Thrombotic microangiopathy and smoldering multiple myeloma after kidney transplant in a patient with MCP mutation

2021 ◽  
pp. 239936932110626
Author(s):  
Marina Almenara Tejederas ◽  
Laura De la Torre Corona ◽  
Fabiola Alonso García ◽  
María Ángeles Rodríguez Pérez ◽  
Rocío Cabrera Pérez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Biopsy ◽  
Kidney Transplant ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Membranoproliferative Glomerulonephritis ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Membrane Cofactor Protein ◽  
Susceptible Patient ◽  
Uremic Syndrome

The most frequent cause of atypical hemolytic uremic syndrome (aHUS) is defective regulation of complement activation because of genetic anomalies. We present the case of 53-year-old man with a kidney transplant and stabilized kidney function (creatinine 2.5 mg/dL; proteinuria 0.4 g/24 h) with mycophenolate/tacrolimus/prednisone who was diagnosed of Thrombotic Microangiopathy (TMA). This diagnosis was associated with creatinine and proteinuria rise (3 mg/dL; 2.4 g/24 h) and a new monoclonal IgA/lambda component. Renal biopsy showed membranoproliferative glomerulonephritis; a pathogenic variant in the Membrane cofactor protein (MCP) gene with a polymorphism ggaac, typically associated to secondary aHUS, was identified. We suspected that immunoglobulin could be acting as a trigger for TMA in a genetically susceptible patient, so “clone-directed” therapy with bortezomib and dexamethasone was initiated.

scholarly journals Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Sigridur Sunna Aradottir ◽  
Ann-Charlotte Kristoffersson ◽  
Lubka T. Roumenina ◽  
Anna Bjerre ◽  
Pavlos Kashioulis ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hemolytic Uremic Syndrome ◽  
Complement Activation ◽  
Membranoproliferative Glomerulonephritis ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Complement Factor ◽  
Gain Of Function ◽  
Factor B ◽  
Glomerular Endothelial Cells ◽  
Uremic Syndrome

Complement factor B (FB) mutant variants are associated with excessive complement activation in kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy and membranoproliferative glomerulonephritis (MPGN). Patients with aHUS are currently treated with eculizumab while there is no specific treatment for other complement-mediated renal diseases. In this study the phenotype of three FB missense variants, detected in patients with aHUS (D371G and E601K) and MPGN (I242L), was investigated. Patient sera with the D371G and I242L mutations induced hemolysis of sheep erythrocytes. Mutagenesis was performed to study the effect of factor D (FD) inhibition on C3 convertase-induced FB cleavage, complement-mediated hemolysis, and the release of soluble C5b-9 from glomerular endothelial cells. The FD inhibitor danicopan abrogated C3 convertase-associated FB cleavage to the Bb fragment in patient serum, and of the FB constructs, D371G, E601K, I242L, the gain-of-function mutation D279G, and the wild-type construct, in FB-depleted serum. Furthermore, the FD-inhibitor blocked hemolysis induced by the D371G and D279G gain-of-function mutants. In FB-depleted serum the D371G and D279G mutants induced release of C5b-9 from glomerular endothelial cells that was reduced by the FD-inhibitor. These results suggest that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations.

scholarly journals HUS and the case for complement

Blood ◽  
2015 ◽  
Vol 126 (18) ◽  
pp. 2085-2090 ◽  
Author(s):  
Edward M. Conway
Keyword(s):  
Escherichia Coli ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Response To Treatment ◽  
Microangiopathic Hemolytic Anemia ◽  
New Knowledge ◽  
Uremic Syndrome

Abstract Hemolytic-uremic syndrome (HUS) is a thrombotic microangiopathy that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Excess complement activation underlies atypical HUS and is evident in Shiga toxin–induced HUS (STEC-HUS). This Spotlight focuses on new knowledge of the role of Escherichia coli–derived toxins and polyphosphate in modulating complement and coagulation, and how they affect disease progression and response to treatment. Such new insights may impact on current and future choices of therapies for STEC-HUS.

Efficacy and Safety of Eculizumab in Kidney Transplant Patients With Primary Atypical Hemolytic-Uremic Syndrome

2021 ◽  
Author(s):  
Cristina Casas González ◽  
Verónica López-Jiménez ◽  
Teresa Vázquez-Sánchez ◽  
Elena Vázquez-Sánchez ◽  
Mercedes Cabello ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Kidney Transplant ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Efficacy And Safety ◽  
Transplant Patients ◽  
Uremic Syndrome ◽  
Kidney Transplant Patients

scholarly journals Complement Activation and Thrombotic Microangiopathies

2019 ◽  
Vol 14 (12) ◽  
pp. 1719-1732 ◽  
Author(s):  
Marta Palomo ◽  
Miquel Blasco ◽  
Patricia Molina ◽  
Miquel Lozano ◽  
Manuel Praga ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hemolytic Uremic Syndrome ◽  
Acute Phase ◽  
Complement Activation ◽  
Hellp Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Malignant Hypertension ◽  
Clinical Relapse ◽  
Thrombotic Microangiopathies ◽  
Uremic Syndrome

Background and objectivesAtypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response.Design, setting, participants, & measurementsComplement activation was assessed by exposing endothelial cells to sera or activated-patient plasma—citrated plasma mixed with a control sera pool (1:1)—to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included.ResultsAcute phase atypical hemolytic uremic syndrome–activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6–9 months. Complement activation in those with malignant hypertension was at control levels.ConclusionsThe proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.

scholarly journals Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome

2019 ◽  
Vol 30 (12) ◽  
pp. 2449-2463 ◽  
Author(s):  
Julien Zuber ◽  
Marie Frimat ◽  
Sophie Caillard ◽  
Nassim Kamar ◽  
Philippe Gatault ◽  
...  
Keyword(s):  
Cohort Study ◽  
Hemolytic Uremic Syndrome ◽  
Kidney Transplant ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Population Based ◽  
Adult Patients ◽  
Transplant Recipients ◽  
Risk Of Recurrence ◽  
Atypical Hus ◽  
Uremic Syndrome

BackgroundAtypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade–based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country.MethodsTo evaluate this strategy’s effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (n=397) between 2007 and 2016.ResultsThe first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients.ConclusionsResults from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.

Sign in / Sign up

Export Citation Format

Share Document