Symposium on Nephrology

[00:00] Ladies and gentlemen, we now comment Symposium 19, focusing on nephrology with updates on vasculitis, lupus nephritis, and hepatorhenal syndrome. I am delighted to invite our chairpersons, Professor Raspi Sharif and Professor Kamani Vanigasuri.

[00:20] career on stage. May I now invite our chairpersons to introduce the speakers and panelists for this session. It's my greatest pleasure to invite all of you today. The first speaker in this nephrology

[00:40] symposium is going to be none other than Professor Montas Patel. You have already heard her at the inauguration. Professor Montas Patel is the president of the Royal College of Physicians London at the moment. And she's also a consultant nephrologist.

[01:00] at the Manchester University Hospital, the NHS Foundation Trust, and the honorary clinical professor at the University of Liverpool. Elected in 2025, she is the first woman of

[01:20] South Asian heritage to lead the Royal College of Physicians London in its 500 year history. So she is a specifically remarkable lady. She is a graduate of the University of Manchester. She qualified in

[01:40] 1996, completed a PhD in the genetics of lupus nephritis in 2006 and was appointed consultant in 2007 with a master's in medical education. She has established and

[02:00] national reputation in post-valued education, assessment and training. She has served as the Royal College of Physicians' senior sensor, the vice president of education and training, and a global

[02:20] Vice President, leading initiatives in education strategy, global engagement, and in women's leadership. She has also held senior NHSN university roles, combining clinical expertise with medical education.

[02:40] education and leadership. The topic that she has chosen for today's symposium is vasculitis and the kidney and overview. Over to you, Montas. Bless you. Thank you so much for the very kind introduction.

[03:00] It always feels like family when I come back to speak here in Sri Lanka. So thank you so much for having me. So as you write, he said, with the nephrology symposium, I was asked to talk about vasculitis and the kidney. In the UK, in the northwest of England, which is where I'm based in Manchester, I run the vasculitis and lupus.

[03:20] service having had the research expertise around both vasculitis and lupus. So what I'm hoping to cover in the next 20 minutes or so, so firstly, no conflicts of interest to declare. What I'm hoping to cover is some of the kind of broader overview. 20, 25 minutes is hardly enough to

[03:40] time to go through the detail of vasculitides. But I'll give you a bit of an overview around the definitions, some of the categories and clinical presentations around vasculitis and the kidney, the epidemiology broadly speaking. And then I've got three cases to illustrate

[04:00] some of the diagnostic and management challenges. I think day to day, since I was a resident doctor, a junior doctor, one of the main challenges was, A, how do you pick it up early enough to make a difference? And then all the different management challenges that go with it, particularly with the balance between the common condition and the patient.

[04:20] complications of the treatment as well as the treatment itself being a success. So I'll kind of go through some case studies to illustrate that. And then the indications and timing of renal biopsy, which is very important and remains the gold standard for the diagnosis, a little around pathogenesis and the role of anchor.

[04:40] And then more around an approach of management. There's so many clinical trials and this is a very research active area and I certainly don't aim to cover every single trial there is, but just to give you an approach and my experience around managing difficult cases and a short mention of.

[05:00] around treatment outcomes. So vasculitis, as far as definitions are concerned, so whenever I'm doing this as a teaching exercise for our medical students, the vasculitis per se is inflammation of the blood vessels. It's a very much a heterogenous group of diseases characterized by inflammation, necrosis, and then it's the

[05:20] damage to the blood vessels and the occlusion of the blood vessels which causes the end organ damage. It can affect any type of blood vessels, any size, location of blood vessels may be involved and it could be primary or secondary and then there's certain mimics around vasculitides that I'll talk about as well. And it could be confined

[05:40] into a single organ such as the skin also, but the ones that I see in nephrology, and I'm sure many of you have seen, are the ones that affect multiple organs. I'm sure many of you are aware of the Chapel Hill consensus framework, and that kind of gives you that overview of categories. And the...

[06:00] classification is very much based on the size of the blood vessel affected and the ones that we see are much more of the small vessel vasculitides, but I do have some patients who have large vessel vasculitis which is predominantly around tachiosus arteritis and giant cell arteritis. The medium vessel ones I do have some patients

[06:20] in clinic with those as well, with bodily arthritis and the dose of kawasaki disease as examples. And then the smaller vessel ones are the ones that we see majority-wise in our renal clinics in particular, which could be the immune complex vasculitides or the anchor-associated small vasculitides, which is predominantly what you associate

[06:40] vasculitis with in our renal clinics. And then of course you've got anti-GBM disease as well. And patients with, you know, the immune complex types could have cranial chryoglobulanemia. One of my patients who I just see last week had chryoglobunemic vasculitides as well. And then IGA vasculitides.

[07:00] And then the treatment pathways for each of these are slightly different as well, which I'll give you an overview on as I go through the cases. So clinical manifestations-wise, again, as I mentioned, it's a multisystem, autoimmune condition. It predominantly affects older age male group. We are diagnosing more patients now.

[07:20] Now it was probably less diagnosed in a tertiary centre like mine. We see it a lot in my clinics. When I have medical students or junior doctors sitting in my clinics, they'll say, gosh, every other patient is vasiolytous. But then I do run the service, so I see much more. But in an average GP centre in the community, they may see one or two cases.

[07:40] in their entire career. So it's not that common, and I'll go through the incidence and prevalence shortly. So it's multifactorial in etiology, widespread clinical manifestations, as you can see, and many times patients present with these nonspecific constitutional symptoms, which they may have for many years before their actual diagnosis.

[08:00] happens and that could be just flu-like symptoms, feeling tired, malaise, arthralgia, rashes, and the diagnosis comes sometimes very much later than the initial presentation. And as you can see, the ones that we see may have the classical chest and renal syndromes.

[08:20] But then ENT involvement is quite common with certain types of vasculitides as well. As far as investigations are concerned, like anything, when I'm doing my teaching, you've got your non-invasive investigations and then your invasive investigations. The invasive investigations like the biopsies still remain gold standard.

[08:40] But then there's many other investigations you can do now. So MRI scans on the right hand side, showing granuloma of one of my patients who presented with ocular fasculitis, which was quite life sort of threatening from an eyesight perspective as well. And then the second is just the plain chest ex-

[09:00] but then you have CTs and further scans that you can do, and that shows the nodular lesions for a patient with vasculitis affecting the lungs. And then the biopsy, renal biopsy findings. So the renal biopsy findings very much the chrysantic change that we talk about, which is lots and lots of activity of macrophages.

[09:20] charges, which can affect the glomerular space and it's the occlusion of the glomerular space which then causes the acute kidney injury and that causes that clinical syndrome of rapidly progressive glomerulophritis which leads to the acute kidney injury. And then on the far right hand side you've got the rashes which are quite pathognomonic of

[09:40] of vasculitis as well that we see in many of our patients as well. So lots of different ways, you know, blood parameters, urine parameters and then your non-invasive imaging but then your biopsies are which are gold standard. You have PET scans as well now which we look for activity.

[10:00] around particularly when it's multi-system disease. So then the further classifications between primary and secondary vasculities, so the primary ones which I've covered when I showed you the previous illustration as well, and then the secondary ones, particularly for lupus. So given I do a lot of lupus patients as well.

[10:20] I have a number of lupus patients who then develop vasculitis or class 4, which I'll talk about different classes of lupus vasculitides as well. And then infections. We see less of this now, but I do have some patients with FBC and HIV patients who then developed secondary vasculitides.

[10:40] and then medications, malignant, coelomatitis, leukemias. And then the mimics on the right hand side that you can see, I had a patient recently with substance abuse with cocaine. You had kind of nose damage and collapse and then presented very much with acute kidney injury and looked as though he may have underlying.

[11:00] vasculitides, but actually it was all cocaine abuse-related renal disease rather than pure vasculitides as well. So there's other things that mimic as well. So keeping an open mind in that sense is important. And then immunosuppressing those patients, you're going to make things worse. So I think just making sure that you've excreted.

[11:20] excluded some of these mimics as well before you start treatment.

[11:40] and certainly north sort of side of things. And then in Asia, there's a predominance of microscopic polyangitis, particularly in Asia. And then their phenotypic as well as genetic factors are very much different both in presentation, but also then how we manage these patients as well.

[12:00] So I'll go through a couple of cases now just to highlight some of these diagnostic and management challenges. So the first patient is a 54-year-old gentleman, an accountant who was referred to our general medical clinic, presenting with a two-month history of general malaise and polyarthralgia. He had a two-week history of shortness of breath, fever, and

[12:20] and then more recently, palpitations having recently been away on a holiday in Mallorca, which is in Spain. And then on examination, he was pyrexial at low grade temperature with some splinter hemorrhages noted and a pancystolic murmur, which was thought to be new. And on urine dipstick, he was found to have hematopoietic urea with blood and

[12:40] and protein. And I guess kind of if I do this as a teaching activity, I'd sort of say, how's the diagnosis of I'll get people to put their hand up. But looking at that presentation with the kind of prodromal symptoms, but then more recently as a new murmur and a temperature and a splint to hemorrhage. The working diagnosis for this gender.

[13:00] management ended up being subacute bacterial endocarditis. And then the management, he was started on IV antibiotics. His trans-thoracic echo showed a mild MR and maybe a suspicious mass in his posterior leaflet of his mitral valve. However, he continued to despite temperatures, despite the antibiotics.

[13:20] and his renal function continued to rise. And as you know, as nephrologists, with the gentamicin and the levels, and always difficult to measure and assess, but his renal function started to go off. His gentamicin levels were high and that were adjusted, but despite that, his renal function continued to rise.

[13:40] to worsen. Subsequent blood cultures were negative and a transthoracic echo following that the transesophageal echo which took a week to arrange then showed no vegetations. By this time the renal team got involved and we came along and hindsight as I say is always a wonderful thing and an exploration of

[14:00] the history further. Epistaxis was noted, ear aches, nasal crusting, and multiple nail bed infarcts. So now the diagnosis was potentially different given that he was treated for a week with endocarditis without any improvement. So now the clinical diagnosis changed to systemic vasculitis and his antifarteric disease was not

[14:20] were stopped. He had an ENT review which excluded acute infection. He had normal-sized kidneys on ultrasound scan and then went on to have his immunology checked, which was strongly positive, with Cianca positive and a PR3 of greater than 80. He was given high dose steroids and a biopsy arranged and as then expected, the biopsy was

[14:40] was very diagnostic to show necrotizing granulomatous lesions, over 50% of cellular crescents with severe arthritis, fibrinoid necrosis, and a strongly positive C3. So histologically, this diagnosis is porcyimmune-decrotizing FSGN, the focal aspect and the segmental aspect. So focal

[15:00] is around, you know, less than 50% of involvement. Segmental is one part of the individual glomerulide being affected and then severe inflammation noted. So he was treated with pulse methopadnisolone, IV cyclophosphamide, and then a lot of other treatment goes in with our patients.

[15:20] so whether it's septrin for antibacterial prophylaxis, antifungal prophylaxis, lansophosphate for PPI protection. And then he was dialyzed for a short period, plasma exchange given his presentation, and he had a good clinical recovery thereafter. And he became dialysis-independent and his renal function.

[15:40] came down to 150. So this highlights the atypical presentation of vasculitis. In general medical clinic, I'm sure you see so many patients with all sorts of presentations, and you don't always pick these patients out, but I guess there's certain features that subsequently came to light, which were diagnostic more for vasculitides.

[16:00] The second patient is a 70-year-old housewife admitted to one of our peripheral hospitals in Manchester with shortness of breath and was diagnosed with a chest infection. Her renal function on presentation showed an acute kidney injury with a creatinine of 334, eGFR of 18, and she was treated with antibiotics after she improved.

[16:20] she was sent home. Now the plan was to recheck her knee function a week after discharge. Now that didn't happen and she was readmitted a month later, more breathless and a chest X-ray was significantly worse, renal function was much worse and she was transferred then to our hospital where she was Ali Olegran Uric.

[16:40] hypoxic and was transferred from a general medical ward to a high dependency and intensive care straight after. She was very hypoxic, fluid overloaded perhaps, or whether this was pulmonary hemorrhage and she had to be intubated, hemafiltered and unfortunately she died four hours later. And a post-mortem

[17:00] diagnosis was then of good pasture syndrome with lung hemorrhage, focal necrotizing, GN, secondary to microscopic polyangitis, and her immunology from the initial blood test, which came back after she died, was positive for pianca and MpO greater than 80. So again, an anti-GBM positive.

[17:20] the urgency of the management as well and sometimes yes we do get it wrong but kind of having a lower threshold of doing some of these investigations early and she fell through the cracks because of you know going home which was fine but they're not perhaps having some of the follow-up investigations which were planned for her.

[17:40] And the last case is a 19-year-old lady whose Caucasian, SLE since age 14, presented with skin and joint involvement. She had a positive double-stranded DNA low complement treated with hydroxychloroquine. She was then subsequently diagnosed, presented with meningococcal sepsis a few years later after her initial diagnosis.

[18:00] And she was treated for that, improved, and then referred to me a month or so later with persistent hematoproteinuria. She was normal-tensive, low-grade proteinuria, low level of immunology, showing activity perhaps of her lupus, and her renal function at that time was normal. And the question was whether

[18:20] you do a biopsy then or not and what may show. So given she's just had a meningococcal sepsis, you could have post-infectious GN and if that's the case, you don't always biopsy these patients. But then given her history of lupus, she may have lupus nephritis as well. So we observed initially for a few weeks and then brought her back and the protein

[18:40] your ear started to go up, still not nephrotic range, just about a gram. A neuronal function was still normal. But when we did the biopsy, she had severe class IV, which is global active changes, proliferative changes of lupus nephritis with crescentic change as well. So, basically,

[19:00] kind of very active change despite the clinical presentation not being so severe. So she was treated with, again, hydrosteroids, pulcyclophosphamide, a urolupus regime. She had improved lupus serology, and then later she was switched over to mycofenolate. She just recently had a little baby girl and she's maintained on.

[19:20] prednisolone and azathioprine. She flared post-natally after her girl was delivered and she's now been managed with ritoxamab. So again, this indicates that clinical presentation doesn't always reflect the biopsy findings and that's quite typical for lupus in particular. So again, in many of my lupus patients, there's a very low flow.

[19:40] threshold of biopsy. So the timing of the biopsy, the initial biopsy should be performed promptly kind of in these cases rapidly, particularly in the first couple of cases, and a delayed diagnosis can cause an increased risk of end-stage renal disease. And many of these patients may need repeat renal biopsies as well.

[20:00] as well to distinguish active versus chronic disease, as well as other features. We had a patient recently who had drug induce interstitial nephritis rather than underlying vasculitides. The role of ANCOV I've hinted on in vasculitides is very important both for the diagnosis as well as the management and the presentation.

[20:20] for PR3 and MPO is quite different, both from the clinical presentation, the histological findings as well as the management features as well. And then the pathogenesis and the biologic agents. So there's so many biologic agents now you can't keep up with the newer ones and newer trials coming in, but certainly for the.

[20:40] and associated vasculitides. The B cell and the T cell activity is there. So a lot of our patients are on sort of rituximab, eclusimab now is coming in for the azinophilic, as well as the complement activation with avacapan has shown promising results and we use that in particularly our refractory patients.

[21:00] as well. And then the presentation, this is a busy slide, but basically showing the clinical as well as the diagnostic differences and the management differences between PR3, MPO, vasculitis as well. So the PR3 patients, more predominance of male patients, versus female predominance

[21:20] in the MPO patients, the Northern Europe, as I mentioned together with the Asia ones, and then more importantly, the clinical presentation factors, the granulomatous presentations in the PR3 vasculitis with ear, nose and throat involvement and more multi-system presentation versus more renal limited and lung involvement in the MPO.

[21:40] patients as well. Management-wise, you've got the induction phase versus the maintenance phase. The induction phase is between three to six months, and my practice still would be some steroids, although a tapering very quickly, and then the choices between cyclophosphamide or rituximab, and then the maintenance phase after.

[22:00] to six months or so would be azathioprine, methotrexate, depending on lung disease or mycophenolate thereafter. And then you have many patients with refractory disease, which are quite difficult to manage, and then some of the newer agents are used thereafter in those. I do aim to cover all the clinical trials, but some of the ones related to rituximab have been.

[22:20] been quite interesting. So the ritoximab has been found to be superior in certain patients against cyclophosphamide, particularly in relaxing disease. So we're using ritoximab much more now and particularly for our younger patients of a child-bearing age. And then the other trials thereafter were around sustained remission, as well as

[22:40] as well. The challenges in vasculitis management is very much getting that balance right. So the benefits are there of immunosuppression, of treating the disease, reducing, controlling the disease, reducing the relapses rate. But it's the side effects. I mean, the first patient I managed as a consultant was

[23:00] was 70 year old with vasculitis and sadly he died of a complication of severe pneumonia with infection following his treatment. And that just, I really remember that because it's the side effects of sometimes which causes the morbidity and mortality and the complications of therapy so you can't forget that and all the steroid use

[23:20] with all the steroid-related side effects, the immunosuppressive sort of effects as well, and then the cancer risk. I've had a number of patients with solid-order tumors later down the line following treatment with vasculitis as well. So addressing comorbidity is important in all of our patients. There's an increased cardiovascular risk for all renal patients.

[23:40] but particularly in vasculitis as well. And treating all of those things are important. So managing their blood pressure, their diabetes, bone protection, lipid reduction, anticoagulation, particularly with those with increased clotting risk and then anti-clatheless and vaccination. That was one of the other learning factors for COVID as well for many of our patients.

[24:00] as well. And then the broader lifestyle changes for protecting our kidneys. We talk about being hydrated, a low-salt diet, and then the wider cardiovascular risk factor management as well, and avoiding all the nephrotoxic drugs as we always talk about as well. So in summary, as I've hopefully demonstrated, the

[24:20] Vasculitis patients do always present in a very typical way. So it's having that low threshold of both diagnosis and picking things up, and then a low threshold for investigation and management. You need to consider the underlying causes of vasculitis. Treating those will then help enable the treatment of the vasculitis itself. In fact,

[24:40] malignancy, secondary causes, and the mimics as well. And the treatment for vasculitis, like I say, looking at the underlying causes and the timing of the biopsy is important, tissue diagnosis still remains gold standard and that earlier diagnosis and starting of treatment, like in anything, improves outcomes. And this challenging and balanced

[25:00] complications of treatment and personalising therapies, particularly with different presentations and a lot of my work was around genetic risk as well as then the management aspect side of things as well. So lots of things to consider and I hope the presentation has been helpful and I'm just on time so that's always good. Thank you very much.

[25:20] Thank you very much, Dr. Patil, for that very interesting presentation. Let's move on to the next lecture. It's by Dr. Ravi Rajakaria, who is a consultant nephrologist and clinical director of renal medicine and class

[25:40] transplantation at Bath's Health and Inaches Trust London. He leads one of the UK's largest renal registries, delivering comprehensive care across northeast London. His clinical expertise spans complex immune mediator renal diseases and he also is an active indigestion.

[26:00] and transplantation services. Over to you. And his lecture is on advances in the management of lupus nephritis. Thank you very much for the generous introduction. My background as a consultant nephrologist at Royal London, my sub-specialty interest is lupus.

[26:20] vasculitis and renal sarcoid. These are my declarations. So I'm just going to run through. I'm not going to talk about lupus as the pathogenesis or the genetics, but I'm going to focus mainly on the treatment options. I have another whole style

[26:40] presentation around managing difficult patients, but that again is not permitted on the time restrictions and also your tension span, as I would imagine. So we'll talk around the remission, the guidance, the CNIs, steroids and anti-CG20s and other biologics.

[27:00] So what about remission? How do you define it? And it's very tight and it saves less than half a gram of protein within 12 months. But the reality is different. It takes up to more than 12 months, often up to 18 months to a year before you can be converted.

[27:20] wins that the patients achieve remission alone. Partial responses less than 50% more than 50% reduction in proteinuria or bringing it to less than 3 grams a day. And around 6 to 12 months, if the patients are not achieving partial remission, then you've got to revise your treatment options.

[27:40] and consider alternative choices. So one of the current guidance, so this has moved very fast in the past two years. You Lovers, first off the mark, published their guidelines in 2023 and they had a very nice colourful schema. Then came KD.

[28:00] We nephrologists love to make it very complicated sometimes. So it's a very complicated summary slide. And then ACR just published their guidelines, et cetera. And as you can imagine, the flavors are slightly different, but the treatment options are pretty much shaded.

[28:20] shared in all those three guidelines. So one of the common themes, firstly, all patients should be on hydroxychloroquine. One of the mistakes I even personally have made is not adjusted to weight and renal function. So to get the optimal treatment, you got to follow guidelines on how to dose hydroxychloroquine.

[28:40] induction should be with IV methylprednisolone. It's shared in all of the guidelines. Interestingly, the key pivotal paper, the Ginsler study with mycophenolate, which is the standard of treatment, did not have IV methylprednisolone induction, but that is now the

[29:00] accepted guidelines and in fact all the newer trials also have IV metal prednisolone as part of the induction regimen. Microphenolate is the standard of care. All the studies, especially the latest ACR guidelines, are now promoting triple therapy either

[29:20] with calcium urine inhibitor or Bellum map. The prednisolone dose should come down to at least five milligrams or less at six months. Now, what are the caveats? So the steroid tapering regimen isn't very clearly defined.

[29:40] And KDGO gives you three different options, and we would need to be guided by some of the newer trials when it comes to steroid tapering. Also one thing that we personally now unit also gives is that we are not very good at adhering to tapering, partly given to people.

[30:00] because we don't give the clear information to our patients. The role of IV cyclophosphamide seems to go on slightly out of favor in all the studies, all the newer guidelines, but we do use IV cyclophosphamide quite a lot, and it's very important to appreciate that the urolupus, which gives.

[30:20] your cumulative dose of 3 grams is not associated with risks to fertility. And it's been based on studies that looked at antimalarian hormone levels, which has shown that, especially in our younger patients under the age of 30, 3 grams is perfectly safe.

[30:40] As always, this is a fast-moving area. There's a lot of nice studies coming out, and the guidelines are already slightly out of date with the publication of the regency trial this year. It's very important. I look after, just like Mumtaz, I look after vasculitis and luteus vasculitis is

[31:00] easy. Leupus is tough. Our patients are difficult for various reasons and we should consider personalising minisuffression and again I'm not got the time to cover that in this. So what's our current practice? We are our standard practice if we go for prednisolones.

[31:20] on hydroxychloroquine microsenolate. And in those with preserved renal function, we will add a calcium urine inhibitor. And we've got the option to give vocclosporin because it's nice approved, so it doesn't come out of my drug budget. So I prescribe it and we all prescribe it.

[31:40] try it to our patients. We do, however, give cyclophosphate. It's a very effective drug. It's intravenous, six doses in a 12-week period, and we tend to give it to people with aggressive disease, especially when they have significant renal injury, because we are old-fashioned.

[32:00] we know it works and we know it works fast. Also, in patients where we are having difficulty in controlling the lupus after six months to a year, often it's the case in our practice it's due to nonadherence. Retriximab is also increasingly coming back into

[32:20] And we tend to use it with renal leukos, especially those with skin embalment and nonadherence and belimimab. We do not use it the way the trials are recommended, but we do prescribe it nevertheless. So let's talk about Vocles 4, in which I appreciate.

[32:40] is not available in the UK in Sri Lanka. It is effective and this is a one year study which has shown that complete renal response and that's looking at less than half a gram a day of protein. Patients on vocosporin achieve this far greater

[33:00] significantly greater than those who are not on voculisporin. But also voculisporin did have a rapid steroid tefel. So you had two doses of IV methylprednisolone at the outset, and then your oral steroid started at 20 to 25 milligrams, significantly less than.

[33:20] we have historically done so. So, a book called how it's got IV methylpred and a rapid steroid tip and that is your standard steroid tip, rapid steroid tip. And this is really important because we do use it and we have now got over 18 patients.

[33:40] on it, and this is an old slide that we've just completed the audit on the one-year data, and we found that there was quite a rapid reduction in the proteinuria with the use of boklosporin. However, it's extensive.

[34:00] I think the UK costs something to around 3,000 a year, pounds a year, which is not cheap, and it's not going to be available or affordable for the vast majority of Sri Lankans. Calcin-urine inhibitors, though, are available, and have been used, and there are other things that are available.

[34:20] There are limited trial data historically of its use and it's shown that it's effective. However, you need to monitor drug levels and the standard most commonly used is the transplant maintenance levels of four to seven cyclists' tachronolimin.

[34:40] or cyclosporine around 100. And it has been shown to be effective in reducing proteinuria. And more importantly, unlike in vocosporin, it's safe in pregnancy. There is no data of vocosporin in pregnancy, and it's not licensed to be used in pregnancy.

[35:00] Again, it's around all CNIs, means lots and lots of more tablets. One of my patients who I recently started on Vocalo said I take 30 tablets in the morning and a few more or less, but quite a lot in the evening and that's a problem. therapeutic duct monitoring as I mentioned.

[35:20] And we are increasingly appreciating hypertension is a problem, right? And that we need to not ignore, especially in our young patients and of course, diabetes. Now, there is a case to be made to reduce endosteroid burden. Without a doubt. High cumulative

[35:40] dose of steroids do increase the risk of infections, osteoporosis, diabetes, and the problem that is previously the whole diabetes talk and around weight gain is a major issue and you are dealing with young patients. They don't want the body image as important as managing their look.

[36:00] Steroid spherin regimens are useful and they're good data that if you use methylprednisolone at the beginning and use a rapid steroid taper, you will lead to an overall reduction in the cumulative steroid burden. And the dose I've looked at is 10.

[36:20] recommend is what is clearly prescribed in the auroratose study, in the voccosporin study. And this is what rheumatologists have been doing for a long time. We nephrologists have been really behind in coming to the party of reducing our steroid burden. So moving on to the biological

[36:40] I used to use retiximab a lot and I was a big fan, but unfortunately these trials were negative. Both Explora and Luna showed that adding retiximab on top of standard of care did not lead to

[37:00] better outcomes in patients with lupus nephritis. I will come to Bellumimab in a minute and I will now go to the most exciting thing that's happened this year is Obenutisir map. This is an anti-CD20 and what it did show was adding Obenutisir map standard of care.

[37:20] With a fairly rapid steroid taper down to 7.5 milligrams in 12 weeks and 5 milligrams in 24 weeks led to significantly better complete renal response in those on oblongitis in that. And looking at

[37:40] At complement levels, double standard DNA, is definitely in favour of the new treatment. But it's also important that unlike in Lune, which gave four doses, two in the beginning, two at six months, they're dosed up to a year and looked at outcomes at 76.

[38:00] weeks, so gave it to that really good new period of time to show efficacy and what it showed was that profound B cell depletion up to 1076 eggs. And so what we know about our venetosimamase gets deeper B and most sustained B cell depletion, both peripheral and non-perfertile.

[38:20] blood as well as tissue which is not, you cannot measure. But there is of course higher adverse events. There is more infusion related reactions, cytopenias and hypergamoglobulanemia which can be a problem. And as I mentioned there is more tissue based cell depletion.

[38:40] And the repopulation is also more delayed. Of course, it's not affordable. I looked on Google. If you want to get an Indian-made rituximab or vinutuximab, it can be something like 400,000 Indian rupees. So it's not.

[39:00] beyond the means of 99.9% of serine pumpkins. So is there an emerging role or a rituximar? One thing I've noticed, rituximar, I use it a lot. I use it in vasculities. I use it in lupus. A lot of my colleagues who do the podocyte clinics use it in minimal change.

[39:20] You are. You don't repopulate that easily. I have patients, 70 year olds with vasculitis, who have started retoxamat, three years down the line, they still B-cell deplete. But the younger you are, you repopulate quite fast. Your young lupus, because we monitor B-cells, sometimes they repopulate at four months.

[39:40] If you have impaired renal function, you don't repopulate. And obviously underlying disease and carb repopulation is much slower than with lufus or minimal change. So my proposal is, yes, use rituximib from the outset, but if you can, and I don't know the answer to this, perhaps I should have asked my friend Chana

[40:00] for this monitor vessels subsets. Because by monitoring vessels subsets, you probably should be redosing it at least every six months or even sooner. So is there a retoximab? Yes, because it's actually relatively affordable compared to many of the other.

[40:20] newer agents, and you can cover many areas. So a lot of our patients with lupus want to get pregnant. Preconception counseling, you can prescribe rituximone up to the second trimester. It is very effective for

[40:40] skin and joint. It certainly will reduce steroid burden if you use it like you would use a CNI and rapid steroid taper, as was also in the regency trial, and clearly it works in those who are non-adherent. So we use rituximab,

[41:00] quite a lot, especially in the non-adherent group to get some level of control. So the summary treatment algorithm is yes, methylprednisolone, two to three doses. Most of the trials did say two doses. Oral pred, but a rapid taper. Remember, we have a responsibility.

[41:20] by our patients and not leave them on steroids and let them get all the other complications. And the way I do it, and I learned this when I started using the rapid taper of the pexivas protocol for vasculitis, is to give a date and tell this is the dose you've got beyond that date. Factoring in the fact that some of our patients have been

[41:40] limited health literacy, they may not be able to count. They may not be able to, you need to factor all that in, in understanding. And hydroxychloroquine, and you either give MMF plus a CNI or MMF plus rituxim. We are fans. I have been a massive fan of protocol biopsy.

[42:00] and I would protocol biopsies every year with the aim to then stop being steroids. You need to redose rituximab and base that on CD19 levels, not just to percentage CD19, but also the CD19 absolutes levels and consider the encyclophosphate.

[42:20] disease and that should come apparent within six months to a year based on renal function, protein, urinary and urinary sediment. So what of a bilemimab? I again appreciate this is a slide that is more relevant where bilemimab is a

[42:40] available. Bellum-Mab has been shown to increase the percentage of complete renal response, and it is in many trials being used as first line. This was in ULA. It's also in ACR. But we at the end of the year, we have been able to get the vaccine to be available.

[43:00] In London, baths and it's fish, also I don't think in most other units I've spoken to do not use bilemmi maverist first line. For a variety of reasons, partly the cost and secondly that it is mostly given as intravenous once a month.

[43:20] huge resource pressure. We did use it and we recently published that in Lupus. So we tended to use it for people with lower GFRs. There were more black patients. There was a higher SLEED I score of 16 versus 20.

[43:40] 12 and it was almost a second and third line reeminent treatment. And what is not said here, because it's really difficult to be certain about is a lot of these patients are non-adherent and they don't tell you the light to your face so much that it is really hard to assess.

[44:00] that. And what we did find was that just by adding a biologic that we can give once a month, you get significant improvement in their sleep ice code, their DSDNAs, their complements, etc. However, it's costly and I appreciate it, but it's coming close to

[44:20] losing is patent, but it will come available. Another thing that we do, there is a study, the B.E.A.D. study, which showed using bileumimab after rituximab in all comers of lipids, not just liposophritis, and that's shown that, and anecdotally we also see that people who have had rituximab pre-disappears.

[44:40] tend to respond better with bellumimab. So when do we need immunosuppression? So we, you know, I came from an era where we never been in immunosuppression as a trainee registrar, then I went through a phase of weaning immunosuppression and have you gone back to not weaning immunosuppression? Partly because

[45:00] the studies are showing if you stop all immunosuppression, they will relapse. And lupus is not an easy disease to manage, and you really don't want relapses. So what I look at is I look at original disease, I look at response, I look at the chronicity, the proteinuria, as well as the protocol biopsy, and then I will try to do that.

[45:20] bring them off steroids, but I leave them on MMM and hydroxychloroquine, and so far I avoid stopping either of the two. Lupus-like, vasculitis-like, any other disease has an impact on the medications we give you, as well as if you're managing a chronic disease.

[45:40] So you've got to manage the proteinuria despite optimal treatment. So A's and R's are pretty standard. Blood pressure targets should be less than 130 or 180. And we are now starting to use SGLT2 inhibitors despite DAPA CKD, MPA CKD, one of the exclusion criteria being immunosupply.

[46:00] expression. Why? Because it's our transplant colleagues, I for a while used to do a diabetes transplant clinic with my diabetologist. I have not stopped doing that now, but we started prescribing SGLT2s there, and increasingly there's a lot of experience showing that it's safe.

[46:20] We know whether it's going to be effective long term. That data, I have not seen any data supporting that as yet. Retinal screening is really important. Every five years, our patients on hydroxychlorine should have their retinas screened. And again, managing their overall risk factors,

[46:40] that's because these factors are paramount to provide optimal care for a longstanding condition. What's on the horizon? So I've talked about rituximab, bilemimab. They are already there for ages. And if furalumab has got face-free data, we don't use it, it's not nice of a problem.

[47:00] I have no experience of using it. And there is, of course, JAK inhibitors, tyrosine kinase inhibitors. There's fusion proteins coming up. This Chinese product, Telitasis, there is some phase 2 data come out. That's shown to be promising.

[47:20] promising in the future. None of these are going to be cheap. What's also very exciting is CAR-T therapy. So I was at ULA a few months ago in Barcelona. There was like literally presentation by the technology.

[47:40] is going getting better and better, looking at it where the key problems that what worries me is the cytokine release syndrome and neurotoxicity and the technologies move to such a level where you can do cardiotherapy as a day case. And there are also other bi-specific antibodies.

[48:00] looking at multiple targets which are already used in cancer are being now trialed in lupus in phase 1 and 2 studies. So as I mentioned vasculinitis is easy to manage. I manage I have a more clinical

[48:20] solely doing vasculitis, but lupus is really hard. And the reason is that our patients are young, they have chaotic lives. Often they're very poor, and they're single parents often, and they don't like taking their medicines. So doing it as a team is really important.

[48:40] important, including a dermatologist. We do a lupus telederm and CNS and working in a single setting, which is what I do. Works. And we don't only socialize at work, we socialize outside because we're building those relationships. And I tell all your young

[49:00] doctors, build a team because that's good for your patients. Thank you very much. Thank you very much Dr. Ravi Rajakar here for that very illuminating lecture. Next we have Professor Andrew Davenport. He's a big name in diaspora.

[49:20] dialysis, I know, from U.K. There is a professor of dialysis and ICU nephrology at the UCL Center for Kidney and Blood Health, Royal Free Hospital, University called it London, and internationally recognized expert on dialysis and critical care on nephrology.

[49:40] He has made a significant contribution to advancing renal replacement therapy, dialysis standards, and renal nutrition. Now, he has served as president of many societies. If I go to...

[50:00] talk about each one of these, it will take his time away. Through his leadership, research and clinical expertise, Professor Davenport continues to play a pivotal role in global nephrology, improving outcome and health.

[50:20] for Patients with Kidney Disease. It's a topic that he has chosen for today is hepato-renal syndrome. Over to you, sir. Thank you very much for that very kind introduction. So today I'm really going to talk about acute kidney injury in patients with chronic liver disease. And for this talk, I have no conflicts.

[50:40] of interest. If you look at the data in England, you can see that over time over the last 10 years, the number of hospital admissions for both men and women has steadily increased. There's a slight dip during COVID, but otherwise as you can see, it's now picked back up. And similarly, if you look at the deaths from liver disease in England, again, you can see a steady

[51:00] rise over the last 10 years or so. So it's becoming a bigger problem in the UK. Just over 10 years ago, we first sat down with the International Club of ascites to try and agree definitions in terms of what is acute kidney injury in patients with chronic liver disease, the so-called HRS-1.

[51:20] type 1. And as you can see, we now have an agree definition between liver doctors and kidney doctors. So very simplistically, it's a simple rise in serum carotenin of 0.3 milligrams per deciliter or greater within a 48-hour period, or a 1.5 to 1.9 times increase within 7 days of a baseline

[51:40] caratinin. And for the liver team, that could be a caratinin within the last three months or using admission caratinin. Or equally, as many liver patients have reduced urine output, a urine output of less than 0.5 mls per kilo per hour for more than six hours. And then stage 2, a 2 to 2.9 times increase, and

[52:00] stage III a three times or greater increase or greater than four or the start of renal replacement therapy. But obviously the patients have to have decompensated cirrhosis. At the time we're making the diagnosis, no evidence of shock, no treatment, current treatment with nephrotoxic medicines, and no response

[52:20] to volume expansion. Technically, there should be absence of parenchymal disease, but as you are probably aware, that we're now treating more patients with diabetes, more patients with hypertension, and so actually, we may now see levels of proteinuria greater than 0.5 grams per day due to underlying parenchymal disease due to diabetes or hypertension, et cetera.

[52:40] but less than about 50 red blood cells. And there should be a vasomosis component, and that means that the urine sodium should be very low, so the fractional excretion of sodium should be about 0.2% or less. So what we're looking at is a definition of AKI based on changes in serum carotenin. So the question is, well, what's the problem? I mean, we all know what carotenin is.

[53:00] and as we measure it, we see it as results every day. But crannin comes from creatine, and creatine requires just three amino acids. And the first of the synthesis steps of creatine of creatine is in the kidney, and then subsequently in the liver. So if a patient has chronic liver disease,

[53:20] they may not be able to convert these amino acids into carotenans. So the production rate goes down, and that's important. And the other issue is that the conversion of creatine to carotenans takes place in muscle. And many patients with chronic avidices have a degree of sarcopenia, loss of muscle mass, and not for

[53:40] physically active, and therefore the generation of creatine and then the generation of creatinine is slower in patients with chronic liver disease. So if you look at this picture here, this is looking at generation rates of creatinine. And so if we were to look at, whoops, I've just gone back two for science, oops, I need to go back, sorry about this.

[54:00] that's going forward. Can we go back? Yes, we can go back. So if we think, gosh, how many problems here, can I go back on this one? Is that back? Yeah, it should be back. I apologize to this.

[54:20] So, if we look at this slide, if you imagine if we have somebody who is producing a lot of carotidin, 20 milligrams per kilogram per day, to go from a carotidin of 1 to 2, to double it, as you can see, takes about 12 hours. To go from 1 to 3 takes just about 30 hours. I mean, if somebody has a very slow

[54:40] low rate of carotid production, five milligrams per kilogram per day, you can see here, if we double it from one to two, you can see it's going to take about over two days. And actually, you can see that after four days, it's not going up to three. So one of the issues is that when we're looking after patients with chronic liver disease, we often look at the carotid, and we often say,

[55:00] oh yes, it's gone up a little bit, a little bit every day. And so we don't quite realize actually that the kidney is getting worse quite significantly day by day and that's a real problem. And the other issue of course is the laboratory measurement. So a lot of laboratories still use a color-based assay, a JAFA type assay.

[55:20] And bilirubin is a color. And so as bilirubin levels rise, it interferes with the colorimetric Jaffa-tape assay and therefore underestimates the true creatinine. And even if we switch to enzymatic assays at very high creatinine levels, there still can be interference with the assay. And so some years ago,

[55:40] Andy Burrows made us perform lots of isotope GFR measurements in our liver patients. And here we're using what's called an IDMS GFR. So this is when your laboratory corrects the creatinine measurement for an isotope dilution creatinine.

[56:00] is that it doesn't matter whether we've used a Cottgroff-Gault equation, which is the top left, or we've used the MDRD4 or MDRD5 equations. You can see that when we use carotidin, it underestimates the true kidney function all the time. And so you can argue, well, okay,

[56:20] is not so good, why don't we use cisatin C? So here's a study from Europe, this is very similar to our own internal data. On the two panels on the right is when you're looking at keratinin measurements of kidney function. Inulin is giving you a true GFR, and as you can see how keratinin measurements overestimate true kidney function.

[56:40] The two in between, hook and larcenar, two of the equations used for checking GFR with cystatin C. And so you could argue they're slightly better than creatinine, but they still overestimate true kidney function. And the other issue with cystatin C is that if there's inflammation, then cystatin C production is increased. So if you go from child to child,

[57:00] you A to B to C, cystatin C levels naturally rise. So there are again, there's confounding with cystatin C. So it's just unfortunately just as bad as carotidin. And the other problem with both of these, whether it's carotidin or cystatin C, they're concentrations. And so if we have a patient with lots of ascites, there's extra fluid.

[57:20] so it dilutes down the cystatin C or the caratinin. So if you look at the simple graph over here, what you notice is as the patients have more ascites, the difference in terms of GFR measured with caratinin compared to at the isotope gets larger. So this dilution effect. So some years ago, we sat down, or Andy Burrow sat down and said,

[57:40] that sat people down, we try and work out if we could come up with an equation to try and work out is what is the true GFR in these patients? And so the Royal Free published the Royal Free equation, which is this one on the top, which uses caratin, urea, the INR, and the age of the patient. And some culture

[58:00] Some of the colleagues from ours in California, in Los Angeles, came up with their own equation, which they use really around the time of liver transplantation. And both of these equations are freely available on the web. You can just put the numbers in. At least it gives you a real idea of actually what the real creatinine or GFR is in these patients. And that's really important to understand.

[58:20] So if we go back to AKA HRS, so what we're saying here is that what we assume is that as the liver deteriorates, the pressure inside the liver rises, this intrahypantic resistance increases the pressure in the portal system, there is lots of nitric oxide on the basodilators in the splanchnic circuit, and eventually the system is

[58:40] spill over into the systemic circulation. This causes a relative hypovolemia. The heart responds by increasing the cardiac output. But unfortunately, the cardiac output doesn't match the drop in systemic vascular resistance, and therefore these patients are relatively hypovolemic. And this then leads to increased sympathetic.

[59:00] system activation, increased noradrenaline production, increased vasopressin, increased angiotensin, etc. And this then leads to the kidney retaining both sodium and water. But if we look at what we're actually seeing now in our patients with AKI, this is European data and it's based on the siron.

[59:20] So in their data, you can see just about 44% of patients with AKI actually were prerenal and generally were volume responsive with a low urinary sodium extretion. About 34% had what we would traditionally call acute tubulin necrosis or ischemic injury to the kidney.

[59:40] But if you see, the mortality here is over 50%. And typically the fractional excretion should be greater than 2 to 3%. But I'll show you some data later that contradicts that. And hepatorhenal syndrome, only about 12%. In our own series, it's down to about 10% now. But again, a very high mortality, almost 50%.

[01:00:00] 50%. And technically these patients shouldn't have shock, their urine should be roughly bland, and really it's a diagnosis excluding prerenal or ACN. Occasionally we'll see a patient with postrenal obstruction and occasionally, again, a patient with glomerular disease. And I've certainly seen patients with IJ nephropathy where we've got red cells that have actually blocked the tubules and have

[01:00:20] cause acute kidney injury. So it is possible for an acute lomerular phoritis, a flare of IgA to cause it, and patients underlying chronic liver disease. But what we are seeing more and more is this concept of ACLF, or acute on chronic liver failure. It's whereby somebody with chronic liver disease compensates cirrhosis or decompensates cirrhosis, that it's a precipitancy fact.

[01:00:40] be an infection, drugs, alcohol, etc., ischemia, surgery, sepsis, etc. And suddenly the patient develops hepatic and other organ complications. And so just as you would have in the intensive care unit, you'd have a sofa score or an apache 2 score, apache 3 score rather. If a liver disease, we now have a cliff.

[01:01:00] European organ score. And essentially, if you score three, that means the organ has failed. So for liver, for example, it'd be a bilirubin over 12 milligrams per deciliter. For the kidney, it'd be a cratin-grated than 3.5, or starting renal replacement therapy. Enecaphylopathy grades three or four. And INR greater or equal to 2.5.

[01:01:20] needing vasopressors for circulation and obviously if you've got poor respiratory function. So you can add these together to get an organ severity. And the reason for this of course is that if patients develop for more organ scores then the risk of mortality really increases. But interestingly, the one thing that really

[01:01:40] pushes patients from what we call no ACLF to ACLF grade 1 is renal failure and renal failure is the major driver behind actually the severity of ACLF and if we look at what happens to patients who come into hospital with decompensated cirrhosis and ACLF if they have just liver failure they actually have a

[01:02:00] very good survival. But actually if they have ACLF grade 1 or greater than 1, then I'm afraid to say the survival is down to around about 50%. And interestingly, the mortality is actually very quick. It's usually within the first 10 days that the patient dies. So we do have additional issues in terms of how to try and manage these patients.

[01:02:20] to

[01:02:40] So if you simply just feel the hand of a patient and it's cold, you know they are volume-deplete. The blood pressure is difficult to interpret because often with the vasodilatation, the blood pressure is the systolic of 19, 95, 100, etc. The JVP is difficult to interpret because these patients have a hypodemic circulation. So a normal JVP is difficult to interpret.

[01:03:00] does not mean the patient is not volume-deplete. In fact, it's probably best to say that if you can't see the JVP, you know they are volume-deplete. So the JVP may well be normal, but the patient is still relatively underfilled. And you can look at things like finger oxygen saturation. But today, what can we do in terms of trying to volume-assess patients?

[01:03:20] Well, traditionally we could sort of lift the legs up in the air and see what happened to the change in systolic blood pressure to diastolic blood pressure, the so-called pulse pressure. We could give a see of what happens to pulse pressure with the bolus of fluid, etc. But today, of course, we have point of care ultrasound, so we can come along with a portable ultrasound machine, look at the inferior vena cava width, get the patient's

[01:03:40] take some big breaths in and out. If the IBC doesn't change, they're obviously severely hypervolemic. If it totally collapses, they're severely hypervolemic. And so we're looking, like, do they have a collapse of more than 50% is what we're looking for is the space to give them some fluid. And the other issue, of course, is to look at what happens to velocity.

[01:04:00] in terms of the VTI, we can do this in terms of IBC, look at the velocity index in terms of what happens when we give them some fluid, the IBC, or similarly look at the cardiac output in terms of what happens in terms of flow out of the aorta during one cardiac cycle. So there are ways of now trying to better assess patients.

[01:04:20] as to where they're going to respond to fluids. So the next question, of course, is what about biomarkers? Well, the biomarker that's been most extensively looked at is obviously NGAL. As you can see here on the right, in terms of serum NGAL, the no real help in terms of differentiating, whether it's prerenal, established kidney disease, ATN, or HRN.

[01:04:40] And actually when it comes to N-galin urine, oops, keep pressing the wrong button here, what you can see in terms of the N-galin urine is that it's actually most, it's highest. It is. It's actually highest actually with ATN. It's much higher than HRS, etc. So not to

[01:05:00] helpful. What we do know is that classically in HRS the fraction excretion of sodium will be much lower compared to ATN or pre-renal. So if you're not giving diuretics then fraction excretion of sodium is actually quite useful. As you can see in terms of urine albumin you can see it progressively increases from pre-renal to HRS to acute

[01:05:20] acute tubular injury. And if you look in terms of other biomarkers, then generally they're not particularly helpful. Although there may be some like KIM1 and IL-18, which are much more likely to be raised with acute tumor ischemia, if you look at the area under the curve, the diagnostic accuracy, they're not very helpful. So biomarkers, I'm afraid, say have not been helpful to try and differentiate.

[01:05:40] differentiate HRS AKI from other forms of acute kidney injury. So what are predictive factors? Well, if the patient's recently had systemic inflammation, if they've recently had some sort of acute hemodynamic changes, recently been treated with spontaneous bacterial perifenitis or other systemic infections, if they had a large volume paracentesis

[01:06:00] without abdomen, or in very early stages of ACLF. And so what's the European management? So the first question in Europe is what are you going to do if the patient doesn't respond? That's a big question because the question is are we going to be active with this patient or are we going to have a more sort of

[01:06:20] end-of-life type management of the patient. That's a big issue in terms of whether we take this patient on for treatment. If we are going to treat them, then we're going to give telepressing a milligram for a six-hourly, or if you give an infusion, there's a constant infusion at just two milligrams per day, and that obviously gives the patient a lower dose and less side effect.

[01:06:40] effects. If the caranine doesn't fall by 25% within two days, steadily increase the dose every couple of days up to a maximum of 12 mg. At the same time, we're giving patients large volumes of albumin. Europeans, the complete response is a serum caranine that goes back down to the baseline within 0.3

[01:07:00] 3 mg per deciliter of the initial baseline. And a partial decrease would be the crackling goes down but not low enough. And what happens if they recur after we've completed the treatment course, the European advice is to retreat. The US is slightly different. So the FDA have slightly different criteria, give us slightly different

[01:07:20] dose of to antidepressant 0.85 milligrams every six hours, one to two days. Here if it's 30%, less than a 30% fall in the serum karate, and then to double the dose to 1.7 milligrams. If obviously there's greater than 30% fall, just continue, and a maximum of 14 days. And they define response differently. Again,

[01:07:40] versus serum creatinine of less than 1.5 milligrams of dessilidata on two consecutive days. Obviously, the problem with telesophageal presidants is it's a potent basic constrictor. So you can't give it to somebody that's had a recent MI, got peripheral ischemia, recent stroke, etc. We're going to monitor the blood pressure, serum creatinine, and respiratory function.

[01:08:00] Because don't forget, you're giving patients albumin at the same time. So albumin has a sodium load, it has a colloid load, and it's very possible that patients develop pulmonary edema. So it's really important to monitor respiratory function. And again, if you look at the actual survival of what happens to patients with HRS in the clinical trials, these are some of the

[01:08:20] larger trials. What you notice is that actually success is only around about 30% at most. And most of the time in terms of side effects and people having to stop telepresence, usually it's around about sort of 6%. But there was one trial where it was about 20%. But in that trial they were giving telepresence and albumin to patients.

[01:08:40] with serum carotidins great in 3 mg per deciliter and really were having problems with respiratory control. So will the patient respond to teledipressin? Obviously if they've got ATN, they're not going to respond very well at all. If there's been no volume expansion with albumin, they're less likely. The higher the carotidin that you start with,

[01:09:00] the less they're likely to sustain or an improvement. Again, higher bilirubins, certainly once you go above 10 milligrams per deciliter, less likely to respond. If the blood pressure doesn't go up by more than 5 milligrams in the first 2 days, they're less likely to respond. And again, if they've got a higher grade of ACLF, they're less likely to respond.

[01:09:20] bond. But one issue is this. Although we always think of HRS as a vasomosa condition, this is staining, this is a biopsy we've taken with capsase 3. So this is looking at cells which are programmed to die. Now obviously as you can see over here with the ATN, you can see the staining for capsase 3.

[01:09:40] But actually, this is HRS and there is some slight staining with HRS. So HRS is more than just vasomotor. And this is now looking at to tol like 2 and 4 receptor staining. And again, you can see inflammation with regulation of TL4 and also TL2 in ATN. But there's also staining.

[01:10:00] with HRS. So there is more than just vasomota. So there is ischemia going on and causing inflammation in the kidney in HRS. And that's one of the issues that if you leave these patients too long, whilst you just watch the crannin go up little bit by little bit, you're going to be less likely to get a response. And this is one of the issues with HRS.

[01:10:20] So, let me try and summarize. Renal dysfunction increases with advancing stages of chronic liver disease and acute on chronic liver failure. Certainly with HRS, we think it's a relative renal hyperperfusion with a reduced effective circulating volume. There certainly is increased renal basic constriction, driven predominantly by sympathetic nervous system and local

[01:10:40] or vasoconstrictors. But there's an inflammatory component, and we're unsure at the moment as to whether this is endotoxin-driven or whether it's just simply driven by ischemia. The other issue, of course, is that we always get asked is what to do about the ascites. So if the ascites are very severe and it is obviously causing the patient great discomfort, then yes.

[01:11:00] please tap it. And there's a difference between what I call acute rise intraabdominal pressure versus chronic. And so if the abdominal has been large for some time and the pressure is not changing, then we probably would leave it well alone. But certainly if the patient is in discomfort, then we advise you to tap the ascites.

[01:11:20] It's common, renal dysfunction in patients with cirrhosis. It's associated with a poor prognosis. The key message really is that serum creatinine and changes in serum creatinine really underestimate the real changes in renal function. And classical HRS, AKI, is pathophysiologically distinct from renal dysfunction in ACLF.

[01:11:40] But many patients now have AKI in the setting of ACLF. And I'd just like to end by thanking all my colleagues I've worked with at the Rawl Free in UCL over the many years in terms of treating patients with chronic liver disease and acute kidney injury. And it's a long, tough road, and thank you. Okay. Thank you.

[01:12:00] Thank you very much, Professor Devonport, for that very interesting lecture. May I invite all three speakers to the stage and also the panelists, Dr. Dhanurath Nipar, Dr. Anurhav Ghegara, Dr. Nishanth Ananya Kar, and Dr. Dilrukshi Pilipittir.

[01:12:20] Thank you.

[01:12:40] audience also to participate and you can start the discussion. You can also have questions from the panelists to the speakers. Shall we start the discussion? Yep.

[01:13:00] Yeah, Andrew, you would like to give some comments and start on the discussion. Yeah. I have a comment and a question from Ravi based on your presentation regarding the place of reticulum.

[01:13:20] that you have given in your treatment algorithm. Now, having said that, the LUNAR 2012 has failed to show that RITAK-C-MAP outperforms, and the guidelines, ACR, EULA, KDCO, has not placed RITAK-C-MAP

[01:13:40] in the induction regime. We still consider that as a rescue therapy, and what made you think that you have promoted it up in the scale, up to a, not up to, say, not a rescue therapy, up to an induction regime.

[01:14:00] basis for that, can you just? So I basically, I mean, I think it's partly influenced by the new to say now. And the reality being that, so if you have a patient who is literate and is willing to take medications and has got preservative function.

[01:14:20] And you can be confident they will take, then I would go with a CNI and a MMS with a more rapid stethosteroids. But then if you have a patient that you're hunch is, they're not going to take medicines, then rituximab might be a reasonable option or IV cycloposmab. So that's where I'm coming from. And I do think that...

[01:14:40] I think when we use rituximab, it is more effective than the Luna or Explorer's suggestions. I think that's where we need to be empowered to use rituximab more now. But it is controversial. It's not based on guidelines.

[01:15:00] question goes to Professor Patel regarding vasculitis. We being a resource poor setting, we don't have anti-MPU antibodies, anti-PR3 antibodies at large. How will it affect our management for diagnosis in the first place and the management and the follow-up of our patients? How will it affect? How do you see re-managing vasculitis patients without anti-PPA?

[01:15:20] ER2N and DPO. Can you imagine? Wow, I mean you always kind of think it's hard even when you have all the investigations let alone when you don't have them. So I guess clinical acumen going back to basics is really important and many times you just get a hunch isn't it that this isn't going right. So

[01:15:40] in addition to the clinical history examination, you're you've got inflammatory markers at least anyway. I guess that's the start. And then imaging whatever you have is kind of good to kind of do. And then access to biopsy. I don't know, again, how easy that is, of course, managing.

[01:16:00] sort of the risk versus the benefits of doing a biopsy. But I think then it will probably be an even lower threshold if you don't have immunological markers. So it's hard, isn't it? I can't even imagine, because we always moan that, you know, people are not doing the immunological tests early enough. But if you don't have them at all, I'm sure that's really hard.

[01:16:20] So I guess clinical acumen and the other investigations that you have and then probably a bit more higher reliance on the biopsies. In lupus, I would biopsy very early. In vasculitis, I guess sometimes if it's very nonspecific, I wouldn't biopsy so early. But then PET scans and other radiological imaging may be the way forward as well.

[01:16:40] stopping treatment without these anti-ampere and anti-perter because the current recommendation stopped at two to three years but we don't know where we are. It's really hard and I think I agree with you when you said about there's been a big move so when I was a trainee nobody stopped any immunosuppression and my consultants would probably shout at me even if I started reducing

[01:17:00] too quickly, and then we went through a phase of stopping. But then there's risk of relapses are so high, and the patients would probably prefer to take low dose of something rather than nothing. So I think that seems to be, again, we've gone back in a little circle. But of course, managing

[01:17:20] the risks around the immunosuppression. So steroid reduction definitely earlier, much earlier than what I perhaps was taught to do years ago, and then sort of smaller doses of the maintenance treatment to continue if you don't have other markers to go with.

[01:17:40] Do we have anything to say? I don't know. A question for Prof. Davenport. So in Sri Lankan setting, I think managing HR is quite tricky because sometimes in certain settings we probably don't have IV albumin and keep aside the IV telepressing.

[01:18:00] So the quickest option would be just to maintain the mean artery pressure with noradrenaline and then to continue a fine fluid balance kind of thing. But probably some settings do have IV albumin and combine it with IV noradrenaline. What do you think of any thoughts, any comments on the practice that we do?

[01:18:20] Thank you.

[01:18:40] press needs can be award-based treatment rather than requiring intensive care support. The other issue though is, as you say, is the colloid. And so the issues there are in terms of trying to maintain a circulation, so questions would one be what's the hemoglobin, is there a space to improve the hematocrit? That would be question one. And then the other issue is what are the hemoglobin types?

[01:19:00] or what other possible colloids can be used. Now the problem there is that unfortunately, quite a lot of the other current colloids which are available actually do have a potential for causing acute kidney injury. So that is a real problem. But I accept that if you just pour normal saline into a patient, they will become incredibly volume overload.

[01:19:20] And I say the real issue that the Americans run into in their large trial was respiratory failure. If you're giving colloid and sodium to patients with, say, karate, karate is over 3. Not surprisingly, they're going to go into pulmonary edema. So that's a real issue and balancing books. But the point I would make is this.

[01:19:40] If you start early in terms of treating with terephthalmosis, you're much more likely to get a response. And I say we often get fooled by the fact that the carotenin seems to be relatively low and it only goes up a little bit. Then we sit on the fence and we say, oh yeah, we'll see what it's like tomorrow. It might turn the corner by tomorrow. It's only gone up by 0.1.

[01:20:00] a boratory error, 0.1 or something. And that's the problem, it's to delay in the treatment. But again, certainly in the UK, we work in the Liver Transplant Center for North London, is this patient suitable for transplantation? What's gonna happen if they don't get better? And that's a big issue, as to whether we should have a more palliative approach.

[01:20:20] And that's a really big decision that we have to make in terms of with the patient, possibly with the family, etc. And that's a big decision as to where to go with the patient.

[01:20:40] which is a sort of useful drug in pregnancy, but I didn't see azathioprine in your sort of presentation. Is there any particular reason or? The maintent, I think the maintent trial showed, the maintent trial showed that agnemics were superior. So we tend to still leave them on a gram, but then I would.

[01:21:00] reduce it to 500 milligrams Bd and live. So that is still thought to be superior to either time frame. But of course a lot of our patients want to start family. So you may make the call after a year to switch them with an express view that they will want to have a start a family. So I think

[01:21:20] Either that brings a reasonable option, especially for women of child-bearing age who plan to have children, but the MMF is thought to be superior. That's personal evidence. We have a few minutes for the audience if we have any questions to the panel or the speakers.

[01:21:40] My question is for the second speaker. This is regarding the lupus nephritis. We have been using cyclophosphate several years ago and it's worked well and now mycofenilate is coming new and it's not working well. So is there a chance of

[01:22:00] Asians and Africans getting less effective in mycophthalate? And is there evidence for that? I am not aware of any evidence of racial bias favored cytoposmide over mycophthalate. And again, it glomps down to adherence.

[01:22:20] So, if you cyclophosphate, you're giving it intravenously six doses, whereas microphenolate is oral. It's also probably more expensive, am I right, compared to... It's available in the government sector. So I suppose that's a cost effect as well. It's available in the government sector now. Pardon? In the government sector in Sri Lanka?

[01:22:40] So we— But a key thing is around adherence, because the data shows that they are equivalent to the Ginzle pepper. But again, I would say cyclophosphate is a very effective drug, because active lupus means the chance of pregnancy is remote, and there's good data that

[01:23:00] three grams doesn't cause infertility. But I think in arms they have shown that my MMF is non-inferior and at the same time in the Asian cohort cyclosmide has an equal efficacy or even better efficacy.

[01:23:20] works and we've never had a treatment failure with cyclovoxacin.

[01:23:40] We have to give the clearance to go ahead for a kidney, sorry, liver transplant and not for us kind of simultaneous liver kidney transplant. So how do we look into it? Which EJ for Calgary should we go with Cockroft cult, MDRD, CKDAP 2021? Oh, you have one which we have never used so far to be frank with you. Sorry.

[01:24:00] Well, I think, right, there are two issues here. There are differences in terms of the concept of transplantation between, say, Europe and the US. And that comes down to money. So the transplant team in the US gets far more money for doing combined liver and kidney transplant than if they do a single kidney and a single liver.

[01:24:20] So that's a big difference. So certainly in the UK and other parts of Europe, we're more like do a liver transplant and then possibly then do a second kidney transplant. And one of the reasons for that is that often during liver transplantation, the blood pressure goes down low. And so often what we found is that if patients have been running with systolic of around about 100, the kidney transplant never works. So we found that to

[01:24:40] to be relatively futile. So the issues for us are we would do one or two things. One, do we want to biopsy the kidney? That's question one. To see if you imagine fibrosis, there is there chronic damage because that would be a big issue in terms of canceling the patient. Yes, you can have a liver transplant, but you're going to need a kidney transplant, well, dialysis,

[01:25:00] transplant some time. As a rule of thumb, we reckon you lose probably about 30% of kidney function with the liver transplant. Roughly that amount is what you lose, to be honest.

[01:25:20] end of this symposium. Once again shall we thank on behalf of the college of physicians I will thank all three speakers and the panelists shall we show our appreciation in the usual way. Can I call upon the speakers to accept the token of appreciation from Professor Sharif.

[01:25:40] Yes.

[01:26:00] Professor Mumtaz-Pacheil, please. I'm sorry, I can't come to you for obvious reasons.

[01:26:20] Good luck. Good luck. See you next time. See you next time. See you next time. See you next time. See you next time. See you next time. See you next time. See you next time. See you next time. See you next time.

[01:26:40] Thank you.

[01:27:00] Thank you.

[01:27:20] invite Dr. Pravin Miretunga to award certificates and letters of appreciation to our chairpersons.

[01:27:40] Bye.