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Paediatrics Nephrology Professor Marks (13.12.2022 - Term 2, 2022)

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Summary

This on-demand teaching session hosted by Professor Stephen Marks is ideal for medical professionals interested in childhood systemic Lupus erythematosus and Lupus nephritis. It will provide an in-depth overview perspective of living with Lupus and the differences between childhood and adult onset disease, followed by epidemiology, management strategies and the latest advances. Professor Marks will also discuss a case study and review the clinical history, investigation and management of a 13 year old female patient.
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Paediatrics Nephrology Professor Marks

Learning objectives

Learning Objectives: 1. Understand the clinical differences between childhood onset and adult onset systemic Lupus erythematosus and Lupus nephritis 2. Able to identify signs and symptoms associated with systemic Lupus erythematosus and Lupus nephritis 3. Understand the management strategies of systemic Lupus erythematosus and Lupus nephritis 4. Be able to recognize overlapping conditions associated with systemic Lupus erythematosus and Lupus nephritis 5. Be able to interpret the renal biopsy and electron microscopy results of a systemic Lupus erythematosus and Lupus nephritis patient.
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Hello. Good afternoon. My name is Professor Stephen Marks. I'm, uh, pediatric nephrologist. I lead the kidney transplant program as well as the GLOMERULAR program and director of our clinical research facility for a high impact clinical trials, Um, at Great Ormond Street Hospital for Children NHS Foundation Trust. Um, I'm professor, pediatric nephrology and transplantation at University College London. And that's part of Great Ormond Street Institute of Child Health. So today I've been asked to speak to you about childhood systemic Lupus erythematosus and Lupus nephritis. So these are, um, conditions which are very close to my heart, clinically and academically over the years. So I think from the patient perspective, living with Lupus is a test for survival every single day. And what I'm going to try and bring out today is the differences between childhood onset and adult onset disease. A little bit about the background of the epidemiology bit of understanding of, um, Lupus nephritis itself, and how we manage Children and young people with systemic Lupus erythematosus or what I call Lupus and Lupus nephritis when they have kidney involvement and then bring it all together, Uh, with some future thoughts. Can I just check. You can see me. Okay? And you can hear me. And the slides are okay. Yes. Yes. Great. Excellent. So I thought it's probably best to start with the clinical history and let you maybe think about. Really, Do you think this patient does well in the long term? Or do you think that there are problems longer term with this patient? So it's a 13 year old girl, and you can see here. You said the three month history. So I think the screen is frozen. We're just seeing the first right. Oh, thank you for interrupting. It was going through mine. Hold on. Do you know what we might do? Is might just, um, just close it down altogether and then bring it back up. Um, thank you. No, no, don't Don't worry. I know that's what That's why I asked you whether you could all see and hear me correctly. Uh, but it sounds like it was working, and then all of a sudden it started freezing. Um, okay, so we're now bringing back the slides and does that look cool? Kit? Yeah, it's on slideshow now, and you just got one slide purview. That's the second one with the picture. Yeah, so living with Lupus every day is a test for survival. Yeah, Now it's been good, So we'll start with a 13 year old Nigerian female. She was on holiday in America and had a history of intermittent occipital headaches, which was felt to be potentially pre Menschel syndrome. There was no vomiting or migrainous symptoms, but she then developed arthralgia my algebra, with some weakness of the shoulders and thighs. There were some lesions on her forehead, which has developed, but there was no evidence of active arthritis, and she was treated with oral amoxicillin by her primary care physician. She then presented with the three week history of swelling of her eyelids and lips with some, uh, flu like symptoms. And as a result of that and deterioration, she presented to the local accident emergency department, where they found that she had been off for food. She had been getting a bit of restlessness on exertion and and had a history of intermittent fevers. But otherwise there was no other past medical or family history of note. When she was seen, she was unwell. She was Parexel, 38 C, the calculation of an estimated weight loss of round about 8 kg. And she had an injection systolic murmur at the lower sternal edge but was otherwise normal intensive. She had a rash on her fingers and tools with some splintered hemorrhages, and she had these possible photosensitive lesion's on her forehead. But she was clinically unwell with the tender abdomen. Early signs of part in is, um, and she had evidence of acute kidney injury, potentially with plasma Crafton of 300 micromoles per liter, with four plus of protein urea and four plus of microscopic hematuria in her urine dipstick. She was reviewed by consultant dermatologist. An accident emergency who agreed that she was very unwell, needed to be transferred for further intervention and came across to us, having commenced intravenous fluids and antibiotics. By the time she came across to Great Ormond Street, she was an uric. She had passed know urine for over 24 hours. She was also in hypovolemic shock hypertensive with systolic BP of 100 millimeters of mercury, a dry mucous membranes, a capillary full time of three seconds. And she had splintered hemorrhages which were affecting her nail beds over fingers and tools and there were some vasculitic lesion's affecting her finger and tool pulps that you can see here. These are the vasculitic lesions that you can see in the discoloration. And also you can see this kind of brown discoloration of the toenails. We've actually biopsied some of these and you get basically hemosiderosis deposition in the presence of acute inflammation in the body. So investigation showed her hemoglobin was 149 g per liter. She had a neutrophilic leucocytosis 13.2 of a total of 17.3 times 10 to the power nine per liter. She was thrown beside a Penick with low platelet count at 94 times 10 to the power nine per liter. Evidence of inflammation with an elevated esr 70 millimeters per hour. And although an abnormal clotting with an elevated thrombin time, it did actually correct. With a 50 50 mix of control plasma, she was hyponatremia. Six. So she had a low sodium at 123 millimoles per liter with hyperkalemia. So an elevated potassium level of 6.1 millimoles per liter. She was acidotic bicarbonate of 17 millimoles per liter. She had evidence, a renal dysfunction with an elevated jury of 39.8 millimoles per liter, an elevated plasma crackin of 330 for micromoles per liter. She had hypoalbuminemia, so she had a low albumin of 21. Um uh, although she had a law, um, total calcium of 1.72 millimoles per liter it was normal, then corrected to 2.2 an elevated phosphate of 3.13 millimoles per liter and elevated Billy Ruben, um Transaminitis with an L t of 1 to 2, but a normal Siri active protein. But an elevated crap man canes, um, as you can see here, over 1000 and elevated amylase over 4000. But they were unable to do a lipase. And she had initial results showing a complement levels 0.62 and C four of 0.7 g per liter with obviously her also antibody is pending. So she was in the hypovolemic shock and with Billy refilled time worsened to four seconds or dry because membranes became even more pronounced and she became even more habitants. It was Stalin BP dropping to double digits at 90 millimeters of mercury, she had this rash that we talked about, but she was deteriorating, possibly because she had increased lending of her abdomen. So she was electively ventilated feelings. She might have vasculitis or potentially as your the Lupus stop. This could be Lupus, complicated by acute pancreatitis or mesenteric vasculitis, and she required kidney replacement therapy with continue continuous venovenous hemofiltration, intravenous antibiotics and anti fungals. Initial results came back showing that she elevated double stranded D N A. Of 131 with normal being less than 30. Locally, she had evidence of staph aureus bacteremia with the positive blood cultures. There was no perforation in a red chest X ray, but she had this diffuse whiteness and her abdominal X ray and evidence of societies, which on ultrasound, which we coincide with the findings on the X ray. And she had a bright and bulky head of pancreas with bright large kidneys that we see in acute kidney injury with poor cortical medullary differentiation. She's a structurally normal heart, with concentric left ventricular hypertrophy and echocardiography, so she was fluid restricted. She had opiate analgesia. She was treated with intravenous fluids and antibiotics, and she was pulse with intravenous methylprednisolone 600 mg from meter squared with a maximum of 1 g once a day for three days. And she was treated with intravenous cyclophosphamide with mesna coverage as well, and was given some plasma exchange to try and see if she could be managed that way as well. So she, as you can see, was clinically unwell. And her management and intensive care was quite tricky. Um, which I think as you can see how unwell she was in, um, this scenario as well. So if we just have a look at how she did, you can see that she was extubated. She returned to the ward in a week, but she developed some lip smacking and she was swearing into mother some clouding of consciousness. But could this be that she was just a teenager? No, because actually, she had neurological signs with brisk upper and absent lower limb reflexes. And she was fluid overloaded, but she started to produce some urine that you can see here. So, has anybody got any ideas what this could be? Well, obviously you're a talk on Lupus or systemic Lupus erythematosus with kidney involvements or Lupus nephritis. Potentially neurological involvement with cerebral Lupus and maybe even spinal involvement with transverse myelitis. But also, I think in this case you have to have a consideration of an overlap syndrome. So clinical evidence of a myopathy Could it be features of juvenile dermatomyositis with an elevated creatinine canes and pancreatitis, which are both well described in J. D. M. But also s can happen in systemic Lupus erythematosus, but less classical features. So she did have reduced complement levels. She was hypocomplementemia. And some of these Children have an inherited genetic complement deficiencies. So she had a low C three and C 4.51 and 0.9 g per liter. There was no C three nephritic factor, but her a n a was positive and speckled to one and 1, 21,281 280 with a positive double stranded DNA of 32.9 and normal anti corridor Lipan negative anchors negative myeloperoxidase these. She had, um, an e g, which I'll show you in a minute. And she had a cranial MRI with lumber puncture. Um, at the same time, she had a renal biopsy to have a look and see what was going on in her CSF. Glucose was 4.2 with a plasma 6.8 and lactate was 1.4 with plasma 0.7. But there was no legal clonal bands and there was no viruses or bacterial cultures to go with an encephalitis. Over here, you can see evidence of a left pleural effusion. So there's additional fluid specifically in the left pleural space. She had this electroencephalogram which showed low amplitude background activity with excessive a regular feet and slow components, which could be just due to her acute kidney injury. But there was definitely quite marked encephalopathy, um, shown by this examination and investigation. Here, you can see the diffuse, um, white matter changes in her MRI scan. But again, there was nothing focal. So we'll talk a little bit about the histology of Lupus nephritis, but on our international Society of Nephrology and Renal Pathology Society. So I s n RPS classification. This was class two or Miss angio proliferative glomerulonephritis and there was a good sample. We aim to get about 10 glomar Eli, but we got managed to get 52 filtering units of the kidney. There was cortex and medulla. There was an increase in the cells within the mesangium with an increase in his angio matrix. Partial sclerosis, a glimmer tuft Highland droplet change normal, insist Isham and blood vessels. And there was a full house deposition with Ms Angel Deposition of immunoglobulins and complement C three and C one Q But an electron microscopy. There was a mesangium hypercellularity with dense deposits. So here you can see the glimmer realists in a pas staying magnified by 200 times and you can see here kind of the mesangium is packed full of cells a lot more than you would see in a normal glomerulus. And I could show this immunohistochemical tree with any of the stains. I g i g m um C one Q complement C three c four. But you can see the lighting up on immunohistochemical tree and the dense deposits that I talked about that you can see an electron microscopy, which is 8000 fold. So this time she was treated with, uh or with pulse intravenous methylprednisolone and then converted on two oral prednisolone high dose of 2 mg for kilograms. She was treated with broad spectrum intravenous antibiotics antivirals and antifungals covering with the acyclovir for encapsulitis. But also in case there was any cerebral involvement either a meningitis, encephalitis. The feeling was to give her some intravenous cyclophosphamide. Um, usually, um, to try and see at the point of time if we could try and reverse her whole body inflammation. So, in summary, she's got systemic Lupus erythematosus. She's got cutaneum slippers. Um, she's got, um, skin involvement, muscle involvement, mesenteric vasculitis with acute pancreatitis, cerebral Lupus, Lupus nephritis with a class to an acute kidney injury with a hype of limit shock and possible nephrotoxicity, which could be reduced to the mini glycosides, but also the background of Lupus nephritis. So if this was her at the age of 13, how do you think she did in the next five years? Do you think she did? Well? Well, prognosis. A good prognosis. I said, poor, poor prognosis. Yeah. Yeah. So? So a poor prognosis if she wasn't treated. And, yeah, I think that's it's the reason I I show this case is because actually with good treatment and the fact that she had a mild kidney involvement with a class to Lupus nephritis were actually able to reverse it. So having followed her for nearly six years, she had seven pulse. It is, um, she's been a cyclophosphamide cumulative dose of programs for me to squared. She developed a bit of insulin dependent diabetes myelitis, which resolved in reducing over cortical steroids. She had a relapse a couple of years later. We're using rituximab a lot more at that point, together with intravenous cyclophosphamide that was maintained on or limited suppression with prednisolone and azathioprine. I think nowadays we would give a lot more mycophenolate mofetil and a lot more rituximab at the same time with somebody who had a severe presentation. And when we followed up to 18 years, she was normal intensive. She had a couple of plus of protein urea, one plus of hematuria but urine albumin to creatine ratio of only 11.2 mg. Familiar mole in a normal kidney function with the plasma crackin of 48 micromoles per liter. So very kidney disease is present at the time of diagnosis and about 40 to 60% of adults and in fact, in our UK GSC League cohort study in the United Kingdom that can actually in Children be up to about 80% partially because many Children will present with an inter current infection. So they may be behind enough fluids that maybe not 100% clinically well, um, an inter current infection, and therefore, as a result, they may have a slightly elevated cramping and high BP. Um, evidence of protein urea. You can see that there's a difference in the ethnicity groups or in the African American Caribbean. It's increased incidents, um, to 17 to 20 per million population attributable to Lupus nephritis. But what do we know about kids? Well, there's limited data on incidents of childhood Lupus incidents in the pediatric population can vary anywhere up to about one in 50,000 Children at risk per year. Um, but the prevalence in pediatric cohort studies can be anywhere up to about one in 2000 Children and young people. And that's looking at various epidemiological studies. And what we know is that Lupus has a variable clinical manifestation, and I think it's difficult to predict the natural history in an individual patient basis because as a progressive clinical course, which is associated with significant morbidity and mortality and up to one in six of proving cases present in childhood with more severe organ involvement than adults. But what we do know is the renal disease is a major determinant of the long term outcome and actually influences our management with the use of immunosuppressive agents. But both the kidney involvement and blood involvement are more severe in Children and young people with systemic Lupus erythematosus than it is compared to adults who are much more likely having cardio Pommery involvement. And we are much more likely in pediatric practice to see cerebral involvement, although we can see cases of multi system involvement with arthritis, autoimmune hepatitis and a macrophage activation syndrome. Now there's lots of considerations with their Children to think about the growing skeleton, what ago called the sex, drugs and rock and roll. So about educating them how to look after themselves as they try and evolve their own identity. Try and get their own quality of life and think about adherence to treatment. And that's why some drugs, such as intravenous rituximab, really gathered steam and you know, much more favored as ways of ensuring that your patient gets their medication. But if you look at any condition and that spans between pediatrics and adult practice in the sphere of rheumatology, then Lupus is really the one condition where we know it's the same autoimmune process. We have very similar classification criteria. The same disease markers, yes, are compliments. See three lymphocyte counts and double stranded DNA. And to be honest, we really have the same drugs as our armamentarium. So what do we mean by Lupus nephritis or kidney involvement? Well, Children can present with kidney involvement is a new presentation of Lupus in this case, where they have barn door kidney involvement so they can actually be a patient who is being followed up with non Lupus that gets a flare of their disease activity. And that flare burns up within the kidney due to the inflammation resulting in potentially protein, urea, microscopic and really microscopic hematuria. You can get a Coca Cola color urine more avert protein urea with nephrotic syndrome. So nephrotic range proteinuria, together with fluid overload and hypertension and evidence, a renal dysfunction. And although we stick a needle in to have a look, there's the pathology of Lupus. Nephritis really cannot be accurately predicted from either clinical and or serological markers, so if you look at the history of Lupus nephritis, histology over the last 50 years from the original World Health Organization classification in the seventies, which was modified in the eighties. And, um, and then again, indeed, in the nineties, with Shargh modifying it further and then, really, the working group that she was published. The first results in 2003 has been the backbone, although there has been, um, recent modifications but basically is an increase in the severity of Lupus nephritis with increasing numbers. Although Classify, which is a members, Nephropathy is a bit unlike the others, in fact, can now be classified as patient's, having features of class three and four together with a class five. So in other words, you can see our patient's got an I S. N. R. P s Class three in class five Lupus nephritis or an I S N. R. P s Class four in class five Lupus nephritis. But what we know is that with increasing Ms Anjel involvement and expansion with Ms Angio Proliferative Lupus nephritis is not really until you get a focal Lupus nephritis in Class three, which is basically when you've got less than 50% of the individual glamour rely involved, and their involvement can either be that there's Active Lesion's. So there's Proliferative Lesion's. There's activity within the memory line, or you can have segmental sclerotic. So this is damaging the kidneys, which of course can result in protein urea as well. And it's not until we get patient's where more than 50% of the commercial are involved. And whereas if you look at each individual glomerulus within the class for Lupus nephritis sample, if it's less than 50% of each individual glamour rely. Then it's a diffuse segmental, whereas if it's more than 50% it's acute. Diffuse global Lupus nephritis and activity can be denoted by a the chronicity, or interstitial fibrosis and Jupiter atrophy can be delineated with the sea for chronicity. But one way to think about it is if there's evidence of any capillary hypercellularity. There's less than 50% of the camera involved. It's a class three Lupus nephritis. If it's 50% or more of the camera involved, it's a class for Lupus nephritis, with a segmental distribution for Class four s and a global distribution for Class four G. If there's no evidence of anti capillary hypercellularity. Then there'll be Ms Angel deposits only on class. Wonder Person fighters with Ms Angio Hypercellularity in class tune some epithelial deposits in a class five Lupus nephritis. So what? Our aims of the treatment. But what we're trying to achieve is an induction, um, of their condition, so that they may have a new flare of Lupus disease activity. We want to get them into remission and maintain that as long as possible with the minimal toxicity, a the maximum effectiveness of therapy and to try and reduce Reno flares as associated with a worse overall prognosis. I give no apologies for, um, this slide from shirt Cameron, who I had the joy to meet when I first came to London 25 years ago, and shirt Cameron was an adult nephrologist who then branched into pediatric nephrology and looked after Children and young people with Lupus and Lupus nephritis. So what this really shows with the hindsight is the fact that despite the fact that natural history shows that patient's were dying in the sixties as soon as we had the advent of cortical steroids and azathioprine the longer term outcomes, as you can see in the 80 to 91 group was much, much better, as you can see with a lot less number. Hope Dex. So what treatments do we use? Well, um, I would say that conventionally, it's been is a thigh a prin partially because of the data on vasculitis and intravenous cyclophosphamide. Although I think we're moving more to using oral microfine Leetmaa photo both as induction inducing and maintenance regimen with other municipal rations such as intravenous rituximab. But I think we should consider different management strategies to, uh, those in different problematic groups. So this was the first study, which is over 20 years ago. It was a brilliant study looking at noninferiority, um, of patient's treated with six months of oral cyclophosphamide, as you can see here versus six months of oral mycophenolate mofetil where it's twice a week and you can see here. This was a non in fear, um, study. So we're trying to show that Mycophenolate Mofetil was just as good as the gold standard in those days. This led to further work, looking to see where there was a difference. You can see there's less deaths amenorrhea heart, hair loss and leukopenia that you can see. But there was slightly more relapse and complete remission in the microphone and more photo group. So, really, if remission is achieved, then renal survival and patient survival were held up to about 94 to 95%. But if you don't achieve remission, so you've still got some baseline protein urine hematuria and you can see here. The renal survival reduces about a 3rd, 10 years and about 3 to 5 Patient's in 10 years, and there is some end stage tends to be highest for those who have a diffused, clarify acttive, um, Lupus nephritis. And although there's recent data analyzing the arms data, there is really worse outcome. If you've got a lower baseline estimated glomerular filtration rate a lower complement C four level If you've had Lupus nephritis for more than a year, if you normalize your compliments, you do better. And if you have a fallen protein urea by eight weeks and over a quarter of patient's, you also do better. So the arms study was one of the first studies to try and get Children and adults so basically recruited from 12 years and upwards to 75 years and patient's again were randomized, open, open label extension to either receiving MMF and cyclophosphamide. And really, it's about the differences between these therapies that you can see here. And we would aim to use 1.5 g per day, especially in big Postpubertal. Um uh, young people and you can see here the cyclophosphamide doors up to 1 g per meter square per month, quick wean of the oral prednisolone and tried to look at the reduction in proteinuria and improving renal function. And what you can see here is that we had over 460 patient's, but we're able to analyze over 100 and 50 so just 300 it completed the 24 week induction phase. So this is a result between mmf and intravenous cyclophosphamide, and you can see that they really do pretty well similarly. But you can see that the patient's responding to treatment was much higher, and the mmf group mycophenolate mofetil than the intravenous cyclophosphamide in the non Caucasian and non aging population. I think it's important to note the black and Hispanic responded more often to mmf than other races, and it worked equally well in I S N R. P s Class five Lupus nephritis. What about the side effect profile were pretty similar, but, um, you can see here more death and diarrhea in the microphone mofetil group and much more nausea, vomiting and Allah. Patience, Cyclophosphamide. So this was the maintenance study, which took those patient's that had gone through arms, then reassigned half to receive mmf and half to switch to um is a type run, and we had over 50 patient's in each arm of the study. We're able to look at the Capitol Mar curves and for the treatment failure in time to renal failure. Flare. And here you can see the risk of treatment failures in a subgroup of patient's. The maintained study went on to study 100 and five patient's with the proliferative nephritis that were treated with cortical steroids and six fortnightly intravenous cyclophosphamide. And although there was a reduction in Reno flare from 25 to 6 to 19% and from there is a thigh applied to Mycophenolate Mofetil group, and this did not reach statistical significance. And this is one of the meta analyses which is prescribed, um, from looking at the differences between cyclophosphamide and microfine. Let more photo. So I think we need to consider patient's that are difficult to treat because they've got a difficult disease which may be severe and they don't respond to therapies. We've got difficulty in a patient where they may be non adherent. And you consider, um, using intravenous, um, cyclophosphamide or even intravenous rituximab and some difficult, confounding factors. How well is the patient? What was the temperature, Why they're coming direct to us? What is going on locally? So the treatment options can be varied consideration. No treatment Using cortical steroid cyclophosphamide, as I said, is a thigpen hydroxychloroquine. But invariably we use much more mycophenolate mofetil with rituximab and actually even sometimes at in plasma exchange. Especially too sick kids such as her. And there's neuro biological agents as well. So do cortical steroids form the basis of all regimens. Well, we'll talk a little bit about the fact that steroids are the best drug to get us out of a danger. But actually with good mycophenolate mofetil doses, you'll get, um, a fairly impressive induction in remission and wondering whether we need to be using less microphone, um, a photo moving forward is a Thigpen's and effective drug for maintenance treatment of Lupus nephritis, but it's not really been studied in adults. Um, so I think that's one thing that that needs to be considered. But this really shows that we need to do more conventional, um, immune suppression trials and a lot more randomized controlled treatments. So here, if you look at what a standard is, we would start patient's on intravenous pulse methylprednisolone and so 600 mg for me to squared. Rheumatologist would say, 30 mg per kilogram once a day. For three days we'd have a high dose oral prednisolone, so some would give two per kilo. I try and see if we can campus at 1 mg per kilogram, but definitely no more than 60 mg induction and maintenance. Mycophenolate Mofetil therapy is so up to 1.2 g for me to squared and consideration for monthly pulses of cyclophosphamide up to 1 g per meter squared for a six month. So let's talk a little bit about evidence based practice and what we want to know about therapies in 2022 how we're going to treat patient's in the future. But there's lots of information out there. There's a kid. I go, there's they're rheumatic diseases. There's a CR American College of Rheumatology guidelines published the guidelines and arthritis care and research. And if we look at the nomenclature as being the strength of recommendations so normally we would hint at Level one where the only recommend, as opposed to suggesting where there was ongoing supporting evidence with high quality of evidence, so confident that there's a true effect close to that of the state of estimate of the effect. But if we look at our guidelines and this is ones that we discussed internationally, we recommend initial therapy with cortical steroids, combined with either cyclophosphamide or MMF. Recommend after initial therapies to complete, then patient's with the class Tween for Lupus nephritis. Receive maintenance therapy with azathioprine, OoRah, MMF and lower dose cortical steroids, and we try and get down to alternative cortical steroids and see if we can really reduce to 10 mg on stadium. If we also look at what we said about Children, we suggest that Children with Lupus nephritis receive the same therapies as adults with dozing based on patient sighs and e g f r. And this led us to the u R E r E T T A. Recommendations for the treatment of adult pediatric Lupus nephritis are meeting. And here we showed the management of pediatric Lupus nephritis. Compared to adult onset disease, the Lupus nephritis was more severe, with increased damage of cruel and more common presentation. But the diagnosis, management and monitoring was quite similar to that of adults. And that gave us a mean score of 9.6 out of 10. In fact, a median of 10. But it was evidence based practice. Well, here you can see, um, that nearly two thirds were either graded very poorly. So did you, um, grading or un graded. But there was 3%. So patient's that were a class one Lupus nephritis 13 and 10% for class four. Um, so our class, um, there were four and three graded, so you can see that the grading one a B to be in to see was really the minority. So this led us to the 2019 update for the u E R E D T A. And we published this more recently. And basically most of the recommendations were unchanged from the 2012 recommendations. We've also got the Coke, uh, the Cochrane collaboration that you can see here again with induction phase introducing Microfine Limato supposed to cyclophosphamide, going to a maintenance phase with MMF or azathioprine and then considering rituximab if there's no response or as a third line agent but remembering to treat a drops the chloroquine hypertension, protein, urea, hypolipidemia, aspirin. If there's anti phospholipids anticardiolipin antibodies anticoagulated of Antiphospholipid syndrome, especially nephrotic, vaccinate patient's with non live vaccines and treat vitamin D deficiency, giving imminent globulin intravenously for those that don't respond to clinical disease plasma exchange. And although the systematic review is negative, there is definitely a rule for plasma exchange, noting as well that there were some good infliximab case reports along the years and also to themselves transplantation with a significant or bit of team mortality. This is membranous Lupus nephritis and just showing the differences and the probability of relapse and really the adult model that unless you've got significant proteinuria, you wouldn't treat with him in a suppression. Whereas I always feel that if you've got protein urea, you've got evidence of, um, inflammation. A biopsy is much more likely going to be coming from the positive inflammation that you've got within the kidney. So this led is to understand a little bit more about the auto antibodies the B cell immunology, which is important for diagnostic and prognostic markers because we know adults and Children without of Lupus disease activity of profound B cell abnormalities. And we already had experience of using rituximab for both the prophylaxis and treatment of adults and then pediatric lymphoma and EBV driven lymphoproliferative disorder, as well as other autoimmune diseases and initially given as a 375 mg per meter squared infusion once a week every week for four weeks as a slow infusion for those Children, young people who have multi systemic presentation of Lupus with life or organ threatening disease. If there's active disease after previous treatment with cyclophosphamide, then it's another reason to consider. So we published the first series of seven Patient's where we saw that there was some degree of, uh, reduction in cell counts. But most patient's were able to retrieve B cell depletion without adverse reporting and a reduction the medium by lag, which is the British Isles Lupus assessment score, whereas the French and the French Canadian group from Williams. It'll who gave them the smaller doors. 350 to 450 mg meter squared in because this was patient's in France and Candida So French Candida in Quebec. Montreal. You can see here that they were actually resulting in up to 12 infusions of cyclophosphamide in pediatrics, and we ended up doubling the dose. So the idea of giving two doses of 750 mg for meter squared of, um rituximab a fortnight apart. So giving the total of 3 g for me to squared dosage, most patient's says still achieve B cell depletion. But there was a lot more, um, side effects, both hematological. And there was a couple of steps is, but maybe that was due to the other medication as well. So we then published the safety and efficacy of 21 treatments types and 19 kids, most of whom were female, between six and 16 years, with a median of 14.5 years with Lupus for over three years and follow up for over 18 months. And here you can see the different therapies, including cortical steroids, azathioprine mycophenolate, mofetil rituximab, um, cyclophosphamide as well as cortical steroids you can see is the mainstay of treatment, and here you can see a reduction in the disease. Activity with British Isles Lupus Assessment Group improved in La Allograph function with improved serum argument protein urea as well as a reduction in the anti nuclear antibody, double stranded DNA antibody and an improvement in the low complement C three and C four. We saw the same humans. Logical parameters improved a reduction. The esr hemoglobin improved, as did the lymphocyte count and platelet count Where, as you can see here, most patient's, uh, did have profound B cell depletion. But what really struck made me first used it. Just in this cohort patient's is that patient is clinically significant improvement in the symptoms and signs, and many had said they never felt so good, with much more energy and much more bouncing and being lively and able to achieve their goals in their daily life. But there was a side effect of one in four patient's developing a zoster infection, and they although there's a theoretical risk of cytokine release syndrome because there's not a huge B cell mass, this doesn't really happen, but they can be infusion related side effects. But we showed the B cell depletion was safe and effective in 21 Children in 1921 treatment episodes of 19 Children. And this was also seen in 63 patient's in a Duel Center study between us, um and, um Liverpool, where there was statistically significant difference and improvement in hemoglobin lymphocyte, yes or a compliment albumin, creatinine, immunoglobulins and double stranded d N A. But we are in a selfie generation, and I think young adults really worry about how they look, so they're not going to take their cortical steroids if they have side effects. So we need to give them treatments to try and wean them off. And this is one patient who had sickle cell anemia with sickle crisis, as well as systemic Lupus erythematosus, where she in fact, had players of her disease activity, and we couldn't sometimes work out whether it was or Lupus or her sickle cell anemia, which had resulted in developing pulmonary hypertension. And she had a class three active and chronic Lupus nephritis, which responded well to intravenous cyclophosphamide and rituximab infusions every six months and She was then maintained on alternative prednisolone a methotrexate with intraarticular, uh, right wrist and left ankle cortical steroid injections. This is a, uh, adolescent teenager who had been looked after locally and had about 7 to 8 years of having Lupus requiring intravenous methylprednisolone and plasma exchange when she developed a steroid induce insulin dependent diabetes myelitis with the cutaneous Lupus and folliculitis. And a class three, um, Lupus nephritis, which also respond to cyclophosphamide and six monthly, uh, intravenous rituximab with alternative bread. So this is a study that we started doing where we wanted to see whether we could actually randomize patient's to receiving methylprednisolone with mmf and rituximab, but not have them in longer term steroids. And we did this to the UK as well as Europe and the United States of America. However, there are your biological agents which have been in the in the market. So you produce samide, um began to lose favor because of the side effect process to, as a cept has come back as a stock, lose a mob after its use in covid 19 ocrelizumab, which is a humanized version. Um, target C D 20 has been considered, but again, didn't reach a conclusion in the initial studies and has fallen off the bandwagon. A batter cept which modulates CD 20 CT 86 A Better Must, which induces B cell tolerance. We have recommended together with regard Remind, which is a split zoom all peptide, which blocks for ignition about I G antibodies and CD four Positive T cells. So, in summary, there's a long list of different agents in the pipeline, including oral anti complement C 51 local, no antibodies. We've also in the situation where stem cell transplantation I've referred a few patient's for stem cell transplantation, but in fact, within your drugs have not had to actually go through with this. Especially when you look at the data, which shows that although the majority of patient's improve, you still have quite a significant patient numb load that improved. But relapse have worsening disease or in fact, end up dying. So I think there's really other options to consider before going down and the root of bone marrow transplantation. So, in summary, Lupus is a multi systemic disease with different spectrum from adults, various subspecialties and unpredictable course with various assessments using disease activity and damaged scores. Quality of Life assessments, noting that Rituximab is are all in treating active disease, with chronic disease being really showing as the importance of collaboration with adult colleagues and longer term outcomes and transition of care. So I think mm F has taken the role of cyclophosphamide and azathioprine as a first line induction of maintenance therapy. It's effective but not proven in randomized control. Trial haven't had enough time to show you today, but belimumab is registered for the use in Lupus. Not really been tested in Lupus nephritis, although we've had a few patient's who've had worsening Lupus nephritis with increasing proteinuria while on the trial. And there are many drugs in the pipeline, and I just wanted to share with you at the end of quotation from a patient. Um, this isn't, uh, British Medical Journal. So it was a patient's journey, and the patient said, basically, without Lupus, I would not have learned so much about myself and about life in general, with support from friends, family and clinicians. Dancing with the wolf is not all gloom and doom. I've left you some slides showing you some of the you Lori R. E D T work, as well as the publication's in pediatric nephrology as well as the share guidelines, which I was the pediatric nephrologist on. And I'm happy to answer any questions. Thank you very much indeed. For listening. Thank you, Professor. Oh, sorry. Someone wants to ask a question. Uh, good option, doctor. So I just wanted to ask like we're staying. Not use, uh, glucocorticoids for young Children and instead with cyclophosphamide mites. So for female patient's, when the cyclophosphamide will have more adverse effects because it affects the ovaries. Yeah. So my my treatment that I now use for most patient's with class 34 Lupus nephritis would be two. Pulse them with intravenous methylprednisolone. Um, so previously we'd give them up to a gram more likely now, giving 500 mg once a day for three doses instead of then going from 2 mg per kilogram once a day. So previously, a maxim used to be 100 or 80 or even 60 mg of cortical steroids of oral prednisolone. I go down to start with 30 mg of prednisolone in an adult body shaped, um, adolescent and I give oral micro friendly ma photo and rituximab so thereby trying to not use cyclophosphamide or long term cortical steroids, which, as you said, will be better for avoiding the side effects of cortical steroids, but also much better in avoiding the side effects of intravenous or oral cyclophosphamide. Thank you. Thank you for all your comments that you put in the chat and for everybody joining us. So I've got another question from two. Who? Who's asking? How does hydro hydroxychloroquine improve Lupus nephritis? It's a very good question. And in fact, um, I like using hydroxychloroquine in all of the patient's. And that's primarily because, um, we generally find that it's good for your cardiovascular morbidity and longer term outcomes, but also is actually very good for reducing lethargy and patient's as well. So definitely see a lot more activity. And patient's, um, I think is at your at your hand up as well. Yes, sir. How's that? Hello. How would we approach for a patient through? We don't know, Might hasn't shown the first sign of Sally's, but we know that the person has a diagnosis of leukemia. But then, while treating leukemia or while having the first signs of leukemia, might also have shown the first signs of SLE. So how would we approach this for the management? And what would the end result of the manager should we go for directly bone marrow transplant, or would we start with the treatment with the SLE first? So I've had a few patient's that along the way one was referred that it was on plasmapheresis is, um for thrombotic thrombocytopenia purpura, Um, so kind of a, you know, features of hemolysis. So hemolytic uremic syndrome. Um but in fact, ended up having features clinically of Lupus with positive serology that when we did a bone marrow and we find features of acute lymphoblastic leukemia. In those instances, I actually stopped the immunosuppression. I go onto the chemotherapy together with the oncologist and then follow those patients' up to see how they are doing on there. Um, chemotherapy, which of course, is going to be immunosuppressive and keep the Lupus at bay. Obviously, you can have drug induced Lupus, so I'd be checking anti his stone antibodies, especially if they were using drugs such as oral hydralazine, for example, for hypertension. Um, so I wouldn't go necessarily straight for bone marrow transplantation, but I would start with the chemotherapy and try and get the disease under control. So I know many of you are in different parts of the world. So thank you for joining also those of you in Ukraine. Our thoughts are really with you, especially coming over to the festive season. I know it's been difficult. It's good to see so many of you joining us today because, uh, I know sometimes it can be a problem with electricity and getting power cuts and not being able to access. So really grateful for you joining us. Please remember to click on the link. There's a feedback form. Uh, it just takes a couple of minutes to fill, and we really need your feedback to keep things going in to improve. Um, so please do let me know. There's a few other comments coming in. So one is Can you use a inhibition and angiotensin receptor blockers for protein urea? Yep. So that was on the slide. And we're definitely using s inhibitors and angiotensin receptor blockers even earlier. And most of the clinical trials and adults, they actually start this from the beginning. And that's because if one of your features is protein urea. Then, if you've got protein urea, which is ongoing, you're never quite sure it's because of active inflammation. Is part of your glomerulonephritis with Proliferative lesion's or whether it's because of chronic damage. So fibrosis and sclerosis and the biopsy. So by actually starting earlier with the ace inhibition and intense and receptible okayed, it means that you maintain them on a steady dose. Then you see if there's any changes in the degree of protein urine albuminuria thereafter as well as that I can see you've got That's my sorry to interrupt you. My question was, can we use an input putting here greater than program? Because your slice states that once is more than 1 g, we use glucocorticoids. So am I. Am I? Can we use the importing area greater than 1 g? Okay. Are you talking about a gram of protein urine? Did you say, Did you say a gram of protein urea per day? Yes, Yes, Doctor, I said, Can we use them if it's more than a gram of Yeah. So I would try and do an early morning urine albumin to creatine ratio, so that's a sport urine. And if after you've treated the initial inflammation. If you're still getting urine albumin, um, to creatinine ratio and the first sample of the day, which is, um, more than 25 mg for minimal. If you've got abnormal kidney function or more than 50 mg for minimal. If you've got normal kidney function, then I would be starting treatment with, um, an ace inhibitor. And I'd be trying to get the urine albumin to creatine ratio down to less than 25 mg for minimal. So really trying to remove as much protein urea as you can is that you've got your hand up again. Is that a legacy? Yes, yes. Uh, the thing about the SLE is sometimes sle is there, and we don't know it's a genetic disposition, and we find out only when we have a certain form of an infection or something to induce it. So let's just see if we have an an infectious disease. Any infectious disease. Uh, on depending on how we start the do we start the first SLE or the treating the, uh, any infectious disease depending upon which could be more fatal. Because SLE, I think is a bit sometimes can be slow progress of compared to the any infectious disease, which it would be just plasmosis or anything, anything, maybe HIV or something. And yes, so I kind of showed that history at the beginning, because very often you have a long standing history, which goes on for a few months. And that patient, if you remember it, actually had evidence of staph aureus sepsis when they were acutely unwell. But we give intravenous antibiotics and anti fungals and cover them for antimicrobial therapy as soon as they present. But actually, if there's rip roaring inflammation, then we would give intravenous methylprednisolone at the same. And you know that there's some ongoing work showing the benefits potentially of cortical steroids and sepsis anyway, So I think it's they're trying to reduce the cytokine response get furthermore, so I wouldn't necessarily say that you needed to have a week of of intravenous antibiotics and then start human suppression. You can get them in suppression. Intravenous pulse methylprednisolone pretty quickly, but I agree that when a patient initially does that first presentation, you're wanting to check if they've got positive cultures. What the C reactive protein is normally patient's with systemic Lupus erythematosus will have an elevated Yes, our throw site sedimentation rate. But a normal C reactive protein in those patient's that have got an elevated C reactive protein at presentation. I'd definitely be worried about infective uh, complications. But remember, recurrent fevers can be a sign of inflammation, but it can also be a sign of infection. So even the same would be for the teratogenic or nosocomial infections as well. Yeah, yeah, exactly. We would treat. And of course, we're not going to know if they've got an inherent complement deficiency, Uh, from the get go, we definitely try and see if we can detect that. But we wouldn't necessarily know that in the instance And the important reason for knowing if we've got genetically confirmed compliment, um, deficiency is the fact that they probably will never normalize the compliments, which, of course, gives them a worsening prognosis. That means that you're not aiming to treat to the complement levels normalized, because that's probably not going to happen in that patient. So just a reminder again to, um, to fill in your evaluation. If you also go into the chat, you can click and download. Um, your talk, um, and your certificate here. Um, so please do do that. Um, and all that remains for me to say is thank you very much for joining. Um, please give feedback, and hopefully I will be able to teach you further in 2023 wishing you all the best over the festive season. I hope things improve in 2023. And, uh, an honor and a privilege to teach you all today and speak to you soon. Take care. All the best. Bye bye. Thank you. Thank you very much. Bye. Bye. Thank you. Thank you so much. You know, my pleasure. And I think that's all the lectures from today. Yeah. This is today's final lecture. If you go on event right, you can book for, um, Thursday's lectures. I'll put the link in the chat. The link is also on the WhatsApp group. Um, so, yeah, please go ahead and book for Thursday's lectures. And we've got our final day is next Tuesday for this term. Um, but yeah, thank you very much. Everyone for attending and thank you very much, Professor. Know a pleasure and just wish you all the best as well. Thank you. You too. Thank you very much. Um, I'll end the meeting in a minute. So, um please find all the links in the chat. You've also got the certificate you can download in the chat. Um, but I'll leave it for another minute, and then I'll end this meeting. Thank you, everyone.

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