Transcript of Anti GBM & Good pasture ds (KDIG0 2020)

good evening my dear friends and colleagues today we will talk about one of the most severe forms of grenadine fries which is anti-glomerular placement membrane disease and good bastard disease this is our agenda the syndrome of renal failure and lung hemorrhage was associated with the name of good pasture ernest could baster as described by stanton and tange in their description of nine cases in 1958 all these nine cases presented by lung hemorrhage and acute renal failure which was very similar to the presentation of a young man who was reported by god butcher himself in 1919 by lung hemorrhage and renal failure nowadays many diseases have been described or associated by alveolar hemorrhage and rapidly progressive gummier nephrites now we will talk about the definitions of these syndromes the first one is balmoneri renal syndrome bulmoneri renal syndrome which describes renal failure and respiratory failure we'll discuss the causes later on the second term is goodbuster syndrome syndrome which include conditions with rbgn and alveolar hemorrhage and we'll discuss the causes later on on the powerpoint the third term is anti-glomerular basement membrane disease in this disease is associated with antibodies from the name anti-gbm antibodies against components of the glomerular replacement membrane the most the most common or the most important cause is good bastard disease and albert syndrome post transplant antigen anti gbm disease include antibodies against components or any component of the gbm it include good bastard disease and anti-gbm disease following transplantation to alport syndrome and what about good bastard disease not syndrome disease combustor disease is associated with antibodies specific very specific to the alpha 3 chain of type 4 collagen of the glomerular basement membrane very specific good bacterial disease is achieved with antibodies antibodies specific for the alpha 3 chain of type 4 collagen of the glomerular basement membrane albert syndrome post-transplant anti-gbm disease is associated with anti-gbm antibodies that develop after renal transplantation in in patient with albert syndrome and albert syndrome these terms are very important pulmonary syndrome good bastard syndrome and tgbm disease and good bastard disease now we'll talk about the etiology and pathogenesis the most important is the autoimmunity is the autoimmunity good bastard disease as we just said is caused by autoimmunity or auto antibodies to the carboxyl terminal non-collagenous domain of type 4 type 4 collagen alpha 3 chain to the alpha 3 chain of type 4 collagen this is the most important this is the main pathogenesis type 4 collagen is is an essential component of all basement membranes it is composed of trimers composing two alpha two alpha one and one alpha two and there all there are also four tissue specific genes alpha three alpha four alpha five alpha six three of these alpha three alpha four alpha five are present in the grammar basement membrane as well as in the basement membrane of alveoli cochlea and parts of the eye again the most important pathogenesis of good vascular disease is antibodies against alpha 3 type 4 collagen what about the predisposing factors for good bastard disease environmental and genetic factors are implicated there are strong associations between good bastard disease and hle class 2 elites specially dr p115 drb115 and dr4 this is very important a very strong association between good partial disease and the rb15 what about the precipitating factors no no specific infectious agents have been consistently identified but hydro hydroxy carbon exposure or hydrocarbon exposure has been linked in many cases as a precipitating factor for the appearance of codebaster disease and the most important one is cigarette smoking cigarette smoking may precipitate lung hemorrhage in patients who already have circulating auto antibodies also in many cases renal trauma or inflammation has preceded the development of disease but the most important precipitating factor is cigarette smoking followed by hydrocarbon exposure this is a summary of what we said the predisposing events associated with the presentation of goodbuster disease some predisposing events that induce the autoimmune response which include small vessel vasculitis membranous nephropathy lithotrapsy of renal syndromes urinary obstruction lymphosumab thera before ms or please posing factors that precipitate pulmonary hemorrhage as we said the most important is cigarette smoking hydrocarbon exposure pulmonary infections and fluid of loot what about the epidemiology good bastard disease is a rare condition with an incidence of around one case per million per year the incidence in plaque population is lower there is a slight male bury dominance lung hemorrhage usually is more common in younger patients and the disease incidence is by model with peaks in the third the third and sixth decade what about the clinical manifestations 50 to 75 percent of patients present with acute lung hemorrhage and acute renal failure this is the most common presentations lung hemorrhage and acute renal failure and usually these symptoms is characterized by very rapid progression during days and in some cases it made a more prolonged cause lack of systemic symptoms is typical but again the most important manifestations or the most important presentation is acute lung hemorrhage and acute renal failure let's talk about the lung hemorrhage in dictates lung hemorrhage can occur with renal disease or isolated lung hemorrhage the main symptoms are cough and hemopsis this lung hemorrhage can result in market iron deficiency anemia can cause dyspnea even in the absence of hemopsis examination usually reveal balor inspiratory crackles signs of consolidation and finally respiratory distress the most sensitive indicator of recent lung hemorrhage is increased uptake of inhaled carbon monoxide and this is a question the most sensitive indicator of recent lung hemorrhage is increased uptake of inhaled carbon monoxide young hemorrhage usually occur with current cigarette smokers as we said before the most important predisposing factor for lung hemorrhage is cigarette smoking what about the glomerulonephritis patients whose germinative rights usually present with dark or red urine and progress to odiguria and about third to half percent of patients germinal flats can occur isolated without lung hemorrhage without lung hemorrhage deterioration of renal function is usually very rapid is usually very rapid and one of the most common causes of rapidly progressive garment friction is good butcher disease urine analysis usually revealed hematuria even in isolated pulmonary diseases there is usual hematuria modest proteinuria dysmorphic rbcs and rbc is cast on microscopy the kidneys due to the acute condition are generally of normal size and can be enlarged due to active inflammation what about the pathology in the light microscopy renal biopsy is essential is essential because it provides diagnostic and prognostic values the typical appearance of course is diffuse proliferative grammar nephritis with variable degree of necrosis and decrease and formation one of the most important causes of crease and tech glomerulonephritis is good bastard disease so in light microscopy is the most important finding is diffuse proliferative gn with chrysantheic chrysantheic formation the degree of crease and formation and tubular loss correlates with the renal prognosis it is the most important item to assess the prognostic of the prognosis of the patient is the crescent and its extent usually the creations are of similar age and singularity this is a picture of the crescent in the bowman's space was collapse of the globular tuft cellular crescent by immune fluorescence or immune histochemistry there is characteristic linear deposition linear deposition this is very important linear deposition of immunoglobulin along the glomerular basement membrane and the immunoglobulin is usually igg linear deposition along the gbm very characteristic sometimes in 10 to 15 percent it can be used iga or igm and rayleigh ige is detected linear deposition also of c3 is detectable in about 70 percent of cases so there is characteristic linear deposition of immunoglobulin plus or minus complement this linear deposition is not pathognomonic for good bastard disease it can occur with other conditions what are the causes of this linear binding or linear deposition this is a very common question and for differential diagnosis causes of linear deposition of immunoglobulins in the biopsy or jgbm can be specific binding to the grammar replacement membrane like in good bastard syndrome and albert syndrome after renal transplantation or non-specific binding like very important diabetes fibrillary cadaveric kidneys light chain disease and systemic loops the most important is diabetes and fibrillary glomerulopathy or fibrillar chromatonic rights this is causes of linear deposition of immunoglobulins very common question and this is the picture of that linear deposition takes the line of the glomerular basement to bring as you are drawing it with a pencil very characteristic what about the laboratory findings in the serum circulating ntgbm antibodies are almost invariably present in all patients can be detected and quantified the tetr of these antibodies of the anti-gbm antibodies correlate with the severity of the nephrites treatment and relapse are often measured by change in the tether so we can use we will use the tether during treatment of the patient to assess the response these antibodies anti-gbm antibodies test can give us false positive and false negative results false positive result can be present in patients with other inflammatory diseases and it can give us false negatives that the patient has good bastard disease but the test is negative and patient with some patient with isolated lung disease or in the very early or sub acute renal disease that can be very low a very important condition is the presence of a double positivity double positivity bothered a patient with anti-gbm antibodies and anker antibodies antineutrophilic cytoplasmic antibody patient with double positive antibodies anti-gbm and anchor antibodies especially my low peroxidase antibody these double positive patients usually have a clinical course and responsive treatment more typical to the vasculitis than than of good muscular disease so the clinical picture and the treatment response is usually similar to the anchor-associated vasculitis course anti-gbm antibodies that tend to be lower in these double positive patients recovery recovery of the renal function tend to be more likely in these double positive patients they have a better prognosis than anti-gbm the good butcher disease with only positive antigen antibodies so the conclusion here that these double booster patients have a clinical course and treatment response similar to vasculitis rather than good muscle disease and the renal recovery is much more common in these double positive patients better prognosis than good butcher disease now we'll talk about the differential diagnosis first we'll talk about the non-immune causes or what we have said in the first two slides in the definition slide balmoneri causes of balmonary renal syndromes causes of pulmonary renal syndrome which is a street with renal failure and respiratory failure the subclavi sub classified two conditions with pulmonary edema like an acute kidney injury with hyper bulimia very common condition with a patient with acute renal failure or acute kidney injury with oliguria and then hypervolimia or in patients with severe heart failure have both aki and rena or respiratory failure or infections like in severe bacterial pneumonia antivirus infection or opportunistic infections in immunocompromised patients causing multiple organ failure again acute respiratory distress syndrome with renal failure in multi-organ failure barack weight poisoning or in patients with renal vein thrombosis and pulmonary emboli these are the causes of pulmonary renal syndrome non-immune causes now we'll talk about causes of lung hemorrhage and rbgn rapidly progressive grammar a very important entity in our clinical practice very common presentation you should know your differential diagnosis one of the most important is our talk today is antibodies to the antigen disease representing about 20 to 40 percent of cases which is a good bastion disease and the other 60 to 80 percent is the presence of systemic vasculitis the most common is wagner granulomatosis or granulomatosis polyangiitis or the xenophilic granulomatous bully angitis or church straws microscopic polyangiitis of course systemic leupothysmatosis one of the most common causes of these lung hemorrhage and rbgn iga vasculitis and oxygen line basic mixed cryoglobal anemia rheumatoid vasculitis and drugs like benecidamine hydralazine and probiothyrosis the most important causes are good bachelor disease wagner church of strauss lupus microscopic bullying rights very important slide in our clinical practice now we'll talk about diagnosis and treatment and we will talk mainly from the kid ego guidelines 2020. kidigo 2020 said about the diagnosis that the diagnosis of anti-gbm should be made very urgently very urgently in all patients with suspected rpg so any patient coming to you presented by rapidly progressive guru nephritis we should ask immediately for anti-global basement membrane antibodies again this is a clarification we should ask for urgently these antibodies may be negative in up to 10 percent of patients and then in these cases the diagnosis is only made by kidney biopsy demonstrating the linear igg deposition along the glomerular basement membrane lung hemorrhage lung hemorrhage is usually most commonly in our clinical practice is diagnosed by high resolution ct this is the practice when a patient was suspected this near or lung hemorrhage we can ask very rapidly for high resolution ct scan kd guidelines recommend it's a recommendation not a suggestion recommendation on the level of evidence 1 c to initiate immunosuppression with cycle of somite and corticosteroids plus plasma ferrises in all patients in all patients with anti-gpm glumenal flights so in all patients with anti-gbm antibodies or antigen in glomerulonephritis we should distort by cyclosamite steroids plasma ferrous except what are the exceptions patients who are dialysis dependent at presentation patients who have 100 degrees and in an adequate biopsy symbol and in patients who don't have pulmonary hemorrhage these are the exceptions to initiate this aggressive regimen in all patients we should start by cyclomysteroid and the plasmapheresis except in these conditions studies have shown that the mortality and look at the numbers mortality from anti-gbm disease decreased from 47 to 8.5 percent from 47 to 8.5 percent with the use of plasma exchange and immunosuppression and five-year patient survival is currently over 90 percent with treatment the treatment for ngbm should be started as soon as possible this is very very important recovery and also look for the numbers recovery of the kidney function is only about five percent recovery is only about five percent in patient with crease and very high percent of increase and about 85 to 100 percent in kidney biopsy and in patient with oliguria and or advanced adrenal failure requiring or and dialysis dependent so in patients who are dialysis dependent or oligoric or have very high proportion of creacent the recovery of kidney function is only five percent very small number so in those patients the decision the decision to initiate therapy with our aggressive regimen should take the uh to take an account this low chance of kidney recovery however the exception is when there is bulmaria hemorrhage if there is pulmonary hemorrhage if there is pulmonary hemorrhage even in these conditions we should use the aggressive regimen but if there is no pulmonary hemorrhage with these conditions dialysis dependent uligoria and very high creases we should differ from this very aggressive regimen which include plasma viruses cyclosomide and steroid due to the very low percentage of recovery again treatment should start without delay even before the diagnosis is confirmed plasma exchange should be continued until the antigen are no longer detectable we should continue this is a very important practical point we should continue plasma exchange until that it is no longer detectable cycle of somite should be con used for two to three months and the steroids should be used to about of six months so cyclosamite three months and desteroid for six months very important practical points this is a suggested algorithm from the kid ego guidelines to how to deal with patients with rbg patient with rbgn we should ask for a ct scan to diagnose if there is alveolar hemorrhage or not if the alveolar hemorrhage is absent in ct scan we should consider conservative approach we should consider conservative approach especially in patients who are oligarch as we said or dialysis dependent or very high proportion of crease but if there if the alveolar hemorrhage is present and confirmed by the high resolution city we should send serology for anti-gbm antibodies anka antinuclear antibody we should also exclude infection we should add presentation or within 24 hours we should obtain a kidney biopsy again we should ask for if there is rbgn and alvolar hemorrhage at presentation we thought we should send serology for anti-gbm antibodies anchor anti-nuclear antibody we should execute infection and we should do renal biopsy we should do renal biopsy if the data back to us within 24 hours confirming the anti-gbm disease we should treat as we said very urgently by steroids plasma exchange and cyclosamite if the data are not available or the results are not available losing 24 hours we should start treatment with steroids and plasma exchange until the data are back to us confirming the diagnosis of anti-gbm disease we should we shouldn't delay the start of treatment if you are high highly suspecting anti-gbm disease if you confirm the diagnosis we should as we said we start treatment by steroids plasma exchange and cyclosamite we should monitor kidney function pulmonary infected and gbm anti-gbm antibody teter and blood counts and modify the treatment appropriately this is a very nice algorithm to start how to deal to a patient presented to you by rbgn and alveolar hemorrhage these are the available options for treatment of good butcher disease include plasma exchange cyclophosphamide and steroids now we'll talk about each one of them in details we should start plasma exchange in a dose of 40 to 50 milli per kg ideal body weight daily take care of that daily by five percent album we can give fresh frozen plasma at the end of the plasma exchange if the patient have alveolar hemorrhage we should use fresh frozen plasma again plasma exchange or plasma ferrous in a dose of 40 to 50 ml kg per day and we use it daily we can use five percent album but if there is alveolar hemorrhage we should use fresh frozen plasma and if we use uh five percent albumin we should let the last 300 to 500 milli should be replaced by fresh frozen blast for how long for how long this the duration of plasma exchange we should do plasma exchange until the circulating antigen antibodies are no longer detectable in the serum usually in about of 14 days cycle of somite in a dose of two to three milli per kg two to three milligram two to three milligram per kg orally orally reduced to 2 milligram per kg in patients who are older than 50 years 55 years of age cyclospide is oral the experience with the iv bulbs sacrosamide is limited and the effects is uncertain so most of the evidence is related to the oral cyclosamite in and those of two to three milligrams per kg the dose of cyclone should be reduced in cases of leukopenia and patients not tolerating or not responding to sacrosamite we can use ritoximab or mycophenolate morphe t for how long we should give cyclosamite sacrosmite should be given for three months steroids should be used of course in the start as a pulse methyl britney saloon one gram per day for three consecutive days followed by britney zone or britain's around 1 milligram per kg orally reduced to 20 milligram per day by six weeks steroids should be used for six months this is an very illustrative descriptive for the treatment options of good butcher disease a very nice slide from comprehensive showing factors that favor the aggressive treatment and factors against aggressive treatment we have said it before but at a very nice light factors favoring aggressive treatment to use this aggressive regimen or the presence of pulmonary hemorrhage that there is no oliguria that there is urine output and patient who is creating less than 5.5 milligram per deciliter in patient with creatine more than 5.5 milligrams liter but with rabid and recent progression or have anchor positive the glomerular affection or the crease and proportion and the biopsy are not not aggressive or not too much or if a patient having plan having a plan for early renal transplantation these conditions are favoring aggressive immune suppression or aggressive but factors against this aggressive aggressive regimen include if there is no pulmonary hemorrhage or if there is oliguria or there is in the kidney function with creatinine more than 5.5 milligram deciliter and the patient is anchor negative or there is severe damage in the kidney biopsy in the form of a reasons more than 85 percent and if there is no desire for early kidney transplantation all of these factors are against aggressive therapy also this is a very practical slide in our practice and in the exams especially the european specialty examination there there is no maintenance therapy there is no mental and therapy for anti-gbm disease because relapses relapses of antigen disease are very uncommon about zero to six percent of cases so relapses are very uncommon which causes that we don't recommend maintenance therapy for anti-gbm disease we should use only for the induction phase for about psychosmite for sex for three months and steroid for six months but smoking should be strongly discouraged again no maintenance therapy for anti-gbm but in patients with a double positivity patients who are possible anti-gbm and anchor antibody should we should give them maintenance therapy as we said before these patients or these double bosti patients usually react or act like vasculitis sure we should give them maintenance therapy and about one-third of patients with anti-gbm grammar flights may be anchor positive so it represents a considerable portion of patients with anti-gbm disease and again as we said that in these patients with a double positivity there is a greater chance of kidney recovery from dialysis dependent than in patient who is on the anti-gbm disease what about the refractory anti-gbm disease in refractory cases which is not common refractory antigen disease is rare and represent about less than 10 percent in these refractory cases we can use retoxymac we can use retoxymap and the experience with ritoximab in antigen disease is limited to only case reports also we can use mycophenolate morphetid instead of cycle of somite or in patient who is refusing psychosomide or intolerant to cyclosome due to toxicity we can use mycophenolate morphetel with a good results in several case records so in these refractory case we can use ritoximab or mycophenolate muffity also there is a little hope with emily fidays which is igg degrading in the peptidase that leaves the human igg into fc fragments and inhibits the anti antibody and complement dependent cytosis so this amlifidaes can degrade or cleaves the anti-gbm antibodies and there is a good response in which should have been used in three anti-gbm patients but the recovery was wasn't complete but there is there was a response and there is a clinical trial now assessing the utility and safety of uh imlifidays in anti-gbm disease also immunoabsorption can be an option to remove these antigen antibody if effectively can be used in with some good results in refractory cases which have caused dialysis dependency was successfully reversed in three out of six patients when using immunoabsorption but the first options in refractory cases remain eritoximab and mycophenolate morphiti what about kidney transplantation the option of transplantation in patients with anti-gbm disease reaching the renal failure transplantation should be postponed until the anti-anti-gbm antibodies are non-detectable are not detectable for at least six months this is very important again we should postpone transplantation until the antibodies are not detectable for at least six months why because the recurrence of anti-gbm disease after transplantation can can be very high approaching 50 percent in patients who perform transplantation with detectable antigen manifolds while the recurrence of this of the disease after transplantation is very low less than three percent in patients who have no antibodies at the time of transplantation so the recurrence will be very high if there is antibodies anti-gbm antibodies form usually occur in five to ten percent of patients with albert syndrome who perform kidney transplantation but over the disease is less frequent than that so the antibodies usually occur in five to ten percent but that the evident disease or the over disease is less frequent and if this if the disease is overt or clinical glomerulonephritis appear it usually starts very early unfortunately leads to graft loss again to perform transplantation we should wait until the antibodies are not detectable for at least six months this is our resources as usual thank you to meet in the next videos inshallah thank you