Abstracts
There is a group of diseases that may manifest with thrombotic microangiopathy and present clinical overlap. Among these we emphasize the thrombotic thrombocytopenic purpura and Hemolytic Uremic Syndrome, and the latter can occur by the action of toxins, systemic diseases, overactivation of the alternative complement system pathway, which can occur due to changes in regulatory proteins (atypical HUS) and finally, idiopathic. You must carry out a series of tests to differentiate them. aHUS is a diagnosis of exclusion of other causes of MAT. The treatment of aHUS with plasma therapy, results in most cases with good shortterm response, especially hematological; however, it is a progressive and devastating disease and can lead to death and terminal chronic renal disease. Treatment with plasma displays great recurrence of long-term disease and renal insufficiency. Eculizumab, a monoclonal antibody anti-C5, has been associated with hematological remission, benefits on renal function and no need of plasma therapy.
acute kidney injury; anemia; child; chronic disease
O grupo de doenças que podem manifestar-se com MAT podem apresentar superposição clínica, dificultando o diagnóstico diferencial. Entre estas ressaltamos a PTT e SHU, sendo que esta última pode ocorrer pela ação de toxinas, doenças sistêmicas, hiperativação da via alterantiva descontrolada por alterações nas proteínas reguladoras desta via (SHUa) e por fim, idiopática. Deve-se proceder a uma série de exames para diferenciá-las. Ressaltando que SHUa é um diagnóstico de exclusão de outras causas de MAT. O tratamento da SHUa com infusão de plasma ou plasmaferese, resulta na maior parte dos casos com boa resposta, especialmente hematológica a curto-prazo, porém é uma doença grave e devastadora e, pode levar a óbito e doença renal crônica terminal. Tratamento com plasma apresenta grande recorrência da doença a longo-prazo e evolução renal desfavorável. Eculizumab, um anticorpo monoclonal anti-C5, tem surgido como uma esperança no prognóstico a curto e a longo-prazo nestes pacientes.
anemia hemolítica; insuficiência renal aguda; insuficiência renal crônica; pediatria
Introduction
Hemolytic uremic syndrome (HUS) is a severe condition which accounts for 0.2 to 4.28
per 100,000 cases of pediatric acute renal failure globally.11. Serna A 4th, Boedeker EC. Pathogenesis and treatment of Shiga
toxin-producing Escherichia coli infections. Curr Opin Gastroenterol 2008;24:38-47.
DOI: http://dx.doi.org/10.1097/MOG.0b013e3282f2dfb8
http://dx.doi.org/10.1097/MOG.0b013e3282...
HUS has been included in the differential diagnosis of
thrombotic microangiopathy (TMA). TMA is a term used to describe the formation of
thrombi that occlude the vessels in the microvasculature.22. Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies.
Annu Rev Pathol 2008;3:249-77. DOI:
http://dx.doi.org/10.1146/annurev.pathmechdis.3.121806.154311
http://dx.doi.org/10.1146/annurev.pathme...
Pathological factors include thickening of the vessel walls,
endothelial cell edema (endotheliosis) and detachment of the basement membrane,
accumulation of debris in the subendothelial space, increased expression of the Von
Willebrand Factor (VWF) - which attracts platelets and leads to the formation of
microthrombi which partially or completely occlude the lumen of the vessels in the
microvasculature. As a result, red blood cells are fragmented by shearing. Figure 1 shows the renal histology of a patient
with HUS indicating the formation of thrombi.
Kidney histology showing endotheliosis and thrombi in the glomerulus of a patient with hemolytic uremic syndrome. Masson’s trichrome stain.
Clinically, TMA has been associated with consumption thrombocytopenia and
nonautoimmune microangiopathic hemolytic anemia. It may also induce ischemia in
different organs, with the kidneys and the brain topping the list, in addition to
involving the gastrointestinal tract and the heart, among others.33. Tsai HM. The molecular biology of thrombotic microangiopathy. Kidney
Int 2006;70:16-23. PMID: 16760911 DOI:
http://dx.doi.org/10.1038/sj.ki.5001535
http://dx.doi.org/10.1038/sj.ki.5001535...
,44. Barbour T, Johnson S, Cohney S, Hughes P. Thrombotic microangiopathy
and associated renal disorders. Nephrol Dial Transplant 2012;27:2673-85. DOI:
http://dx.doi.org/10.1093/ndt/gfs279
http://dx.doi.org/10.1093/ndt/gfs279...
Therefore, symptoms vary depending on which organs are affected.
Patients often present with severe anemia caused by hemolysis, which introduces
intense pallor, thrombocytopenia, and kidney damage, detected by the presence of
edema, oliguria in addition to altered proteinuria, hematuria, impaired renal,
glomerular or tubular function, and acute renal failure. Brain damage, when present,
can introduce neurological disorders, seizures, decreased level of consciousness, and
coma. TMA in the gastrointestinal tract may produce bloody diarrhea, even in
infection-free patients.
Table 1 shows the main causes of TMA. In
practical terms, the causes of TMA are thrombotic thrombocytopenic purpura (TTP) and
HUS caused by the hyperactivation of the alternative complement pathway, subdivided
into typical HUS (associated with toxins), atypical HUS (related to primary anomalies
in the alternative complement pathway), secondary aHUS (associated with systemic
diseases, transplant, drugs, pregnancy, sepsis, malignant hypertension, and tumors),
and idiopathic HUS.55. Nester CM, Thomas CP. Atypical hemolytic uremic syndrome: what is it,
how is it diagnosed, and how is it treated? Hematology Am Soc Hematol Educ Program
2012;2012:617-25. PMID: 23233643 Patients with "secondary"
aHUS were found to have mutations in regulatory proteins of the alternative
complement pathway, revealing that individuals who develop aHUS along with these
diseases have a favorable genotype to manifest them. Noris et
al.66. Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic
thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr
Nephrol 2009;24:19-29. DOI:
http://dx.doi.org/10.1007/s00467-008-0863-5
http://dx.doi.org/10.1007/s00467-008-086...
studied patients with
"secondary" aHUS and found that 51% of them had regulatory protein mutations.
Therefore, for the sake of proper terminology, the name secondary aHUS should be
replaced with aHUS associated with coexisting conditions or diseases.
In the last decade there was significant progress in the elucidation of the molecular mechanisms mediating TMA, mainly as a result of genetic studies carried out in vitro, in vivo, and with animal models. However, the establishment of differential diagnosis is still challenging when overlapping clinical factors occur.
Differential diagnosis between HUS and TTP
HUS must be differentiated from TTP, despite the overlapping clinical and morphological sings, since therapy is specific for each condition. Both diseases share TMA factors caused by endothelial cell activation and damage, although by distinct mechanisms. In HUS, TMA is triggered by the hyperactivation of the alternative complement pathway, while in TTP it is initiated by a severe deficiency in the activity of a metalloprotease that cleaves VWF multimers (ADAMTS13 - A disintegrin and metalloprotease with thrombospondin type 1 repeats-13).
Previous studies reported that in HUS involvement is confined to the glomerular
endothelium, while in TTP endothelial damage is more systemic. Additionally,
neurological involvement and thrombocytopenia were thought to prevail in TTP and
kidney involvement in HUS. HUS was also seen as a pediatric disease, while TTP was
thought to affect adults more often.77. Furlan M, Robles R, Lämmle B. Partial purification and
characterization of a protease from human plasma cleaving von Willebrand factor to
fragments produced by in vivo proteolysis. Blood 1996;87:4223-34. PMID:
8639781 However,
it is known today that HUS can occur in a significant percentage of the adult
population, just as TTP can affect children; and that neurological involvement may
occur in HUS and severe renal impairment in TTP.44. Barbour T, Johnson S, Cohney S, Hughes P. Thrombotic microangiopathy
and associated renal disorders. Nephrol Dial Transplant 2012;27:2673-85. DOI:
http://dx.doi.org/10.1093/ndt/gfs279
http://dx.doi.org/10.1093/ndt/gfs279...
,77. Furlan M, Robles R, Lämmle B. Partial purification and
characterization of a protease from human plasma cleaving von Willebrand factor to
fragments produced by in vivo proteolysis. Blood 1996;87:4223-34. PMID:
8639781 Therefore, given the
overlapping signs and symptoms, the differential diagnosis between these two
conditions may be challenging and take longer to complete.
The discovery of the specific involvement of protease ADAMTS13 in the pathogenesis of
TTP enabled better discrimination between these two forms of TMA.88. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med
2009;361:1676-87. PMID: 19846853 DOI:
http://dx.doi.org/10.1056/NEJMra0902814
http://dx.doi.org/10.1056/NEJMra0902814...
In patients with TTP, ADAMTS13 activity is
dramatically reduced (< 5% of normal levels).77. Furlan M, Robles R, Lämmle B. Partial purification and
characterization of a protease from human plasma cleaving von Willebrand factor to
fragments produced by in vivo proteolysis. Blood 1996;87:4223-34. PMID:
8639781 This discovery led to the identification of greater numbers of cases of
pediatric TTP. Severe drops in ADAMTS13 activity may be of genetic origin, such as in
the rare cases of Upshaw-Schulman syndrome (autosomal recessive), or caused by
anti-ADAMTS13 autoantibodies.77. Furlan M, Robles R, Lämmle B. Partial purification and
characterization of a protease from human plasma cleaving von Willebrand factor to
fragments produced by in vivo proteolysis. Blood 1996;87:4223-34. PMID:
8639781
VWF is a multimeric glycoprotein produced in megakaryocytes and endothelial cells. It is secreted into plasma and plays a key role in platelet adhesion and aggregation. Cellular compartments contain larger amounts of large VWF than plasma, as ADAMTS13 cleavage occurs simultaneously with the secretion process. Larger multimers contain more platelet binding sites. In the microvasculature, blood flow leads to the unfolding of VWF and increases the exposure of platelet binding sites. Decreased ADAMTS13 activity leads to increased presence of large multimers in the circulation and hence a greater number of exposed sites for platelet adhesion, which induces the formation of platelet thrombi in the microvasculature and triggers the onset of TMA.77. Furlan M, Robles R, Lämmle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 1996;87:4223-34. PMID: 8639781
In patients with the Upshaw-Schulman syndrome (USS) and anomalies in the ADAMTS13 gene, manifestations occur more often in the neonatal period, while subsequent episodes may be triggered by factors such as infection and immunization. Treatment is based on plasma transfusion to supply patients with ADAMTS13 protein. In cases of acquired disease, i.e., in the presence of anti-ADAMTS13 antibodies, manifestations are more delayed and treatment includes plasmapheresis, steroids and, in selected cases, rituximab (chimeric monoclonal antibody directed against cell surface protein CD20).77. Furlan M, Robles R, Lämmle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 1996;87:4223-34. PMID: 8639781 It is important to realize that these are severe cases which require immediate attention. Thus, plasmapheresis is indicated when it is not known whether the patient has circulating anti-ADAMTS13 antibodies. However, such procedure is not widely available and, in small children, it can be challenging to perform. In these cases, plasma transfusion must be offered promptly.
Complement system
In HUS, TMA stems from the hyperactivation of the alternative pathway of the complement system. Therefore, the authors of this review decided to add a brief explanation of the mechanisms of activation of the complement system, its importance, and correlations with the coagulation system.
The complement system comprises plasmasoluble proteins and proteins expressed on the
cell membrane which are part of the innate immune system. Their goal is to remove
"damaged" cells and aid the adaptive immune defenses against pathogens through
processes such as opsonization, chemotaxis, and cell lysis.66. Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic
thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr
Nephrol 2009;24:19-29. DOI:
http://dx.doi.org/10.1007/s00467-008-0863-5
http://dx.doi.org/10.1007/s00467-008-086...
There are three main activation pathways of the complement
system: the classical pathway, the lectin pathway, and the alternative pathway. Figure 2 shows the mechanisms of activation of the
complement system.
Complement system activation pathways. IC: Immune complexes (antigen-antibody); MBP: Mannose-binding protein; C3bi: C3b inactivated; MCP: Membrane cofactor protein; TM: Thrombomodulin; MAC: Membrane attack complex; ** Amplification loop.
Activation mechanisms of the complement system
-
1. The classical pathway: It is activated when immune complexes (antigen-antibody) bind to the C1q component of the complement system. Subsequently there is the activation of C1r and C1s, both C1qcomplexed proteases. Activated C1s cleaves C4 to form C4a and C4b, which bind to the cell surface; C2 is cleaved into C2a which binds to C4b to form the C4b2a complex (C3 convertase). C3 convertase cleaves C3 to form C3b, which binds to C4b2a (C3 convertase) to form C4b2a3b complex (C5 convertase). C5 convertase in turn cleaves C5 into C5a and C5b, and the latter triggers the formation of the membrane attack complex (MAC, C5b9), the final step in the complement cascade that leads to cell lysis. C4b and C3b promote opsonization, while C4a and C5a are anaphylatoxins with chemotactic properties and inflammatory response.
-
2. The lectin pathway: Activation of this pathway is similar to the activation of the classical pathway. It is triggered when mannose-binding proteins (MBP) found in complexes of lectin-binding proteases (MASP) recognize the mannose on the surface of a pathogen. As these proteins bind to mannose, they are activated to cleave C4 and C2. The rest of the activation pathway is similar to the classical pathway.44. Barbour T, Johnson S, Cohney S, Hughes P. Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transplant 2012;27:2673-85. DOI: http://dx.doi.org/10.1093/ndt/gfs279
http://dx.doi.org/10.1093/ndt/gfs279... -
3. The alternative pathway: It can be activated in conjunction with the classical and lectin pathways, but may be constitutively activated at any time. The hydrolysis of C3 triggers its activation to form C3a and C3b. C3b binds to the cell surface and interacts with Factor B, which is cleaved by Factor D to generate fragment Bb. Fragment Bb is capable of binding to other C3b molecules on the cell surface to form C3bBb (C3 convertase). C3 convertase triggers an amplification loop to increase the hydrolysis of C3. The ensuing surplus of C3b binds to C3 convertase and promotes conversion to C5 convertase (C3b2Bb). C5 convertase then cleaves C5 to form C5a and C5b, and the latter factor (C5b) leads to the formation of MAC. C3a and C5a are anaphylatoxins.
A system of regulatory proteins, one of them being factor I, acts to prevent
uncontrolled activation of the alternative pathway by inactivating C3b into C3bi
(inactivated C3b). Factor H, the membrane cofactor protein (MCP, CD46), and
thrombomodulin act as factor I cofactors to inactivate C3b (Figure 3).99. Keir LS, Saleem MA. Current evidence for the role of complement in
the pathogenesis of Shiga toxin haemolytic uraemic syndrome. Pediatr Nephrol 2013 Jul
11. [Epub ahead of print]. DOI:
http://dx.doi.org/10.1007/s00467-013-2561-1
http://dx.doi.org/10.1007/s00467-013-256...
In the event
these regulatory proteins fail to perform their duties, the alternative complement
pathway is over-activated causing uncontrolled cell damage.
Regulatory mechanism for the activation of the alternative complement pathway. Factor I plays a key role in the inactivation of the alternative pathway; in order for it to function, cofactors must be found to the membrane: MCP (membrane cofactor protein, CD46) and TM (thrombomodulin) and circulating Factor H.
There is a correlation between the complement system and the coagulation cascade.
Both systems are made of proteases, some of which have similar structure and target
sites.1010. Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, et al.
Molecular intercommunication between the complement and coagulation systems. J
Immunol 2010;185:5628-36. PMID: 20870944 DOI:
http://dx.doi.org/10.4049/jimmunol.0903678
http://dx.doi.org/10.4049/jimmunol.09036...
There is evidence that components
of the coagulation cascade can activate the complement system and vice versa. As an
example, thrombin may directly cleave the complement C5 component,1010. Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, et al.
Molecular intercommunication between the complement and coagulation systems. J
Immunol 2010;185:5628-36. PMID: 20870944 DOI:
http://dx.doi.org/10.4049/jimmunol.0903678
http://dx.doi.org/10.4049/jimmunol.09036...
,1111. Krisinger MJ, Goebeler V, Lu Z, Meixner SC, Myles T, Pryzdial EL, et
al. Thrombin generates previously unidentified C5 products that support the terminal
complement activation pathway. Blood 2012;120:1717-25. PMID: 22802338 DOI:
http://dx.doi.org/10.1182/blood-2012-02-412080
http://dx.doi.org/10.1182/blood-2012-02-...
and anaphylatoxin C5a can activate the tissue factor, which, in turn,
activates thrombin.1010. Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, et al.
Molecular intercommunication between the complement and coagulation systems. J
Immunol 2010;185:5628-36. PMID: 20870944 DOI:
http://dx.doi.org/10.4049/jimmunol.0903678
http://dx.doi.org/10.4049/jimmunol.09036...
Thrombomodulin (TM) is a
protein that interacts with the complement system and the coagulation cascade to
inactivate C3b of the factor I-mediated complement, in addition to binding to
thrombin, thus activating anticoagulant protein C.1212. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, et
al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med
2009;361:345-57. PMID: 19625716 DOI:
http://dx.doi.org/10.1056/NEJMoa0810739
http://dx.doi.org/10.1056/NEJMoa0810739...
These findings suggest a close relationship between these two systems,
which is certainly relevant for the onset of TMA.
Typical hemolytic-uremic syndrome
Ninety percent of the pediatric cases of HUS are triggered by Shiga toxin-producing
Escherichia coli (STEC), particularly in children aged between two and six
years.99. Keir LS, Saleem MA. Current evidence for the role of complement in
the pathogenesis of Shiga toxin haemolytic uraemic syndrome. Pediatr Nephrol 2013 Jul
11. [Epub ahead of print]. DOI:
http://dx.doi.org/10.1007/s00467-013-2561-1
http://dx.doi.org/10.1007/s00467-013-256...
Incidence in children under the age
of five has been recorded at 6.1/100,000 cases per year.1313. Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of
Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol
2008;23:1749-60. DOI: http://dx.doi.org/10.1007/s00467-008-0935-6 Although E. coli O157:H7 is the most recognized serotype,
other serotypes of this pathogen such as O26, O45, O111, O121, O103, and O145 account
for approximately 71% of the outbreaks not caused by serotype O157:H7.1414. Kalchayanand N, Arthur TM, Bosilevac JM, Schmidt JW, Wang R,
Shackelford SD, et al. Evaluation of commonly used antimicrobial interventions for
fresh beef inoculated with Shiga toxin-producing Escherichia coli serotypes O26, O45,
O103, O111, O121, O145, and O157:H7. J Food Prot 2012;75:1207-12. PMID: 22980002 DOI:
http://dx.doi.org/10.4315/0362-028X.JFP-11-531
http://dx.doi.org/10.4315/0362-028X.JFP-...
Strain O104:H4 was present in one of the
largest outbreaks in history, affecting 3,816 people and resulting in 845 cases of
HUS and 54 deaths in Germany in 2011.1515. Bielaszewska M, Mellmann A, Zhang W, Köck R, Fruth A, Bauwens A, et
al. Characterisation of the Escherichia coli strain associated with an outbreak of
haemolytic uraemic syndrome in Germany, 2011: a microbiological study. Lancet Infect
Dis 2011;11:671-6. Food
borne contamination may result in a wide variety of clinical manifestations with
different levels of severity, ranging from innocuous cases of diarrhea to hemorrhagic
colitis and HUS. Three to eight days after contamination patients present with
abdominal pain and profuse, occasionally bloody, watery diarrhea. Approximately 24
hours later, 10% to 15% of the patients develop hemolytic anemia, thrombocytopenia,
and acute kidney injury (AKI).1313. Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of
Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol
2008;23:1749-60. DOI: http://dx.doi.org/10.1007/s00467-008-0935-6
The diagnosis of STEC-HUS can be done through stool cultures, tests for the presence
of Shiga toxins (Stx) by immunoassays and PCR,1616. He X, Patfield S, Hnasko R, Rasooly R, Mandrell RE. A Polyclonal
Antibody Based Immunoassay Detects Seven Subtypes of Shiga Toxin 2 Produced by
Escherichia coli in Human and Environmental Samples. PLoS One 2013;16;8:e76368. PMID:
24146860,1717. Skinner C, Patfield S, Stanker L, He X. Development of Monoclonal
antibodies and immunoassays for sensitive and specific detection of Shiga toxin
Stx2f. PLoS One 2013;8:e76563. DOI:
http://dx.doi.org/10.1371/journal.pone.0076563
http://dx.doi.org/10.1371/journal.pone.0...
and tests for the
presence of serum antibodies against STEC.1818. Palmeira P, Carbonare SB, Guth BE, Carbonare CB, Pontes GN,
Tino-De-Franco M, et al. Acquisition of serum antibodies reactive with
enterohemorrhagic Escherichia coli virulence-associated factors by healthy Brazilian
children and adults. Pediatr Infect Dis J 2009;28:1089-94. DOI:
http://dx.doi.org/10.1097/INF.0b013e3181aa6b2d
http://dx.doi.org/10.1097/INF.0b013e3181...
The pathogenesis of this condition is not fully understood and, therefore, there is
no targeted therapy. Death occurs in 1% to 5% of the cases.1919. Spinale JM, Ruebner RL, Copelovitch L, Kaplan BS. Long-term outcomes
of Shiga toxin hemolytic uremic syndrome. Pediatr Nephrol 2013;28:2097-105. DOI:
http://dx.doi.org/10.1007/s00467-012-2383-6
http://dx.doi.org/10.1007/s00467-012-238...
Seventy-five percent of the pediatric patients recover with
only support care measures, which include hydroelectrolytic and metabolic control,
renal replacement therapy when indicated, hypertension management, and correction of
anemia and thrombocytopenia when needed.99. Keir LS, Saleem MA. Current evidence for the role of complement in
the pathogenesis of Shiga toxin haemolytic uraemic syndrome. Pediatr Nephrol 2013 Jul
11. [Epub ahead of print]. DOI:
http://dx.doi.org/10.1007/s00467-013-2561-1
http://dx.doi.org/10.1007/s00467-013-256...
However, approximately 30% of the patients have sequelae in the form of persistent
proteinuria, hypertension, and end-stage renal disease, requiring permanent dialysis
or kidney transplantation.2020. Rosales A, Hofer J, Zimmerhackl LB, Jungraithmayr TC, Riedl M, Giner
T, et al.; German-Austrian HUS Study Group. Need for long-term follow-up in
enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome due to
late-emerging sequelae. Clin Infect Dis 2012;54:1413-21. DOI:
http://dx.doi.org/10.1093/cid/cis196
http://dx.doi.org/10.1093/cid/cis196...
Complications may
occur years after the acute stages of the condition. Therefore, long-term follow-up
is recommended.1919. Spinale JM, Ruebner RL, Copelovitch L, Kaplan BS. Long-term outcomes
of Shiga toxin hemolytic uremic syndrome. Pediatr Nephrol 2013;28:2097-105. DOI:
http://dx.doi.org/10.1007/s00467-012-2383-6
http://dx.doi.org/10.1007/s00467-012-238...
Clinical factors that help
predict the risk of chronic renal involvement include the number of days of oliguria
or time on dialysis, high leukocytosis, and need for plasma replacement.2121. Gianviti A, Tozzi AE, De Petris L, Caprioli A, Ravà L, Edefonti A,
et al. Risk factors for poor renal prognosis in children with hemolytic uremic
syndrome. Pediatr Nephrol 2003;18:1229-35. DOI:
http://dx.doi.org/10.1007/s00467-003-1262-6
http://dx.doi.org/10.1007/s00467-003-126...
Brain involvement has also been associated
with worse prognosis.2222. Trachtman H, Austin C, Lewinski M, Stahl RA. Renal and neurological
involvement in typical Shiga toxin-associated HUS. Nat Rev Nephrol 2012;8:658-69.
DOI: http://dx.doi.org/10.1038/nrneph.2012.196
http://dx.doi.org/10.1038/nrneph.2012.19...
Antibiotic therapy is usually not indicated for the treatment of infections by
STEC,2323. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the
hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7
infections. N Engl J Med 2000;342:1930-6. PMID: 10874060 DOI:
http://dx.doi.org/10.1056/NEJM200006293422601
http://dx.doi.org/10.1056/NEJM2000062934...
since it does not offer benefits to
patients.2424. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia
coli and haemolytic uraemic syndrome. Lancet 2005;365:1073-86. PMID:
15781103 Instead, it may increase the
risk of HUS, particularly when administered in the early stages of the disease, by
increasing the production and release of Stx, the main virulence factor of STEC
involved in the pathogenesis of HUS.2323. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the
hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7
infections. N Engl J Med 2000;342:1930-6. PMID: 10874060 DOI:
http://dx.doi.org/10.1056/NEJM200006293422601
http://dx.doi.org/10.1056/NEJM2000062934...
,2424. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia
coli and haemolytic uraemic syndrome. Lancet 2005;365:1073-86. PMID:
15781103
Other joint treatment options such as plasma infusion or plasmapheresis showed no
benefits for individuals with STEC-HUS.2525. Keir L, Coward RJ. Advances in our understanding of the pathogenesis
of glomerular thrombotic microangiopathy. Pediatr Nephrol 2011;26:523-33. DOI:
http://dx.doi.org/10.1007/s00467-010-1637-4
http://dx.doi.org/10.1007/s00467-010-163...
HUS has also been observed in infections by Shighella dysinteriae type 1 and
Campylobacter.2626. Michael M, Elliott EJ, Craig JC, Ridley G, Hodson EM. Interventions
for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic
review of randomized controlled trials. Am J Kidney Dis 2009;53:259-72. DOI:
http://dx.doi.org/10.1053/j.ajkd.2008.07.038
http://dx.doi.org/10.1053/j.ajkd.2008.07...
Invasive infection by Streptococcus pneumoniae can also cause HUS.
Previous studies described it as a rare cause of HUS associated with poor prognosis.
More recently, HUS associated with invasive disease caused by
pneumococcus was reported to account for 5% of the pediatric
cases of HUS and for 40% of the cases not associated with STEC.2727. Constantinescu AR, Bitzan M, Weiss LS, Christen E, Kaplan BS, Cnaan
A, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course.
Am J Kidney Dis 2004;43:976-82. DOI:
http://dx.doi.org/10.1053/j.ajkd.2004.02.010
http://dx.doi.org/10.1053/j.ajkd.2004.02...
The incidence of HUS after invasive pneumococcal infection
ranges between 0.4% and 0.6%, but it is possible that these figures are
underestimated. Unlike in other conditions, the direct Coombs test yields a positive
result in specific cases of HUS triggered by pneumococcus. This is
due to the important role the Thomsen-Friedenreich (T) antigen plays in the
pathophysiology of HUS by pneumococcus.2828. von Vigier RO, Seibel K, Bianchetti MG. Positive Coombs test in
pneumococcus-associated hemolytic uremic syndrome. A review of the literature.
Nephron 1999;82:183-4. PMID: 10364712
This antigen is normally "hidden" by neuraminic acid, but is exposed by pneumococcal
neuraminidase. The T antigen binds to the surface of glomerular endothelial cells,
platelets, and red blood cells. Preformed host antibodies can bind to the surface of
cells expressing this antigen, triggering a series of events that lead to HUS. The
direct Coombs test often detects these antibodies bound to T antigens and yields
positive results in 90% of the cases of HUS by pneumococcus.2929. von Vigier RO, Fossali E, Crosazzo L, Bianchetti MG. Positive Coombs
test in postpneumococcal hemolytic-uremic syndrome. Pediatr Infect Dis J
2005;24:1028-9. DOI:
http://dx.doi.org/10.1097/01.inf.0000187032.38556.b3
http://dx.doi.org/10.1097/01.inf.0000187...
The differential diagnosis between HUS
triggered by invasive pneumococcal disease and sepsis with disseminated intravascular
coagulation has not been definitively established.
Past studies reported high mortality rates, but more recent trials have revealed
improvements in this area due to enhancements in intensive care. Copelovitch
et al.3030. Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated
hemolytic uremic syndrome: classification and the emergence of serotype 19A.
Pediatrics 2010;125:e174-82. PMID: 20026500 DOI:
http://dx.doi.org/10.1542/peds.2007-2017
http://dx.doi.org/10.1542/peds.2007-2017...
looked into a
series of 14 confirmed cases of HUS by pneumococcus and observed
that 64% of the patients recovered without sequelae in the long-term follow-up,
similarly to what had been seen in individuals with STEC-HUS. Higher risk for
end-stage kidney disease was correlated with being on dialysis for more than 20 days,
while death was correlated with meningitis, not pneumonia. The authors also drew
attention to bacterial serotype 19A in patients with HUS.
Other relevant infections correlated with pediatric HUS include infection by the
acquired immunodeficiency virus, the Epstein-Barr virus, and neonatal congenital
viral infections. A case of HUS in a patient infected by Mycoplasma
pneumoniae was recently reported.3131. Godron A, Pereyre S, Monet C, Llanas B, Harambat J. Hemolytic uremic
syndrome complicating Mycoplasma pneumoniae infection. Pediatr Nephrol
2013;28:2057-60. DOI: http://dx.doi.org/10.1007/s00467-013-2541-5
http://dx.doi.org/10.1007/s00467-013-254...
The mechanism by which these pathogens and consequently their toxins can trigger TMA
and HUS is related to the activation of the alternative complement pathway. Evidence
of such activation was first reported in 1980, when fragments of the breakage of C3
and factor B, involved in the activation of the alternative pathway of the complement
system, were detected in patients with STEC-HUS.3232. Monnens L, Molenaar J, Lambert PH, Proesmans W, van Munster P. The
complement system in hemolytic-uremic syndrome in childhood. Clin Nephrol
1980;13:168-71. PMID: 7379368,3333. Kim Y, Miller K, Michael AF. Breakdown products of C3 and factor B
in hemolytic-uremic syndrome. J Lab Clin Med 1977;89:845-50. Subsequently,
lower serum C3 and decreased deposition of C3 were described in the kidneys of these
patients.3434. Robson WL, Leung AK, Fick GH, McKenna AI. Hypocomplementemia and
leukocytosis in diarrhea-associated hemolytic uremic syndrome. Nephron 1992;62:296-9.
PMID: 1436342 DOI: http://dx.doi.org/10.1159/000187063
http://dx.doi.org/10.1159/000187063...
More recently, Thurman
et al.3535. Thurman JM, Marians R, Emlen W, Wood S, Smith C, Akana H, et al.
Alternative pathway of complement in children with diarrhea-associated hemolytic
uremic syndrome. Clin J Am Soc Nephrol 2009;4:1920-4. DOI: http://dx.doi.org/10.2215/
CJN.02730409
http://dx.doi.org/10.2215/...
found fragments
of factor B and MAC (C5b -9) in the serum of 17 patients with STEC-HUS on admission
and normal test results after 28 days, showing that activation of the alternative
pathway occurs early in the course of the disease.
All evidence indicates that Stx binds and inhibits complement factor H, making cells
vulnerable to the formation of MAC and leading to cell lysis. Therefore, factor H can
be active in the subject's bloodstream, but not at the level of the cell, as
similarly observed in the case of mutations with loss of factor H function.99. Keir LS, Saleem MA. Current evidence for the role of complement in
the pathogenesis of Shiga toxin haemolytic uraemic syndrome. Pediatr Nephrol 2013 Jul
11. [Epub ahead of print]. DOI:
http://dx.doi.org/10.1007/s00467-013-2561-1
http://dx.doi.org/10.1007/s00467-013-256...
Other studies confirmed the activation of the
alternative complement pathway in infection by STEC-HUS, and this model can be
transported to cases with other infectious agents.99. Keir LS, Saleem MA. Current evidence for the role of complement in
the pathogenesis of Shiga toxin haemolytic uraemic syndrome. Pediatr Nephrol 2013 Jul
11. [Epub ahead of print]. DOI:
http://dx.doi.org/10.1007/s00467-013-2561-1
http://dx.doi.org/10.1007/s00467-013-256...
Therefore, toxins may potentially activate or hamper the control of the
alternative complement pathway and trigger the onset of TMA.
Interestingly, only 10% to 15% of the patients with STEC infection develop HUS.1313. Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of
Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol
2008;23:1749-60. DOI: http://dx.doi.org/10.1007/s00467-008-0935-6 Which factor triggers the disease? With that
question in mind, Fang et al.3636. Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M,
Goodship TH, et al. Membrane cofactor protein mutations in atypical hemolytic uremic
syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood
2008;111:624-32. PMID: 17914026 DOI:
http://dx.doi.org/10.1182/blood-2007-04-084533
http://dx.doi.org/10.1182/blood-2007-04-...
reported the case of a child with confirmed STEC-HUS and MCP mutation
(CD46). The authors speculated that aHUS, for which this child was genetically
predisposed, may have been elicited by diarrheal disease caused by STEC.
Atypical hemolytic-uremic syndrome
Atypical HUS (aHUS), i.e., HUS without coexisting disease and not associated with
STEC or pneumococcal neuraminidase, is seen in 5% to 10% of the cases. It affects
people of all ages and may be sporadic or familial.3737. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F,
Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on
clinical presentation, response to treatment, and outcome. Blood 2006;108:1267- 79.
PMID: 16621965 DOI: http://dx.doi.org/10.1182/blood-2005-10-007252
http://dx.doi.org/10.1182/blood-2005-10-...
,3838. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et
al. Relative role of genetic complement abnormalities in sporadic and familial aHUS
and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59. DOI:
http://dx.doi.org/10.2215/CJN.02210310
http://dx.doi.org/10.2215/CJN.02210310...
Atypical HUS
stems from chronic uncontrolled activation of the alternative complement pathway,
which causes endothelial damage. The prognosis for patients with aHUS is poor. In
its first clinical manifestation, 33% to 40% of the patients die or progress to
ESRD.3737. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F,
Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on
clinical presentation, response to treatment, and outcome. Blood 2006;108:1267- 79.
PMID: 16621965 DOI: http://dx.doi.org/10.1182/blood-2005-10-007252
http://dx.doi.org/10.1182/blood-2005-10-...
,3838. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et
al. Relative role of genetic complement abnormalities in sporadic and familial aHUS
and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59. DOI:
http://dx.doi.org/10.2215/CJN.02210310
http://dx.doi.org/10.2215/CJN.02210310...
Within the first year of diagnosis, 65% of the patients
die, require dialysis, or present permanent renal injury, despite plasmapheresis
and/or plasma infusion.3737. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F,
Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on
clinical presentation, response to treatment, and outcome. Blood 2006;108:1267- 79.
PMID: 16621965 DOI: http://dx.doi.org/10.1182/blood-2005-10-007252
http://dx.doi.org/10.1182/blood-2005-10-...
In the last decade, a growing number of mutations in genes encoding proteins
involved in the formation or regulation of the alternative pathway have been
associated with aHUS.3737. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F,
Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on
clinical presentation, response to treatment, and outcome. Blood 2006;108:1267- 79.
PMID: 16621965 DOI: http://dx.doi.org/10.1182/blood-2005-10-007252
http://dx.doi.org/10.1182/blood-2005-10-...
38. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et
al. Relative role of genetic complement abnormalities in sporadic and familial aHUS
and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59. DOI:
http://dx.doi.org/10.2215/CJN.02210310
http://dx.doi.org/10.2215/CJN.02210310...
-3939. Roumenina LT, Loirat C, Dragon-Durey MA, Halbwachs- Mecarelli L,
Sautes-Fridman C, Fremeaux-Bacchi V. Alternative complement pathway assessment in
patients with atypical HUS. J Immunol Methods 2011;365:8-26. DOI:
http://dx.doi.org/10.1016/j.jim.2010.12.020
http://dx.doi.org/10.1016/j.jim.2010.12....
Therefore, aHUS is emerging as a
paradigmatic disease caused by inefficient protection of the endothelium against
complement attack. Dysregulation of C3 convertase induces excessive cleavage of C3
and subsequent exacerbated cleavage of C5, leading to endothelial cell damage,
platelet recruitment, and formation of thrombi in the renal microvasculature, in a
condition histologically characterized as TMA.4040. Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC. C3
glomerulopathy: a new classification. Nat Rev Nephrol 2010;8:494-9. DOI:
http://dx.doi.org/10.1038/nrneph.2010.85
http://dx.doi.org/10.1038/nrneph.2010.85...
Genetic anomalies in aHUS patients have been found to involve
componentes of the alternative complement pathway, including factors H and I,
membrane cofactor protein (MCP), factor B, complement component C3, and
thrombomodulin.3737. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F,
Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on
clinical presentation, response to treatment, and outcome. Blood 2006;108:1267- 79.
PMID: 16621965 DOI: http://dx.doi.org/10.1182/blood-2005-10-007252
http://dx.doi.org/10.1182/blood-2005-10-...
38. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et
al. Relative role of genetic complement abnormalities in sporadic and familial aHUS
and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59. DOI:
http://dx.doi.org/10.2215/CJN.02210310
http://dx.doi.org/10.2215/CJN.02210310...
39. Roumenina LT, Loirat C, Dragon-Durey MA, Halbwachs- Mecarelli L,
Sautes-Fridman C, Fremeaux-Bacchi V. Alternative complement pathway assessment in
patients with atypical HUS. J Immunol Methods 2011;365:8-26. DOI:
http://dx.doi.org/10.1016/j.jim.2010.12.020
http://dx.doi.org/10.1016/j.jim.2010.12....
-4040. Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC. C3
glomerulopathy: a new classification. Nat Rev Nephrol 2010;8:494-9. DOI:
http://dx.doi.org/10.1038/nrneph.2010.85
http://dx.doi.org/10.1038/nrneph.2010.85...
The mechanism of aHUS involves primarily
the activation of MAC, C5b-9.
Mutations in regulatory proteins have been detected in about 61% of the patients
with atypical aHUS.4141. Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon- Durey
MA, Ngo S, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a
nationwide French series comparing children and adults. Clin J Am Soc Nephrol
2013;8:554-62. DOI: http://dx.doi.org/10.2215/CJN.04760512
http://dx.doi.org/10.2215/CJN.04760512...
Table 2 shows the contribution of certain
regulatory proteins, their sites of synthesis, responsible gene, location, and
percent contribution to cases of aHUS. Atypical HUS may occur in the absence of
identified mutations.
Some regulatory proteins of the alternative complement pathway, genes, production sites, action sites, and contribution to the occurrence of atypical hemolytic uremic syndrome. Modified from3636. Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M, Goodship TH, et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 2008;111:624-32. PMID: 17914026 DOI: http://dx.doi.org/10.1182/blood-2007-04-084533
http://dx.doi.org/10.1182/blood-2007-04-...
Investigation of the complement system in aHUS patients
Recent guidelines recommend that HUS patients be tested for complement anomalies,
whenever possible.4242. de Jorge EG, Macor P, Paixão-Cavalcante D, Rose KL, Tedesco F, Cook
HT, et al. PMID: 21148255.The development of atypical hemolytic uremic syndrome
depends on complement C5. J Am Soc Nephrol 2011;22:137-45.,4343. Pickering MC, de Jorge EG, Martinez-Barricarte R, Recalde S,
Garcia-Layana A, Rose KL, et al. Spontaneous hemolytic uremic syndrome triggered by
complement factor H lacking surface recognition domains. J Exp Med 2007;204:1249-56.
PMID: 17517971 DOI: http://dx.doi.org/10.1084/jem.20070301
http://dx.doi.org/10.1084/jem.20070301...
Tests can be used to measure total complement
activity in serum (CH50), activity of the alternative pathway (AH50), and activity of
complement system components C3, C4, factor H, and factor I. One should bear in mind
that most tests assess the presence of the protein, not its activity. Additionally,
complement regulation anomalies may occur only at the level of the endothelial cell
surface, and not systemically. Therefore, serum levels of components of the
complement system may be normal in patients with altered activity regulation, thus
not allowing complement system genetic anomalies to be ruled out. Ariceta et
al.4444. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et
al.; European Paediatric Study Group for HUS. Guideline for the investigation and
initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol
2009;24:687-96. DOI: http://dx.doi.org/10.1007/s00467-008-0964-1
http://dx.doi.org/10.1007/s00467-008-096...
reported normal C3 and C4
levels in 80% of individuals with aHUS, while Noris et al.3838. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et
al. Relative role of genetic complement abnormalities in sporadic and familial aHUS
and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59. DOI:
http://dx.doi.org/10.2215/CJN.02210310
http://dx.doi.org/10.2215/CJN.02210310...
found normal levels of factor H in 40/46 (87%)
patients with identified mutations on gene CFH.
Usually, small amounts of C3b are deposited on the cell surface, but these molecules are rapidly eliminated by Factor I with the aid of cofactors factor H, MCP (membrane cofactor protein, CD46), and thrombomodulin. In cases of mutation leading to loss of factor function, the C3b deposits are not completely wiped out, thus triggering uncontrolled activation of the complement system and subsequent cell damage, as seen with endothelial cells.
Mutations with function gains in molecules involved in the activation of the
alternative pathway, such as factor B and C3, induce endothelial damage, even in the
presence of functional regulators.3838. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et
al. Relative role of genetic complement abnormalities in sporadic and familial aHUS
and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59. DOI:
http://dx.doi.org/10.2215/CJN.02210310
http://dx.doi.org/10.2215/CJN.02210310...
In some patients, anti-factor H antibodies may contribute to the disease and have
been associated with deletions in proteins 1 and 3 related to factor H
(CFHR1/3).4545. Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP,
et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4,
and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic
uremic syndrome. Blood 2010;115:379-87. PMID: 19861685 DOI:
http://dx.doi.org/10.1182/blood-2009-05-221549
http://dx.doi.org/10.1182/blood-2009-05-...
Incomplete penetrance in aHUS
It is important to mention that some individuals with factor H, factor I, and MCP
mutations do not develop the disease.66. Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic
thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr
Nephrol 2009;24:19-29. DOI:
http://dx.doi.org/10.1007/s00467-008-0863-5
http://dx.doi.org/10.1007/s00467-008-086...
This
finding indicates that genetic alterations are not the only entity responsible for
the occurrence of the disease, and points out to the need for an environmental factor
to act as the trigger of the complement cascade and for the disease to occur.
Caprioli et al.3737. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F,
Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on
clinical presentation, response to treatment, and outcome. Blood 2006;108:1267- 79.
PMID: 16621965 DOI: http://dx.doi.org/10.1182/blood-2005-10-007252
http://dx.doi.org/10.1182/blood-2005-10-...
showed that
in 77% of the patients with factor H, factor I, or MCP mutations the manifestation of
clinical symptoms was preceded by symptoms of influenza, gastroenteritis, and other
infections.
Diagnosing aHUS
Atypical HUS is diagnosed by ruling out other causes of TMA, without the aid of a
definitive diagnostic test; therefore, all relevant tests must be performed to ensure
the assessment of the variables that may impact the diagnosis, including the search
for coexisting conditions and comorbidities (Table
1). Atypical HUS has been diagnosed in patients with tumors, malignant
hypertension, systemic disease, glomerulopathies, in association with pregnancy or
use of calcineurin inhibitors,3838. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et
al. Relative role of genetic complement abnormalities in sporadic and familial aHUS
and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59. DOI:
http://dx.doi.org/10.2215/CJN.02210310
http://dx.doi.org/10.2215/CJN.02210310...
presenting
anomalies in the proteins of the alternative complement pathway and identified
mutations.
The differential diagnosis between aHUS and STEC-HUS is of great importance. STEC-HUS
must be ruled out even for the 10% of the patient population that does not present
diarrhea,4646. Westra D, Wetzels JF, Volokhina EB, van den Heuvel LP, van de Kar
NC. A new era in the diagnosis and treatment of atypical haemolytic uraemic syndrome.
Neth J Med 2012;70:121-9. PMID: 22516576 and despite the fact that
gastrointestinal tract TMA may cause diarrhea in the absence of infectious
pathogens.3838. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et
al. Relative role of genetic complement abnormalities in sporadic and familial aHUS
and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59. DOI:
http://dx.doi.org/10.2215/CJN.02210310
http://dx.doi.org/10.2215/CJN.02210310...
The possibility of mutations
in complement regulatory proteins must be considered for patients with suspected
STEC-HUS, incompatible disease evolution patterns, and persistent TMA.
Specifically in the neonatal period, inborn errors of cobalamin metabolism due to
alterations in the MMACHC gene responsible for the production of factor cobalamin-b
(Clc-b), a key element in the metabolism of cobalamin, causing methylmalonic
acidemia, must be ruled out.4747. Menni F, Testa S, Guez S, Chiarelli G, Alberti L, Esposito S.
Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and
homocystinuria. Pediatr Nephrol 2012;27:1401-5. DOI:
http://dx.doi.org/10.1007/s00467-012-2152-6
http://dx.doi.org/10.1007/s00467-012-215...
Without Clc-b,
methylmalonic acid and homocysteine accumulate and lead to an increase in the levels
of free radicals, thus introducing cell damage, increased platelet aggregation,
increased binding of tissue plasminogen activator in the endothelium, and increased
expression of local procoagulant factors.4747. Menni F, Testa S, Guez S, Chiarelli G, Alberti L, Esposito S.
Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and
homocystinuria. Pediatr Nephrol 2012;27:1401-5. DOI:
http://dx.doi.org/10.1007/s00467-012-2152-6
http://dx.doi.org/10.1007/s00467-012-215...
Lab workup diagnostic criteria for aHUS
-
Nonautoimmune hemolytic anemia: CBC showing low hemoglobin levels, negative direct Coombs test, positive test result for schistocytes in peripheral blood, low haptoglobin, increased serum lactate dehydrogenase (LDH) levels;
-
Thrombocytopenia: CBC showing thrombocytopenia (count < 150,000/mm3 or drop greater than 25% from previous measure);
-
Renal involvement: may be present with hematuria, proteinuria, edema, oliguria, hypertension, increased serum levels of urea and creatinine;
-
Tests for involvement of other organs and systems should be carried out depending on clinical findings; TMA can affect any organ, the neurological system, the gastrointestinal tract, the heart, pancreas, liver etc.;4848. Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Frémeaux- Bacchi V, Legendre C. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol 2011;7:23-35. DOI: http://dx.doi.org/10.1038/nrneph.2010.155
http://dx.doi.org/10.1038/nrneph.2010.15... ,4949. Dragon-Durey MA, Sethi SK, Bagga A, Blanc C, Blouin J, Ranchin B, et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol 2010;21:2180-7. DOI: http://dx.doi.org/10.1681/ASN.2010030315
http://dx.doi.org/10.1681/ASN.2010030315... -
Negative test results for STEC-HUS; rule out other causes of typical HUS;
-
ADAMTS13 activity > 5%; if value is under 5, look for anti-ADAMTS13 antibodies;
-
AH50, CH50, C3, and C4 activity: aHUS may be accompanied by decreased serum C3 and reduced alternative pathway activity measured by AH50; these findings, however, are not definitive, as even normal levels do not rule aHUS out.
Assessing components of the complement system
-
Test for mutations in complement regulatory proteins. When available, it is valid to test for mutations of factors involved in complement system control as factor H, factor I, MCP, TM, C3, and factor B, regardless of serum levels. The presence of anti-factor H antibodies can be tested using enzyme-linked immunosorbent assays (ELISA). However, it is important to note that mutations have been identified in about 60% of the cases of aHUS and, therefore, tests negative for mutations cannot be used to rule aHUS out.4141. Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon- Durey MA, Ngo S, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 2013;8:554-62. DOI: http://dx.doi.org/10.2215/CJN.04760512
http://dx.doi.org/10.2215/CJN.04760512...
Previously advocated therapy for atypical hemolytic uremic syndrome
Plasmapheresis and administration of plasma
Before the advent of new treatment options for aHUS, such as complement blockade
targeted therapy, plasma therapy was recommended despite the lack of controlled
randomized trials.5050. Zuber J, Le Quintrec M, Morris H, Frémeaux-Bacchi V, Loirat C,
Legendre C. Targeted strategies in the prevention and management of atypical HUS
recurrence after kidney transplantation. Transplant Rev (Orlando) 2013;27:117-25.
DOI: http://dx.doi.org/10.1016/j.trre.2013.07.003
http://dx.doi.org/10.1016/j.trre.2013.07...
Cohort studies showed that plasmapheresis reduces mortality by 25%.66. Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic
thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr
Nephrol 2009;24:19-29. DOI:
http://dx.doi.org/10.1007/s00467-008-0863-5
http://dx.doi.org/10.1007/s00467-008-086...
Treatment with plasma therapy proved
beneficial in the short term for the disease's hematologic activity; however, the
prognosis for renal involvement was poor.3737. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F,
Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on
clinical presentation, response to treatment, and outcome. Blood 2006;108:1267- 79.
PMID: 16621965 DOI: http://dx.doi.org/10.1182/blood-2005-10-007252
http://dx.doi.org/10.1182/blood-2005-10-...
Plasma administration was deemed sufficient in cases of absent or anomalous complement system regulatory proteins. However, in the initial stages of disease without an established diagnosis, plasmapheresis was considered ideal as long as it was able to remove antibodies, when they were present. Plasma transfusion was recommended when plasmapheresis could not be offered, in order to replace the altered regulatory proteins of the alternative complement pathway.
After the initial period of treatment with plasmapheresis, reduced activation of complement system could be achieved with plasma transfusion, unless antibodies were present, which meant patients had to undergo plasmapheresis.
Previous guidelines from the European HUS4444. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et
al.; European Paediatric Study Group for HUS. Guideline for the investigation and
initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol
2009;24:687-96. DOI: http://dx.doi.org/10.1007/s00467-008-0964-1
http://dx.doi.org/10.1007/s00467-008-096...
study group recommended starting plasmapheresis within 24 hours of the
diagnosis.4444. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et
al.; European Paediatric Study Group for HUS. Guideline for the investigation and
initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol
2009;24:687-96. DOI: http://dx.doi.org/10.1007/s00467-008-0964-1
http://dx.doi.org/10.1007/s00467-008-096...
,5151. 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;148:37-47. PMID: 19821824 DOI:
http://dx.doi.org/10.1111/j.1365-2141.2009.07916.x
http://dx.doi.org/10.1111/j.1365-2141.20...
Technically, the recommendation was to
replace 1.5 volume (60 to 75 ml/kg) with fresh plasma. The guideline group claimed
that plasmapheresis had to be done daily for five days, then in five sessions per
week for two weeks, and then in three sessions per week for two weeks.4444. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et
al.; European Paediatric Study Group for HUS. Guideline for the investigation and
initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol
2009;24:687-96. DOI: http://dx.doi.org/10.1007/s00467-008-0964-1
http://dx.doi.org/10.1007/s00467-008-096...
In plasma transfusion in the absence of
plasmapheresis, the recommendation was to start with 30 to 40 ml/kg and then move
to 10 to 20 ml/kg per day.5252. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V.;
French Study Group for aHUS/C3G. Use of eculizumab for atypical haemolytic uraemic
syndrome and C3 glomerulopathies. Nat Rev Nephrol 2012;8:643-57. DOI:
http://dx.doi.org/10.1038/nrneph.2012.214
http://dx.doi.org/10.1038/nrneph.2012.21...
The best parameters to monitor response were platelet count, LDH and hemoglobin levels levels, which account for hematologic remission. Haptoglobin often stays at lower levels after hematologic remission and, therefore, is not used as a parameter in the short term.
There was no parameter to assess time of treatment, but it was recommended to keep
patients on treatment for at least two days after complete remission.5252. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V.;
French Study Group for aHUS/C3G. Use of eculizumab for atypical haemolytic uraemic
syndrome and C3 glomerulopathies. Nat Rev Nephrol 2012;8:643-57. DOI:
http://dx.doi.org/10.1038/nrneph.2012.214
http://dx.doi.org/10.1038/nrneph.2012.21...
However, some patients with aHUS could
become dependent on plasmapheresis; additionally, infections and immunization
could trigger new TMA episodes, which required patients to return to
plasmapheresis. Other factors that may triggered endothelial injury had to be
controlled, such as hypercholesterolemia and hypertension.
Atypical HUS is a chronic disease and longterm treatment with plasma (plasma
transfusion or plasmapheresis) leads to high rates of new TMA episodes,
progression to ESRD, and death.3838. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et
al. Relative role of genetic complement abnormalities in sporadic and familial aHUS
and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59. DOI:
http://dx.doi.org/10.2215/CJN.02210310
http://dx.doi.org/10.2215/CJN.02210310...
Additionally, comorbidities such as infection and thrombosis, particularly in
plasmapheresis with a central line, are more frequent, and antibodies appear with
repeated plasma transfusions. It is worthwhile mentioning that plasmapheresis can
be a challenging procedure to perform in young pediatric patients. Plasma
transfusions in hypervolemic patients to replace altered proteins can also be
difficult.
Transplantation
The prognosis for renal transplant patients with aHUS is quite poor. Approximately
50% of the patients experience recurrence and lose their grafts. There is no
single factor to predict recurrence, though the use of calcineurin inhibitors has
been associated with increased recurrence rates.5353. Jokiranta TS, Zipfel PF, Fremeaux-Bacchi V, Taylor CM, Goodship TJ,
Noris M. Where next with atypical hemolytic uremic syndrome? Mol Immunol
2007;44:3889-900. PMID: 17768107 DOI:
http://dx.doi.org/10.1016/j.molimm.2007.06.003
http://dx.doi.org/10.1016/j.molimm.2007....
Patients with aHUS are also more likely to develop acute rejection,
which adversely affects graft survival.5050. Zuber J, Le Quintrec M, Morris H, Frémeaux-Bacchi V, Loirat C,
Legendre C. Targeted strategies in the prevention and management of atypical HUS
recurrence after kidney transplantation. Transplant Rev (Orlando) 2013;27:117-25.
DOI: http://dx.doi.org/10.1016/j.trre.2013.07.003
http://dx.doi.org/10.1016/j.trre.2013.07...
Knowledge of genetic defects may improve the prognosis. Patients with factor H
mutations experience recurring disease in 75% to 90% of the cases; patients with
factor I mutations relapse 45% to 80% of the time; in C3 mutations the chance of
recurrence ranges between 40% and 70%; patients with MCP mutations have a low
probability of experiencing recurrence.66. Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic
thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr
Nephrol 2009;24:19-29. DOI:
http://dx.doi.org/10.1007/s00467-008-0863-5
http://dx.doi.org/10.1007/s00467-008-086...
In
order to minimize the risk of recurrence, it is recommended to avoid prolonged
ischemia and stay off calcineurin inhibitors.
One of the options to treat recurrence is plasmapheresis and, when possible,
prophylactic plasmapheresis sessions before and after transplantation.66. Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic
thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr
Nephrol 2009;24:19-29. DOI:
http://dx.doi.org/10.1007/s00467-008-0863-5
http://dx.doi.org/10.1007/s00467-008-086...
Some authors also advocate the use of
simultaneous liver and kidney (SLK) transplants in cases with higher chances of
recurrence, such as patients with known factor H or factor I mutations.5454. Loirat C, Fremeaux-Bacchi V. Hemolytic uremic syndrome recurrence
after renal transplantation. Pediatr Transplant 2008;12:619-29. DOI:
http://dx.doi.org/10.1111/j.1399-3046.2008.00910.x
http://dx.doi.org/10.1111/j.1399-3046.20...
However, SLK transplantation significantly
increases morbimortality.
Live donor kidney transplantation can only be offered if the donor is free of
mutations; and only 60% of the mutations are currently known.4141. Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon- Durey
MA, Ngo S, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a
nationwide French series comparing children and adults. Clin J Am Soc Nephrol
2013;8:554-62. DOI: http://dx.doi.org/10.2215/CJN.04760512
http://dx.doi.org/10.2215/CJN.04760512...
Atypical HUS can be triggered in previously undiagnosed
patients submitted to live donor transplants merely by the manipulation of the
kidney during surgery. The most conservative approach is transplantation from a
deceased donor.
Endothelial involvement causing aHUS recurrence may be triggered after kidney
transplantation by the use of immunosuppressive drugs, viral infections, or
rejection, even in subjects with mild genetic susceptibility.66. Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic
thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr
Nephrol 2009;24:19-29. DOI:
http://dx.doi.org/10.1007/s00467-008-0863-5
http://dx.doi.org/10.1007/s00467-008-086...
Although environmental factors account for most of the cases of recurrent aHUS,
approximately 40% of the patients have genetic anomalies.5555. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, et al.
Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic
uremic syndrome. Clin J Am Soc Nephrol 2011;6:1488-94. DOI:
http://dx.doi.org/10.2215/CJN.10181110
http://dx.doi.org/10.2215/CJN.10181110...
To minimize the risk caused by environmental factors, it is
recommended to adequately manage hypertension and hypercholesterolemia, and to
offer calcineurin inhibitors judiciously.
A new era in the treatment of aHUS - eculizumab
Increased knowledge on the pathogenesis of aHUS was accompanied by the emergence of
eculizumab, a drug that acts as an inhibitor of the terminal pathway of the
complement cascade,5656. Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, et al.
Effect of eculizumab on hemolysis and transfusion requirements in patients with
paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004;350:552-9. PMID: 14762182 DOI:
http://dx.doi.org/10.1056/NEJMoa031688
http://dx.doi.org/10.1056/NEJMoa031688...
considered the standard
for the treatment of paroxysmal nocturnal hemoglobinuria.5757. Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H,
et al. Long-term safety and efficacy of sustained eculizumab treatment in patients
with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013;162:62-73. DOI:
http://dx.doi.org/10.1111/bjh.12347
http://dx.doi.org/10.1111/bjh.12347...
Eculizumab is a humanized monoclonal antibody registered as
the drug of choice for the treatment of aHUS by the FDA and the EMEA. The drug acts
specifically by binding to complement factor C5, blocking the cleavage of C5 into
C5b, and preventing the formation of anaphylatoxin C5a and MAC, C5b-9. Its use has
been associated with one significant adverse effect: increased risk of infection by
Neisseria.5858. Bouts A, Monnens L, Davin JC, Struijk G, Spanjaard L. Insufficient
protection by Neisseria meningitidis vaccination alone during eculizumab therapy.
Pediatr Nephrol 2011;26:1919- 20. DOI:
http://dx.doi.org/10.1007/s00467-011-1929-3
http://dx.doi.org/10.1007/s00467-011-192...
As the clearance of Neisseria
meningitidis is highly dependent on MAC, patients treated with eculizumab are at a
higher risk of infection by this pathogen. Therefore, patients must be given the
polyvalent vaccine at least two weeks before starting treatment, and if the
medication is used before this period, patients must be offered prophylactic
antibiotic therapy. As the vaccine available in our area does not protect against all
Neisseria serotypes, non-stop prophylaxis is recommended;5858. Bouts A, Monnens L, Davin JC, Struijk G, Spanjaard L. Insufficient
protection by Neisseria meningitidis vaccination alone during eculizumab therapy.
Pediatr Nephrol 2011;26:1919- 20. DOI:
http://dx.doi.org/10.1007/s00467-011-1929-3
http://dx.doi.org/10.1007/s00467-011-192...
patient family members and physicians must be aware of this
diagnostic possibility.5858. Bouts A, Monnens L, Davin JC, Struijk G, Spanjaard L. Insufficient
protection by Neisseria meningitidis vaccination alone during eculizumab therapy.
Pediatr Nephrol 2011;26:1919- 20. DOI:
http://dx.doi.org/10.1007/s00467-011-1929-3
http://dx.doi.org/10.1007/s00467-011-192...
Eculizumab has been shown to alter the course of aHUS. The drug has retrieved native
kidney function and prevented post-transplant recurrence. Studies on series of aHUS
patients on eculizumab reported increased platelet counts and improved renal function
after the first dose. While on eculizumab, patients did not need dialysis or
plasmapheresis, and tolerated the medication well.5959. Gruppo RA, Rother RP. Eculizumab for congenital atypical
hemolytic-uremic syndrome. N Engl J Med 2009;360:544-6. PMID: 19179329 DOI:
http://dx.doi.org/10.1056/NEJMc0809959
http://dx.doi.org/10.1056/NEJMc0809959...
,6060. Ariceta G, Arrizabalaga B, Aguirre M, Morteruel E, Lopez-Trascasa M.
Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. Am J
Kidney Dis 2012;59:707-10. DOI:
http://dx.doi.org/10.1053/j.ajkd.2011.11.027
http://dx.doi.org/10.1053/j.ajkd.2011.11...
Legendre
et al.6161. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et
al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N
Engl J Med 2013;368:2169-81. DOI:
http://dx.doi.org/10.1056/NEJMoa1208981
http://dx.doi.org/10.1056/NEJMoa1208981...
looked into 37
patients with aHUS and ages above 12 years on eculizumab. Twenty of the patients had
longstanding disease (mean of 48.3 months, ranging from 0.7 to 285.8 months), mostly
with renal involvement, and were either on dialysis or in hematologic remission due
to plasma therapy.
The remaining 17 patients had shorter course disease (mean of 9.7 months, ranging
from 0.3 to 235.9 months) and signs of hematologic activity; some were on plasma
therapy and had impaired renal function, while others were on dialysis. The most
important finding described in this study was the possibility of retrieving renal
function, even for patients on dialysis for months on end, achieving hematologic
remission without signs of new episodes of TMA, and improving quality of life during
a follow-up of 26 to 62 weeks. No cases of meningococcal infection were reported, as
all patients were immunized and offered prophylactic antibiotics.6161. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et
al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N
Engl J Med 2013;368:2169-81. DOI:
http://dx.doi.org/10.1056/NEJMoa1208981
http://dx.doi.org/10.1056/NEJMoa1208981...
The reported adverse effects included
hypertension (three cases), peritonitis (one case), venous sclerosis at the site of
infusion (one case), asymptomatic bacteriuria (one case), and infection by the
influenza virus (one case). Cases of meningococcal infection were not observed in
this study.6161. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et
al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N
Engl J Med 2013;368:2169-81. DOI:
http://dx.doi.org/10.1056/NEJMoa1208981
http://dx.doi.org/10.1056/NEJMoa1208981...
Recently, Delmas et al.6262. Delmas Y, Loirat C, Muus P, Legendre C, Douglas K, Hourmant M, et al. Sustained Efficacy and Safety of Eculizumab in Patients with Atypical Hemolytic Uremic Syndrome with Long Disease Duration and Chronic Kidney Disease: 3-Year Update. Pôster no Encontro Anual da American Society of Nephrology Kidney Week 2013, 5-10 de Novembro, Atlanta, Georgia. updated the study by Legendre et al., following patients with longstanding aHUS and chronic kidney disease (stages 3, 4, and 5) for three years. The authors reported hematologic and renal function improvements with the use of the drug. Another finding was greater numbers of patients free of new TMA episodes: 26 weeks into follow-up 16/20 (80%) were free of TMA events; 17/20 (85%) one year into follow-up; 19/20 (95%) after two years of follow-up; and 19/20 (95%) after three years of follow-up. The authors also reported a higher number of subjects with normal hematologic findings: 18/20 (90%) 26 weeks into follow-up; the ratio was kept unchanged three years into follow-up.
Considering renal function, serum creatinine levels dropped by ≥ 25% in 15% of the
patients after 26 weeks of treatment, in 35% of the patients after one year, in 55%
of the cases after two years of treatment, and was kept constant from then until the
third year of follow-up; glomerular filtration rates increased by ≥ 15 ml/min/1.73
m22. Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies.
Annu Rev Pathol 2008;3:249-77. DOI:
http://dx.doi.org/10.1146/annurev.pathmechdis.3.121806.154311
http://dx.doi.org/10.1146/annurev.pathme...
in 5% of the patients after 26 weeks of
follow-up, and the ratio improved to 15% after one year, 40% after two years, and was
kept stable after three years of drug therapy, with 60% of the patients improving
from CKD by one or more stages by the third year of treatment. No cases of
meningococcal infection or adverse side effects were reported.
A recent prospective study6363. Greenbaum LA, Fila M, Tsimaratos M, Ardissino G, Al-Akash S, Evans
J, et al. Eculizumab Inhibits Thrombotic Microangiopathy and Improves Renal Function
in Pediatric Patients with Atypical Hemolytic Uremic Syndrome. Pôster no Encontro
Anual da American Society of Nephrology Kidney Week 2013, 5-10 de Novembro, Atlanta,
Georgia. with 22 pediatric
patients showed that the use of eculizumab provides rapid and sustained improvement
(26 weeks of treatment) in hematological parameters and ongoing improvements in renal
function. More specifically, complete remission from TMA was observed in 64% of the
cases; normal hematologic parameters in 82%; increase in the GFR ≥ 15 ml/min/1.73
m22. Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies.
Annu Rev Pathol 2008;3:249-77. DOI:
http://dx.doi.org/10.1146/annurev.pathmechdis.3.121806.154311
http://dx.doi.org/10.1146/annurev.pathme...
in 86% of the patients (mean of 64
ml/min/1.73 m22. Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies.
Annu Rev Pathol 2008;3:249-77. DOI:
http://dx.doi.org/10.1146/annurev.pathmechdis.3.121806.154311
http://dx.doi.org/10.1146/annurev.pathme...
); and nine of eleven patients
could stop dialysis. No cases of meningococcal infection were reported and adverse
effects were similar to those reported in previous studies, namely hypertension in
two patients, upper airway infection in two individuals, viral gastroenteritis in two
subjects, and fever in two patients. Based on the outcomes of this study, eculizumab
has been recommended as the first line treatment for pediatric aHUS, supporting the
recommendations of previous studies.
Transplantation protocols are advocating the use of eculizumab in patients with aHUS.
Reports of live donor transplants support the combination of plasmapheresis the week
prior to transplantation in the induction stage and after surgery during maintenance,
with good outcomes.5555. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, et al.
Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic
uremic syndrome. Clin J Am Soc Nephrol 2011;6:1488-94. DOI:
http://dx.doi.org/10.2215/CJN.10181110
http://dx.doi.org/10.2215/CJN.10181110...
The literature on
deceased donor transplants contains reports in which plasmapheresis was performed the
day before and the day after transplant surgery in association with eculizumab;5555. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, et al.
Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic
uremic syndrome. Clin J Am Soc Nephrol 2011;6:1488-94. DOI:
http://dx.doi.org/10.2215/CJN.10181110
http://dx.doi.org/10.2215/CJN.10181110...
however, more recent case reports tell of good
outcomes using eculizumab alone.6464. Román-Ortiz E, Mendizabal Oteiza S, Pinto S, López-Trascasa M,
Sánchez-Corral P, Rodríguez de Cordoba S. Eculizumab long-term therapy for pediatric
renal transplant in aHUS with CFH/CFHR1 hybrid gene. Pediatr Nephrol 2014;29:149-53.
DOI: http://dx.doi.org/10.1007/s00467-013-2591-8
http://dx.doi.org/10.1007/s00467-013-259...
In this
situation, it is recommended to administer the first dose six hours before
transplantation and repeat it the following day, then once a week for the next four
weeks, and after that every 15 days; dosage must be adjusted based on the subject's
bodyweight.6363. Greenbaum LA, Fila M, Tsimaratos M, Ardissino G, Al-Akash S, Evans
J, et al. Eculizumab Inhibits Thrombotic Microangiopathy and Improves Renal Function
in Pediatric Patients with Atypical Hemolytic Uremic Syndrome. Pôster no Encontro
Anual da American Society of Nephrology Kidney Week 2013, 5-10 de Novembro, Atlanta,
Georgia.
Notably, aHUS may occur in newborns and treatment in these cases is quite
complicated, since plasmapheresis is difficult to perform in individuals in this age
range. Additionally, dependence and antibody formation with successive plasma
transfusions may occur, along with severe adverse events and sustained renal
involvement. Reports have described the benefits in hematological recovery and renal
function improvement in neonates treated with eculizumab.6060. Ariceta G, Arrizabalaga B, Aguirre M, Morteruel E, Lopez-Trascasa M.
Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. Am J
Kidney Dis 2012;59:707-10. DOI:
http://dx.doi.org/10.1053/j.ajkd.2011.11.027
http://dx.doi.org/10.1053/j.ajkd.2011.11...
,6565. Besbas N, Gulhan B, Karpman D, Topaloglu R, Duzova A, Korkmaz E, et
al. Neonatal onset atypical hemolytic uremic syndrome successfully treated with
eculizumab. Pediatr Nephrol 2013;28:155-8. DOI:
http://dx.doi.org/10.1007/s00467-012-2296-4
http://dx.doi.org/10.1007/s00467-012-229...
Eculizumab is not indicated for patients with typical HUS. However, in a recent
outbreak in Germany, individuals with severe STEC-HUS and particularly patients with
neurological impairment were offered the drug, and many adult patients benefitted
from it.99. Keir LS, Saleem MA. Current evidence for the role of complement in
the pathogenesis of Shiga toxin haemolytic uraemic syndrome. Pediatr Nephrol 2013 Jul
11. [Epub ahead of print]. DOI:
http://dx.doi.org/10.1007/s00467-013-2561-1
http://dx.doi.org/10.1007/s00467-013-256...
The drug did not impact the
prognosis of the pediatric group followed during the outbreak, but the medication was
administered later on. Therefore, it is not clear yet whether eculizumab is
beneficial for patients with typical HUS.6666. Morigi M, Galbusera M, Gastoldi S, Locatelli M, Buelli S, Pezzotta
A, et al. Alternative pathway activation of complement by Shiga toxin promotes
exuberant C3a formation that triggers microvascular thrombosis. J Immunol
2011;187:172-80. PMID: 21642543 DOI:
http://dx.doi.org/10.4049/jimmunol.1100491
http://dx.doi.org/10.4049/jimmunol.11004...
Conclusion
Differential diagnosis can be challenging in the group of diseases prone to manifesting TMA, as they may present overlapping clinical signs and symptoms. This group includes TTP and HUS, the latter of which may occur by the action of toxins, systemic diseases, uncontrolled activation of the alternative pathway due to alterations in pathway regulatory proteins (aHUS), or for unknown causes. A series of tests is required to differentiate these conditions. The diagnosis of aHUS is achieved by ruling out other causes of TMA. In most cases, patients respond well to the treatment of aHUS with plasma transfusion or plasmapheresis, particularly when it comes to short term hematologic parameters. However, aHUS is a severe chronic condition that may cause patients to die or develop end-stage renal disease.
Treatment with plasma is characterized by significant rates of recurrent disease in the long term and unfavorable renal outcome. Eculizumab, an anti-C5 monoclonal antibody, has emerged as a new hope for the improvement of patient short and long term prognosis, and has been recommended as the drug of choice in the treatment of aHUS.
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Publication Dates
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Publication in this collection
Apr-Jun 2014
History
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Received
16 Sept 2013 -
Accepted
25 Sept 2013