitor that patient and normally, as their pyrexia, and their stress, their seizures, or the extremes of temperature resolve, that patient's proteinuria should resolve as well, without the need for specific therapy. So it's, it's worth being aware of those situations because we don't want to jump in with a diagnosis of, of proteinuria, in one of these patients and start, . Specific therapy for it because it likely isn't indicated.
And within the pathologic causes of proteinuria, there's generally three areas of the kidney that can be diseased, and, and lead to protein loss within the urine, and that's the glommeulus, a tubular disease or an interstitial disease. Now this is an important message to sort of mention next. When we're talking about renal proteinuria, we start to get concerned when it is persistent renal proteinuria.
So we've already said that with certain states such as, you know, pyrexia and stress, you can have transient proteinuria. To really worry about protein urine and to start to institute therapy, it needs to be persistent and to classify proteinuria as persistent. The sort of well accepted definition is that the proteinuria is documented on 3 or more occasions, each occasion at intervals of 2 or more weeks apart, OK?
So that's an important take home message. We don't tend to diagnose persistent proteinuria on a single, one-off test and institute treatment at that point unless it was particularly high. Generally, what we do instead is we identify proteinuria, we recheck at a later date, identify that it still is persistent, and then once more before we then start to initiate therapy and perhaps further investigations.
So that's, the definition of persistent renal proteinuria. I mentioned that you can have lesions within three different parts of the kidney, that can lead to proteinuria. And just to sort of reiterate those, the first one is, glomerular capillary lesions.
So diseases there will alter the permeability of the glomerular barrier, leading to increased loss of plasma proteins through the glomeulus into the renal tubule. We then have tubular lesions themselves, and these are lesions that impair the reabsorption of the smaller proteins that are normally filtered through the glomerulus within the proximal renal tubule. And then we've got interstitial lesions and these essentially are generally inflammatory lesions, and they actually cause active exudation of proteins from the interstitium into the tubular lumen itself, OK?
So disease in in any of these areas can lead to renal proteinuria, but by far the most commonly affected area that we see in small animals are lesions of the er glomeulus, OK? Leading to increased, filtration of plasma proteins. And essentially there there is a long list of causes of glomeular disease, but they can be most simply remembered as simply diseases that increase, intra-glomerular hypertension or diseases, that are associated with immune complexes, within the, glomulus, damaging, that membrane and allowing, increased permeability and proteins to pass across it.
So we're gonna talk a little bit more now about glomeular diseases themselves, simply because they are such an important cause of renal proteinuria. And they can sometimes be the, the, the ones that require the most investigation. And the most aggressive treatments as well, because they can be the ones that can be the most serious and, and progress, you know, and, carry quite, quite, you know, variable prognoses that, that can be really quite poor, in some circumstances.
So within this list of glomerular diseases, we have memronoproliferative, glomeulonephritis, membranous nephropathy, misangul proliferative glomeulonephritis, amyloidosis, glomerulosclerosis, minimal change disease, focal segmental glomerulosclerosis, and other hereditary glomulopathies, and renal dysplasia. So quite a long list of causes really. And essentially the way that we can remember them more simply is that they are either diseases associated with, immune complex deposition, within the, within the kidneys, or those that aren't associated with that, OK?
So basically those diseases that have an immune mediated component and those that don't, OK? Within the, patients who have an immune mediated component, there's two, ways in which, that can occur. And this is generally, antibody mediated injury of the, glomerulus.
And that can either happen directly or in situ as we call it, where we actually have antibodies that are produced within the plasma that directly target antigens within the glomerular wall. So antibodies free in the plasma, target the antigens themselves of the glomeular wall. Forming antibody antigen complexes within the wall in situ, and that damages the wall causing inflammation and increased permeability.
The glomerulus. We then have the other group of patients, . With immune complex glomeulonephritis, where the immune complex is formed elsewhere in the body.
OK. So what happens in these patients is we have a disease somewhere else. It's often something that's very inflammatory in nature, so immune-mediated diseases like immune-mediated polyarthritis or immune-mediated hemolytic anaemia or.
Other very inflammatory diseases such as infectious diseases, I mentioned bacterial endocarditis a bit earlier. So those are diseases that are in in other areas of the body. And what they do is they stimulate an immune mediated response that causes antibodies to bind to antigens at distant sites.
Within the body, and then these form antibody antigen complexes that are sort of floating around, within the plasma. So they float around the whole body and eventually they actually get deposited within the glomerular wall, and there again they incite inflammation and damage, which causes to an increased, glomerular permeability. So those are the two sort of different types of glomeulonephritis that we see involving immune complexes.
So the direct targeting, if you will, of the glomulus itself versus a a a disease process somewhere else in the body, and the glommeulonephritis occurs secondary to that, OK. So you could think of those as primary and secondary. So when we have a patient with glomerular disease, it can often be associated with pretty severe proteinuria, as I said, previously, requiring er quite sort of intensive therapy and ongoing monitoring.
It's worth being aware that glomerular disease is much more common in dogs. Than it is in cats. And any age of patient can be affected, but it is most common in middle aged to older dogs with one study identifying.
The median age of presentation of being 8.3 years. Dogs with nephrotic syndrome, however, may present a little bit younger, unfortunately, and the median in, in, in one of those papers was, 6.2 years of age at presentation.
Now, nephrotic syndrome is almost, . An advanced form of glomeular disease that leads to a situation where we have so much protein loss through the urine that our patient becomes hypoalbuinemic. And in these patients, the hypoalbinemia becomes so severe, often.
You know, below 16 grammes per litre, that these patients develop either peripheral edoema, so fluid buildup underneath the skin, typically of the distal limbs, or the face because of a lack of oncotic pressure, within the plasma itself, or they may develop, third spacing of fluid, so plural, pericardial, or peritoneal effusions, again, because of a loss of oncotic pressure within the bloodstream. So patients with nephrotic syndrome have hypoalbuminemia, they have peripheral edoema or effusions, and they have very severe proteinuria and also elevated cholesterol levels as well. So that combination of signs is what we call nephrotic syndrome.
And when we see that, that unfortunately does carry a much poorer prognosis, obviously than patients who don't have nephrotic syndrome. And it generally requires much more aggressive therapy and often er more investigation as well. So those cases, you know, that you identify with nephrotic syndrome can be very, very challenging to manage, and I definitely recommend, you know, consultation.
With an internal medicine, you know, advanced practitioner or specialist or even referral, you know, if, if you've not dealt with one of those before, . Younger dogs, who have glomeular disease are more likely to have infectious or inflammatory causes if they have the secondary form of glomerulo nephritis. So.
As I said, on the previous slide, an inflammatory disease such as amine-mediated polyarthritis or, you know, an infectious disease because they've got a travel history and picked up a leashmania or something like that. Older dogs who have the secondary form of glomerulonephritis, are more likely to have neoplasia as their cause, you know, it's, it's common sense really. Multiple myeloma and lymphoma generally occur in middle age to slightly, well, certainly multiple myeloma in older animals.
And patients who have familial disease, so soft-coated wheat and terriers, for instance, they can manifest at a much earlier age, unfortunately. So these are the kind of sort of signalments we can be thinking about when we, detect a patient with, significant proteinuria. With glomerular disease, the clinical signs really can vary quite dramatically and a lot of the time that depends primarily on the severity of the proteinuria itself and the complications of that, and the presence of azotemia.
So early on, patients with proteinuria and glomerular disease often have really subtle non-specific signs. Some patients might be PUPD, they might not. I've certainly seen patients have really subtle changes, in behaviour.
I think the first case of, of a proteins nephropathy I ever diagnosed, was in a dog that just presented because it was drinking its own urine, weirdly enough, and had no other clinical signs. Some of these patients, you know, may have a degree of lethargy or exercise, sorry, lethargy or reduced appetite, but that's often as subtle as it is, when these patients are simply proteinuric, . If the proteinuria leads to nephrotic syndrome, because it's particularly severe, then obviously I've described the signs of that already.
We may have peripheral edoema, we may have abdominal distention because of ascites, we may present with breathing difficulties because of pleural effusions. And if our patient has . Progressed from renal proteinuria into renal failure and developed azotemia, then a lot of those patients will present with PUPD and signs of uremia.
So, hypoorexia, reduced appetite, lethargy, weight loss, vomiting, oral ulcerations, that kind of thing. I mentioned, a little bit earlier that patients with proteinuria are at increased risk of thromboembolic disease, because of a hypercoagulable disease state. And sometimes our patients with nephrotic syndrome will present.
Primarily because of thromboembolic complications. And I suppose the most common of those would be, a pulmonary thromboembolism causing the patient to become acutely dyspneic, but we can have other sites of embolization as well, to, to be, to be well aware of. So you can certainly embolize blood clots to your kidneys, for instance, and have sudden deterioration in kidney function, for instance.
As we'll get on to a little bit later on, patients, with kidney disease obviously are at increased risk of having systemic hypertension, but as I also mentioned earlier on as well, patients with systemic hypertension are at increased risk of proteinuria. So, our proteinuric patient may well have hypertension, and they may also present because of complications of their hypertensive disease, because of target organ damage. So that target organ damage might be neurological signs, due to a cerebrovascular accident within the brain.
They may be ocular signs, particularly in cats, because of retinal detachment or haemorrhage, . And, you know, those would be the most common to sort of target organ damage signs that the clients will, will notice. But obviously, with chronic hypertension, we also get target organ damage to our heart and kidneys themselves, but again, we'll touch on that a bit more in the treatment section.
So as you can see, there really is a wide range of presentations, and a wide range of causes, for proteinuria and small animals. I thought I'd just quickly flag up this paper, cos it's quite a recent paper and it's kind of changed, perhaps the way we describe, glomeulonephritis and glomeulopathy in the UK. So, we've said, a little bit earlier that traditionally immune complex glomeulonephritis, whether that's primary or secondary, has typically been described as the most common form of glomeular disease in, in, in several studies in US certainly, and in Europe, .
Accounting for about 50% of all, glomerular diseases. However, this recent study from the UK identified that actually in this, retrospective cohort of patients, immune complex glomeulonephritis. Made up only 27% of the total population of the cases.
And then actually glomerulosclerosis, was the most common diagnosis in the dogs undergoing renal biopsy, from this study. So I just mention it because It sort of shifts perhaps, the way that we approach these patients a little bit more in the UK in that if you read publications, from the US and Europe, we talk about primary immune mediated, glomerulonephritis, whereas that it's now apparently less common in the UK. Than it is in other areas.
And one reason why that might be the case, perhaps, is because of less sort of endemic, polysystemic diseases in the UK compared to, mainland Europe and the US, you know, such as heartworm, leishmaniasis, that sort of thing. out of, this paper, there was a few of the little, things that were identified, and one of those was that, mycophenolate Moffattil, which we touched on in the treatment section a little bit later on, was actually the most commonly used immunosuppressant for cases of immune complex glomerulonephritis. So looking at a few different retrospective studies, the survival times for patients with immune complex, glomeruonephritis does vary dramatically, .
Primarily based on the severity of their proteinuria, you know, and presence of azotemia at presentation. And depending on the severity of presentation and, the, the sort of definitive diagnosis of the treatment plan, the survival times can vary from a very measly few days, in some patients up to several years in others. And I think that kind of highlights early on the importance of a thorough.
Diagnostic evaluation to really know exactly what is wrong with that patient, to be able to give them the most optimal therapeutic plan to try and maximise, you know, survival times and their outlook. We do know that if you have an immune complex, glomeulonephritis, the prognosis is definitely, better with immunosuppressive therapy than without it, which kind of makes sense, . And that the presence of nephrotic syndrome in several studies was identified as conferring a significantly poorer prognosis for patients with immune complex glomerulonephritis than those without the signs of nephrotic syndrome and that.
Obviously kind of makes sense really. Within cats, infectious diseases are sort of more common than they are in dogs even. And some of the common, bugs that we think about are, feline infectious peritonitis, feline leukaemia virus, feline immunodeficiency virus, and toxoplasmosis.
Although they can certainly be affected by chronic inflammatory and neoplastic diseases as well. And we obviously see a lot of chronic kidney disease in geriatric cats, and we're going to do a lot of screening of those guys for proteinuria, but it's interesting to remember that actually, chronic kidney disease in cats, is not associated generally with that, significant proteinuria. You know, so if you do have a cat that has got renal dysfunction, and you do test them for protein urine, their protein levels are really very, very high, I wouldn't just attribute those to the fact that they've got, chronic kidney disease.
I would certainly screen for other possible underlying causes such as infectious inflammatory and neoplastic diseases as well, OK. So we've talked a lot there about renal proteinuria. We then have patients with post renal proteinuria.
So this is . Protein present within the urine because of disease, within the lower urinary tract, and that's normally inflammation or haemorrhage. So within the urinary bladder, or within the urethra, and we'll commonly see post renal proteinuria in patients with lower urinary tract infections, urolithiasis, neoplasia.
Feline idiopathic cystitis. So really any disease, you know, inflammatory, you know, or infectious disease of the lower urinary tract, you will get a degree of post renal proteinuria. And do bear in mind as well that we can get extra urinary proteinuria because of inflammation or haemorrhage within the genital tract.
So if we're simply just testing. Free catch urine samples, you know, we can detect, protein in there that's actually come from the genital tracts rather than the lower urinary tract. And this is a situation where cystocentesis, to collect urine samples can be used to exclude extra urinary disease as the cause of the protein urea.
We'll talk about cystocentesis in just a couple of slides. So we've nicely grouped our causes of proteinuria into pre-renal, renal and post-renal. And it's certainly the renal causes that need the most investigation, so it's useful to be able to exclude pre and post renal causes, early on in the investigation of that patient, and that really is quite easy to do based on.
The history of the patient, does this patient have signs referable to lower urinary tract disease? So poachyuria, stranguria, that sort of thing, inappropriate urination in cats that would lead us to think this, this sounds like it's actually a lower urinary tract problem. .
Does the patient on physical examination, have any evidence of pre-renal or post renal causes, so is it a dog that's got a severe peripheral lymphadenopathy, you know, and perhaps we think it could have, lymphoma, for instance, . Does it, is it a dog that has a hooded vulva and lots of urine scalding around its vulva, which might indicate, you know, lower urinary tract disease. But ultimately, the best way to exclude pre-renal and post renal causes is with a complete urinalysis and blood tests.
So our blood tests are going to be used to exclude pre-renal causes because we're gonna look for. High globulin levels within the bloods that would be consistent with Ben Jones proteinuria, and we're going to look for evidence of hemoglobinemia and myoglobinemia as well on those blood tests. Our urinalysis itself, is going to be really useful for ruling out lower urinary tract disease because we're gonna look on there for evidence of an inflammatory, sediment.
We're gonna look for bacteria, we're gonna look for crystals within the urine, that kind of thing to kind of push us more towards, lower urinary tract disease. So that's the way that I kind of approach our pre and post renal a proteinuria. Fabulous, so we're now gonna start to talk about how we actually document proteinuria, OK, if we are thinking about screening a patient for protein loss.
And I'm gonna start off talking about the utility of urine specific gravity and the dipstick. So these are great because they're very cheap, they're readily available, and they're very rapid to perform, but there are some limitations, OK. That we have to be aware of.
So the protein dipstick is what we call a semi-quantitative test. So you kind of have, no protein or 12 or 3 plus protein in the urine. So it is semi, quantitative, which is, which is useful.
. But one thing that we have to be, very sort of aware of is that when we are looking at the the protein pad on a urine dipstick, we have to interpret it relative to the urine specific gravity. And that's one of the reasons why we should always measure the USG on a refractometer whenever we're performing a urine dipstick. So patients who have very dilute urine, we get more concerned about the presence of protein urea on a dipstick.
Whereas patients who have very concentrated urine, we get a bit less concerned. So what I mean by that is that. If you have, say, 1 plus, on your protein, dipstick, but your urine specific gravity is 1050, so very concentrated, that's really not a lot of proteinuria, and you could probably, you know, sort of dismiss that and not really get too worried about it.
However, if you've just done that, dipstick, On a patient with a USG of 1008, so, very dilute urine and their protein is 1 plus, that is much more significant and certainly would be more likely to push you down the route of further investigations. So do interpret the protein dipstick in light of your in specific gravity, OK. Do bear in mind as well that false positives on the protein pad can occur due to very alkaline urine.
Patients who have an active sediment within their urine, and in patients with prolonged contact of urine and the pads. We generally get more false positives in cats than we do in dogs. But we can also get false negatives as well, due to Ben Jones proteins in the urine, very dilute urine or very acidic urine.
So Essentially, a protein dipstick is a pretty good, cheap and cheerful, easy way of starting to screen for proteinuria. And I think the take home advice would be if you have a positive dipstick, in a patient's urine that has an inactive sediment, then that warrants, further investigation, OK? And the next slide we'll talk about the next test that we're gonna go to.
So the, the dipstick itself, as I've said, is certainly not infallible. We do get false positives and false negatives, and the specificity has been reported to be 81% in dogs, 90% in, in cats, and the specificity, 48% in dogs and 11% in cats respectively. So, if we are identifying protein on a dipstick and we want to investigate further, the next thing that we should consider is performing a urine protein creatinine ratio or a UPC.
So whenever we perform a UPC we always need to perform it with a sediment examination. So whether that's done in-house with you spinning down the urine, staining it up and having a look at it under the microscope for evidence of white blood cells or bacteria. Or you're sending it to the external lab, you know, and allowing them sort of to do that for you.
It doesn't really matter, but we do have to do a sediment with the UPC. And the reason for that, as I've said earlier, is that when we're doing this UPC we are saying, have we got loss of protein through the kidneys, renal proteinuria, how bad is it? If we have lower urinary tract infection and an active sediment, that will increase the UPC, OK?
And it's not because of renal loss of protein, but because of inflammation within the lower urinary tract. So we always have to make sure there's no evidence of lower urinary tract, inflammation or haemorrhage on a sediment before we submit a UPC cos otherwise it'll be falsely elevated. So UPCs are classed as normal when they are below 0.2.
A UPC of 0.2 to 0.5 in dogs, and a UPC of 0.2 to 0.4 in cats is considered borderline proteinuria and definitely, as a minimum.
Ongoing monitoring is warranted. However, patients, with, persistent proteinuria, with levels of over 0.5 in dogs and over 0.4 in cats definitely need, ongoing monitoring.
And or further investigation depending on how elevated they are. Generally a UPC ratio over 2.0 is indicative of certainly a degree of glomeular proteinuria, whereas patients who have UPCs in the order of 0.5 to 0.2, it tends to be more common, with renal tubular disease, OK?
So. There are certainly lots of exceptions to that rule, and it's not a hard cut off, but you know, if you've got a patient with chronic kidney disease and a UPC between 0.5 and 2.0, you probably don't need to launch too aggressively into, further workup of underlying causes, but you know, a, a UPC over 2.0 and certainly significantly over 2.0, .
Would warrant further investigations really and more aggressive therapy. So another top tip to mention at this point. Is that when we're performing UPC ratios, we can perform those via a cystocentesis, and that can help exclude extra urinary disease.
But if we're happy that we've not got extra urinary disease, we certainly can do a UPC on a free catch urine sample. As I say, we're definitely gonna do a sediment to make sure there's no evidence of lower urinary tract disease, but a free catch is, is fine to determine. The UPC on a patient.
And because the UPC can actually fluctuate, throughout the day, what we tend to recommend is to get, the most accurate representation of that patient's UPC it's, recommended to collect 3, free catch urine samples. Three consecutive ones or over 3 separate days doesn't really matter too much. And to really pull those 3 samples together to then submit for UPC cos it's just going to increase, the sort of reliability of that test a little bit more.
So what I tend to do is tell owners to bring in, you know, 3 consecutive, well, 3 P samples for 3 consecutive days. And I take a millilitre out of each of those samples, combine them into a 3 mil sample and then perform the UPC on that. Now, bear in mind that when we're measuring UPC it's protein to creatinine ratio.
So that is pretty stable. So it ideally should be a refrigerated sample, but you're fine, you know, for these to be collected and not run for several days, hence why you can collect, these 3 samples over 3 consecutive days, OK? Fab.
So we've talked about how we're gonna screen for proteinuria and diagnose proteinuria based on the UPC. We are then gonna think about how we're gonna investigate that proteinuria in more detail. And there is quite a lot of tests that we might have to consider, depending on the individual patient, and their severity of of proteinuria.
So we're definitely gonna want to perform a serum chemistry, . To look for things like hypoalbuinemia, to look at renal function, so a urea and creatinine to see if we're starting to develop, evidence of, of chronic kidney disease. We're going to look at, the globulins to screen for pre-renal causes of, of proteinuria.
We're gonna check a total T4 in all the cats cause hyperthyroidism can contribute it, and we're gonna look for other changes on the biochem in dogs that might make us think perhaps this patient, you know, with consistent clinical signs could have Cushing's disease, for instance, such as an elevated ALP and cholesterol. So lots of things that we're going to look for on our chemistry. We're gonna perform a CBC as well, and that's to help us, screen, really for evidence of inflammatory, disease.
You know, are we looking at this protein neuric patient, doing a CBC and seeing, you know, marked, moderate or marked neutrophilia and monocytosis to indicate, inflammation somewhere in the body and then, you know, we go and and hunt the source of that inflammation. But we're also gonna check, . PCV, or hematocrit as well in these patients, particularly if they have any evidence of, chronic kidney disease in case they've got an anaemia of renal disease.
We'll probably want to consider, or, or definitely consider really, the use of SDMA, in these patients as well as, as an early marker. Of kidney disease. Do bear in mind as well, however, that SDMA sort of similar to proteinuria, we have to document at least 2 consecutively elevated SDMA samples over a period of at least sort of 4 weeks, for that to be a reliable indicator of early kidney disease.
So don't diagnose early kidney dysfunction just off the back of a single elevated STMA, . We're then gonna want to, I mean we probably have already done quite a bit of urine analysis. We know at least a USG dipstick, sediment and UPCR but we'd recommend as well performing a culture on any urine of a patient that has protein urea.
And whenever you're performing cultures, it really should be taken via a cystocentesis sample, not free catch and not catheterization because we significantly increase the risk. Of culturing commensal organisms of the external genitalia, and then it becomes very confusing deciding on those patients, have we just cultured bugs that are, you know, on the, on the prep use of this patient or are these organisms actually in the urinary bladder? We might then want to do some testing for infectious diseases, if we're suspicious that there could, be an immune complex, glomerulonephritis, for instance.
And the testing we might want to do would be, something like, an IDEX 4DX snap, to screen for various diseases that are associated with travel. You know, we might want to screen for leachmania. We might want to screen for, FIV, FELV, etc.
Etc. So base the, the, infectious disease testing, that you're going to do on the patient's travel history. So check which infectious diseases could be endemic in any region the patient has travelled to, and then, you know, start to test as appropriate for those.
There is quite a long list of possible infectious causes, and it's sort of beyond the scope of this lecture to, to go through every one of them. We want to perform a blood pressure, estimation because as we've said earlier, systemic hypertension can itself cause, proteinuria. We're then gonna look at some imaging.
And the imaging will be again to look for distant causes of protein urea in our patients, as well as look at the kidneys and the lower urinary tract themselves as well, just to see if there's any structural evidence of renal disease and to be categorically sure, there's no evidence of lower urinary tract disease such as urothelial cell carcinoma or urolith, you know, on imaging. So generally we're gonna be looking at doing ultrasound of the abdomen, er, thoracic radiography or potentially if you have access to it, maybe CT scanning of the chest and abdomen. We're then gonna look at specific testing for any diseases that we are suspecting the patient may have.
So a dog that presents with chronic, sort of vomiting, large bowel diarrhoea, intermittent abdominal pain and reduced appetite, that has proteinuria, we might think of chronic pancreatitis as a possible cause for that and then obviously perform a SE CPLI to screen for it. If we've got a dog presenting, and we've diagnosed proteinuria in it and it has, generalised joint pain and stiffness, we're going to want to tap those joints to see if it's got an IMPA, you know, a dog that's got significant proteinuria. And a newly diagnosed heart murmur, we might want to screen with an echocardiogram for endocarditis, you know, etc.
Etc. Etc. The the list sort of goes on, but essentially, any of those many, many diseases that at the beginning, you know, are described as a possible cause of proteinuria, if you're suspecting one of those could be present in that patient, then, you know, screen for it.
Ultimately, if we find an underlying cause of the proteinuria, having done this initial testing, that's great. We can then treat the underlying cause and see if the proteinuria resolves. And if, however, we don't diagnose an underlying cause for the proteinuria and all these tests are really unremarkable, then we more than likely, have an immune complex glomulonephritis, or glomelosclerosis or one of those other.
Many glomerular diseases that are listed earlier and we now need to proceed to renal biopsy to complete the set of tests. So I'm just gonna go through renal biopsy, not in a huge amount of detail, but just to make people, aware of it and it's importance really, in the diagnosis and treatment of patients with, sort of particularly severe, proteinuria. So renal biopsy should be considered, the gold standard for investigation.
Of glomerular disease, because it gives you a histopathologic diagnosis of what's going in, what's going on in those kidneys. And we should most strongly consider performing a renal biopsy in patients that are not aotemic. But have moderate to severe proteinuria and particularly those patients that we've already put on medical management of their proteinuria, and they've not responded as successfully as we would like them to.
So we do it generally non-azotemic patients, because those patients who are azotemic, the damage really has already been done. And it's perhaps unlikely that what we diagnose on that renal biopsy, will actually significantly alter the treatment plan because ultimately that azotemia is present because of irreversible, kidney damage, because of chronic, kidney disease in those patients. So for that reason, it's often not that useful in azotemic patients, it doesn't really change the treatment options, a huge a huge heap.
It also is a worry in aotemic patients because, one of the things that can happen is you can get, a worsening of, of renal function following a biopsy. And if you already are esotemic and sort of struggling with your azotemia, the last thing we want to do is worsen that and precipitate a worsening of the patient's clinical signs. So we don't tend to do it in patients that are aoemic, and it's generally in patients that are moderate to severely proteinuric.
You know, if you are very mildly proteinuric and sort of responding to therapy reasonably well, it's, you know, less likely that that mild level of persistent proteinuria will lead to significant, complications such as nephrotic syndrome, or azotemia. So, essentially, you know, catch those patients as early as you can, with your screening for proteinuria before they become aotemic. If we're gonna do a renal biopsy, we need to check the clotting function first.
Obviously, if you've got a coagulopathy, the last thing we want to do is go sticking, a, a large bore needle into the kidney, which is a very, very vascular organ. And we need to check that patients are normotensive as well. .
The biopsies are taken from the renal cortex and not from the medulla, and these are normally taken with a true cut ultrasound guided technique. So that is certainly something that is no light undertaking. And really should be reserved for practitioners who are very, very competent and confident with ultrasound guided true cuts of intra-abdominal organs.
So certainly, you know, if you, if you've never done one before, this is not one of those procedures where it's a case of just give it a go, I'm sure you'll be all right. . And also, you know, as I say, true cook method is, is, is the best because of, well, a variety of reasons.
So yeah, we, we wouldn't tend to recommend, open abdominal surgery for sort of wedge biopsies of the kidneys, anything like that. When we take biopsies from the kidneys, two of the important tests that we need to perform on those are electron microscopy. Which is looking at, the cells at a subcellular level and immunofluorescent, antibody testing as well.
So these are two tests that we will run alongside our regular sort of routine H&E staining for histopathology. So it's really important to mention that here, because the last thing we want to do is go to the effort of performing a renal biopsy in a patient and simply submit it to a routine pathology lab for standard histopathology, OK? So we definitely don't want to do that.
All renal biopsies should be submitted for electron microscopy and aminofluorescent antibody testing. So the the electron microscopy is able to detect the immune deposits at a subcellular level, within. The basement membrane and any podocyte abnormalities, and the IFA also is another way of helping to detect immune deposits as well.
And so to be able to submit these successfully, what you're best doing is contacting a specialist or a specialist laboratory and order in a renal biopsy kit. Prior, to, to, performing, that renal biopsy itself, and that will include special media and instructions on where, and how to submit the biopsy. And two labs that are worth mentioning are the International Veterinary Renal Pathology Service in the US and the European Veterinary Renal Pathology Service, .
In Italy, so as I say, just pre-plan for renal biopsies, make sure we've got a renal biopsy kit and we're submitting to a specially, a specialist renal pathology lab, OK? Fantastic. So just to be aware of the risk factors and potential complications of renal biopsy, so the main complication that we need to worry about is renal haemorrhage, and that can be really quite severe in some cases.
So 10% of dogs in one study, the haemorrhage was severe enough to need a blood transfusion, and 17% of the cats undergoing biopsy, needed transfusion. With an associated mortality rate of about 3%, so it's, it's no light, you know, undertaking. There are some risk risk factors, for performing renal biopsies.
So if we identify any of these, you know, we have to, make our clients aware of the increased risk or even consider not performing them. And those are, the presence of anaemia, prior to biopsy, severe azotemia, and in very small sized patients, OK. Fab.
So hopefully, we're all happy on how we're going to screen for proteinuria, how we're going to think about the causes of proteinuria, and get to the point of a definitive diagnosis in these patients, whether that's blood work, urinalysis and imaging, or, renal biopsy even. So now we're gonna move on to the treatment of these patients and certainly if we have an underlying cause of the proteinuria, the treatment of that underlying cause and monitoring for resolution of the proteinuria is absolutely, you know, the best way to go. However, if there is no identifiable cause of the proteinuria, because we've ruled out all the other causes and maybe the patient can't, the client can't afford or doesn't want to undertake renal biopsy, or if the underlying cause, for instance, such as chronic kidney disease, you know, is, is just not treatable itself successfully, then obviously we need to start medical management of the proteinuria.
And we tend to recommend treatment in all patients in which the UPC values are greater than 2.0 in non-azotemic cats and dogs, or in any patient, with a UPC greater than 0.4 to 0.5.
In azotemic cats and dogs, respectively. So basically, in patients that are azotemic, we're a bit more aggressive with our, therapy of proteinuria than those that are non-azotemic. OK, so just use those guidelines to help guide you.
The aim of therapy is obviously to achieve the lowest level of proteinuria or get resolution of the proteinuria. So we tend to say, a good goal in all patients is of course to aim for a UPC below 0.5 to 1.0, or if that's not achievable, at least a 50% reduction in the proteinuria from baseline, OK?
And there will certainly be, a moderate to large number of patients out there, you know, particularly those that have quite, severe proteinuria, you know, that, that we will not be able to normalise their UPC and that a 50% or more reduction might be, the best that we can achieve in those patients. With regards to treatment, what we've often found is that a multifaceted approach is most successful. So we'll talk about all those in a sec, but we're talking about diet, nutraceuticals, and combinations of various drugs to get the best outcome in our patients.
And a really good, paper to look at, is the, . ACVIM, consensus statement on the therapy of glomerular disease in dogs, and this was published in the Journal of Veterinary Internal Medicine in 2013. And that, of course, is an open access journal, so anyone can log on to that journal, download it and read this paper.
And that's a really, really nice consensus statement, really highlighting, the, important guidelines for the recommendation of, of treatment, and it has all the drugs that are recommended in all the various dosages is certainly, worth a read. So when we're looking at a multifaceted approach to the treatment of proteinuria, the main thing that we're going to do with our drugs is try and, inhibit, the Renin angiotensin aldosterone system, OK? Because inhibition of this, system will help to improve, protein loss, from the urine, OK?
Now in humans, they have, renin inhibitors. That are able to target wrenin, but unfortunately they're not, commercially available in animals, so we're not going to talk about those. And the ones that we are gonna talk about, of course, are ACE inhibitors.
So angiotensin converting, enzyme inhibitors that act on ACE to inhibit it. And prevent the conversion of angiotensin 1 into angiotensin 2. We're also gonna talk about the angiotensin receptor blockers.
So these drugs block the effects of angiotensin 2 at the 81 and 80 2 receptors. And then we're gonna touch on aldosterone receptor antagonists, which antagonise the aldosterone receptors. Again, all of these, being different ways that we can try and down regulate or inhibit, the RAS.
So the first of these drugs is gonna be one that we're all very accustomed to using, so of the ACE inhibitors, we're gonna be talking about Benazapril, which is of course licenced in the UK for cats and dogs. So Benazapril. Is able to, decrease efferent arteriola resistance, which decreases the intraglomerular blood pressure.
And this drug has been shown to reduce proteinuria in studies. And delay the progression of azotemia in proteinuric patients. So this is generally the go to first choice of drug, OK?
And what we tend to do is start it at 0.5 MB per gig per day. And then we monitor our response to therapy every 4 weeks and we gradually up titrate the dose by an extra 0.5 mg per gig per day until we're at a maximum dose of 2 mgs per gig per day.
OK, so that's slowly done, every 4 weeks, slow, steady up titration of the dosage. That, total daily dose can be divided and given BID because there is some evidence that, that might be potentially more effective, in some individuals. And one thing that we've got to bear in mind is that, with this drug, we are, causing.
a, a, a, a selective vasodilation of the efferent arteriole. And what that does do is it does reduce glomerular filtration rate, OK, across the glomerulus, which unto itself, will cause some increases in some patients of creatinine levels simply because of the reduction in the GFR that this drug causes. So we'll just touch on that in a couple more slides when we mention how we monitor.
Patients that are put on ACE inhibitors. So Benazapril is our sort of go to first choice drug. What we often end up doing, to achieve appropriate control of proteinuria is we'll look titrate the dose of Benazapril, but eventually we'll often end up adding in a second drug and the next best choice would be an angiotensin receptor blocker or an ARB.
So tellmesartan. Is licenced in the form of eintra for cats in the UK and telemisartan has been found in studies to be at least as effective as ACE inhibitors in reducing proteinuria and may even be more effective than ACE inhibitors over a more chronic period of time. They've also been shown to potentially be more effective than ACE inhibitors at treating hypertension, which is good to know because, one of the things that we've said is that hypertension is a cause of proteinuria, and of course, patients who have persistent proteinuria can lead to chronic kidney disease and that itself can precipitate in systemic hypertension.
It definitely is safe, and there's published evidence on the combination of, telmisartan with ACE inhibitors. So it's safe to use those two, together. And in a very similar fashion to Benazapril, we simply start this drug at 0.5 mg per gig per day and again increase the dose by 0.5 mg per gig per day every 4 weeks until we're on a maximum dose of 2 mg per gig per day.
That tends to be given just once daily. Again, as per, Benazapril, the decrease in GFR that we can see associated with this drug can lead to some increases in creatinine levels. So how do we monitor patients that we've put on ARBs and ACE inhibitors?
Well, whenever you start a patient on one of these drugs, whether it is for proteinuria, or congestive heart failure, for instance, whenever you start one of these drugs, or whenever you increase the dose of one of these drugs, it's important to recheck, the renal values one week later. And that's just to check on how much or whether or not, in fact, the creatinine has gone up based on starting that new drug or a dose increase. And what we say is that in patients with Irish stage one or Irish stage 2 chronic kidney disease, so those with either no elevations in creatinine or very mild elevations in creatinine.
We can increase the, the creatinine, concentration by up to 30% with one of these drugs and not get too worried about it, OK? So, recheck, creatinine levels 1 week later, and as long as the creatinine has not gone up by more than 30% in a patient with diary stage 1 or stage 2 CKD, that's OK. However, we have to be more cautious with more advanced chronic kidney disease.
So if we're in iris stage 3, even a 10% or more increase in the creatinine is not acceptable and would mean that we would have to reduce the dose of that drug or discontinue that drug. And any patient who is in the most advanced stages. Of chronic kidney disease, so Irish stage 4, with very elevated creatinine levels, really any increase in the creatinine from one of these drugs could justify discontinuing that drug altogether.
And that's simply because that patient might just about be coping with their level of azotemia. And if we increase their creatinine level, we could precipitate a uremic crisis in that patient. And they could become really poorly, you know, to the, to the extent that they end up being euthanized, you know, because of their underlying disease.
So we can generally a bit, be a bit more gung ho, with our anti-proteinuric therapy in the earlier stages of kidney disease and a bit more cautious, you know, in the later stages. Do bear in mind that hyperkalemia may also be seen secondary to these drugs, although it's often, you know, quite mild and not clinically relevant. And very rarely anorexia, vomiting, and diarrhoea have been reported with these drugs as well.
. So, this is just, a little flow diagram that again is taken from that consensus statement, that I mentioned, a little bit earlier on. It's just a really nice way to help you work through, starting, and monitoring, . ACE inhibitor therapy in patients, with proteinuria.
So again, I highly recommend, you know, you do read that paper. And to be honest, I certainly have that saved, you know, on my work laptop and, and I'm regularly accessing that and using it as, you know, a reference, with my proteinuria cases. So what else can we do for these proteinuric, cats and dogs?
Well, we can look at some nutritional supplementation. And one thing that we can definitely recommend is starting omega 3 fatty acid supplementation. So the best way to get this into our patients.
Is with something like a fish oil, so not cod liver oil, which contains potentially too much vitamin, A for our patients, but fish oils, which, basically increase, the patient's omega 3 to omega 6 ratio. And this has been shown in some studies er to delay progression of proteinuria to chronic kidney disease and to also help reduce the magnitude of proteinuria itself. So very cheap, .
You know, very few sort of contraindications other than, you know, a patient who has got, for instance, chronic pancreatitis, you know, giving them, fish oil supplementation could precipitate, you know, an acute flare up. Because of it's, it's fat content, but otherwise generally this is very well tolerated, and we would recommend starting it at a dose range of 0.25 to 0.5 grammes per kilogramme per day.
The next drug to mention as well, is the aldosterone, receptor blockers. And of course the one that we're talking about here is soronolactone, you know, which is licenced for use in the UK so. Spironolactone is an aldosterone receptor blocker and as we showed on that diagram a bit earlier of the RAS, aldosterone is kind of the endpoint of that system, and aldosterone again has lots of negative effects in patients with proteinuria.
So normally by, inhibiting the RAS with an ACE inhibitor or an ARB or both, we often get, significant reductions in aldosterone levels. However, what we found is that, Over more chronic periods of time, patients who are on ACE inhibitors and even patients who are on ACE inhibitors, and ARBs can end up, with aldosterone sort of escaping the effects of inhibition, and there's a subset of patients, maybe around 20-30%, who actually, despite, ACE and ARB therapy, can develop elevated aldosterone levels. So.
It, it's certainly in the patients with sort of quite refractory proteinuria, it'd be sensible to monitor aldosterone levels and consider the use of spironolactone in these patients to help treat this aldosterone breakthrough phenomenon, that occurs in these guys. And we tend to use the drug at a dosage of 1 to 2, makes per gig given orally, twice daily. We then move on to antiplatelet therapy.
So as I said earlier, patients with glomelo, nephropathies and, and, and, and proteinuria are at increased risk of thromboembolic disease because of their hypercoagulable state, the state. And, a prevalence of up to 25% in dogs has been reported in some studies. So it's, it's a pretty significant and serious complication, you know, if our patients do develop it.
. We believe it to be due to losses in albumin and antithrombin through the kidneys and increases in procoagulant factors such as 5 and 8, as well as increasedbinogen levels and increased platelet activity. So, patients who've got significant proteinuria, we do want to look at antiplatelet therapy, long term to try and reduce their risk of thromboembolic disease. And the two drugs that we would look at using are clopidogrel.
Either or, aspirin. Clopidogrel, is available, from compound pharmacies, as the sort of generic drug or it's otherwise, you know, available as the human form Plavix. And that's dosed at 1.1 mg per gig, per day.
Aspirin obviously is just generic and that's used at low dose at 0.5 to 1.0.
Me picking once daily. Now, there's no strong evidence to say in proteinuric patients which of these two would be more beneficial. But certainly with some evidence saying that doses above 0.5 to 1 mg per gig per day might be required in some individuals for effective aspirin therapy.
And given the fact that a small number of patients that that are put on aspirin can develop Gastrointestinal, sort of side effects. Certainly, I think people are moving more and more towards the use of clopidogrel, you know, in, in preference to aspirin. But there is the option of using either of those and or combination therapy of those two drugs, long term to help reduce.
The likelihood of a thromboymbolic event. We're then gonna talk about anti-hypertensive therapy. So, there again is another fantastic consensus statement published, to the AC, VIM.
And this is quite a recent one, from 2018, and these were the revised guidelines for the identification, evaluation and management of systemic hypertension in dogs and cats. So again, this is available open access through the Journal of Veterinary Internal Medicine. And what this, More recent consensus statement did, is it just slightly changed, our sort of, categories of severity of hypertension and, and when to treat and what our treatment goals are.
So we tend to say that normotensive is a systolic blood pressure below 140, and this would really equate to a very low, if not minimal risk of target organ damage, so damage to the brain, the eyes, the heart, and the kidneys. We then have this category pre-hypertensive, which used to be mild hypertension, and they've renamed it pre-hypertensive, and instead of it being 150 to 160 millimetres of mercury, it's dropped down now from 140 to 160 millimetres of mercury. So these are patients that are low target, low risk of target organ damage, but certainly should be monitored as a minimum, if not, considered for treatment.
We've then got patients who are classed as hypertensive and have a moderate risk of target organ damage, and those are the patients with systolic blood pressures of 160 to 180. And then, the severely hypertensive patients, which are those with blood pressures systolic blood pressures of over 180. So those are the guys that absolutely need, aggressive hyper anti-hypertensive therapy.
So why do we have to treat hypertension? Well, we've said to limit, target organ damage, but also because we know that hypertension accelerates renal dysfunction. It increases proteinuria and the frequency of uremic crises, .
So a lot of our patients are gonna already be started on an ACE inhibitor as the cornerstone of their proteinuria therapy. And ACE inhibitors definitely do reduce blood pressure, but it's quite a modest reduction, often in the order of 10 to 15%, which equates normally to about 20 or 30, millimetres of mercury at best. So if we've got a patient with a blood pressure of 220 millimetres of mercury systolic and we put them on an ACE inhibitor, you know, we might expect to get them down to 190, which is still in, you know, the, the, the highest disease category and still puts them at high risk of target organ damage.
So we often have to use additional anti-hypertensive therapy as well. And amlodipine would be the go to drug after an ACE inhibitor. In order to control hypertension, and we start this at a low dose and then we slowly up titrate over time to a sort of dose of 0.75 mg per gig orally once daily.
When we start patients on anti-hypertensive therapy, we want to monitor the blood pressure every 2 to 3 weeks, OK? And then slowly up titrate our dosages, based on systolic blood pressures at those intervals. We can, however, sometimes monitor, patients more frequently and increase the dose a bit more quickly.
And that's particularly in patients that either are, in stage 3 or 4, iris stage 3 or 4 chronic kidney disease, . You know, or patients who already have clinical signs of target organ damage, so cats that come in with, retinal detachment, you know, or significant retinal haemorrhage or neurological signs, those patients want to treat more aggressively and actually recheck blood pressure, more frequently, perhaps every 3 to 5 days and, and more quickly uptitrate our dosages. Again, another flow diagram, this one's from, that ACVIM consensus statement on the treatment of, systemic hypertension.
So again, great resource and highly recommend, you know, you look at it, . Fab, so we're getting towards the end now, you'll be glad to hear. And we're just gonna touch very briefly on immunosuppressive therapy.
So this is reserved for those patients that have had a renal biopsy and have a definitive diagnosis, and that definitive diagnosis justifies the use of immunosuppressive therapy. So this is generally those patients that either are severely proteinuric, patients that, have, . Azotemia because of their proteinur already have a diagnosis, or patients who have severe hypoalbinemia, so concentrations below 20 grammes per litre, .
There's lots of different drugs that have been recommended and used and of those perhaps mycophenolate appears to be the most commonly used and perhaps the most successful, but there are other recommendations of using cyclosporin, chlorambuil, azathioopine and even prednisolone in some cases, . In patients with different forms of the disease. So again, this sort of an in-depth discussion of this is way beyond the scope of, of this webinar, but you know, refer to sort of specialist advice or, you know, consensus statements for, for further information on these.
And when we do start immunosuppressive therapy, we tend to then monitor, you know, our patients' proteinuria and things at 1 to 2 weekly intervals initially, then monthly and then at 3 monthly intervals long term. But obviously bear in mind the sort of specific side effects of all of these different drugs and how we might have to monitor those. You know, so, azathioprine checking complete blood counts for evidence of myelosuppression, and, and liver enzymes for evidence of elevation of those, for instance.
Diet is, definitely part of the treatment plan of proteinuria, and what we tend to recommend are moderately protein restricted diets, as they're a way, to reduce the overall, renal protein loss by reducing the, circulating protein concentrations to help reduce the overload across that filtration barrier. And therefore reduce the amount of tubular er protein reabsorption that needs to occur. So diet has been shown to have, a large effect on the magnitude of proteinuria, and, help reduce the progression of kidney disease and, and prolonged survival.
So it is recommended that we start a renal prescription diet in in our proteinuric patients, OK? But do bear in mind that too severe, protein restriction can lead, to, loss of body weight and decreased, plasma protein concentrations. So we do have to bear that in mind in individual circumstances.
So finally, just the last bit on monitoring. So monitoring is recommended every 3 to 6 months in patients that have pretty stable disease, OK? But patients who have unstable disease, need to be monitored a lot more frequently, and, you know, perhaps every 2 to 4 weeks initially, and certainly any patient who has, a new drug added or a change in dosage needs to be evaluated in, in, you know, a maximum of 2 to 4 weeks' time.
If not sooner, to check creatinine concentrations as I've already touched on a bit earlier. When we are monitoring these patients, the things that we're primarily going to look at our urine, protein creatinine ratios, of course, albumin levels within the blood, our renal markers. Our blood pressure and physical examination and history.
Fab. So, I hope everybody has taken home some useful sort of hints and tips really on diagnosing and treating proteinuria. And I wish you all the very best for the future, take care.