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Thrombotic microangiopathies and the kidney
SYSTEMIC DISEASE AND THE KIDNEY
Thrombotic microangiopathies and the kidney
What’s new? C
C
Heather Kerr
Use of eculizumab for managing plasma-resistant atypical haemolytic uraemic syndrome (aHUS)10 Rituximab for treatment of antibody-mediated aHUS6 and thrombotic thrombocytopenic purpura14
Anna Richards and red blood cell fragmentation. Their symptoms and signs result from ischaemia caused by an initiating endothelial cell injury and subsequent thrombosis in arterial microcirculations, often involving the kidneys.1
Abstract The thrombotic microangiopathies are a group of conditions characterized by microvascular bed thrombosis, haemolytic anaemia and thrombocytopenia. Renal involvement, due to occlusion of glomerular capillaries and renal arterioles by platelet-fibrin thrombi, is a common though not universal finding. Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are examples of thrombotic microangiopathies that illustrate learning points for the diagnosis, pathogenesis, management and prognosis for this group of conditions. There have been significant advances in understanding the separate aetiologies of these conditions in the last 10 years, which will increasingly influence treatment. HUS has prominent renal involvement and is classified into two major subtypes. Diarrhoeal HUS (Dþ HUS) is associated with a preceding diarrhoeal illness, commonly caused by Escherichia coli O157:H7. Atypical HUS (aHUS) is associated with mutations in proteins of the alternative pathway of complement, particularly complement factor H. TTP has prominent neurological involvement and is caused by an inherited or acquired deficiency of the von Willebrand factor-cleaving metalloprotease, ADAMTS13. Rapid instigation of plasma exchange is the mainstay of treatment for TTPand aHUS and has significantly improved survival. Genetic testing is available in the UK to guide counselling and management decisions in those with a positive family history.
Differential diagnosis of thrombocytopenia and anaemia (Table 1) The differential diagnosis of a patient presenting with thrombocytopenia and anaemia is broad (Table 1). Careful history, examination and investigation can differentiate most causes. A pregnancy test should be included in all women of child-bearing age. Renal biopsy is usually performed in those with significant renal impairment, after discussion with renal services and haematology, platelet count permitting.
Epidemiology, pathogenesis and management of TMA (Table 2) Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are classical examples of TMA where our understanding of pathogenesis and management has significantly increased. Additional, less well understood causes are detailed in Table 2. HUS Diarrhoea-associated HUS (Dþ HUS)2,3 is the main cause of acute renal failure in children under 3 years in the UK. It is related to preceding infection with verocytotoxin-producing Escherichia coli (O157:H7 strain in 70% of U.K. cases) or Shigella bacterial strains worldwide. It usually occurs after a prodromal episode of diarrhoea that is frequently bloody. The annual incidence of the disease in North America and Western Europe is 2e3 per 100,000 children under 5 years old.2 The haematological manifestations usually resolve within 2 weeks. Hypertension is common, and severe renal failure occurs in up to two-thirds of cases.3 Extrarenal complications, including cardiac arrhythmias, seizures, pancreatitis and bowel perforation, may occur. Antibiotics and plasma exchange are not used routinely as about 90% of cases will recover with supportive care.3 Data from a meta-analysis suggest that death or end-stage renal failure (ESRF) occurs in about 12%, and permanent renal sequelae (hypertension/proteinuria) are reported in up to 25% of cases.4 Long-term follow-up of these patients is therefore recommended. If renal transplantation is required, recurrence is rare. The UK support group website can be found at http://www.ecoli-uk.com
Keywords ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats); atypical haemolytic uraemic syndrome (aHUS); complement factor H (CFH); diarrhoeal-associated haemolytic uraemic syndrome (Dþ HUS); Eculizumab; microangiopathic haemolytic anaemia (MAHA); plasma exchange; thrombotic microangiopathy (TMA); thrombotic thrombocytopenic purpura (TTP)
Definition The thrombotic microangiopathies (TMA) are a group of disorders characterized by thrombocytopenia, haemolytic anaemia
Heather Kerr BA (Cantab) MB BS is a Speciality Trainee in Renal Medicine at the Royal Infirmary, Edinburgh, UK. Conflicts of interest: none declared. Anna Richards PhD MRCP MBBS(Hons) BMedSci(Hons) is a Wellcome Intermediate Clinical Fellow at Queen’s Medical Research Institute and Senior Lecturer in Nephrology, Royal Infirmary, Edinburgh, UK. Conflicts of interest: Dr Richards has received an honorarium consulting for In House Research regarding the role of C5 inhibitors in renal transplantation and is co-author on a patent application investigating recombinant Factor H as a bio-therapeutic agent.
MEDICINE 39:8
Atypical HUS is rare, with an incidence of 2 cases per million population and affects children (including those aged <6 months) and adults. Mutations in the genes for complement proteins including factors H, I, B, C3 and membrane cofactor protein (CD46) are associated with approximately 50% of cases of aHUS.5 Factor H
478
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
Pathogenesis and treatment of thrombotic microangiopathies
Differential diagnosis of thrombocytopenia and anaemia
Diagnosis Diagnosis
Differentiating features
Sepsis/Infections
CRP, blood cultures, HIV
Disseminated intravascular coagulation
Low fibrinogen, elevated fibrin degradation products, prolonged activated partial thromboplastin time
Auto-immune diseases Idiopathic thrombocytopenia Systemic lupus erythematosus Anti-phospholipid syndrome
Supportive care/ dialysis Antibiotics for Shigella Pneumococcal S. pneumoniae Antibiotics HUS Washed blood products NO plasma exchange Intramuscular Cyanocobalamin Hereditary defect in hydroxycobalamin, (cblC)-HUS vitamin B12 metabolism oral folic acid and betaine Atypical HUS Factor H mutations 30% Plasma exchange Factor H autoantibodies 1e2 plasma volumes 10% FFP or cryoprecipitate Membrane cofactor EXPERTeEculizumab protein mutations 1015% Factor I mutations 15% Factor B mutations 3% C3 mutations 10% Thrombomodulin mutations 5% TTP ADAMTS13 mutations Corticosteroids, Antibodies to plasma exchange ADAMTS13 1e2 plasma volumes FFP or cryoprecipitate EXPERT e rituximab Drug-induced Antibodies to Stop medication TTP ADAMTS13 plasma exchange Pre-eclampsia/ Excess sFlt1, autoAb Delivery of baby HELLP to AT1 Unknown ACE inhibitors Scleroderma renal crisis Anti-VEGF TMA Reduced podocyte Stop causal agent VEGF
Isolated thrombocytopenia, purpura dsDNA Ab Anti-cardiolipin/antiphospholipid Ab
Vitamin B12 or folate deficiency Alcohol history, Low B12/folate
Dþ HUS Pneumococcal HUS aHUS Pregnancy-related HUS TTP Drug-induced TTP Pregnancy-related TTP
Haemolysis e fragments on blood film, elevated LDH, low haptoglobin, normal clotting parameters E. coli O157:H7/Shigella stool culture/serology Empyema, streptococcal (T) antigen Family history, age <6 months 3rd trimester or post-partum Purpura, prominent neurological signs Ticlodipine, Clopidogrel, Quinine (HUS also) 3rd trimester
Rare causes associated with TMA Pre-eclampsia 3rd trimester, oedema, elevated urate Pregnancy, elevated liver Haemolysis, Elevated Liver enzymes, Low Platelets (HELLP) enzymes BP, papilloedema Malignant hypertension Clinical features, anti-Scl-70, ACA Systemic sclerosis Cancer/chemotherapy Adenocarcinoma (gastric/ associated TMA prostate), Mitomycin Anti-VEGF-related TMA Use of bevacixumab, hypertension, proteinuria Postetransplantation/whole Bone marrow/renal body irradiation transplantation, Ciclosporin, Tacrolimus
Ab, antibodies; ACE, angiotensin-converting enzyme; anti-VEGF, anti-vascular endothelial growth factor; AT1, angiotensin receptor 1; FFP, fresh frozen plasma; HELLP, haemolysis, elevated liver enzymes, low platelets; HUS, haemolytic uraemic syndrome; sFlt1, soluble vascular endothelial growth factor receptor 1; TMA, thrombotic microangiopathies; TTP, thrombotic thrombocytopenic purpura.
Table 2
antibodies have been reported in 8e10% of patients.6 Compared with Dþ HUS, there is a higher risk of death, disease recurrence and/or chronic renal disease. Penetrance of disease in those with mutations is incomplete, requiring a confluence of genetic risk factors (mutations and single nucleotide polymorphic haplotypes) in addition to an environmental trigger (e.g. pregnancy, infection).5 Prognosis is dictated by the underlying genetic predisposition; mutations in Factor H caused death/end-stage renal failure in about 80% of cases but this outcome is rare for those with CD46 mutations.5,7 Current treatment of aHUS is plasma exchange, initially daily, using one to two plasma volumes per session in
Ab, antibodies; ACA, anti-centromere antibodies; aHUS, atypical haemolytic uraemic syndrome; anti-VEGF, anti-vascular endothelial growth factor; BP, blood pressure; CRP, C-reactive protein; HUS, haemolytic uraemic syndrome; LDH, lactate dehydrogenase; TMA, thrombotic microangiopathies; TTP, thrombotic thrombocytopenic purpura.
Table 1
MEDICINE 39:8
Treatment
Diarrhoeal HUS E. coli 0157:H7 Shigella
Bone marrow failure Pancytopenia, splenomegaly, (e.g. myelofibrosis, malignancy) malignancy
Thrombotic microangiopathies
Pathogenesis
479
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
3 Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 2008; 10: 1749e60. 4 Garg AX, Suri RS, Barrowman N, et al. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA 2003; 290: 1360e70. 5 Hirt-Minkowski P, Dickenmann M, Schifferli JA. Atypical hemolytic uremic syndrome: update on the complement system and what is new. Nephron Clin Pract 2010; 114: c219e35. zsi M, Zipfel PF, Dragon-Durey MA, Fremeaux-Bacchi V. 6 Skerka C, Jo Autoantibodies in haemolytic uraemic syndrome (HUS). Thromb Haemost 2009; 101: 227e32. 7 Kavanagh D, Richards A, Goodship T, Jalanko H. Transplantation in atypical hemolytic uremic syndrome. Semin Thromb Hemost 2010; 36: 653e9. 8 Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 2009; 24: 687e96. 9 Taylor CM, Machin S, Wigmore SJ, Goodship TH, working party from the Renal Association, the British Committee for Standards in Haematology and the British Transplantation Society. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 2010; 148: 37e47. 10 Waters AM, Licht C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol 2011; 26: 41e57. 11 Saland JM, Ruggenenti P, Remuzzi G. Consensus Study Group. Liverkidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 2009; 20: 940e9. 12 Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol 2008; 23: 1951e6. 13 Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008; 112: 11e8. 14 Elliott MA, Heit JA, Pruthi RK, Gastineau DA, Winters JL, Hook CC. Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated severe ADAMTS13deficiency: a report of four cases and a systematic review of the literature. Eur J Haematol 2009; 83: 365e72.
adults and 50e100 ml/kg in children. This removes factor H autoantibodies and replaces mutant complement proteins. Duration and frequency of treatment are determined by the subsequent clinical response, serum lactate dehydrogenase and platelet count.8,9 More recently, the complement inhibitor, eculizumab, has been successfully used to treat aHUS, potentially heralding a new era in aHUS management.10 In those individuals who do develop ESRF, the outcome after transplantation is also determined by the genetic predisposition.7 Those with mutations in the serum regulators, complement factor H (CFH) and complement factor I (CFI) (predominantly produced in liver) have more than an 80% chance of aHUS recurrence in an isolated renal allograft. Combined liverekidney transplantation has been used successfully11 and clinical trials investigating the efficacy of eculizumab, a monoclonal antibody against complement protein C5, following isolated renal transplantation are planned.10 Pneumococcal HUS is recognized as a rare complication of Streptococcal pneumoniae infections in children.12 Pathogenesis is thought to relate to the bacterial production of neuraminidase enzyme, which causes endothelial cell injury by desialylation of the glycocalyx exposing the Thomsen-Friedenreich (T)-antigen on endothelium, platelets and erythrocytes. Management is supportive with addition of antibiotic therapy to treat the underlying pneumococcal infection. Plasma exchange is contraindicated due to concerns that preformed immunoglobulin M (IgM) antibodies to the T-antigen in replacement plasma would further exacerbate haemolysis and renal injury. Thrombotic thrombocytopenic purpura13,14 characteristically has more severe thrombocytopenia and a prominent association with neurological disturbance. A deficiency of the von Willebrand factorcleaving protease, ADAMTS13, causes platelet thrombosis. Inherited TTP usually presents in childhood, due to homozygous or compound heterozygote mutations in ADAMTS13. Concentrations of ADAMTS13 are very low (<5%) and the condition frequently relapses. Acquired TTP occurs due to the development of inhibitory autoantibodies to ADAMTS13 in adults. Renal involvement in patients with acquired TTP is usually mild. Management involves plasma exchange to replace ADAMTS13 and/or remove autoantibodies. This has significantly improved survival in a previously fatal condition. Rituximab (a monoclonal antibody to CD20, expressed on plasma cells) has been successfully used off label to manage relapsing, acquired TTP.14 A
Practice points C
C
REFERENCES 1 Bellamy COC. Microangiopathies and malignant vascular injury in the kidney. Curr Diagn Pathol 2004; 10: 36e51. 2 Noris M, Remuzzi G. Haemolytic uraemic syndrome. J Am Soc Nephrol 2005; 16: 1035e50.
MEDICINE 39:8
C
480
Plasma exchange (with plasma, not albumin) should be instigated within 24 hours if a diagnosis of thrombotic thrombocytopenic purpura or atypical haemolytic uraemic syndrome (aHUS) is suspected Patients with residual hypertension, proteinuria or renal dysfunction require long-term follow-up Genetic screening is required prior to renal transplantation in patients with aHUS (http://www.genetest.org)
Ó 2011 Elsevier Ltd. All rights reserved.
Thrombotic microangiopathies and the kidney
What’s new? C
C
Heather Kerr
Use of eculizumab for managing plasma-resistant atypical haemolytic uraemic syndrome (aHUS)10 Rituximab for treatment of antibody-mediated aHUS6 and thrombotic thrombocytopenic purpura14
Anna Richards and red blood cell fragmentation. Their symptoms and signs result from ischaemia caused by an initiating endothelial cell injury and subsequent thrombosis in arterial microcirculations, often involving the kidneys.1
Abstract The thrombotic microangiopathies are a group of conditions characterized by microvascular bed thrombosis, haemolytic anaemia and thrombocytopenia. Renal involvement, due to occlusion of glomerular capillaries and renal arterioles by platelet-fibrin thrombi, is a common though not universal finding. Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are examples of thrombotic microangiopathies that illustrate learning points for the diagnosis, pathogenesis, management and prognosis for this group of conditions. There have been significant advances in understanding the separate aetiologies of these conditions in the last 10 years, which will increasingly influence treatment. HUS has prominent renal involvement and is classified into two major subtypes. Diarrhoeal HUS (Dþ HUS) is associated with a preceding diarrhoeal illness, commonly caused by Escherichia coli O157:H7. Atypical HUS (aHUS) is associated with mutations in proteins of the alternative pathway of complement, particularly complement factor H. TTP has prominent neurological involvement and is caused by an inherited or acquired deficiency of the von Willebrand factor-cleaving metalloprotease, ADAMTS13. Rapid instigation of plasma exchange is the mainstay of treatment for TTPand aHUS and has significantly improved survival. Genetic testing is available in the UK to guide counselling and management decisions in those with a positive family history.
Differential diagnosis of thrombocytopenia and anaemia (Table 1) The differential diagnosis of a patient presenting with thrombocytopenia and anaemia is broad (Table 1). Careful history, examination and investigation can differentiate most causes. A pregnancy test should be included in all women of child-bearing age. Renal biopsy is usually performed in those with significant renal impairment, after discussion with renal services and haematology, platelet count permitting.
Epidemiology, pathogenesis and management of TMA (Table 2) Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are classical examples of TMA where our understanding of pathogenesis and management has significantly increased. Additional, less well understood causes are detailed in Table 2. HUS Diarrhoea-associated HUS (Dþ HUS)2,3 is the main cause of acute renal failure in children under 3 years in the UK. It is related to preceding infection with verocytotoxin-producing Escherichia coli (O157:H7 strain in 70% of U.K. cases) or Shigella bacterial strains worldwide. It usually occurs after a prodromal episode of diarrhoea that is frequently bloody. The annual incidence of the disease in North America and Western Europe is 2e3 per 100,000 children under 5 years old.2 The haematological manifestations usually resolve within 2 weeks. Hypertension is common, and severe renal failure occurs in up to two-thirds of cases.3 Extrarenal complications, including cardiac arrhythmias, seizures, pancreatitis and bowel perforation, may occur. Antibiotics and plasma exchange are not used routinely as about 90% of cases will recover with supportive care.3 Data from a meta-analysis suggest that death or end-stage renal failure (ESRF) occurs in about 12%, and permanent renal sequelae (hypertension/proteinuria) are reported in up to 25% of cases.4 Long-term follow-up of these patients is therefore recommended. If renal transplantation is required, recurrence is rare. The UK support group website can be found at http://www.ecoli-uk.com
Keywords ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats); atypical haemolytic uraemic syndrome (aHUS); complement factor H (CFH); diarrhoeal-associated haemolytic uraemic syndrome (Dþ HUS); Eculizumab; microangiopathic haemolytic anaemia (MAHA); plasma exchange; thrombotic microangiopathy (TMA); thrombotic thrombocytopenic purpura (TTP)
Definition The thrombotic microangiopathies (TMA) are a group of disorders characterized by thrombocytopenia, haemolytic anaemia
Heather Kerr BA (Cantab) MB BS is a Speciality Trainee in Renal Medicine at the Royal Infirmary, Edinburgh, UK. Conflicts of interest: none declared. Anna Richards PhD MRCP MBBS(Hons) BMedSci(Hons) is a Wellcome Intermediate Clinical Fellow at Queen’s Medical Research Institute and Senior Lecturer in Nephrology, Royal Infirmary, Edinburgh, UK. Conflicts of interest: Dr Richards has received an honorarium consulting for In House Research regarding the role of C5 inhibitors in renal transplantation and is co-author on a patent application investigating recombinant Factor H as a bio-therapeutic agent.
MEDICINE 39:8
Atypical HUS is rare, with an incidence of 2 cases per million population and affects children (including those aged <6 months) and adults. Mutations in the genes for complement proteins including factors H, I, B, C3 and membrane cofactor protein (CD46) are associated with approximately 50% of cases of aHUS.5 Factor H
478
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
Pathogenesis and treatment of thrombotic microangiopathies
Differential diagnosis of thrombocytopenia and anaemia
Diagnosis Diagnosis
Differentiating features
Sepsis/Infections
CRP, blood cultures, HIV
Disseminated intravascular coagulation
Low fibrinogen, elevated fibrin degradation products, prolonged activated partial thromboplastin time
Auto-immune diseases Idiopathic thrombocytopenia Systemic lupus erythematosus Anti-phospholipid syndrome
Supportive care/ dialysis Antibiotics for Shigella Pneumococcal S. pneumoniae Antibiotics HUS Washed blood products NO plasma exchange Intramuscular Cyanocobalamin Hereditary defect in hydroxycobalamin, (cblC)-HUS vitamin B12 metabolism oral folic acid and betaine Atypical HUS Factor H mutations 30% Plasma exchange Factor H autoantibodies 1e2 plasma volumes 10% FFP or cryoprecipitate Membrane cofactor EXPERTeEculizumab protein mutations 1015% Factor I mutations 15% Factor B mutations 3% C3 mutations 10% Thrombomodulin mutations 5% TTP ADAMTS13 mutations Corticosteroids, Antibodies to plasma exchange ADAMTS13 1e2 plasma volumes FFP or cryoprecipitate EXPERT e rituximab Drug-induced Antibodies to Stop medication TTP ADAMTS13 plasma exchange Pre-eclampsia/ Excess sFlt1, autoAb Delivery of baby HELLP to AT1 Unknown ACE inhibitors Scleroderma renal crisis Anti-VEGF TMA Reduced podocyte Stop causal agent VEGF
Isolated thrombocytopenia, purpura dsDNA Ab Anti-cardiolipin/antiphospholipid Ab
Vitamin B12 or folate deficiency Alcohol history, Low B12/folate
Dþ HUS Pneumococcal HUS aHUS Pregnancy-related HUS TTP Drug-induced TTP Pregnancy-related TTP
Haemolysis e fragments on blood film, elevated LDH, low haptoglobin, normal clotting parameters E. coli O157:H7/Shigella stool culture/serology Empyema, streptococcal (T) antigen Family history, age <6 months 3rd trimester or post-partum Purpura, prominent neurological signs Ticlodipine, Clopidogrel, Quinine (HUS also) 3rd trimester
Rare causes associated with TMA Pre-eclampsia 3rd trimester, oedema, elevated urate Pregnancy, elevated liver Haemolysis, Elevated Liver enzymes, Low Platelets (HELLP) enzymes BP, papilloedema Malignant hypertension Clinical features, anti-Scl-70, ACA Systemic sclerosis Cancer/chemotherapy Adenocarcinoma (gastric/ associated TMA prostate), Mitomycin Anti-VEGF-related TMA Use of bevacixumab, hypertension, proteinuria Postetransplantation/whole Bone marrow/renal body irradiation transplantation, Ciclosporin, Tacrolimus
Ab, antibodies; ACE, angiotensin-converting enzyme; anti-VEGF, anti-vascular endothelial growth factor; AT1, angiotensin receptor 1; FFP, fresh frozen plasma; HELLP, haemolysis, elevated liver enzymes, low platelets; HUS, haemolytic uraemic syndrome; sFlt1, soluble vascular endothelial growth factor receptor 1; TMA, thrombotic microangiopathies; TTP, thrombotic thrombocytopenic purpura.
Table 2
antibodies have been reported in 8e10% of patients.6 Compared with Dþ HUS, there is a higher risk of death, disease recurrence and/or chronic renal disease. Penetrance of disease in those with mutations is incomplete, requiring a confluence of genetic risk factors (mutations and single nucleotide polymorphic haplotypes) in addition to an environmental trigger (e.g. pregnancy, infection).5 Prognosis is dictated by the underlying genetic predisposition; mutations in Factor H caused death/end-stage renal failure in about 80% of cases but this outcome is rare for those with CD46 mutations.5,7 Current treatment of aHUS is plasma exchange, initially daily, using one to two plasma volumes per session in
Ab, antibodies; ACA, anti-centromere antibodies; aHUS, atypical haemolytic uraemic syndrome; anti-VEGF, anti-vascular endothelial growth factor; BP, blood pressure; CRP, C-reactive protein; HUS, haemolytic uraemic syndrome; LDH, lactate dehydrogenase; TMA, thrombotic microangiopathies; TTP, thrombotic thrombocytopenic purpura.
Table 1
MEDICINE 39:8
Treatment
Diarrhoeal HUS E. coli 0157:H7 Shigella
Bone marrow failure Pancytopenia, splenomegaly, (e.g. myelofibrosis, malignancy) malignancy
Thrombotic microangiopathies
Pathogenesis
479
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
3 Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 2008; 10: 1749e60. 4 Garg AX, Suri RS, Barrowman N, et al. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA 2003; 290: 1360e70. 5 Hirt-Minkowski P, Dickenmann M, Schifferli JA. Atypical hemolytic uremic syndrome: update on the complement system and what is new. Nephron Clin Pract 2010; 114: c219e35. zsi M, Zipfel PF, Dragon-Durey MA, Fremeaux-Bacchi V. 6 Skerka C, Jo Autoantibodies in haemolytic uraemic syndrome (HUS). Thromb Haemost 2009; 101: 227e32. 7 Kavanagh D, Richards A, Goodship T, Jalanko H. Transplantation in atypical hemolytic uremic syndrome. Semin Thromb Hemost 2010; 36: 653e9. 8 Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 2009; 24: 687e96. 9 Taylor CM, Machin S, Wigmore SJ, Goodship TH, working party from the Renal Association, the British Committee for Standards in Haematology and the British Transplantation Society. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 2010; 148: 37e47. 10 Waters AM, Licht C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol 2011; 26: 41e57. 11 Saland JM, Ruggenenti P, Remuzzi G. Consensus Study Group. Liverkidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 2009; 20: 940e9. 12 Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol 2008; 23: 1951e6. 13 Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008; 112: 11e8. 14 Elliott MA, Heit JA, Pruthi RK, Gastineau DA, Winters JL, Hook CC. Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated severe ADAMTS13deficiency: a report of four cases and a systematic review of the literature. Eur J Haematol 2009; 83: 365e72.
adults and 50e100 ml/kg in children. This removes factor H autoantibodies and replaces mutant complement proteins. Duration and frequency of treatment are determined by the subsequent clinical response, serum lactate dehydrogenase and platelet count.8,9 More recently, the complement inhibitor, eculizumab, has been successfully used to treat aHUS, potentially heralding a new era in aHUS management.10 In those individuals who do develop ESRF, the outcome after transplantation is also determined by the genetic predisposition.7 Those with mutations in the serum regulators, complement factor H (CFH) and complement factor I (CFI) (predominantly produced in liver) have more than an 80% chance of aHUS recurrence in an isolated renal allograft. Combined liverekidney transplantation has been used successfully11 and clinical trials investigating the efficacy of eculizumab, a monoclonal antibody against complement protein C5, following isolated renal transplantation are planned.10 Pneumococcal HUS is recognized as a rare complication of Streptococcal pneumoniae infections in children.12 Pathogenesis is thought to relate to the bacterial production of neuraminidase enzyme, which causes endothelial cell injury by desialylation of the glycocalyx exposing the Thomsen-Friedenreich (T)-antigen on endothelium, platelets and erythrocytes. Management is supportive with addition of antibiotic therapy to treat the underlying pneumococcal infection. Plasma exchange is contraindicated due to concerns that preformed immunoglobulin M (IgM) antibodies to the T-antigen in replacement plasma would further exacerbate haemolysis and renal injury. Thrombotic thrombocytopenic purpura13,14 characteristically has more severe thrombocytopenia and a prominent association with neurological disturbance. A deficiency of the von Willebrand factorcleaving protease, ADAMTS13, causes platelet thrombosis. Inherited TTP usually presents in childhood, due to homozygous or compound heterozygote mutations in ADAMTS13. Concentrations of ADAMTS13 are very low (<5%) and the condition frequently relapses. Acquired TTP occurs due to the development of inhibitory autoantibodies to ADAMTS13 in adults. Renal involvement in patients with acquired TTP is usually mild. Management involves plasma exchange to replace ADAMTS13 and/or remove autoantibodies. This has significantly improved survival in a previously fatal condition. Rituximab (a monoclonal antibody to CD20, expressed on plasma cells) has been successfully used off label to manage relapsing, acquired TTP.14 A
Practice points C
C
REFERENCES 1 Bellamy COC. Microangiopathies and malignant vascular injury in the kidney. Curr Diagn Pathol 2004; 10: 36e51. 2 Noris M, Remuzzi G. Haemolytic uraemic syndrome. J Am Soc Nephrol 2005; 16: 1035e50.
MEDICINE 39:8
C
480
Plasma exchange (with plasma, not albumin) should be instigated within 24 hours if a diagnosis of thrombotic thrombocytopenic purpura or atypical haemolytic uraemic syndrome (aHUS) is suspected Patients with residual hypertension, proteinuria or renal dysfunction require long-term follow-up Genetic screening is required prior to renal transplantation in patients with aHUS (http://www.genetest.org)
Ó 2011 Elsevier Ltd. All rights reserved.