scholarly journals CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

2020 ◽  
Vol 31 (2) ◽  
pp. 241-256 ◽  
Author(s):  
Peter F. Zipfel ◽  
Thorsten Wiech ◽  
Emma D. Stea ◽  
Christine Skerka
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Kidney Diseases ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Human Kidney ◽  
Copy Number Variations ◽  
Factor H ◽  
C3 Glomerulopathy ◽  
Hybrid Proteins ◽  
Genetic Modifications ◽  
Uremic Syndrome

Sequence and copy number variations in the human CFHR–Factor H gene cluster comprising the complement genes CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, and Factor H are linked to the human kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alterations, deletions, or duplications generate hybrid or mutant CFHR genes, as well as hybrid CFHR–Factor H genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging: CFHR1, CFHR3, and Factor H gene alterations combined with intact CFHR2, CFHR4, and CFHR5 genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the five CFHR genes in the context of an intact Factor H gene are described in C3 glomerulopathy. These genetic modifications influence complement function and the interplay of the five FHR proteins with each other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology is of high interest for diagnosis and therapy.

scholarly journals Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia

2018 ◽  
Vol 29 (7) ◽  
pp. 1928-1937 ◽  
Author(s):  
Yoshiyasu Ueda ◽  
Takashi Miwa ◽  
Damodar Gullipalli ◽  
Sayaka Sato ◽  
Daisuke Ito ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Murine Model ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
C3 Glomerulopathy ◽  
P Deficiency ◽  
Renal Histology ◽  
Uremic Syndrome ◽  
Alternative Pathway Of Complement

Background Properdin (P) is a positive regulator of the alternative pathway of complement activation. Although P inhibition is expected and has been shown to ameliorate the alternative pathway of complement-mediated tissue injury in several disease models, it unexpectedly exacerbated renal injury in a murine model of C3 glomerulopathy. The role of P in atypical hemolytic uremic syndrome (aHUS) is uncertain.Methods We blocked P function by genetic deletion or mAb-mediated inhibition in mice carrying a factor H (FH) point mutation, W1206R (FHR/R), that causes aHUS and systemic thrombophilia with high mortality.Results P deficiency completely rescued FHR/R mice from premature death and prevented thrombocytopenia, hemolytic anemia, and renal disease. It also eliminated macrovessel thrombi that were prevalent in FHR/R mice. All mice that received a function-blocking anti-P mAb for 8 weeks survived the experimental period and appeared grossly healthy. Platelet counts and hemoglobin levels were significantly improved in FHR/R mice after 4 weeks of anti-P mAb treatment. One half of the FHR/R mice treated with an isotype control mAb but none of the anti-P mAb-treated mice developed stroke-related neurologic disease. Anti-P mAb-treated FHR/R mice showed largely normal renal histology, and residual liver thrombi were detected in only three of 15 treated mice.Conclusions These results contrast with the detrimental effect of P inhibition observed in a murine model of C3 glomerulopathy and suggest that P contributes critically to aHUS pathogenesis. Inhibition of P in aHUS may be of therapeutic benefit.

Atypical Hemolytic Uremic Syndrome Associated with Complement Factor H Mutation and IgA Nephropathy: A Case Report Successfully Treated with Eculizumab

Nephron ◽  
2017 ◽  
Vol 138 (4) ◽  
pp. 324-327 ◽  
Author(s):  
Hironori Nakamura ◽  
Mariko Anayama ◽  
Mutsuki Makino ◽  
Yasushi Makino ◽  
Katsuhiko Tamura ◽  
...  
Keyword(s):  
Case Report ◽  
Hemolytic Uremic Syndrome ◽  
Iga Nephropathy ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Uremic Syndrome ◽  
Factor H Mutation

scholarly journals Factor H gene variants in Japanese: Its relation to atypical hemolytic uremic syndrome

2011 ◽  
Vol 49 (1-2) ◽  
pp. 48-55 ◽  
Author(s):  
Saki Mukai ◽  
Yoshihiko Hidaka ◽  
Masako Hirota-Kawadobora ◽  
Kazuyuki Matsuda ◽  
Noriko Fujihara ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Gene Variants ◽  
H Gene ◽  
Uremic Syndrome

scholarly journals Case Report: Lipoprotein Glomerulopathy Complicated by Atypical Hemolytic Uremic Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Lara Kollbrunner ◽  
Patricia Hirt-Minkowski ◽  
Javier Sanz ◽  
Elena Bresin ◽  
Thomas J. Neuhaus ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor ◽  
Inherited Disease ◽  
Lipoprotein Glomerulopathy ◽  
Gene Encoding ◽  
Alternative Complement ◽  
Uremic Syndrome ◽  
The Complement System

Lipoprotein glomerulopathy (LPG) is a rare inherited disease caused by mutations in the APOE gene, encoding apolipoprotein E (apoE). Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by overactivation of the alternative complement pathway. Here we report the case of a 21-year-old man with LPG who developed aHUS. A functional complement assay demonstrated an overactivation of the complement system. Complementary genetic analysis revealed a homozygous aHUS risk allele for complement factor-H related 1 (CFHR1), CFHR1*B. To the best of our knowledge, this is the first report of an aHUS in a patient with LPG.

scholarly journals Familial Atypical Hemolytic Uremic Syndrome with Positive pS1191L (c.3572C> T) Mutation in CFH A Single-Center Experience

2019 ◽  
Author(s):  
Fadime ERSOY DURSUN ◽  
Gözde YESIL ◽  
Hasan DURSUN ◽  
Gülşah SASAK
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Family History ◽  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Gene Mutations ◽  
Factor H ◽  
The Other ◽  
History Of ◽  
Uremic Syndrome

Abstract Background: Atypical hemolytic uremic syndrome is a condition characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, which can exhibit a poor prognosis. Gene mutations play a key role in this disease, which may be sporadic or familial. Methods: We studied, 13 people from the same family were investigated retrospectively for gene mutations of familial atypical hemolytic uremic syndrome after a patient presented to our emergency clinic with atypical hemolytic uremic syndrome and reported a family history of chronic renal failure. Results: The pS1191L mutation in the complement factor H gene was heterozygous in 6 people from the family of the patient with atypical hemolytic uremic syndrome. One of these people was our patient with acute renal failure and the other two are followed up by the Nephrology Clinic due to chronic renal failure. The other 3 persons showed no evidence of renal failure. The index case had a history of 6 sibling deaths; two of them died of chronic renal failure. Plasmapheresis and fresh frozen plasma treatment was given to our patient. When patient showed no response to this treatment, eculizumab therapy was started. Conclusions: The study demonstrated that a thorough family history should be taken in patients with atypical hemolytic uremic syndrome. These patients may have familial type of the disease and they should be screened genetically. Eculizumab should be the first choice in the treatment with plasmapheresis. It should be kept in mind that the use of eculizumab as prophylaxis in post-transplant therapy is extremely important for prevention of rejection.

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