COVID-19: a trigger for severe thrombotic microangiopathy in a patient with complement gene variant

Abstract The evidence regarding thrombotic microangiopathy (TMA) related to Coronavirus Infectious Disease 2019 (COVID-19) in patients with complement gene mutations as a cause of acute kidney injury (AKI) are limited. We presented a case of a 23-year-old male patient admitted with an asymptomatic form of COVID-19, but with uncontrolled hypertension and AKI. Kidney biopsy showed severe lesions of TMA. In evolution patient had persistent microangiopathic hemolytic anemia, decreased level of haptoglobin and increased LDH level. Decreased complement C3 level and the presence of schistocytes were found for the first time after biopsy. Kidney function progressively decreased and the patient remained hemodialysis dependent. Complement work-up showed a heterozygous variant with unknown significance in complement factor I (CFI) c.-13G>A, affecting the 5' UTR region of the gene. In addition, the patient was found to be heterozygous for the complement factor H (CFH) H3 haplotype (involving the rare alleles of c.-331C>T, Q672Q and E936D polymorphisms) reported as a risk factor of atypical hemolytic uremic syndrome. This case of AKI associated with severe TMA and secondary hemolytic uremic syndrome highlights the importance of genetic risk modifiers in the alternative pathway dysregulation of the complement in the setting of COVID-19, even in asymptomatic forms.

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

Case Reports in Internal Medicine ◽

10.5430/crim.v4n2p13 ◽

2017 ◽

Vol 4 (2) ◽

pp. 13 ◽

Cited By ~ 1

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.

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Thrombotic Microangiopathy with Complement Factor H Gene Mutations Unassociated with Atypical Hemolytic Uremic Syndrome

Turkish Journal of Hematology ◽

10.4274/tjh.2015.0084 ◽

2015 ◽

Vol 32 (3) ◽

pp. 275-276

Author(s):

Yesim Oymak ◽

Tuba Hilkay Karapınar ◽

Yılmaz Ay ◽

Esin Özcan ◽

Neryal Müminoğlu ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Thrombotic Microangiopathy ◽

Atypical Hemolytic Uremic Syndrome ◽

Gene Mutations ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

H Gene ◽

Uremic Syndrome

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

Journal of Experimental Medicine ◽

10.1084/jem.20070301 ◽

2007 ◽

Vol 204 (6) ◽

pp. 1249-1256 ◽

Cited By ~ 192

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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Use of eculizumab in pregnancy-associated atypical hemolytic uremic syndrome

Case Reports in Perinatal Medicine ◽

10.1515/crpm-2017-0038 ◽

2018 ◽

Vol 7 (1) ◽

Author(s):

Meenal Misal ◽

Megha Gupta ◽

Lawrence D. Platt ◽

Neil S. Silverman ◽

Christina S. Han

Keyword(s):

Hemolytic Uremic Syndrome ◽

Clinical Evaluation ◽

Thrombotic Microangiopathy ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Complement Factor ◽

Complement Inhibitor ◽

Complement Pathway ◽

Uremic Syndrome ◽

Terminal Complement

Abstract Pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) is a rare disorder, with an estimated incidence of 1 in 25,000 pregnancies [Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S, Couzi L, et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859–67.]. Unlike classic hemolytic uremic syndrome (HUS), aHUS is not related to Escherichia coli 0157:H7 infections. Rather, it arises from uncontrolled alternative complement pathway activation leading to diffuse endothelial damage. The formation of the resulting fibrin and platelet microthrombi in the vasculature leads to hemolysis, thrombocytopenia and ischemic end-organ damage in the form of acute kidney injury [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; 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; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Triggers for hyperactivation of the complement pathway include infection, inflammation, malignancy, endothelium-affecting drugs, maternal-fetal hemorrhage and pre-eclampsia [Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Thirty percent of individuals with aHUS are found to have mutations in the genes encoding complement regulatory proteins, such as protein factor H, complement factor I and complement 3 [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.]. Outcomes of an untreated aHUS are poor: up to 50% of patients with aHUS progress to end-stage renal disease within a year and 25% die during the acute phase [Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Laurence J, Haller H, Mannucci PM, Nangaku M, Praga M, Rodriguez de Cordoba S. Atypical hemolytic uremic syndrome (aHUS): essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol. 2016;14(Suppl 11):2–15.]. We present an unusual case of a 37-year-old primigravida who developed p-aHUS in the setting of hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. She was successfully treated with a relatively novel medication; eculizumab, a terminal complement inhibitor. In contrast to previous reports of long-term treatment, she received a total of six doses of eculizumab and remained in remission at 12 months postpartum.

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Postoperative Atypical Hemolytic Uremic Syndrome Associated with Complement C3 Mutation

Case Reports in Nephrology ◽

10.1155/2014/784943 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Eiji Matsukuma ◽

Atsushi Imamura ◽

Yusuke Iwata ◽

Takamasa Takeuchi ◽

Yoko Yoshida ◽

...

Keyword(s):

Renal Failure ◽

Hemolytic Uremic Syndrome ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Complement C3 ◽

Causative Mutation ◽

Polymorphism Analysis ◽

Complement Factor ◽

Metabolic Conditions ◽

Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) can be distinguished from typical or Shiga-like toxin-induced HUS. The clinical outcome is unfavorable; up to 50% of affected patients progress to end-stage renal failure and 25% die during the acute phase. Multiple conditions have been associated with aHUS, including infections, drugs, autoimmune conditions, transplantation, pregnancy, and metabolic conditions. aHUS in the nontransplant postsurgical period, however, is rare. An 8-month-old boy underwent surgical repair of tetralogy of Fallot. Neurological disturbances, acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia developed 25 days later, and aHUS was diagnosed. Further evaluation revealed that his complement factor H (CFH) level was normal and that anti-FH antibodies were not detected in his plasma. Sequencing of his CFH, complement factor I, membrane cofactor protein, complement factor B, and thrombomodulin genes was normal. His ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin-1 repeats 13) activity was also normal. However, he had a potentially causative mutation (R425C) in complement component C3. Restriction fragment length polymorphism analysis revealed that his father and aunt also had this mutation; however, they had no symptoms of aHUS. We herein report a case of aHUS that developed after cardiovascular surgery and was caused by a complement C3 mutation.

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Anti-Factor H Antibodies in Egyptian Children with Hemolytic Uremic Syndrome

International Journal of Nephrology ◽

10.1155/2021/6904858 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Shereen Shawky ◽

Hesham Safouh ◽

Mona Gamal ◽

Mohammed M. Abbas ◽

Azza Aboul-Enein ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

High Frequency ◽

Alternative Pathway ◽

Atypical Hemolytic Uremic Syndrome ◽

Disease Onset ◽

Factor H ◽

Enzyme Linked Immunosorbent Assay ◽

Complement Factor ◽

Egyptian Children ◽

Uremic Syndrome

Background. Atypical hemolytic uremic syndrome (aHUS) is an important cause of acute kidney injury in children. It is primarily caused by dysregulation of the complement alternative pathway due to genetic mutations, mainly in complement factor H genes, or due to anti-factor H autoantibodies (anti-FH), leading to uncontrolled overactivation of the complement system. Early diagnosis and treatment of autoimmune HUS (AI-HUS) is essential and leads to a favorable outcome. Methods. Fifty pediatric HUS patients and 50 age- and sex-matched controls were included in the study. Patients were subjected to full history taking, clinical examination, and laboratory testing. All candidates were subjected to an assessment of anti-FH in serum by a homemade enzyme-linked immunosorbent assay technique. Results. A high frequency of serum anti-FH was detected in our aHUS patients. The disease onset of AI-HUS was mainly observed in March and April, with significantly higher rates in school-aged males. All patients who started immunosuppressives early together with plasmapheresis upon detection of their anti-FH had complete renal function recovery. Conclusion. The high frequency of AI-HUS revealed in Egyptian HUS children in our study highlights the importance of implementing anti-FH testing in Egypt to provide early recognition for immediate proper management, including early immunosuppressive therapy, and hence improving patient outcomes.

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IgM Autoantibodies to Complement Factor H in Atypical Hemolytic Uremic Syndrome

Journal of the American Society of Nephrology ◽

10.1681/asn.2020081224 ◽

2021 ◽

pp. ASN.2020081224

Author(s):

Massimo Cugno ◽

Silvia Berra ◽

Federica Depetri ◽

Silvana Tedeschi ◽

Samantha Griffini ◽

...

Keyword(s):

Bone Marrow ◽

Hemolytic Uremic Syndrome ◽

Bone Marrow Transplant ◽

Thrombotic Microangiopathy ◽

Atypical Hemolytic Uremic Syndrome ◽

Marrow Transplant ◽

Factor H ◽

Complement Factor ◽

Uremic Syndrome ◽

Factor H Autoantibodies

BackgroundAtypical hemolytic uremic syndrome (aHUS), a severe thrombotic microangiopathy, is often related to complement dysregulation, but the pathomechanisms remain unknown in at least 30% of patients. Researchers have described autoantibodies to complement factor H of the IgG class in 10% of patients with aHUS but have not reported anti-factor H autoantibodies of the IgM class.MethodsIn 186 patients with thrombotic microangiopathy clinically presented as aHUS, we searched for anti-factor H autoantibodies of the IgM class and those of the IgG and IgA classes. We used immunochromatography to purify anti-factor H IgM autoantibodies and immunoenzymatic methods and a competition assay with mapping mAbs to characterize interaction with the target protein.ResultsWe detected anti-factor H autoantibodies of the IgM class in seven of 186 (3.8%) patients with thrombotic microangiopathy presented as aHUS. No association was observed between anti-factor H IgM and homozygous deletions involving CFHR3-CFHR1. A significantly higher proportion of patients with bone marrow transplant–related thrombotic microangiopathy had anti-factor H IgM autoantibodies versus other patients with aHUS: three of 20 (15%) versus four of 166 (2.4%), respectively. The identified IgM autoantibodies recognize the SCR domain 19 of factor H molecule in all patients and interact with the factor H molecule, inhibiting its binding to C3b.ConclusionsDetectable autoantibodies to factor H of the IgM class may be present in patients with aHUS, and their frequency is six-fold higher in thrombotic microangiopathy forms associated with bone marrow transplant. The autoantibody interaction with factor H’s active site may support an autoimmune mechanism in some cases previously considered to be of unknown origin.

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Anti-Factor H Antibody-Associated Atypical Hemolytic Uremic Syndrome: A Case Report

PRILOZI ◽

10.2478/prilozi-2021-0029 ◽

2021 ◽

Vol 42 (2) ◽

pp. 109-115

Author(s):

Nora Abazi-Emini ◽

Emilija Sahpazova ◽

Jovana Putnik ◽

Velibor Tasic

Keyword(s):

Case Report ◽

Hemolytic Uremic Syndrome ◽

Alternative Pathway ◽

Atypical Hemolytic Uremic Syndrome ◽

Disease Onset ◽

Factor H ◽

Complement Factor ◽

Uremic Syndrome ◽

One Year ◽

Urine Testing

Abstract Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy, caused by dysregulation of the complement alternative pathway. Deletion of the complement factor H–related genes, CFHR1 and CFHR3, together with the presence of CFH autoantibodies are reported in aHUS patients, representing 10% of cases of patients with aHUS. Case presentation: We report here on a case of 4-year-old girl with anti-CFH antibody-associated aHUS. The measurement of complement factors and anti-factor H antibodies, was the main guideline for making an accurate diagnosis and providing the appropriate therapy, with the patient responding positively to plasma exchanges (PEs) and cyclophosphamide pulses. We then, one year after disease onset, continued with glucocorticoids and mycophenolate mofetil (MMF), as maintenance therapy. There were no complications during the therapy other than neutropenia. Now, one year after the cessation of the immune suppression therapy, she is in remission with normal kidney function, no signs of hemolysis, normal C3 levels, and normal range proteinuria. The anti-factor H autoantibody titer decreased but still remained positive, the factor H antigen values remained low all throughout. Close follow-up is applied with frequent urine testing and complete blood count with an intention for early detection of relapse of the disease. Conclusion: The purpose of this case report is to emphasize the value of complement factor measurements and also to separate anti-CFH antibody-associated aHUS as an entity, because immunosuppressive therapy provides an excellent response..

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