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1 R. Coward has documented that he has received cooperative grants from Takeda and Novo Nordisk
2 Advances in our understanding of the pathogenesis of glomerular thrombotic microangiopathy Lindsay Keir Richard Coward Ped Neph (2011) 26:
3
4 Introduction Thrombotic microangiopathy (TMA) is a pathological term to describe occlusive microvascular thrombus formation. 1 st described in Pathological features:
5 Trigger of Vascular Injury Genetic/Host Predisposing Conditions Basement Membrane Endothelial Cell Thrombotic Microangiopathy RBC Partial/Complete vessel occlusion Swelling of endothelial cells Detachment of endothelial cells Platelets Intravascular platelet thrombosis Increased vessel wall thickness Accumulation on subendothelial space
6 TMA most commonly associated with Haemolytic Uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) HUS is the leading cause of AKI in children ( people per 100,000) TTP predominantly adult and neurological. HUS predominantly paediatric and kidney. HUS can be typical infection-associated (90%) or atypical (10%) TMA can have multiple precipitants
7 Infection Induced: -Shigatoxin HUS -Strep Pneumoniae HUS Disorders of Complement regulation -Genetic mutations -Acquired defects e.g. antibodies Defective cobalamin metabolism Drugs: -Quinine induced -Tacrolimus, ciclosporin -Bleomycin, mitomycin, cisplatin -rifampicin -Clopidopogrel TMA Malignancy ADAMTS 13 abnormalities: -genetic abnormality -Autoantibodies HIV Connective tissue disorders: -SLE -Antiphospholipids syndrome Pregnancy
8 Normal complement cascade Group of 30 proteins that complement the antibacterial properties of antibodies. Proteins can be plasma based (fluid) or membrane bound (solid) Three main branches Classical (antigen-antibody binding) Lectin (serum lectin binding to mannosecontaining carbohydrates on bacteria or viruses) Alternative (binding to surface of pathogens)
9 ALTERNATIVE COMPLEMENT CASCADE Spontaneous hydrolysis, bacteria/virus C3 Convertases FB= Factor B FD=Factor D MAC= Membrane attack Complex C5 convertase
10 Atypical HUS This is predominantly linked to the alternative complement pathway. Most due to a loss in the regulation of complement pathway but there are some activating mutations (C3 and factor B) Factor H, I and Membrane co-factor protein (MCP) account for approximately 50% of cases.
11 C3 Spontaneous hydrolysis, bacteria/virus C3 convertases CFH= Complement factor H CFI= Complement factor I GAG= Glycosaminoglycan MCP= Membrane co-factor protein ic3b= inactivated C3b TM=Thrombomodulin TAFI=thrombin-activatable fibronolysis inhibitor C3b C3a Cleaves C3a and C5a TAFI-activated CFI CFI CFI Bb CFH GAGCFH C3b C3b ic3b C3b MCP CFH GAG TM TAFI Thrombin TM C3b Endothelial Cell Inactivated
12 Serum-based factors- Factor H Predominantly produced by liver regulatory member of alternative complement pathway. Autosomal dominant with variable penetrance. Normal factor H levels do not rule out functional issues. Antibodies v factor H can be an issue. Mutations account for approximately 10% of cases of ahus
13 Complement regulatory section of factor H= N terminal C terminus has membrane binding section Mouse models factor H null MPGN Mouse with loss of C terminal HUS (these were homozygous in comparison to humans..)
14 Serum based factors- Factor I Again predominantly produced from the liver Depends on a number of co-factors for its function (including factor H and C4-binding protein. Factor I knockout mice develop uncontrolled alternative pathway activation but do not develop HUS but rather mesangial C3 deposits. Patients with mutations or antibodies v serum based factors relapse post- transplantation. Consider combined liver- kidney transplant.
15 Membrane bound complement factors (MCP or CD46) Found on almost every cell except erythrocytes. Mutations cause the protein to be incorrectly processed and remain intracellular or exhibit sub-optimal C3b binding. Autosomal dominant and recessive. Some patients have a mutation but do not develop HUS suggesting a multi hit mechanism. No mouse model can be made as mice lack MCP in their glomeruli. They do have complementary regulatory protein (crry). These are embryonic lethal. However a crry/ C5 knockout does exist. When kidneys from this mouse are transplanted into a normal mouse the kidneys fail due to uncontrolled complement activity.
16 Thrombomodulin Recently found that mutations in this molecule can trigger ahus Another solid component of complement pathway Accelerates activation of protein C which down-regulates further thrombin generation and suppression of clot formation. Interestingly there was a case report of a patient with a transplant recurrence despite being a solid phase complement factor.
17
18 Thrombotic thrombocytopenic purpura (TTP) Most common in females aged years. Pentad of symptoms microangiopathic haemolytic anaemia - thrombocytopenia -Neurological involvement -Renal damage -Fever
19 ADAMTS13 metalloproteinase that cleaves the bond between ultra-large von Willibrand factor and platelets. Deficiency of ADAMTS13 accounts for most congenital TTP. Antibodies v this molecule for most acquired disease. Plasma exchange with FFP the treatment of choice ADAMT13 KO mouse on an SV129 background is fine until challenged with platelet or endothelial agonists
20 Infection associated HUS Most common cause. Fatal in 3-5% of cases O157 E Coli in West but can also be caused by other shiga toxin producing bacteria (Shigella, campylobacter) Cellular level the target for stx is Gb3, a glycophospholipid receptor. This is found on glomerular endothelial cells, podocytes and tubular cells in the kidney but species differences
21 Gb3 synthase null mice are fully protected from shiga toxin injections. Gb3 expression is greater in children which may be why the young are particularly susceptible. Animal models of infection HUS greyhounds fed raw meat containing E Coli-- > developed glomerular TMA. Also babboons. Mice models have been challenging as mice do not express Gb3 in their glomeruli. To date they develop tubular disease with renal failure. Further studies are required into this.
22 Streptococci Pneumoniae Follows invasive pneumococcal disease Children under age 2 most commonly affected days after the infection has started. 10% ESRF / 12% mortality (often related to meningitis) Pathobiology is due to exposure of the Thomsen-Friedenreich antigen on erythrocytes, platelets and glomerular endothelial cells. This is normally masked with neuraminic acid. This is cleaved with neuraminidase produced by the Steptococci. TF is also found on hepatocytes and this explains why hepatic dysfunction is not uncommon.
23 Vascular Endothelial Growth Factor (VEGF)
24
25 Conclusions or unanswered questions 1. Why does HUS predominantly affect the kidney and TTP the brain? 2. Why does HUS mostly affect children and TTP adults? 3. What is the renal pathogenesis of D+ HUS? Does it have a link to complement or VEGF-A? 4. Why does E Coli O157 lead to HUS in only 10-15% of children? Is there a genetic component? 5. Could you manipulate the complement pathway in patients with ahus to switch off the relentless alternative complement pathway activation?
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