Which should be the correct treatment for monoclonal gammopathy of renal significance with complement alternative pathway dysregulation (C3 glomerulopathy and atypical hemolytic uremic syndrome): clone-directed or anticomplement therapy?

2018 ◽  
Vol 50 (7) ◽  
pp. 1365-1366 ◽  
Author(s):  
Mariana Ciocchini ◽  
Carlos G. Musso
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Monoclonal Gammopathy ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
C3 Glomerulopathy ◽  
Complement Alternative Pathway ◽  
Correct Treatment ◽  
Uremic Syndrome ◽  
Pathway Dysregulation

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.

scholarly journals C3 Glomerulopathy and Atypical Hemolytic Uremic Syndrome: Two Important Manifestations of Complement System Dysfunction

2018 ◽  
Vol 8 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Ravneet Bajwa ◽  
John A. DePalma ◽  
Taimoor Khan ◽  
Anmol Cheema ◽  
Sheila A. Kalathil ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Hemolytic Uremic Syndrome ◽  
Renal Dysfunction ◽  
Female Patient ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Organ Injury ◽  
C3 Glomerulopathy ◽  
Kidney Involvement ◽  
Uremic Syndrome

The advances in our understanding of the alternative pathway have emphasized that uncontrolled hyperactivity of this pathway causes 2 distinct disorders that adversely impact the kidney. In the so-called atypical hemolytic uremic syndrome (aHUS), renal dysfunction occurs along with thrombocytopenia, anemia, and target organ injury to multiple organs, most commonly the kidney. On the other hand, in the so-termed C3 glomerulopathy, kidney involvement is not associated with thrombocytopenia, anemia, or other system involvement. In this report, we present 2 cases of alternative pathway dysfunction. The 60-year-old female patient had biopsy-proven C3 glomerulopathy, while the 32-year-old female patient was diagnosed with aHUS based on renal dysfunction, thrombocytopenia, anemia, and normal ADAMTS-13 level. The aHUS patient was successfully treated with the monoclonal antibody (eculizumab) for complement blockade. The patient with C3 glomerulopathy did not receive the monoclonal antibody. In this patient, management focused on blood pressure and proteinuria control with an angiotensin-converting enzyme inhibitor. This article focuses on the clinical differences, pathophysiology, and treatment of aHUS and C3 glomerulopathy.

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 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.

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 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
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