Clinical Sciences 22.10 - Glomerular Diseases PDF

An Approach to Glomerular disease - NB to understand glomerular disease - And understand the pathophysiological concepts that underly glomerular disease - Glomerular disease: o Commonest cause of End stage Kidney Disease in Europe and the US o Minimal change glomer...

An Approach to Glomerular disease - NB to understand glomerular disease - And understand the pathophysiological concepts that underly glomerular disease - Glomerular disease: o Commonest cause of End stage Kidney Disease in Europe and the US o Minimal change glomerular nephritis is the commonest cause of nephrotic syndrome in children o IgA nephropathy is the commonest cause of recurrent haematuria in young adults o Focal Segmental Glomerulosclerosis is the commonest cause of nephrotic syndrome in Sub-Saharan Africa ▪ NB in our setting due to the genetic background and high HIV rate; abbreviated FSGS Definition - Glomerular disease: o Any abnormality of the glomerulus o The glomerulus is shown in the image below and there are between 600 000 and 1.2 million glomeruli in each kidney The glomerulus consists of an afferent arteriole bringing blood into the capillary network which are lined by highly specialised cells called podocytes. The podocyte which we shall see is very important in filtration - There are three categories of glomerular disease: o Podocytopathy (disease specifically of the podocyte) – look at this in detail and this forms part of the epithelial layer that’s sitting on the GBM  o Glomerulonephritis (inflammation of the glomerulus) o Structural abnormalities of the GBM o These can overlap and you can have combinations that may co-exist (this can be significant) - In addition – the three pathologies listed above affect the glomerular filtration barrier Key Concepts: - When we are talking about a syndrome we are not talking about a diagnosis - “Syndrome” ≠ “Diagnosis” - “Syndrome” = Clinical presentation o Therefore syndrome refers to a clinical presentation o We can look at nephrotic syndrome vs nephritic syndrome as an example - Clinical presentation depends on nature of glomerular insult (≈ histology) o The manifestation of the clinical presentation depends on the underlying glomerular insult which correlates to the histological parameters which is seen in biopsy - Nature of glomerular insult depends on underlying disease pathophysiology o Use a combination of understanding the underlying disease pathophysiology and the histological manifestations and the histological presentations in order to decide upon the treatment and ultimate prognosis - Treatment and prognosis depends on underlying disease, nature of glomerular insult, and clinical presentation Structure and Function of the glomerulus - Knowing where the pathology is can help produce the clinical presentation - We need to be aware of the normal glomerular function in order to spot pathology and determine where the pathology is occurring - Filtration o This is reliant on the hydrostatic and osmotic pressures that drive a net filtration pressure in order to filter out ultrafiltrate that eventually becomes urine through the nephron processes Afferent Arterioles The afferent arteriole branches into the capillary Efferent network and the efferent arteriole then leaves the - brance Arterioles capillary network in the glomerulus. The importance of this capillary network is that it has very high blood pressures so the blood pressure here is the highest than any other capillary bed and this is to ensure that there are high hydrostatic pressures within the capillary network in order to facilitate filtration from the capillaries and into the urine space - Protein “sieving” o The ultrastructure of the kidney is NB in achieving this  This structure is NB Filtration is facilitated by the podocytes - Podocytes are specialised cell lying on the outside of the glomerular capillaries in the urine space - Thay have the major processes which fit into minor processes and these minor processes interdigitate Filtration slits: - Prevents protein from leaking into the tubular fluid - The size and the charge of the filtration slits play a role; proteins are too large to fit through and charge therefore prevents leakage - Here you can see the interdigitation of the minor GBM processes of the podocytes - These podocytes are specialised epithelial cells that have enlarged cell bodies and numerous foot processes that interdigitate across the GBM - This whole image is the glomerular filtration barrier which is composed of the podocytes, filtration slits (indicated by the arrows) and the GBM Lumen - It is important to note that the endothelial cell Endothelial has big gaps between them cell - Therefore the gaps that are between the podocyte foot processes are small and negatively charged which therefore this retards the filtration of large molecules namely protein into the tubules The clinical presentation depends on the histology - We are now going to look more at the histology  GBM Podocytes Glomerular Capillary Endothelium Lumen of capillary Mesangial cell supporting the capillary - The reason that the histology is important is that the nature of the injury that determines these glomerular diseases determines the presentation – if for example, you have got something (an antigen – unknown protein, or an antibody) which is relatively small and less negatively charged than when it passes through these filtration gaps in the endothelial cells and to the basement membrane and then because of the filtration it can get lodged underneath the podocytes. When this happens this foreign protein, antigen, antibody is in essence hidden from the circulating immune system in the glomerular capillaries and this is important as whatever damage is caused is then localised to the podocyte and you don’t get an inflammatory response - Often when we talk about podocytopathy we talk about non-inflammatory or we talk about non-proliferative disease - Proliferation means that the number of cells is increased in the glomerulus and the reason that the cell number is increased is because of all the inflammatory cells and therefore because these substances are not in contact with the inflammatory cells - In contrast if you have an antigen or antibody or immune complex which is very negatively charged that can’t pass the basement membrane or is deposited on the basement membrane or mesangium and because of the location and the deposition – this is therefore visible to circulating components of the immune system which will provoke an inflammatory reaction and proliferation of cells. - This is seen and explained in the slide below: Types of Glomerular Disease - Primary Glomerular Disease o This is where the glomerulus or the kidney itself is the core issue o Disorders in which the glomeruli are the sole or predominant tissue involved and affected by the disease process o May be idiopathic (unknown) or with described pathophysiology (sometimes related to IS dysfunction) o Most commonly we don’t understand the pathophysiology that drives the glomerular damage and we need to understand this because the processes involve small, microscopic particles which is therefor difficult to determine cause o Podocytopathy which is damage to the podocytes is primary or secondary in nature - Secondary Glomerular Disease o Glomerular injury is a feature of a systemic disease involving multiple organs or systems o Directly targeted or accidently targeted o An example here is SLE where lupus nephritis would be the renal manifestation of the glomerular disease o All glomerular nephritis is secondary because it is secondary to an underlying autoimmune condition that affects the glomerulus Structural abnormalities of the glomerular basement membrane - If you have abnormalities of the collagen makeup of the basement membrane, you will have abnormalities in the way that the endothelial cells attach to the basement membrane and the way in which the podocytes attach to the basement membrane and these  abnormalities in basement membrane and subsequent abnormalities in the endothelial cells and podocytes will allow blood cells present when in the glomerular capillary to be squeezed out into the urine which is known as asymptomatic haematuria which is asymptomatic because this disease process does not result in activation of the immune system because there isn’t an abnormal protein that the immune system responds to – these are also sometimes called hereditary nephritis because of the presence of the red blood cells in the urine and these are markers of glomerular nephritis - There are two structural abnormalities in the basement membrane that we need to be aware of o Thin basement membrane o Alport’s syndrome - Below is an image of a normal GBM – we will then look at the two structural abnormalities separately - Thin basement membrane lesion - Here you can see that the glomerular basement is very thin - Alport’s syndrome In Alport’s syndrome there are abnormalities in collagen which results in this loosely woven basement membrane which results in abnormalities in podocytes  - These are inherited abnormalities in the basement membrane therefore these both have genetic abnormalities associated - The GBM is an important size barrier and prevents erythrocytes straying into Bowman’s space - Abnormalities of the GBM result in glomerular (dysmorphic) haematuria - No inflammatory response occurs as these are STRUCTURAL lesions - There is therefore NO nephritic syndrome - The haematuria is therefore ASYMPTOMATIC (Alports may develop CKD) Glomerulonephritis - Glomerulonephritis is inflammation and damage to the filtering part of the kidneys (glomeruli). It can come on quickly or over a longer period of time - Abnormal protein (antigen), antibody or immune complex (antigen bound to antibody) which can get deposited in the glomerulus on the BM, mesangium or endothelium and this is visible to the immune system resulting in an inflammatory response - Importantly these need to be relatively large otherwise if they were small you would get these complexes moving past the basement membrane and getting deposited instead under the filtration barrier of the podocytes - Therefore most glomerulonephritis is an autoimmune inflammatory response to the deposition or proteins or antibodies in the glomerulus - In order to stimulate an inflammatory response, complexes must be deposited at sites where they are exposed to circulating leukocytes present in the capillary lumen, ie: o On the endothelium o Between the endothelium and the GBM (“subendothelially”) o On the GBM o In the mesangium - The relatively large size of immune complexes usually (but not always, see later) prevents deposition between the GBM and the podocyte (“subepithelially”) Podocyte Injury (podocytopathy) - Podocytes can be injured due to a number of mechanisms: o Immune (antibodies): ▪ As part of an immune process so you can get autoimmune diseases that cause podocytopathy as well as glomerulonephritis. ▪ For this to happen the antibodies that you are making need to be the right size and shape so that they can pass the basement membrane and be deposited along the protein of the podocytes ▪ This means that there are specific antibodies that are related to podocytopathy namely: IgG2/IgG4 conformation favours translocation through endothelial / GBM barriers ▪ Again here the point is that these are underneath the filtration barrier – you don’t get an inflammatory response o Infection of podocyte ▪ Can also cause damage to the podocyte ▪ HIV, PB19, vaccines (live attenuated) o Drugs ▪ IFN – used to treat multiple sclerosis o Ischaemia ▪ When the podocyte is starved of O2 ▪ Hypertension, Diabetes Mellitus, ACEI (vasoconstriction), heroin o Inherited defects of structure ▪ This is NB in a south African structure where there are various abnormalities in the structure of the chromosome ▪ Typically these mutations are in genes that control cytoskeletal structure like those listed below  ▪ NEPH1 ,APOL1/MYH9 mutations ▪ Pts in sub-saharan Africa have greater risks of these types of podocytopathies ▪ One of the contributing factors for the above statement is that some of these mutations protect against sleeping sickness which the parasite is endemic in sub Saharan Africa but the mutations still cause damage to the podocytes Functional anatomy determines presentation - The next thing to consider is that injury to these different areas result in the clinical presentation - We have spoken about the basement membrane and why you get dysmorphic red cells and glomerular nephritis etc - In the podocyte – you will interrupt the filtration barrier – remember this barrier acts like a protein sieve and because it is very narrow and negatively charged you prevent large proteins from moving into the urine so therefore if you damage this barrier in a diffuse way in which the majority of the filtration barrier/podocytes are damaged, there will be a lot of protein in the urine and that will lead to nephrotic syndrome - If you have a process where you have damaged any part of the GBM, epithelium, mesangium or basement membrane, you can provoke an inflammatory response – that inflammatory response will cause glomerulonephritis and the nephritic diseases Clinical Presentation depends on the histology - Damage to the podocytes results in the gaps becoming larger and increase loss of protein into the urine - Remember that this is not immunological or inflammatory, there are other forms like ischemic forms or more minor damage to the podocytes but also includes genetic damage to glomerular structure - “Podocytopathy” = pathology of the podocyte - Not necessarily immunological / inflammatory injury - Includes genetic defects in structure and function, acquired podocyte injury from non- immune causes (drugs, toxins, infections…) - The podocyte filtration barrier prevents loss of large molecules (proteins) to urine o However you will not have loss of smaller molecules into the kidney and therefore the U&E remains normal o This is due to the fact that the tubules are not affected by the glomerular disease and elicit compensatory mechanisms in order to compensate for the increased electrolytes in the urine - Primary feature of a podocytopathy is therefore proteinuria resulting in nephrotic syndrome - Does not prevent filtration of smaller molecules (electrolytes, urea, creatinine) - Damage to or dysfunction of barrier will therefore cause proteinuria as primary clinical feature - Proteinuria will be of variable severity depending on severity of podocyte injury - Milder injury to the podocytes are usually referred to as Extra-glomerular/extra-renal proteinuria which is covered and explained below Extra-glomerular proteinuria - No INTRINSIC INJURY / DEFECT in podocyte barrier - EXTRA-RENAL factors cause barrier DYSFUNCTION, hence mild (< 1g/24hr) proteinuria - Mainly caused by glomerular hypertension  - Because of the stretch of the podocytes you will have some loss of protein but not as much as with a podocytopathy - Examples: pregnancy, sepsis (pyrexia), anaemia, cardiac failure (cardio-renal syndrome type 1) - With these conditions, vasodilation will sustain circulation resulting in increased pressure in the glomerulus which pulls the podocytes apart which causes leak of proteins into the urine but not as much as we see when the podocyte is being directly damaged - The podocyte is therefore the main intrinsic part to be damaged we then call this glomerular proteinuria Glomerular Proteinuria - INTRINSIC (intra-glomerular) INJURY / DEFECT in podocyte barrier results in significant proteinuria, i.e.: NEPROTIC SYNDROME - Also need to look at how podocyte injury manifests and how we link that to clinical presentation - Podocytes respond to injury in a predictable manner - The mechanism of injury therefore determines histological response and hence clinical presentation - All podocytopathies share EM features of podocyte injury - Root of all podocyte injuries result in foot process EFACEMENT AND EFFUSION o These podocytes release from the basement membrane and spread out and as they do this they disrupt the filtration barrier and lead to protein being released into the urine - The hallmark of podocytopathies in nephrotic syndrome is excessive loss of protein in the urine – more than 3,5g in 24 hours which results in hypalbuminaemia – loss of albumin which causes a loss of oncotic pressure - The other protein losses are seen below and their clinical effects seen Clinical Consequences of proteinuria: development of nephrotic syndrome  - The loss of protein leads to hypalbuminaemia as discussed above - This also causes malnutrition which increases the risk of infection - The loss of immunoglobulins also occurs because of the loss of protein and this also drives infection and other susceptibilities - Other proteins that get lost in the urine include coagulation factors and these processes can result in thrombosis etc - There is also a loss of regulation factors which results in problems in cholesterol balance - If you damage the podocyte sufficiently and in a diffuse way and most podocytes are injured you will lose enough protein to manifest as nephrotic syndrome - Syndrome is the clinical manifestation of symptoms e.g. infection, oedema, clotting imbalances etc as seen as a consequence of the effects of the damage to the podocytes - NB to understand the underlying disease process that is causing the damage to the podocytes which can be a number of things Glomerulonephritis - Glomerulonephritis is caused when you have deposition of an antigen or abnormal protein or immune complex on the endothelium, basement membrane or mesangium because when it is deposited here because these then become visible to certain immune reactions - You can have a sub manifestation of glomerulonephritis which is crescentic glomerulonephritis where the inflammation is still involved in the bowmans space - Can also have a situation where you have inflammation of the mesangium which is mesangioproliferative glomerulonephritis - Most glomerulonephritis is called proliferative endocapillary glomerulonephritis so here the immune complexes are simulating an immune response causing an influx of white cells that causes damage to the endothelium, basement membrane or podocytes which then allows the leakage of some proteins into the urine but also white cells and red cells - All of these conditions favour the increase in cells present in the glomerular capillaries which is why they are called proliferative disorders - This proliferation can be focal which therefore involves less than half of the glomerulus or diffuse which is where more than half of the glomerulus are involved - Crossover condition is membranoproliferative glomerulonephritis which involves podocyte damage as well as glomerulonephritis - The image below shows what happens when you get glomerulonephritis - The antigen is present on the endothelium or the basememnt memberane and the antigen is deposited which then binds an antibody to form an immune complex - Or you have an antigen or antibody already formed as an immune complex present in the circulation which is then deposited in the glomerulus - That then results in the activation of complement which causes chemotaxis and therefore pulls in white cells and that activation of complement and activation of white cells results in damage to the structures of the glomerulus including damage to the endothelium, basement membrane and some focal disruption and damage to the podocytes - The damage can cause clot formation or proliferation of the remaining wall of cells causing an immune response - You can imagine though that as we are pulling in cells to the glomerular capillary network, and or clotting up the glomerular capillary network and causing the proliferation of capillary endothelial cells we are going to cause glomerular capillaries to occlude therefore hindering some of the filtration therefore there will be less bloodflow through the glomerular capillary which is why you get nephritis which leads to: o Fluid retention – oedematous o Renal dysfunction – in association with the glomerulonephritis basically because clotting causes retardation of filtering - The other hallmarks of glomerulonephritis is that this inflammation spreads out into the urine space which means white cells leak out into the urine and that promote crescentic glomerulonephritis and those white cells can be detected when you send urine to the lab and ask for MCS (no infection) - Disruption to the glomerular architecture of the capillaries allows red cells under high pressure that forces red cells out into the urine space but as they get forced through the  basement membrane, filtration barrier and podocyte layer they undergo torsion and therefore become dysmorphic which is another hallmark of glomerulonephritis - Therefore the hallmarks of glomerulonephritis are: o Dysmorphic haematuria o Leukocyturia o Hypertension o Renal dysfunction Overiview of the immune system activation - The above image gives the same details as explained previously in glomerulonephritis. The steps are as follows o Antigen binding to antibody which itself can cause damage to the tissues which then can cause injury o Complement activation is also simulated with this binding and complement forms a membrane attack complex which damages surrounding tissue and you therefore get complement mediated cytotoxicity o Complement activation causes the recruitment of white cells into the site of inflammation through chemotaxis and those white cells then cause further damage to the glomerulus causing cellular cytotoxicity - You therefore have this system that augments itself causing more damage to the glomerulus - so why does this matter?  o This is because of the reasons listed in the slide image below o The more complement that you activate the more efficiently that you are going to activate white cells therefore the more white cells in the urine indicate how much of this disease process is activated and immune response – this helps with diagnosis and how quickly you need to treat this patient Antigens/antibodies implicated in glomerulonephritis - There are certain diseases that are better at activating complement than others such as: o Post infectious glomerulonephritis  o Lupus o Other illnesses Proliferative Glomerular Diseases - The non-specific (general) response to injury is for the remaining cells of a particular cell type to proliferative in an attempt to replace the lost cells: o Proliferation of endothelium – endocapillary o Proliferation of mesangium – mesangioproliferation o Proliferation of the Bowman’s epithelium – extra capillary - More complement that you activate the more white cells will be brought in - Glomerular cellular proliferation is largely related to deposition of complexes in the mesangial sub-endothelium. - The degree of complement activation also seems to play a role. - Patients with hypocomplementemia almost always have a proliferative GN BUT not all proliferative GN is hypocomplementemic - Also proliferative changes may involve part of the glomerulus or all of it therefore being: o Focal o Diffuse Glomerular Diseases associated with low complement levels - These are diseases that activate complement - Post infectious GN - SLE - Membranoproliferative GN (MPGN) - Cryoglobulinemia associated GN - Atheroembolic disease Glomerular cell response to injury: Crescentic glomerulonephritis  - Crescentic glomerulonephritis is indicated in the slide above and what happens here is the proliferative inflammatory response present in the glomerulus ruptures out into Bowman’s space - Sometimes people talk about RPGN and crescentic GN interchangeable – when we talk about crescentic glomerulonephritis we are talking about a condition where on biopsy – more than 50% on biopsy of the glomerular are shown to be crescents - We will appreciate that if any autoimmune condition drives crescentic GN must be clinically aggressive - Also the formation of a crescent has the ability to impact the glomerular function as it is going to collapse down on the glomerulus and stop it from filtering properly so it is not uncommon for this to therefore lead to RPGN which is defined as rapidly proliferative GN which is a condition where renal function is greatly impacted – therefore clinical diagnosis dependent on the amount of renal function while crescentic GN is a diagnosis based on the pattern of inflammation The nature of the underlying disease determines the glomerular injury - The part of the glomerulus that gets damaged depends on the antibodies that you are forming - For example IgG 1 you get deposition on the mesangium in the form of lupus - IgG3 leads to deletion of the endothelium and subendothelium also in lupus nephritis and is linked to SLE class 3 and SLE class 4 (DPGN) - Deposition of antibodies therefore affect the site affected and the presentation thereof Classification of Glomerulonephritis - How is Pauci-immune possible: o Defined as: A rare small vessel vasculitis associated with rapidly progressive glomerulonephritis (GN) and clinically characterized by renal manifestations. o This is possible because of the autoimmune o This uses a histological term which comes from a long time ago when you are staining you are looking for types of antibodies present in the glomerulus o There are certain conditions where you can see the antibodies present and some where you cannot - When you look at the gross microscopy in the images above you will see: o All are shown a proliferative response as the cells are increased and you can see that the capillaries are blocked leading to the lack of filtration, oedema and renal dysfunction associated with GN - Here you can see that the crescents are causing compression of the glomerulus so they all look the same under the light microscope but the difference comes in when you stain them with immunofluorescence o You stain for specific antibodies which gives the patterns seen in the above image o Immune you see and pauci-immune you don’t because you need to stain specifically for antineutrophil cytoplasmic antibodies (ANCA) and if you do this you see neutrophils stimulated by this antibody moving through the afferent blood vessel travelling through the capillaries and causes all types of damage o Therefore pauci-immune glomerulonephritis is the same as a condition that we know as ANCA vasculitides which is two ways in which to attack the kidney namely polyangiitis granulomatosis and polyarthiritis nodosa - Immune forms – antibodies deposited on the basement membrane in a linear fashion and you see this it is AntiGBM disease and the pt has antibodies against the basement membrane  - All other causes of GN give a diffuse pattern seen in the last image - Therefore glomerulonephritis is a systemic autoimmune condition leading to damage to the glomerulus favored by antigen, antibody or immune complex deposition which results in clotting of the capillaries leading to renal dysfunction, oedema, hypertension, haematuria and leukocyturia Injury, Histology and presentation: MPGN - This is usually passed as a podocytopathy - Important to appreciate that this is an overlap between GN and podocytopathy - Basically what happens here is we have a process – GN process that involves white cell recruitment, inflammatory cell recruitment which damages the endothelium and then spills over to damage the podocytes so that you leak protein - These pts present with nephritic syndrome – Glomerulonephritis or podocytopathy and nephrotic syndrome or a combination of both and this is characteristically caused by abnormalities in complement activation so you need to keep complement under control otherwise it causes damage to endothelium - Some people are born with conditions lacking complement regulatory factors which are proteins that control the complement system while other people get antibodies that damage complement regulatory factors themselves and then complement becomes activated and initiated - Similar processes in nephrotic and nephritic e.g. o Lupus IgG 2 or 4 = podocytopathy o IgG1 you get GN  - But there are other factors that modify disease processes that we see which are patient related for example diseases Factors modifying mechanisms of injury – Looking at HIV - This depends on the ethnic origin and the genes associated - APOL1 mutation is a mutation that arose in defence against Schistosomiasis - Caucasoid origin – white or Asian origin tend to include autoimmune abnormalities - HIV on the background of these ethnic related mutations you will impact the clinical presentation found - Same disease process with slight variation impacts nephrotic vs nephritic - Some degree it does not matter whether the pt has nephrotic or nephritic syndrome when they present to you: o What matters is prognosis and treatment - How do you get autoimmune disease if HIV affects the CD4 cells o There are other types of immune cells and HIV also affects regulatory T cells therefore causing dysregulation of the immune system History and Examination - When a pt presents they present with symptoms of the disease process - Swelling of extremities especially periorbital in the morning o Can also have oedema  o Ankle oedema and anasarca, ascites or pleural effusion o Recall in nephrotic syndrome we said that we leak out proteins dropping the oncotic pressure causing oedema o In nephritic syndrome you stop filtering there get retention of water and salt which causes oedema - Foamy or bubbly urine (can help you differentiate) o Excessive protein in the urine – leak fat with the protein causing foamy appearance o With nephrotic syndrome leads to protein leakage and fat which changes the surface tension giving the bubbly appearance - Dark urine o Tea colour o Signs of dysmorphic haematuria o Nephritic syndrome indicative of GN - Regardless you need to test the urine whether GN or nephrotic - Decreased urine output, fatigue and weakness - Ankle and leg oedema in the morning, if excessive systemic fluid retention occurs then anasarca, ascites, pleural effusions - When you have kidney disease, you cannot examine the renal system – you have to do special investigations and here you must include urinalysis (dipsticks and to the lab) Urinalysis - With this, you need to screen but you also need to send urine to the lab - Examination of the renal system IS NOT complete WITHOUT urinalysis - Urinalysis confirms the presence of RENAL (kidney) pathological processes and can indicate aetiology - Dipstix is a screening test ONLY – semi quantifiable o Therefore needs formal quantification with urine protein : creatinine ratio and microscopy o Doesn’t actually tell you the amount of protein in the urine - Caveats: o Ensure adequate sample has been collected ▪ Meatus to be cleaned with saline – no contamination ▪ Fresh catch midstream specimen (early morning) ▪ Analyse timeously – the longer it sits the more impact it will have on the cells present o Ensure adequate dipstix ▪ Check use-by date  ▪ Check container: keep closed, cool environment as specified by manufacturer Nephrotic Vs Nephritic syndrome Causes excess loss of protein in the urine This is NB in the definition More than 80% of the red cells must be dysmorphic - These are part of a spectrum Injury determines treatment in glomerulonephritis - Must remove the source of antigen that is stimulating the immune system o Antibiotics in post-strep GN o Antivirals in HBV / HCV - Must remove the antibody o This is done to treat the autoimmune o Plasmapheresis (plasma exchange) – removes antibodies and therefore the protein in the bloodstream (especially in patients who are deteriorating quickly) o High dose steroids (solumedrol) o Cyclophosphamide o MMF, AZA, rituximab… - Prognosis will depend on the disease (post-strep = good, ANCA vasculitis = bad) and how severe the glomerular injury is (focal proliferative > diffuse proliferative > RPGN) - Biopsy is NB due to diseases determines prognosis and varies by disease process - NB low threshold to refer to specialists – must not be treated by non specialist Injury determines the treatment in nephrotic syndrome - In nephrotic syndrome we can start symptomatic treatment and then specific treatment as seen in the slide below  - All nephrotic syndromes are usually treated with ACEI and statins because as we have said the podocytes move away from the basement membrane and spread out and the ACEI and statins help pull podocytes back and give them their normal structure - This treatment can be done at a subspecialist level but realistically because there are other disease processes that can underly nephrotic syndrome they should be referred to find out if the disease is primary or secondary and they should be referred in order to treat the underlying cause Histology determines the clinical presentation - Therefore underlying histological damage is what helps you understand the presentation - Nephrotic syndrome = damage to the podocyte which results in protein in the urine - How the podocyte gets damaged determines the gross histological presentation - There are 4 ways in which change is seen in microscopy and these are: o Minimal change o Membranous o Crescentic GN o Focus sclerosis - As you move from minimal change through to the other types there is increasing amounts of damage associated Disease processes  - Different disease processes acting in different ways cause damage to different parts of the glomerulus which gives rise to different manifestations – these disease processes are affected by different thinks - Patient factors and disease factors determine presentation - Podocyte get MCN to FSGS/MPGN - Endothelium get MPGN/Focal/diffuse proliferative GN - Knock out both you get somewhere in the middle - This is thus indicating the spectrum of disease that is possible with these disorders Conclusions - The glomerulus is vulnerable to injury because: o High volume of blood flow → large volume of immune complex / toxin delivered / large exposure to blood-borne infections (viruses) o Nature of the ultrafilter (good at retaining proteins) → immune complexes extensively deposited o Extensive glomerular surface area → vulnerable to inflammatory injury from circulating leukocytes o High glomerular pressure → podocytes already under strain, vulnerable to increased intraglomerular pressure under conditions of hyperdynamic circulation - The underlying disease process (disease-related factors) and modifying patient-related factors determine how the glomerulus is injured - A single disease process can therefore produce multiple histological forms of injury  o e.g.: HIV and HIVAN (collapsing FSGS) / HIVICK (MPGN) - A similar histological pattern can be produced by different disease processes o e.g.: MN can be produced by SLE, HIV, cancer… - The histological pattern determines the clinical presentation - The image below is NB – when we have a pt with oedema we need to see id there is some form of nephrotic or nephritic syndrome Lecture 2: An approach to proteinuria - This links to nephrotic syndrome o Proteinuria = hallmark of nephrotic syndrome o >3,5g in a 24 hour period collection also uses the spot U&C ratio in a single sample o Oedema o Hypalbuminaemia (