Overactivation of Complement Alternative Pathway in Postpartum Atypical Hemolytic Uremic Syndrome Patients with Renal Involvement

2015 ◽  
Vol 74 (4) ◽  
pp. 345-356 ◽  
Author(s):  
Di Song ◽  
Xiao-juan Yu ◽  
Feng-mei Wang ◽  
Bing-ning Xu ◽  
Ying-dong He ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Renal Involvement ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Complement Alternative Pathway ◽  
Uremic Syndrome

scholarly journals Atypical Hemolytic Uremic Syndrome after ChAdOx1 nCoV-19 Vaccination in a Patient with Homozygous CFHR3/CFHR1 Gene Deletion

Nephron ◽  
2021 ◽  
pp. 1-5
Author(s):  
Francisco Ferrer ◽  
Marisa Roldão ◽  
Cátia Figueiredo ◽  
Karina Lopes
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
Time Lapse ◽  
Normal Activity ◽  
Factor H ◽  
Complement Alternative Pathway ◽  
Uremic Syndrome

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) affecting the kidneys. Compared with typical HUS due to an infection from shiga toxin-producing <i>Escherichia coli</i>, atypical HUS involves a genetic or acquired dysregulation of the complement alternative pathway. In the presence of a mutation in a complement gene, a second trigger is often necessary for the development of the disease. We report a case of a 54-year-old female, with a past medical history of pulmonary tuberculosis, who was admitted to the emergency service with general malaise and reduction in urine output, 5 days after vaccination with ChAdOx1 nCoV-19. Laboratory results revealed microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Given the clinical picture of TMA, plasma exchange (PEX) was immediately started, along with hemodialysis. Complementary laboratory workup for TMA excluded thrombotic thrombocytopenic purpura and secondary causes. Complement study revealed normal levels of factors H, B, and I, normal activity of the alternate pathway, and absence of anti-factor H antibodies. Genetic study of complement did not show pathogenic variants in the 12 genes analyzed, but revealed a deletion in gene CFHR3/CFHR1 in homozygosity. Our patient completed 10 sessions of PEX, followed by eculizumab, with both clinical and laboratorial improvement. Actually, given the short time lapse between vaccination with ChAdOx1 nCoV-19 and the clinical manifestations, we believe that vaccine was the trigger for the presentation of aHUS in this particular case.

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Blood ◽  
2013 ◽  
Vol 122 (2) ◽  
pp. 282-292 ◽  
Author(s):  
Marie Frimat ◽  
Fanny Tabarin ◽  
Jordan D. Dimitrov ◽  
Caroline Poitou ◽  
Lise Halbwachs-Mecarelli ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Hemolytic Uremic Syndrome ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Cell Surfaces ◽  
Complement Alternative Pathway ◽  
Key Points ◽  
Uremic Syndrome

Key Points Heme activates complement alternative pathway in serum and on endothelial cell surfaces. Heme-induced complement activation in the presence of complement mutations contributes as a secondary hit to the development of aHUS.

scholarly journals Mutations in Proteins of the Alternative Pathway of Complement and the Pathogenesis of Atypical Hemolytic Uremic Syndrome

2008 ◽  
Vol 52 (1) ◽  
pp. 171-180 ◽  
Author(s):  
Cynthia Abarrategui-Garrido ◽  
Marta Melgosa ◽  
Antonia Peña-Carrión ◽  
Elena Goicoechea de Jorge ◽  
Santiago Rodríguez de Córdoba ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Uremic Syndrome ◽  
Alternative Pathway Of Complement

scholarly journals Novel Complement Factor H mutation, a case report of atypical hemolytic uremic syndrome

2017 ◽  
Vol 4 (2) ◽  
pp. 13 ◽  
Author(s):  
Rodrigo Andrés Sepúlveda ◽  
Rodrigo Tagle ◽  
Aquiles Jara
Keyword(s):  
Renal Failure ◽  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Severe Renal Failure ◽  
Uremic Syndrome ◽  
I Factor

 Atypical hemolytic uremic syndrome (aHUS) is a rare but catastrophic disease. It is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. When the aHUS is primary, the cause is due to mutations in proteins that regulate the alternative pathway of complement, such as Factor H, Factor I, Factor B, C3, Membrane Co-Factor Protein and Thrombomodulin. Usually primary aHUS is associated with other amplifiers complement factors. We present a case of aHUS in a 25-year-old female patient; she presented with malignant hypertension and severe renal failure. After a widespread study, the etiology of the aHUS was a mutation in the complement factor H, not previously described in the literature (p.Tyr1177His). After treatment with Eculizumab (C5 inhibitor monoclonal antibody), she recovered renal function with not hemodialysis requirements. 

scholarly journals Nephrotic syndrome associated with primary atypical hemolytic uremic syndrome

2020 ◽  
Author(s):  
Diana Carolina Bello-Marquez ◽  
John Fredy Nieto-Rios ◽  
Lina Maria Serna-Higuita ◽  
Alfonso Jose Gonzalez-Vergara
Keyword(s):  
Nephrotic Syndrome ◽  
Hemolytic Uremic Syndrome ◽  
Renal Dysfunction ◽  
Rare Disease ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Genetic Mutations ◽  
Microangiopathic Hemolytic Anemia ◽  
Uremic Syndrome ◽  
Alternative Pathway Of Complement

Abstract Primary atypical hemolytic-uremic syndrome is a rare disease characterized by non-immune microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction; it is related to alterations in the regulation of the alternative pathway of complement due to genetic mutations. The association with nephrotic syndrome is unusual. We present here a pediatric patient diagnosed with primary atypical hemolytic-uremic syndrome associated with nephrotic syndrome who responded to eculizumab treatment.

A Novel Hybrid CFH/CFHR1–3 Gene in Atypical Hemolytic Uremic Syndrome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4644-4644
Author(s):  
Mehmet F. Hepgur ◽  
Preeti Chaudhary ◽  
Sarmen Sarkissian ◽  
Richard J. H. Smith ◽  
Howard Liebman ◽  
...  
Keyword(s):  
Renal Failure ◽  
Genetic Testing ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Conflicts Of Interest ◽  
Late Onset ◽  
Past History ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Uremic Syndrome

Abstract Abstract 4644 Background: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and renal failure in the absence of Shiga toxin exposure. Dysregulation of the alternative pathway by mutations in complement regulatory proteins or antibodies to these proteins have been implicated in the pathogenesis of the disorder. Aims: We report the late onset of aHUS in association with heterozygous deletion of two genes, CFHR1 and CFHR3, and a mutation in CFH, c.497G>T, p.Arg166Leu. The latter mutation has not previously been reported with aHUS. Methods: A 20-year-old female whose past history was unremarkable with the exception of a spontaneous abortion 3 months earlier, presented to an emergency room with abdominal pain and bloody diarrhea three days after eating raw fish. Within 4 days of hospitalization she developed MAHA, thrombocytopenia and renal failure. Studies were negative for Shiga toxin and showed an ADAMTS13 level of 40%. A diagnosis of aHUS was made. Treatment was initiated with daily plasma exchange (PE) which was increased to twice daily for 6 weeks. Response was poor. After discontinuing PE, the patient was treated on an IRB-approved compassionate-use protocol with eculizumab 900 mg weekly for four weeks followed by 1200 mg every two weeks. Results: The patient responded slowly to eculizumab. PK values of eculizumab were sub-therapeutic at week 4. On week 5, she was switched to the maintenance dose of 1200 mg every two weeks, which resulted in a rapid normalization of her platelet count and LDH, with further improvement of her renal function and normalization of her mental status. The patient is doing well on continued eculizumab treatment. Genetic testing revealed a known copy-number variation (CNV), hemizygosity for CFHR1 and CFHR3, and a mutation in short consensus repeat (SCR) 3 of CFH, p.Arg166Leu. Summary/Conclusions: This patient presented with aHUS unresponsive to PE, but responsive to eculizumab treatment. Genetic testing of complement regulatory genes identified a known CNV and a mutation in CFH, p.Arg166Leu. This mutation lies in SCR3 of CFH, a region of the protein important for fluid-phase regulation of the C3 convertase. Although it has been seen in a rare case of dense deposit disease, it has not has not been reported with aHUS. This patient's poor response to PE suggests that additional genetic factors may be present in this patient that affected the course of disorder. Her slow response to eculizumab may have been due to third spacing of the drug secondary to hypoalbuminemia with anasarca as documented sub-therapeutic levels were present on week 4. When the dose was increased to 1200 mg every two weeks, the patient rapidly improved with resolution of the aHUS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains

2007 ◽  
Vol 204 (6) ◽  
pp. 1249-1256 ◽  
Author(s):  
Matthew C. Pickering ◽  
Elena Goicoechea de Jorge ◽  
Rubén Martinez-Barricarte ◽  
Sergio Recalde ◽  
Alfredo Garcia-Layana ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Risk Haplotype ◽  
Complement Factor ◽  
Age Related ◽  
Uremic Syndrome

Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype–phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS.

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