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Bocanegra V, Luna M, Costantino VV, Lorenzo AFG, Marino R, Miatello R, Cacciamani V, Benardon ME, Godoy CP, Pinto S, de Córdoba SR, Vallés PG. The role of the complement system in Shiga toxin-associated hemolytic uremic syndrome. Pediatr Nephrol 2025; 40:1711-1722. [PMID: 39792253 DOI: 10.1007/s00467-024-06629-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/21/2024] [Accepted: 11/22/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND This research explores complement activation products involvement and risk and protective polymorphisms in the complement alternative pathway genes in Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS) pathogenesis. METHODS We analyzed the levels of complement activation products, C3a, C5a and soluble C5b-9 (sC5b-9) and plasma concentrations of Factor H (FH) and FH-related protein 1 (FHR-1) in 44 patients with STEC-HUS, 12 children with STEC-positive diarrhea (STEC-D), and 72 healthy controls (HC). STEC-HUS cases were classified as "severe" or "non-severe". Genetic analysis was performed for complement genes (CFH, CFB, MCP, C3). RESULTS No significant differences in the frequency of atypical HUS (aHUS) complement risk polymorphisms were found between groups. In severe STEC-HUS, the risk haplotypes CFH-H3 and MCPggaac were identified in three patients each, all in homozygosity. Patients with STEC-HUS had significantly elevated C3a, C5a and sC5b-9 levels at admission compared to HC and STEC-D, with higher sC5b-9 levels in severe cases. Increased ratio between FHR-1 and FH (FHR-1/FH) was demonstrated in STEC-HUS vs. HC, with significantly higher FHR-1/FH ratio in severe STEC-HUS patients. Principal component analysis revealed significant changes in sC5b-9 direction and magnitude in STEC-HUS. Pearson correlation showed a significant relationship between FH and sC5b-9. Logistic regression indicated sC5b-9, leukocytosis, creatinine, and anuria duration as independent factors for severe STEC- HUS. CONCLUSIONS This study highlights the significant activation of the alternative complement pathway in STEC-HUS, particularly sC5b-9 in severe cases, and suggests a limited contribution of complement risk polymorphisms in STEC-HUS. FHR-1 may represent a promising target for future investigations related to STEC-HUS pathogenesis.
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Affiliation(s)
- Victoria Bocanegra
- Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Mariana Luna
- Hospital Pediátrico H. Notti, Mendoza, Argentina
| | - Valeria V Costantino
- Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | | | - Raul Marino
- Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Roberto Miatello
- Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Valeria Cacciamani
- Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - M Eugenia Benardon
- Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | | | - Sheila Pinto
- Centro de Investigaciones Biológicas Margarita Salas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain
| | - Santiago Rodríguez de Córdoba
- Centro de Investigaciones Biológicas Margarita Salas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain
| | - Patricia G Vallés
- Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina.
- Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
- Hospital Pediátrico H. Notti, Mendoza, Argentina.
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Lax N, Davidovits M, Chodick G, Bernfeld Y, Peled O. Eculizumab is efficacious and safe in pediatric patients with various forms of hemolytic uremic syndrome: a retrospective clinical experience of a tertiary center. Front Pharmacol 2025; 16:1535407. [PMID: 40255570 PMCID: PMC12006164 DOI: 10.3389/fphar.2025.1535407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/25/2025] [Indexed: 04/22/2025] Open
Abstract
Background Eculizumab, a terminal complement inhibitor, prevents thrombotic microangiopathy (TMA) and multiorgan damage in hemolytic uremic syndrome (HUS). We evaluated its efficacy and safety in pediatric patients with TMA sub-types: atypical HUS (aHUS), Shiga toxin-producing Escherichia coli (STEC)-HUS, and transplant-associated TMA (TA-TMA). Methods This retrospective study included all pediatric patients treated with eculizumab for HUS at Schneider Children's Medical Center (2011-2020), including those with pre-existing end-stage kidney disease. Clinical and laboratory parameters were analyzed over 28 weeks. The primary endpoint was achievement of complete TMA response, defined by sustained normalization of hematologic parameters and renal function. Secondary endpoints included TMA event-free status and additional clinical improvements. Results Twenty-four pediatric patients (median age 5.8 years) were included: 13 with aHUS, 5 with STEC-HUS, and 6 with TA-TMA. A complete TMA response was achieved in 12 (50%) of the patients overall: 7 (54%) with aHUS, 3 (60%) with STEC-HUS, and 2 (33%) with TA-TMA. TMA event-free status was reached in 15 (63%) patients. Significant improvements were observed in platelet count (63%), lactate dehydrogenase levels (76% within the first week), hemoglobin (60%), and estimated glomerular filtration rate (79%); while CH-50 levels decreased. No severe adverse events were attributed to eculizumab. Chronic kidney disease stage improved for 17 (90%). Conclusion The efficacy and safety of eculizumab for three TMA subtypes in pediatric patients potentially expands its therapeutic applications. The complete TMA response rate in aHUS supports eculizumab as a first-line use, while the response rate in STEC-HUS suggests potential efficacy beyond eculizumab's primary indication. The early hematologic responses and reduced CH-50 levels confirm the role of eculizumab complement-mediated HUS and underscore the need for further research in TA-TMA.
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Affiliation(s)
- Naama Lax
- Department of Pharmacy, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
| | - Miriam Davidovits
- Institute of Nephrology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Gabriel Chodick
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel
| | - Yael Bernfeld
- Department of Pharmacy, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
| | - Orit Peled
- Department of Pharmacy, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
- Adelson School of Medicine, Ariel University, Ariel, Israel
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Abe T, Saito K, Nagano T, Yamada Y, Ochiai H. Complement system activation through the alternative pathway associates with disseminated intravascular coagulation to increase mortality in sepsis. Thromb Res 2025; 247:109281. [PMID: 39952229 DOI: 10.1016/j.thromres.2025.109281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/04/2025] [Accepted: 02/03/2025] [Indexed: 02/17/2025]
Abstract
BACKGROUND Sepsis-induced disseminated intravascular coagulation (DIC) increases mortality in sepsis patients. Complement system activation is concomitant with sepsis-induced DIC; however, it is unclear how these two pathologies influence clinical parameters of sepsis individually and in combination, and which of the complement pathways activation is predominantly associated with mortality. METHODS In this ancillary analysis of a prospective observational study, 49 adult sepsis patients were assigned to four groups according to the absence/presence of DIC and complement activation. Effects of complement activation and DIC on clinical demographics including parameters of DIC, systemic severities, and 60-days all-cause mortality were assessed by comparing the groups. We analyzed each complement pathway by comparing Bb, C3a/C3 ratio, SC5b-9/C3 ratio, C4d, C4d/C4 ratio, C3a, C5a, and SC5b-9 between survivors/non-survivors both in all the patients and in the DIC+ subgroup. RESULTS Complement system activation induced thrombocytopenia and enhanced sepsis severity measured as APACHE2 and SOFA scores. 60-days all-cause mortality was different between groups, with 0 % in the complement activation alone group, 14 % in the DIC alone group and 66 % in the combined DIC and complement activation group. Bb and C3a/C3 and SC5b-9/C3 ratios were higher in non-survivors, with Bb and SC5b-9/C3 ratio still higher in DIC+ non-survivors. CONCLUSION Complement activation worsen the severity of sepsis and cause thrombocytopenia. Co-occurrence of complement activation and DIC increased sepsis mortality. The alternative pathway of complement activation plays a major role in sepsis mortality.
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Affiliation(s)
- Tomohiro Abe
- Department of Emergency and Critical Care Medicine, University of Miyazaki Hospital, Miyazaki, Japan; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
| | - Katsutoshi Saito
- Department of Emergency and Critical Care Medicine, University of Miyazaki Hospital, Miyazaki, Japan; Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
| | - Takehiko Nagano
- Department of Emergency and Critical Care Medicine, University of Miyazaki Hospital, Miyazaki, Japan; Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
| | - Yusuke Yamada
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan; Yamada Clinic, Akune, Kagoshima, Japan
| | - Hidenobu Ochiai
- Department of Emergency and Critical Care Medicine, University of Miyazaki Hospital, Miyazaki, Japan
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Inatomi A, Tokoro S, Katsura D, Sawai T, Murakami T. The Critical Importance of Diagnosing Atypical Hemolytic Uremic Syndrome in Postpartum Renal Dysfunction in a Patient With Systemic Lupus Erythematosus: A Case Report and Comprehensive Review. Cureus 2025; 17:e78989. [PMID: 40092016 PMCID: PMC11910887 DOI: 10.7759/cureus.78989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2025] [Indexed: 03/19/2025] Open
Abstract
This case report describes a rare instance of a 33-year-old woman with systemic lupus erythematosus (SLE) who experienced a pregnancy complicated by preeclampsia, eclampsia, and postpartum atypical hemolytic uremic syndrome (aHUS). At 28 weeks and four days of gestation, the patient presented with severe hypertension, proteinuria, and a loss of consciousness, leading to an emergency cesarean section. Postoperatively, the patient developed acute kidney injury, respiratory failure, and thrombotic microangiopathy (TMA). Although she exhibited the classic triad of hemolytic anemia, thrombocytopenia, and renal dysfunction, normal complement levels ruled out postpartum exacerbation of SLE, and aHUS was not diagnosed during hospitalization. Differential diagnoses, including HELLP (Hemolysis, Elevated Liver Enzyme levels, and Low Platelet levels) syndrome, thrombotic thrombocytopenic purpura, and Shiga toxin-producing Escherichia coli (STEC)-HUS, were excluded. Schistocytes appeared on postoperative day 5, leading to the cessation of tacrolimus and the initiation of prednisolone. Continuous hemodiafiltration and mechanical ventilation facilitated gradual recovery, and the patient was discharged on postoperative day 26. Post-discharge genetic testing revealed no pathogenic mutations; however, the clinical presentation supported a diagnosis of aHUS. aHUS driven by excessive complement activation requires prompt recognition and treatment with plasma exchange or anti-complement monoclonal antibodies (e.g., eculizumab). In this case, delayed recognition of aHUS precluded the use of such therapies. This case highlights the importance for clinicians to consider the possibility of aHUS in postpartum patients with severe renal dysfunction and TMA symptoms, even if the patient has an underlying SLE, as early diagnosis and treatment of aHUS is necessary to improve maternal outcomes.
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Affiliation(s)
- Ayako Inatomi
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Otsu, JPN
| | - Shinsuke Tokoro
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Otsu, JPN
| | - Daisuke Katsura
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Otsu, JPN
| | - Toshihiro Sawai
- Department of Pediatrics, Shiga University of Medical Science, Otsu, JPN
| | - Takashi Murakami
- Department of Obstetrics and Gynecology, Shiga University of Medical Science, Otsu, JPN
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Kaname S, Ong ML, Mathias J, Gatta F, Law L, Wang Y. Outcomes in patients with thrombotic microangiopathy associated with a trigger following plasma exchange: A systematic literature review. Transfus Apher Sci 2025; 64:104048. [PMID: 39729821 DOI: 10.1016/j.transci.2024.104048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2024]
Abstract
Plasma exchange (PE) outcomes in patients with trigger-associated thrombotic microangiopathy (TMA) have not been comprehensively reviewed. Embase and MEDLINE® were searched on 03/14/2022 for English language articles published after 2007, alongside a congress materials search (2019-2022; PROSPERO: CRD42022325170). Studies with patients with trigger-associated TMA (excluding thrombotic thrombocytopenic purpura, 'typical' hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli, post-partum TMA, and TMAs with known genetic cause) who received PE or plasma infusion (PI) and reported treatment response (including measures), safety, patient-/caregiver-reported outcomes, or economic burden data were examined. The NICE quality appraisal checklist assessed bias risk. After screening 695 articles, 49 PE or PI studies were identified, of which 42 reported PE exclusively; most were retrospective observational studies (n = 37). The most common TMA trigger was transplantation (n = 12). The median number of PE sessions was 3.5-25.0. Outcomes following PE varied by trigger type. Treatment response rates and definitions varied (0-100 %; 24 studies); in studies of > 25 patients, response rates were 5-63 %. TMA relapse rates were 0-67 % (7 studies). Mortality was 10-91 % (23 studies). Progression to chronic kidney disease (CKD; 5 studies) and end-stage renal disease (ESRD; 6 studies) occurred in 0-93 % and 17-100 % of patients, respectively. Two serious adverse events were identified (transfusion-related injury, acute lung injury; 10 studies; 231 patients). Patients with trigger-associated TMA may experience a substantial burden in terms of mortality, relapse, and progression to CKD and ESRD following PE, leading to increased healthcare resource utilization. Additional interventions may be required.
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Affiliation(s)
- Shinya Kaname
- Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
| | - Moh-Lim Ong
- Alexion, AstraZeneca Rare Disease, 121 Seaport Blvd, Boston, MA 02210, USA.
| | - Jonathan Mathias
- Alexion, AstraZeneca Rare Disease, 121 Seaport Blvd, Boston, MA 02210, USA.
| | - Francesca Gatta
- Alexion Pharma GmbH, AstraZeneca Rare Disease, Neuhofstrasse 34, Baar 6340, Switzerland.
| | - Lisa Law
- At the Time of the Study: Oxford PharmaGenesis Ltd, Tubney Warren Barn, Tubney, Abingdon, Oxford OX13 5QJ, UK.
| | - Yan Wang
- Alexion, AstraZeneca Rare Disease, 121 Seaport Blvd, Boston, MA 02210, USA.
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Yang Y, Li XJ, Yuan HY, Xiong JJ, Li PF, Wang Z. Severe pregnancy-associated atypical hemolytic uremia syndrome in the context of the COVID-19 pandemic: a novel survival case report. BMC Pregnancy Childbirth 2025; 25:93. [PMID: 39885445 PMCID: PMC11780773 DOI: 10.1186/s12884-025-07212-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 01/21/2025] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND Pregnancy-associated atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by uncontrolled activation of the complement system during pregnancy or the postpartum period. In the intensive care unit, aHUS must be differentiated from sepsis-related multiple organ dysfunction, thrombotic thrombocytopenic purpura (TTP), hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome. Early recognition of aHUS is critical for effective treatment and improved prognosis. Although tests such as the ADAMTS13 level, peripheral blood smears, complement testing, and blood cultures are useful for diagnosing aHUS, these tests are time-consuming and may not be widely available. This report describes a case of severe aHUS in a pregnant woman during the coronavirus disease 2019 (COVID-19) pandemic. CASE PRESENTATION A 26-year-old patient with a history of four pregnancies and one delivery (P4G1) presented at 30 weeks and 2 days of gestation with vaginal fluid leakage and fetal growth restriction detected by ultrasound at a different hospital. During labor induction, the patient developed a high fever and coagulopathy, followed by heart failure, acute kidney injury, anemia, and severe thrombocytopenia. The patient remained alert and coherent, with no evidence of neurological dysfunction. She was transferred to our department and was given invasive respiratory support, blood transfusion, continuous renal replacement therapy, capacity management, and other comprehensive treatments. Due to the ongoing COVID-19 pandemic, ADAMTS13 testing and complement inhibitor therapy were unavailable. A diagnosis of pregnancy-associated aHUS was made based on the patient's history, clinical presentation, and standard laboratory results. The patient was prescribed 13 sessions of hemodialysis. Post-treatment evaluation showed normalized complement C3 and C4 levels, stabilized platelet and hemoglobin levels, and gradual normalization of liver function. Renal function improved gradually, and a bone marrow biopsy revealed no fragmented red blood cells. The patient was transferred to the Department of Nephrology on day 40 and back to the local hospital on day 42. The patient was followed up for 3 years, during which her renal function returned to normal, with no recurrence of thrombocytopenia or microangiopathic hemolytic anemia. CONCLUSIONS This case highlights the challenges and importance of diagnosing and managing pregnancy-associated aHUS and multiple organ failure in a low-resource setting.
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Affiliation(s)
- Yan Yang
- Department of Intensive Care Medicine, Army Medical Center of PLA, No. 10 Changjiang Road, Yuzhong District, Chongqing, 400010, People's Republic of China
| | - Xiao-Jin Li
- Department of Neurology, Nanchuan Hospital Affiliated to Chongqing Medical University, 16 South Street, Nanchuan District, Chongqing, China
| | - Hua-Yan Yuan
- Department of Intensive Care Medicine, Army Medical Center of PLA, No. 10 Changjiang Road, Yuzhong District, Chongqing, 400010, People's Republic of China
| | - Jing-Jing Xiong
- Department of Intensive Care Medicine, Army Medical Center of PLA, No. 10 Changjiang Road, Yuzhong District, Chongqing, 400010, People's Republic of China
| | - Peng-Fei Li
- Department of Intensive Care Medicine, Army Medical Center of PLA, No. 10 Changjiang Road, Yuzhong District, Chongqing, 400010, People's Republic of China.
| | - Zhen Wang
- Department of Intensive Care Medicine, Army Medical Center of PLA, No. 10 Changjiang Road, Yuzhong District, Chongqing, 400010, People's Republic of China.
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Landivar SM, Melli LJ, Maiztegui C, Schesi C, Baschkier A, Francisetti V, Chinen I, Miliwebsky E, Rivas M, Comerci DJ, Ugalde JE, Ciocchini AE. A novel multiplex and glycoprotein-based immunochromatographic serologic IgM test for the rapid diagnosis of Escherichia coli O157 and O145 causing bloody diarrhea and hemolytic uremic syndrome. J Clin Microbiol 2024; 62:e0100324. [PMID: 39480070 PMCID: PMC11633091 DOI: 10.1128/jcm.01003-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 10/01/2024] [Indexed: 11/02/2024] Open
Abstract
Shiga toxin-producing Escherichia coli (STEC) are the main etiological agents of hemolytic uremic syndrome (HUS). Good clinical management of STEC infections and HUS depends on early, rapid, and accurate diagnosis. Here, we have developed and evaluated the first multiplex and glycoprotein-based immunochromatographic test for the detection of IgM antibodies against the O-polysaccharide of the lipopolysaccharide of E. coli O157 and O145 in human serum samples. A retrospective study was carried out resulting in a diagnostic sensitivity of the E. coli O157/O145 LFIA (lateral flow immunoassay) of 97.1% and 98.9% for O157 and O145, respectively, and 97.9% for both serogroups. The diagnostic specificity was 98.7% for O157 and O145, and the overall specificity 97.4%. In samples obtained before 3 days after the onset of diarrhea, the detection percentage was 83%, increasing to 100% from 3 days onward. Finally, the association of bloody diarrhea (BD) or HUS cases to an STEC infection increased from 22.8% to 77.2% when stool culture and stx/Stx detection were combined with serology by LFIA. Our results demonstrate that the E. coli O157/O145 LFIA is a highly accurate and serospecific test for the early and rapid diagnosis of E. coli O157 and O145 infections in BD or HUS cases. This test allows the detection of specific IgM antibodies very early in the course of the infection, making it an ideal diagnostic tool to be implemented in pediatric emergencies and, thus, avoid delays in the application of the correct supportive or specific treatment and prevent complications associated with HUS.
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Affiliation(s)
- Stella M. Landivar
- Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín, San Martín, Buenos Aires, Argentina
| | - Luciano J. Melli
- Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín, San Martín, Buenos Aires, Argentina
- Chemtest Argentina S. A., San Martín, Buenos Aires, Argentina
| | - Cynthia Maiztegui
- Laboratorio Nacional de Referencia, Servicio Fisiopatogenia, Instituto Nacional de Enfermedades Infecciosas-ANLIS Dr. Carlos G. Malbrán, Ciudad Autónoma de Buenos Aires, Argentina
| | - Carla Schesi
- Laboratorio Nacional de Referencia, Servicio Fisiopatogenia, Instituto Nacional de Enfermedades Infecciosas-ANLIS Dr. Carlos G. Malbrán, Ciudad Autónoma de Buenos Aires, Argentina
| | - Ariela Baschkier
- Laboratorio Nacional de Referencia, Servicio Fisiopatogenia, Instituto Nacional de Enfermedades Infecciosas-ANLIS Dr. Carlos G. Malbrán, Ciudad Autónoma de Buenos Aires, Argentina
| | - Valeria Francisetti
- Laboratorio Central de la Provincia de Córdoba, Ministerio de Salud de la Provincia de Córdoba, Córdoba, Argentina
| | - Isabel Chinen
- Laboratorio Nacional de Referencia, Servicio Fisiopatogenia, Instituto Nacional de Enfermedades Infecciosas-ANLIS Dr. Carlos G. Malbrán, Ciudad Autónoma de Buenos Aires, Argentina
| | - Elizabeth Miliwebsky
- Laboratorio Nacional de Referencia, Servicio Fisiopatogenia, Instituto Nacional de Enfermedades Infecciosas-ANLIS Dr. Carlos G. Malbrán, Ciudad Autónoma de Buenos Aires, Argentina
| | - Marta Rivas
- Laboratorio Nacional de Referencia, Servicio Fisiopatogenia, Instituto Nacional de Enfermedades Infecciosas-ANLIS Dr. Carlos G. Malbrán, Ciudad Autónoma de Buenos Aires, Argentina
- Inmunova S. A., San Martin, Buenos Aires, Argentina
| | - Diego J. Comerci
- Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín, San Martín, Buenos Aires, Argentina
| | - Juan E. Ugalde
- Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín, San Martín, Buenos Aires, Argentina
| | - Andrés E. Ciocchini
- Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín, San Martín, Buenos Aires, Argentina
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Fodor TA, Schmook MT, Brücke C. Pearls & Oy-sters: Neurologic Involvement in Shiga Toxin-Associated Hemolytic Uremic Syndrome. Neurology 2024; 103:e209881. [PMID: 39378389 DOI: 10.1212/wnl.0000000000209881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024] Open
Abstract
Shiga toxin-producing Escherichia coli (STEC) is among the most common pathogens that cause bacterial enteritis. They can also lead to extraintestinal manifestations including hemolytic uremic syndrome (HUS), which is defined by the triad of hemolytic anemia, thrombocytopenia, and acute renal dysfunction due to Shiga toxin-mediated damage to the vascular endothelium with a subsequent inflammatory reaction and thrombotic microangiopathy. The thrombotic microangiopathy mainly affects the small blood vessels of the kidneys and brain. Neurologic involvement, especially in adults, is rare but can include nonspecific symptoms such as a decreased consciousness, altered mental status, seizures, and hyperreflexia. Although HUS is often assumed to cause isolated involvement of small vessels, in this case report, a 52-year-old woman with a STEC-HUS-encephalopathy developed multiple craniocervical dissections during the course of her disease in the absence of any trauma or cardiovascular risk factors. This case thus could possibly indicate that Shiga toxin-mediated damages are not limited to the small vessels but can also affect larger vessels.
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Affiliation(s)
- Tekla A Fodor
- From the Department of Neurology (T.A.F., C.B.), and Department of Biomedical Imaging and Image-guided Therapy (M.T.S.), Medical University of Vienna, Austria
| | - Maria T Schmook
- From the Department of Neurology (T.A.F., C.B.), and Department of Biomedical Imaging and Image-guided Therapy (M.T.S.), Medical University of Vienna, Austria
| | - Christof Brücke
- From the Department of Neurology (T.A.F., C.B.), and Department of Biomedical Imaging and Image-guided Therapy (M.T.S.), Medical University of Vienna, Austria
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Stark K, Kilani B, Stockhausen S, Busse J, Schubert I, Tran TD, Gaertner F, Leunig A, Pekayvaz K, Nicolai L, Fumagalli V, Stermann J, Stephan F, David C, Müller MB, Heyman B, Lux A, da Palma Guerreiro A, Frenzel LP, Schmidt CQ, Dopler A, Moser M, Chandraratne S, von Brühl ML, Lorenz M, Korff T, Rudelius M, Popp O, Kirchner M, Mertins P, Nimmerjahn F, Iannacone M, Sperandio M, Engelmann B, Verschoor A, Massberg S. Antibodies and complement are key drivers of thrombosis. Immunity 2024; 57:2140-2156.e10. [PMID: 39226900 DOI: 10.1016/j.immuni.2024.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 05/17/2024] [Accepted: 08/07/2024] [Indexed: 09/05/2024]
Abstract
Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcμR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.
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Affiliation(s)
- Konstantin Stark
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany.
| | - Badr Kilani
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Sven Stockhausen
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Johanna Busse
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Irene Schubert
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Thuy-Duong Tran
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Florian Gaertner
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany; Institute of Science and Technology Austria, Klosterneuburg, Austria
| | - Alexander Leunig
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Kami Pekayvaz
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Leo Nicolai
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Valeria Fumagalli
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Julia Stermann
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Felix Stephan
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Christian David
- Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel Center for Experimental Medicine, Biomedical Center (BMC) LMU Munich, Munich, Germany
| | - Martin B Müller
- Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany; Department of Anaesthesiology, University Hospital, LMU Munich, Munich, Germany
| | - Birgitta Heyman
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Anja Lux
- Department of Biology, Institute of Genetics, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; Medical Immunology Campus Erlangen (MICE), Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Alexandra da Palma Guerreiro
- Department I of Internal Medicine, University Hospital Cologne, Cologne 50937, Germany; Center of Integrated Oncology ABCD, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50937, Germany
| | - Lukas P Frenzel
- Department I of Internal Medicine, University Hospital Cologne, Cologne 50937, Germany; Center of Integrated Oncology ABCD, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50937, Germany
| | - Christoph Q Schmidt
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
| | - Arthur Dopler
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
| | - Markus Moser
- Department of Molecular Medicine, Max-Planck-Institute of Biochemistry, Martinsried, Germany; Institute of Experimental Hematology, TranslaTUM, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Sue Chandraratne
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Marie-Luise von Brühl
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Michael Lorenz
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Thomas Korff
- Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
| | - Martina Rudelius
- Institute of Pathology, Ludwig-Maximilian University, Munich, Germany
| | - Oliver Popp
- Max Delbrück Center for Molecular Medicine (MDC) and Berlin Institute of Health (BIH), Berlin, Germany; German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
| | - Marieluise Kirchner
- Max Delbrück Center for Molecular Medicine (MDC) and Berlin Institute of Health (BIH), Berlin, Germany; German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
| | - Philipp Mertins
- Max Delbrück Center for Molecular Medicine (MDC) and Berlin Institute of Health (BIH), Berlin, Germany; German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
| | - Falk Nimmerjahn
- Department of Biology, Institute of Genetics, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; Medical Immunology Campus Erlangen (MICE), Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Matteo Iannacone
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Markus Sperandio
- Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel Center for Experimental Medicine, Biomedical Center (BMC) LMU Munich, Munich, Germany
| | - Bernd Engelmann
- Institut für Laboratoriumsmedizin, University Hospital, LMU Munich, Munich, Germany
| | - Admar Verschoor
- Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany; Department of Otorhinolaryngology, Technische Universität München and Klinikum Rechts der Isar, Munich, Germany.
| | - Steffen Massberg
- Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, Munich, Germany
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10
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Carrara C, Mataj B, Gastoldi S, Ruggenenti P, Sciascia S, Roccatello D. Case report: Timing of eculizumab treatment in catastrophic antiphospholipid syndrome. Front Immunol 2024; 15:1460317. [PMID: 39318635 PMCID: PMC11419984 DOI: 10.3389/fimmu.2024.1460317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 08/20/2024] [Indexed: 09/26/2024] Open
Abstract
Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening condition of small-vessel thrombosis with acute multiple-organ involvement and visceral damage. In this report, we present a case of a patient with CAPS who is refractory to conventional therapy. For the first time in a patient with CAPS, marked C5b-9 formation was demonstrated on microvascular endothelial cells, suggesting the usefulness of therapeutic complement inhibition in this setting. Eculizumab, a C5-blocking monoclonal antibody, is remarkably effective in the treatment of different forms of thrombotic microangiopathy by controlling complement system hyperactivation. It halted the "thrombotic storm" and promptly achieved full recovery of thrombocytopenia. However, kidney function did not recover, possibly because eculizumab was administered too late. Conceivably, the timing of treatment is crucial to achieving disease remission before irreversible structural damage occurs in target organs, thereby preventing their complete functional recovery.
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Affiliation(s)
- Camillo Carrara
- Unit of Nephrology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
- Istituto di Ricerche Farmacologiche Mario Negri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bergamo, Italy
| | - Blerina Mataj
- Unit of Nephrology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Sara Gastoldi
- Istituto di Ricerche Farmacologiche Mario Negri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bergamo, Italy
| | - Piero Ruggenenti
- Unit of Nephrology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
- Istituto di Ricerche Farmacologiche Mario Negri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bergamo, Italy
| | - Savino Sciascia
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) with Nephrology and Dialysis Unit and Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hub Hospital ASL Città di Torino and Department of Clinical and Biological Sciences, Turin, Italy
| | - Dario Roccatello
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) with Nephrology and Dialysis Unit and Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hub Hospital ASL Città di Torino and Department of Clinical and Biological Sciences, Turin, Italy
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11
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Wei S, Mei W, Wang Y. Association of thrombotic microangiopathy with interferon therapy for hepatitis B: a case report. J Med Case Rep 2024; 18:321. [PMID: 38965631 PMCID: PMC11225129 DOI: 10.1186/s13256-024-04635-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 06/02/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Thrombotic microangiopathy is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. The pathological features include vascular damage that is manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall. Thrombocytopenia is one of the common adverse effects of interferon therapy. However, a more serious but rare side effect is thrombotic microangiopathy. CASE PRESENTATION We report the case of a 36-year-old Asian male patient with clinical manifestations of hypertension, blurred vision, acute renal failure, thrombocytopenia, and thrombotic microangiopathy. Renal biopsy showed interstitial edema with fibrosis, arteriolar thickening with vitreous changes, and epithelial podocytes segmental fusion. Immunofluorescence microscopy showed C3(+), Ig A(+) deposition in the mesangial region, which was pathologically consistent with thrombotic microangiopathy renal injury and Ig A deposition. The patient had a history of hepatitis B virus infection for more than 5 years. Lamivudine was used in the past, but the injection of long-acting interferon combined with tenofovir alafenamide fumarate was used since 2018. The comprehensive clinical investigation and laboratory examination diagnosed the condition as thrombotic microangiopathy kidney injury caused by interferon. After stopping interferon in his treatment, the patient's renal function partially recovered after three consecutive therapeutic plasma exchange treatments and follow-up treatment without immunosuppressant. The renal function of the patient remained stable. CONCLUSIONS This report indicates that interferon can induce thrombotic microangiopathy with acute renal injury, which can progress to chronic renal insufficiency.
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Affiliation(s)
- Shan Wei
- Nephrology Department, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Nanchang University, Nanchang, 330031, China
| | - Wenjuan Mei
- Nephrology Department, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Ying Wang
- Nephrology Department, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
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12
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Alhomoud M, Scordo M, Perales MA. Successful use of narsoplimab to treat allogeneic transplant-associated thrombotic microangiopathy while maintaining sirolimus. Bone Marrow Transplant 2024; 59:904-906. [PMID: 38467748 DOI: 10.1038/s41409-024-02263-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 03/04/2024] [Accepted: 03/05/2024] [Indexed: 03/13/2024]
Affiliation(s)
- Mohammad Alhomoud
- Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Scordo
- Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Miguel-Angel Perales
- Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, New York, NY, USA.
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13
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Frimat M, Gnemmi V, Stichelbout M, Provôt F, Fakhouri F. Pregnancy as a susceptible state for thrombotic microangiopathies. Front Med (Lausanne) 2024; 11:1343060. [PMID: 38476448 PMCID: PMC10927739 DOI: 10.3389/fmed.2024.1343060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/12/2024] [Indexed: 03/14/2024] Open
Abstract
Pregnancy and the postpartum period represent phases of heightened vulnerability to thrombotic microangiopathies (TMAs), as evidenced by distinct patterns of pregnancy-specific TMAs (e.g., preeclampsia, HELLP syndrome), as well as a higher incidence of nonspecific TMAs, such as thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, during pregnancy. Significant strides have been taken in understanding the underlying mechanisms of these disorders in the past 40 years. This progress has involved the identification of pivotal factors contributing to TMAs, such as the complement system, ADAMTS13, and the soluble VEGF receptor Flt1. Regardless of the specific causal factor (which is not generally unique in relation to the usual multifactorial origin of TMAs), the endothelial cell stands as a central player in the pathophysiology of TMAs. Pregnancy has a major impact on the physiology of the endothelium. Besides to the development of placenta and its vascular consequences, pregnancy modifies the characteristics of the women's microvascular endothelium and tends to render it more prone to thrombosis. This review aims to delineate the distinct features of pregnancy-related TMAs and explore the contributing mechanisms that lead to this increased susceptibility, particularly influenced by the "gravid endothelium." Furthermore, we will discuss the potential contribution of histopathological studies in facilitating the etiological diagnosis of pregnancy-related TMAs.
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Affiliation(s)
- Marie Frimat
- CHU Lille, Nephrology Department, Univ. Lille, Lille, France
- Inserm, Institut Pasteur de Lille, Univ. Lille, Lille, France
| | | | | | - François Provôt
- CHU Lille, Nephrology Department, Univ. Lille, Lille, France
| | - Fadi Fakhouri
- Service of Nephrology and Hypertension, CHUV and University of Lausanne, Lausanne, Switzerland
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14
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Carroll M, Blake L, Sharma S. Eculizumab in severe Shiga toxin-mediated haemolytic uraemic syndrome. BMJ Case Rep 2024; 17:e256524. [PMID: 38238162 PMCID: PMC10806934 DOI: 10.1136/bcr-2023-256524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2024] [Indexed: 01/23/2024] Open
Abstract
Shiga toxin (Stx)-producing Escherichia coli-mediated haemolytic uraemic syndrome is a primary thrombotic microangiopathy, typified by the development of microangiopathic haemolytic anaemia, thrombocytopaenia and acute renal failure. It is a leading cause of acute renal failure in paediatrics, with a second peak in prevalence in adults over the age of 60. Presentations of Stx-producing E. coli-mediated haemolytic uraemic syndrome in young adults are rare. We present the case of a previously well female in her early 30s presenting with Stx-producing E. coli-mediated haemolytic uraemic syndrome with severe renal and neurological manifestations. Eculizumab was administered due to the severity of presentation and disease trajectory refractory to initial supportive therapy. A significant clinical and biochemical improvement was observed following eculizumab.
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Affiliation(s)
- Mitchell Carroll
- General Medicine, Grampians Health Ballarat, Ballarat, Victoria, Australia
| | - Louise Blake
- General Medicine, Barwon Health, Geelong, Victoria, Australia
| | - Susheel Sharma
- Renal Medicine, Grampians Health Ballarat, Ballarat, Victoria, Australia
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15
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Cordero L, Cavero T, Gutiérrez E, Trujillo H, Sandino J, Auñón P, Rivero M, Morales E. Rational use of eculizumab in secondary atypical hemolytic uremic syndrome. Front Immunol 2024; 14:1310469. [PMID: 38274833 PMCID: PMC10808527 DOI: 10.3389/fimmu.2023.1310469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 12/20/2023] [Indexed: 01/27/2024] Open
Abstract
Background Secondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in secondary aHUS, since the two main series that investigated this subject showed discrepant results. Our work aims to reassess the efficacy of eculizumab in treating secondary aHUS. Methods Observational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 23 patients diagnosed with secondary aHUS who received treatment with eculizumab and compared them with a control cohort of 14 patients. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets. Results We found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 52.3% of patients and partial in 23.8%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (90.9% in the eculizumab cohort and 85.7% in the control cohort). Conclusion Early and short-term use of eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, assuring better renal recovery compared to patients who do not receive complement blockade.
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Affiliation(s)
- Lucía Cordero
- Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Teresa Cavero
- Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Eduardo Gutiérrez
- Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Hernando Trujillo
- Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Justo Sandino
- Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Pilar Auñón
- Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Marta Rivero
- Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Enrique Morales
- Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
- Instituto de Investigación, Hospital Universitario 12 de Octubre (imas12), Madrid, Spain
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16
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Emirova KM, Orlova OM, Chichuga EM, Muzurov AL, Avdonin PP, Avdonin PV. A Moderate Decrease in ADAMTS13 Activity Correlates with the Severity of STEC-HUS. Biomolecules 2023; 13:1671. [PMID: 38002352 PMCID: PMC10669222 DOI: 10.3390/biom13111671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/16/2023] [Accepted: 11/18/2023] [Indexed: 11/26/2023] Open
Abstract
Atypical hemolytic uremic syndrome (HUS) develops as a result of damage to the endothelium of microvasculature vessels by Shiga toxin produced by enterohemorrhagic Escherichia coli (STEC-HUS). STEC-HUS remains the leading cause of acute kidney injury (AKI) in children aged 6 months to 5 years. The pathomorphological essence of the disease is the development of thrombotic microangiopathy (TMA). One of the key causes of TMA is an imbalance in the ADAMTS13-von Willebrand factor (vWF)-platelet system. The goal of the work was to clarify the role of a moderate decrease in ADAMTS13 activity in the pathogenesis of STEC-HUS. The activity of ADAMTS13 was determined in 138 children (4 months-14.7 years) in the acute period of STEC-HUS and the features of the course of the disease in these patients were analyzed. The study revealed a decrease in the activity and concentration of ADAMTS13 in 79.8% and 90.6% of patients, respectively. Measurements of von Willebrand factor antigen content and the activity of von Willebrand factor in the blood plasma of part of these patients were carried out. In 48.6% and 34.4% of cases, there was an increase in the antigen concentration and the activity of the Willebrand factor, respectively. Thrombocytopenia was diagnosed in 97.8% of children. We have demonstrated that moderately reduced ADAMTS13 activity correlates with the risk of severe manifestations of STEC-HUS in children; the rate of developing multiple organ failure, cerebral disorders, pulmonary edema, and acute kidney injury with the need for dialysis increases. It is assumed that reduction in ADAMTS13 activity may serve as a predictor of disease severity.
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Affiliation(s)
- Khadizha M. Emirova
- Department of Pediatrics, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia; (K.M.E.); (O.M.O.)
- St. Vladimir Children’s City Clinical Hospital, Moscow 107014, Russia;
| | - Olga M. Orlova
- Department of Pediatrics, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia; (K.M.E.); (O.M.O.)
- St. Vladimir Children’s City Clinical Hospital, Moscow 107014, Russia;
| | - Ekaterina M. Chichuga
- Department of Hospital Pediatrics, N.N. Burdenko Voronezh State Medical University, Voronezh 394036, Russia;
| | - Alexander L. Muzurov
- St. Vladimir Children’s City Clinical Hospital, Moscow 107014, Russia;
- Russian Medical Academy of Continuous Professional Education, Moscow 123995, Russia
| | - Piotr P. Avdonin
- Koltsov Institute of Developmental Biology, Moscow 119334, Russia;
| | - Pavel V. Avdonin
- Koltsov Institute of Developmental Biology, Moscow 119334, Russia;
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17
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Lasorsa F, Rutigliano M, Milella M, Ferro M, Pandolfo SD, Crocetto F, Simone S, Gesualdo L, Battaglia M, Ditonno P, Lucarelli G. Complement System and the Kidney: Its Role in Renal Diseases, Kidney Transplantation and Renal Cell Carcinoma. Int J Mol Sci 2023; 24:16515. [PMID: 38003705 PMCID: PMC10671650 DOI: 10.3390/ijms242216515] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 11/15/2023] [Accepted: 11/18/2023] [Indexed: 11/26/2023] Open
Abstract
The crosstalk among the complement system, immune cells, and mediators of inflammation provides an efficient mechanism to protect the organism against infections and support the repair of damaged tissues. Alterations in this complex machinery play a role in the pathogenesis of different diseases. Core complement proteins C3 and C5, their activation fragments, their receptors, and their regulators have been shown to be active intracellularly as the complosome. The kidney is particularly vulnerable to complement-induced damage, and emerging findings have revealed the role of complement system dysregulation in a wide range of kidney disorders, including glomerulopathies and ischemia-reperfusion injury during kidney transplantation. Different studies have shown that activation of the complement system is an important component of tumorigenesis and its elements have been proved to be present in the TME of various human malignancies. The role of the complement system in renal cell carcinoma (RCC) has been recently explored. Clear cell and papillary RCC upregulate most of the complement genes relative to normal kidney tissue. The aim of this narrative review is to provide novel insights into the role of complement in kidney disorders.
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Affiliation(s)
- Francesco Lasorsa
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Monica Rutigliano
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Martina Milella
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Matteo Ferro
- Division of Urology, European Institute of Oncology, IRCCS, 71013 Milan, Italy
| | - Savio Domenico Pandolfo
- Department of Neurosciences and Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Felice Crocetto
- Department of Neurosciences and Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Simona Simone
- Department of Precision and Regenerative Medicine and Ionian Area-Nephrology, Dialysis and Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area-Nephrology, Dialysis and Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Michele Battaglia
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Pasquale Ditonno
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Giuseppe Lucarelli
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
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Nording H, Baron L, Sauter M, Lübken A, Rawish E, Szepanowski R, von Esebeck J, Sun Y, Emami H, Meusel M, Saraei R, Schanze N, Gorantla SP, von Bubnoff N, Geisler T, von Hundelshausen P, Stellos K, Marquardt J, Sadik CD, Köhl J, Duerschmied D, Kleinschnitz C, Langer HF. Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor-modulating factors. Blood Adv 2023; 7:6411-6427. [PMID: 37257194 PMCID: PMC10598500 DOI: 10.1182/bloodadvances.2021006891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/16/2023] [Accepted: 02/26/2023] [Indexed: 06/02/2023] Open
Abstract
In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driven revascularization. We assessed the relevance of the anaphylatoxin receptor C5aR1 on platelets in patients with coronary artery disease as well as those with peripheral artery disease and used genetic mouse models to characterize its significance for ischemia and growth factor-driven revascularization. The presence of C5aR1-expressing platelets was increased in the hindlimb ischemia model. Ischemia-driven angiogenesis was significantly improved in C5aR1-/- mice but not in C5-/- mice, suggesting a specific role of C5aR1. Experiments using the supernatant of C5a-stimulated platelets suggested a paracrine mechanism of angiogenesis inhibition by platelets by means of antiangiogenic CXC chemokine ligand 4 (CXCL4, PF4). Lineage-specific C5aR1 deletion verified that the secretion of CXCL4 depends on C5aR1 ligation on platelets. Using C5aR1-/-CXCL4-/- mice, we observed no additional effect in the revascularization response, underscoring a strong dependence of CXCL4 secretion on the C5a-C5aR1-axis. We identified a novel mechanism for inhibition of neovascularization via platelet C5aR1, which was mediated by the release of antiangiogenic CXCL4.
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Affiliation(s)
- Henry Nording
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
| | - Lasse Baron
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Manuela Sauter
- Cardioimmunology Group, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Antje Lübken
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Elias Rawish
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Rebecca Szepanowski
- Department of Neurology and Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
| | - Jacob von Esebeck
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Ying Sun
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Hossein Emami
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Moritz Meusel
- University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Roza Saraei
- University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Nancy Schanze
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sivahari Prasad Gorantla
- Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Lübeck, Germany
| | - Nikolas von Bubnoff
- Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Lübeck, Germany
| | - Tobias Geisler
- Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tuebingen, Germany
| | - Philipp von Hundelshausen
- Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Konstantinos Stellos
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of Cardiovascular Research, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jens Marquardt
- First Department of Medicine, University of Schleswig-Holstein, Lübeck, Germany
| | | | - Jörg Köhl
- Institute for Systemic Inflammation Research, University of Schleswig-Holstein, Lübeck, Germany
| | - Daniel Duerschmied
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Kleinschnitz
- Department of Neurology and Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
| | - Harald F. Langer
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
- Cardioimmunology Group, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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19
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彭 智, 颜 海, 卢 秀, 张 新, 黄 娇, 肖 政. [Value of complement component 3 in predicting the prognosis of children with sepsis]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2023; 25:941-946. [PMID: 37718400 PMCID: PMC10511224 DOI: 10.7499/j.issn.1008-8830.2304041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/03/2023] [Indexed: 09/19/2023]
Abstract
OBJECTIVES To investigate changes in complement component 3 (C3) levels in children with sepsis and its correlation with the severity of sepsis and to explore the significance of C3 in predicting mortality in children with sepsis. METHODS A retrospective analysis was conducted on 529 children with sepsis who were admitted to the Pediatric Intensive Care Unit in Hunan Children's Hospital between November 2019 and September 2021. The children were categorized into two groups based on their prognosis at day 28 after sepsis diagnosis: the survival group (n=471) and the death group (n=58). Additionally, the children were divided into normal C3 group (n=273) and reduced C3 group (n=256) based on the median C3 level (0.77 g/L) within 24 hours of admission. Clinical data and laboratory markers were compared between the groups, and assess the predictive value of C3 levels in relation to sepsis-related mortality. RESULTS The death group exhibited significantly lower C3 levels compared to the survival group (P<0.05). Multivariate logistic regression analysis revealed that higher pediatric Sequential Organ Failure Assessment (p-SOFA) scores and lower C3 levels were closely associated with sepsis-related mortality (P<0.05). The receiver operating characteristic curve (ROC) analysis demonstrated that combination of p-SOFA scores and C3 levels yielded an area under the ROC curve of 0.852, which was higher than that of each indicator alone (P<0.05). CONCLUSIONS C3 can serve as an indicator to assess the severity and prognosis of sepsis in children. The combination of p-SOFA scores and C3 levels holds good predictive value for mortality in children with sepsis.
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20
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Rojas-Rivera JE, García-Carro C, Ávila AI, Espino M, Espinosa M, Fernández-Juárez G, Fulladosa X, Goicoechea M, Macía M, Morales E, Quintana LF, Praga M. Diagnosis and treatment of lupus nephritis: a summary of the Consensus Document of the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Clin Kidney J 2023; 16:1384-1402. [PMID: 37664575 PMCID: PMC10468759 DOI: 10.1093/ckj/sfad055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Indexed: 09/05/2023] Open
Abstract
Lupus nephritis (LN) is the most frequent serious manifestation of patients with systemic lupus erythematosus (SLE). Up to 60% of SLE patients develop LN, which has a significant impact on their quality of life and prognosis. Recent advances have improved the diagnostic approach to LN, and new drugs that block specific pathways and kidney damage progression have been developed. Several randomized and well-powered clinical trials have confirmed the efficacy of these agents in terms of proteinuria remission and preservation of kidney function in the medium and long term, with an acceptable safety profile and good tolerance. The combination of different therapies allows for reduction of the dose and duration of corticosteroids and other potentially toxic therapies and leads to an increase in the number of patients achieving complete remission of the disease. This consensus document carried out by the Spanish Group for the Study of Glomerular Diseases (GLOSEN) provides practical and updated recommendations, based on the best available evidence and clinical expertise of participating nephrologists.
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Affiliation(s)
- Jorge E Rojas-Rivera
- Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
- Departament of Medicine, Universidad Autónoma de Madrid
| | | | | | - Mar Espino
- Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | | | - Xavier Fulladosa
- Hospital Universitario de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
| | | | - Manuel Macía
- Hospital Universitario Nuestra Señora de la Candelaria, Tenerife, Spain
| | - Enrique Morales
- Hospital Universitario 12 de Octubre, Madrid, Spain
- Instituto de Investigación Hospital Universitario 12 de Octubre, Madrid, Spain
- Departament of Medicine, Universidad Complutense, Madrid, Spain
| | - Luis F Quintana
- Hospital Clínic de Barcelona, Barcelona, Spain
- Departament of Medicine, Universidad de Barcelona, IDIBAPS, Barcelona, Spain
| | - Manuel Praga
- Instituto de Investigación Hospital Universitario 12 de Octubre, Madrid, Spain
- Departament of Medicine, Universidad Complutense, Madrid, Spain
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21
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Donadelli R, Sinha A, Bagga A, Noris M, Remuzzi G. HUS and TTP: traversing the disease and the age spectrum. Semin Nephrol 2023; 43:151436. [PMID: 37949684 DOI: 10.1016/j.semnephrol.2023.151436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenia purpura (TTP) are rare diseases sharing a common pathological feature, thrombotic microangiopathy (TMA). TMA is characterized by microvascular thrombosis with consequent thrombocytopenia, microangiopathic hemolytic anemia and/or multiorgan dysfunction. In the past, the distinction between HUS and TTP was predominantly based on clinical grounds. However, clinical presentation of the two syndromes often overlaps and, the differential diagnosis is broad. Identification of underlying pathogenic mechanisms has enabled the classification of these syndromes on a molecular basis: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypical HUS or complement-mediated TMA (aHUS/CM-TMA) associated with genetic or acquired defects leading to dysregulation of the alternative pathway (AP) of complement; and TTP that results from a severe deficiency of the von Willebrand Factor (VWF)-cleaving protease, ADAMTS13. The etiology of TMA differs between pediatric and adult patients. Childhood TMA is chiefly caused by STEC-HUS, followed by CM-TMA and pneumococcal HUS (Sp-HUS). Rare conditions such as congenital TTP (cTTP), vitamin B12 metabolism defects, and coagulation disorders (diacylglycerol epsilon mutation) present as TMA chiefly in children under 2 years of age. In contrast secondary causes and acquired ADAMT13 deficiency are more common in adults. In adults, compared to children, diagnostic delays are more frequent due to the wide range of differential diagnoses. In this review we focus on the three major forms of TMA, STEC-HUS, aHUS and TTP, outlining the clinical presentation, diagnosis and management of the affected patients, to help highlight the salient features and the differences between adult and pediatric patients which are relevant for management.
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Affiliation(s)
- Roberta Donadelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Italy
| | - Aditi Sinha
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi
| | - Arvind Bagga
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi
| | - Marina Noris
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Italy.
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22
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Uwatoko R, Shindo M, Hashimoto N, Iio R, Ueda Y, Tatematsu Y, Kato N, Maruyama S, Hayashi T. Relapse of atypical hemolytic uremic syndrome triggered by COVID-19: a lesson for the clinical nephrologist. J Nephrol 2023; 36:1439-1442. [PMID: 36877369 PMCID: PMC9986860 DOI: 10.1007/s40620-023-01595-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 01/30/2023] [Indexed: 03/07/2023]
Affiliation(s)
- Ryuta Uwatoko
- Department of Kidney Disease and Hypertension, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-Ku, Osaka, 558-8558, Japan.
| | - Mayu Shindo
- Department of Emergency Medicine, Osaka General Medical Center, Osaka, Japan
| | - Nobuhiro Hashimoto
- Department of Kidney Disease and Hypertension, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-Ku, Osaka, 558-8558, Japan
| | - Rei Iio
- Department of Kidney Disease and Hypertension, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-Ku, Osaka, 558-8558, Japan
| | - Yoshiyasu Ueda
- Department of Kidney Disease and Hypertension, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-Ku, Osaka, 558-8558, Japan
| | - Yoshitaka Tatematsu
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Noritoshi Kato
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Terumasa Hayashi
- Department of Kidney Disease and Hypertension, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-Ku, Osaka, 558-8558, Japan
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23
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Qin C, Yin D, Liu F, Qiu H. Thrombotic thrombocytopenic purpura in a patient on long-term alpha-interferon therapy for essential thrombocythemia: a case report. BMC Nephrol 2023; 24:143. [PMID: 37221468 DOI: 10.1186/s12882-023-03200-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 05/12/2023] [Indexed: 05/25/2023] Open
Abstract
BACKGROUND Thrombotic thrombocytopenic purpura (TTP) is rare and severe thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and renal dysfunction. In contrast, essential thrombocythemia (ET) is a myeloproliferative disease associated with an abnormal increase in platelet numbers. Previous studies reported several cases of the development of ET in patients with TTP. However, the case of an ET patient complicated with TTP has not been previously reported. In this case study, we present a patient with TTP who was previously diagnosed with ET. Therefore, to the best of our knowledge, this is the first report of TTP in ET. CASE PRESENTATION A 31-year-old Chinese female who was previously diagnosed with ET presented with anemia and renal dysfunction. The patient had been on long-term treatment with hydroxyurea, aspirin, and alpha interferon (INF-α) for ten years. The diagnosis of TTP was confirmed by clinical features, schistocytes noted on the peripheral blood smear, and lower ADAMTS13 activity (8.5%), together with the renal biopsy results. INF-α was discontinued, and the patient was then treated with plasma exchange and corticosteroids. After one year of follow-up, the patient had a normal hemoglobin level and platelet numbers, and her ADAMTS13 activity had improved. However, the patient's renal function remains impaired. CONCLUSIONS We report a case of an ET patient complicated with TTP that was possibly due to INF-α, highlighting the potential complications associated with long-term ET therapy. The case also highlights the importance of considering TTP in patients with pre-existing ET who present with anemia and renal dysfunction, extending the spectrum of known studies.
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Affiliation(s)
- Chunmei Qin
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- Department of Nephrology, Luzhou People's Hospital, Luzhou, China
| | - Dan Yin
- Bioinformatics Under Biology Department, University of California-San Diego, San Diego, USA
| | - Fang Liu
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
| | - Hongyu Qiu
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China.
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Bruno V, Mühlig AK, Oh J, Licht C. New insights into the immune functions of podocytes: the role of complement. Mol Cell Pediatr 2023; 10:3. [PMID: 37059832 PMCID: PMC10104987 DOI: 10.1186/s40348-023-00157-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 03/24/2023] [Indexed: 04/16/2023] Open
Abstract
Podocytes are differentiated epithelial cells which play an essential role to ensure a normal function of the glomerular filtration barrier (GFB). In addition to their adhesive properties in maintaining the integrity of the filtration barrier, they have other functions, such as synthesis of components of the glomerular basement membrane (GBM), production of vascular endothelial growth factor (VEGF), release of inflammatory proteins, and expression of complement components. They also participate in the glomerular crosstalk through multiple signalling pathways, including endothelin-1, VEGF, transforming growth factor β (TGFβ), bone morphogenetic protein 7 (BMP-7), latent transforming growth factor β-binding protein 1 (LTBP1), and extracellular vesicles.Growing literature suggests that podocytes share many properties of innate and adaptive immunity, supporting a multifunctional role ensuring a healthy glomerulus. As consequence, the "immune podocyte" dysfunction is thought to be involved in the pathogenesis of several glomerular diseases, referred to as "podocytopathies." Multiple factors like mechanical, oxidative, and/or immunologic stressors can induce cell injury. The complement system, as part of both innate and adaptive immunity, can also define podocyte damage by several mechanisms, such as reactive oxygen species (ROS) generation, cytokine production, and endoplasmic reticulum stress, ultimately affecting the integrity of the cytoskeleton, with subsequent podocyte detachment from the GBM and onset of proteinuria.Interestingly, podocytes are found to be both source and target of complement-mediated injury. Podocytes express complement proteins which contribute to local complement activation. At the same time, they rely on several protective mechanisms to escape this damage. Podocytes express complement factor H (CFH), one of the main regulators of the complement cascade, as well as membrane-bound complement regulators like CD46 or membrane cofactor protein (MCP), CD55 or decay-accelerating factor (DAF), and CD59 or defensin. Further mechanisms, like autophagy or actin-based endocytosis, are also involved to ensure podocyte homeostasis and protection against injury.This review will provide an overview of the immune functions of podocytes and their response to immune-mediated injury, focusing on the pathogenic link between complement and podocyte damage.
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Affiliation(s)
- Valentina Bruno
- Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada
- Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada
| | - Anne Katrin Mühlig
- University Children's Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pediatric Nephrology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jun Oh
- University Children's Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pediatric Nephrology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Licht
- Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada.
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
- Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
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25
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Fuhrman DY, Thadani S, Hanson C, Carcillo JA, Kellum JA, Park HJ, Lu L, Kim-Campbell N, Horvat CM, Arikan AA. Therapeutic Plasma Exchange Is Associated With Improved Major Adverse Kidney Events in Children and Young Adults With Thrombocytopenia at the Time of Continuous Kidney Replacement Therapy Initiation. Crit Care Explor 2023; 5:e0891. [PMID: 37066071 PMCID: PMC10097539 DOI: 10.1097/cce.0000000000000891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2023] Open
Abstract
Therapeutic plasma exchange (TPE) has been shown to improve organ dysfunction and survival in patients with thrombotic microangiopathy and thrombocytopenia associated with multiple organ failure. There are no known therapies for the prevention of major adverse kidney events after continuous kidney replacement therapy (CKRT). The primary objective of this study was to evaluate the effect of TPE on the rate of adverse kidney events in children and young adults with thrombocytopenia at the time of CKRT initiation. DESIGN Retrospective cohort. SETTING Two large quaternary care pediatric hospitals. PATIENTS All patients less than or equal to 26 years old who received CKRT between 2014 and 2020. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We defined thrombocytopenia as a platelet count less than or equal to 100,000 (cell/mm3) at the time of CKRT initiation. We ascertained major adverse kidney events at 90 days (MAKE90) after CKRT initiation as the composite of death, need for kidney replacement therapy, or a greater than or equal to 25% decline in estimated glomerular filtration rate from baseline. We performed multivariable logistic regression and propensity score weighting to analyze the relationship between the use of TPE and MAKE90. After excluding patients with a diagnosis of thrombotic thrombocytopenia purpura and atypical hemolytic uremic syndrome (n = 6) and with thrombocytopenia due to a chronic illness (n = 2), 284 of 413 total patients (68.8%) had thrombocytopenia at CKRT initiation (51% female). Of the patients with thrombocytopenia, the median (interquartile range) age was 69 months (13-128 mo). MAKE90 occurred in 69.0% and 41.5% received TPE. The use of TPE was independently associated with reduced MAKE90 by multivariable analysis (odds ratio [OR], 0.35; 95% CI, 0.20-0.60) and by propensity score weighting (adjusted OR, 0.31; 95% CI, 0.16-0.59). CONCLUSIONS Thrombocytopenia is common in children and young adults at CKRT initiation and is associated with increased MAKE90. In this subset of patients, our data show benefit of TPE in reducing the rate of MAKE90.
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Affiliation(s)
- Dana Y Fuhrman
- Department of Critical Care Medicine, Division of Pediatric Critical Care Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
- Department of Pediatrics, Division of Nephrology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
- The Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Sameer Thadani
- Department of Pediatrics, Division of Nephrology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Claire Hanson
- Department of Critical Care Medicine, Division of Pediatric Critical Care Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Joseph A Carcillo
- Department of Critical Care Medicine, Division of Pediatric Critical Care Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
- The Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA
| | - John A Kellum
- The Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Hyun Jung Park
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Liling Lu
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA
| | - Nahmah Kim-Campbell
- Department of Critical Care Medicine, Division of Pediatric Critical Care Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Christopher M Horvat
- Department of Critical Care Medicine, Division of Pediatric Critical Care Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
- Department of Pediatrics, Division of Health Informatics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Ayse Akcan Arikan
- Department of Pediatrics, Division of Nephrology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
- Department of Pediatrics, Division of Critical Care Medicine, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
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26
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Abstract
The complement and hemostatic systems are complex systems, and both involve enzymatic cascades, regulators, and cell components-platelets, endothelial cells, and immune cells. The two systems are ancestrally related and are defense mechanisms that limit infection by pathogens and halt bleeding at the site of vascular injury. Recent research has uncovered multiple functional interactions between complement and hemostasis. On one side, there are proteins considered as complement factors that activate hemostasis, and on the other side, there are coagulation proteins that modulate complement. In addition, complement and coagulation and their regulatory proteins strongly interact each other to modulate endothelial, platelet and leukocyte function and phenotype, creating a potentially devastating amplifying system that must be closely regulated to avoid unwanted damage and\or disseminated thrombosis. In view of its ability to amplify all complement activity through the C3b-dependent amplification loop, the alternative pathway of complement may play a crucial role in this context. In this review, we will focus on available and emerging evidence on the role of the alternative pathway of complement in regulating hemostasis and vice-versa, and on how dysregulation of either system can lead to severe thromboinflammatory events.
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Affiliation(s)
- Marina Noris
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Miriam Galbusera
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Abstract
Dysregulation and accelerated activation of the alternative pathway (AP) of complement is known to cause or accentuate several pathologic conditions in which kidney injury leads to the appearance of hematuria and proteinuria and ultimately to the development of chronic renal failure. Multiple genetic and acquired defects involving plasma- and membrane-associated proteins are probably necessary to impair the protection of host tissues and to confer a significant predisposition to AP-mediated kidney diseases. This review aims to explore how our current understanding will make it possible to identify the mechanisms that underlie AP-mediated kidney diseases and to discuss the available clinical evidence that supports complement-directed therapies. Although the value of limiting uncontrolled complement activation has long been recognized, incorporating complement-targeted treatments into clinical use has proved challenging. Availability of anti-complement therapy has dramatically transformed the outcome of atypical hemolytic uremic syndrome, one of the most severe kidney diseases. Innovative drugs that directly counteract AP dysregulation have also opened new perspectives for the management of other kidney diseases in which complement activation is involved. However, gained experience indicates that the choice of drug should be tailored to each patient's characteristics, including clinical, histologic, genetic, and biochemical parameters. Successfully treating patients requires further research in the field and close collaboration between clinicians and researchers who have special expertise in the complement system.
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Affiliation(s)
- Erica Daina
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Monica Cortinovis
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Zhang B, Xing G. Thrombotic microangiopathy mediates poor prognosis among lupus nephritis via complement lectin and alternative pathway activation. Front Immunol 2022; 13:1081942. [PMID: 36582241 PMCID: PMC9792970 DOI: 10.3389/fimmu.2022.1081942] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
Objective The pathogenesis of thrombotic microangiopathy (TMA) in lupus nephritis (LN) remains complicated. This study aimed to detect the deposition of complement lectin pathway (LP) and alternative pathway (AP) components in renal tissues, then evaluate the clinicopathological characteristics and risk factors for renal survival between patients with or without TMA in LN cohorts. Methods We included 79 patients with biopsy-proven LN-associated TMA and matched the same number of LN patients without TMA as the control group. The deposition of mannose binding lectin (MBL), MBL-associated serine proteases 1/3 (MASP1/3), complement factor B (CFB), complement factor D (CFD), C4d, and von Willebrand factor (VWF) in renal tissue was assessed by immunohistochemistry and immunofluorescence. Besides, co-localization of C5b-9 and CD34 was detected by confocal microscopy. Results In our retrospective cohort, the incidence of acute kidney injury (30% vs. 14%, p = 0.013), acute hemodialysis (35% vs. 5%, p < 0.001), and interstitial fibrosis (43% vs. 13%, p < 0.001) is higher in the TMA, compared with the control group. Despite aggressive steroids pulse, plasma exchange, and immunosuppressive therapy among TMA group, they still had significantly inferior 3-year renal survival rates (68% vs. 89%, p = 0.002) than those in the non-TMA group. COX regression analysis identified that TMA (HR 4.807, 95% CI [2.052, 11.263], p < 0.001) is a risk factor in LN. MBL, MASP1/3, CFB, CFD, C4d, and VWF deposited along the glomerulus among LN, while TMA had stronger staining intensity and deposition. The co-localized expression of CD34 and C5b-9 in the endothelial cells was also observed in the renal tissues. Conclusions TMA is an independent risk factor for renal survival in LN patients. Moreover, LP and AP activation are involved in the pathogenesis of LN-associated TMA.
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Michael M, Bagga A, Sartain SE, Smith RJH. Haemolytic uraemic syndrome. Lancet 2022; 400:1722-1740. [PMID: 36272423 DOI: 10.1016/s0140-6736(22)01202-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 11/05/2022]
Abstract
Haemolytic uraemic syndrome (HUS) is a heterogeneous group of diseases that result in a common pathology, thrombotic microangiopathy, which is classically characterised by the triad of non-immune microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In this Seminar, different causes of HUS are discussed, the most common being Shiga toxin-producing Escherichia coli HUS. Identifying the underlying thrombotic microangiopathy trigger can be challenging but is imperative if patients are to receive personalised disease-specific treatment. The quintessential example is complement-mediated HUS, which once carried an extremely high mortality but is now treated with anti-complement therapies with excellent long-term outcomes. Unfortunately, the high cost of anti-complement therapies all but precludes their use in low-income countries. For many other forms of HUS, targeted therapies are yet to be identified.
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Affiliation(s)
- Mini Michael
- Division of Pediatric Nephrology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
| | - Arvind Bagga
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Sarah E Sartain
- Pediatrics-Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA
| | - Richard J H Smith
- Department of Otolaryngology, Pediatrics and Molecular Physiology & Biophysics, The University of Iowa, Iowa City, IA, USA
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Boldig K, Batra R, Villegas A. COVID-19: A Rare Cause of Hemolytic Uremic Syndrome. Cureus 2022; 14:e27962. [PMID: 36120203 PMCID: PMC9466298 DOI: 10.7759/cureus.27962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2022] [Indexed: 11/24/2022] Open
Abstract
Hemolytic uremic syndrome (HUS) is a multisystemic condition characterized by a triad of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. HUS can be classified as atypical or typical, depending upon its association with the Shiga toxin-producing Escherichia coli (STEC). Approximately 90-95% of cases are classified as typical, while only 5-10% of cases are atypical. The pathogenesis of atypical HUS (aHUS) occurs when the complement cascade is activated and causes membrane attack complex (MAC) deposition in the renal tubular epithelium. Various infectious triggers have been associated with aHUS. A new and compelling correlation to this rare and potentially deadly diagnosis of aHUS is COVID-19 infection or vaccination. We present a case of COVID-19-induced exacerbation of a patient with a known history of aHUS. In addition, we performed a literature review of previously reported COVID-19-induced aHUS cases and identified the potential pathogenesis of the disease state.
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31
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Patriquin CJ, Pavenski K, Garland J, Girard LP, Isenring P. Complement-Amplifying Conditions in Atypical Hemolytic Uremic Syndrome: A Canadian Case Series. Can J Kidney Health Dis 2022; 9:20543581221100288. [PMID: 35615072 PMCID: PMC9125052 DOI: 10.1177/20543581221100288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/31/2022] [Indexed: 11/24/2022] Open
Abstract
Rationale Thrombotic microangiopathies (TMAs) are systemic disorders that often affect the kidneys and encompass a heterogeneous group of conditions, including atypical hemolytic uremic syndrome (aHUS). The complement pathway is thought to play a crucial role in the pathogenesis of aHUS, and a favorable response can be obtained through complement C5 inhibition. There is emerging evidence to suggest that the same is also true for several other forms of TMA. Objective The purpose of this series is to report cases of aHUS in which both an innate defect of the alternative complement pathway and a complement-amplifying condition were suspected. Methods This case series describes 8 patients who were managed in Canadian tertiary centers for aHUS and who presented initially with complement-amplifying conditions. Results In all cases, aHUS was associated with organ dysfunction and in some, with an innate defect of the alternative complement pathway. The complement-amplifying conditions identified were diverse including immune disorders, pregnancy, and a Shiga toxin infection. Patients improved rapidly when treated with eculizumab or plasma exchange. Conclusions These observations illustrate the seriousness of secondary aHUS. They also add to existing lines of evidence that the complement pathway is potentially involved in this condition and that it should be considered as a therapeutic target of interest under such circumstances.
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Affiliation(s)
| | - Katerina Pavenski
- St. Michael’s Hospital, Unity Health Toronto, University of Toronto, ON, Canada
| | - Jocelyn Garland
- Division of Nephrology, Department of Medicine, Queen’s University, Kingston, ON, Canada
| | | | - Paul Isenring
- Nephrology Research Group, Department of Medicine, L’Hôtel-Dieu de Québec Institution, Laval University, Québec, QC, Canada
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32
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Kellum JA, Formeck CL, Kernan KF, Gómez H, Carcillo JA. Subtypes and Mimics of Sepsis. Crit Care Clin 2022; 38:195-211. [DOI: 10.1016/j.ccc.2021.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Leone VF, Imeraj A, Gastoldi S, Mele C, Liguori L, Condemi C, Ruggenenti P, Remuzzi G, Carrara C. Case Report: Tackling Complement Hyperactivation With Eculizumab in Atypical Hemolytic Uremic Syndrome Triggered by COVID-19. Front Pharmacol 2022; 13:842473. [PMID: 35295324 PMCID: PMC8920243 DOI: 10.3389/fphar.2022.842473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/07/2022] [Indexed: 01/08/2023] Open
Abstract
Hemolytic uremic syndrome (HUS) is a rare life-threatening disease of unrestrained complement system dysregulation, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure in genetically predisposed individuals. In this report, we describe two cases of SARS-CoV-2–associated HUS treated with eculizumab, a C5-blocking monoclonal antibody reported to be remarkably effective in the treatment of HUS. Detailed biochemical and genetic complement system analysis is reported, and the prompt clinical response after C5 pharmacological blockade is documented. Our report provides the rationale and supports the use of terminal complement pathway inhibition for the treatment of SARS-CoV-2–associated HUS.
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Affiliation(s)
- Valentina Fanny Leone
- Unit of Nephrology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Amantia Imeraj
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Sara Gastoldi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Caterina Mele
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Lucia Liguori
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Carmelita Condemi
- Unit of Nephrology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Piero Ruggenenti
- Unit of Nephrology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
- *Correspondence: Piero Ruggenenti,
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
| | - Camillo Carrara
- Unit of Nephrology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
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Cortes C, Desler C, Mazzoli A, Chen JY, Ferreira VP. The role of properdin and Factor H in disease. Adv Immunol 2022; 153:1-90. [PMID: 35469595 DOI: 10.1016/bs.ai.2021.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The complement system consists of three pathways (alternative, classical, and lectin) that play a fundamental role in immunity and homeostasis. The multifunctional role of the complement system includes direct lysis of pathogens, tagging pathogens for phagocytosis, promotion of inflammatory responses to control infection, regulation of adaptive cellular immune responses, and removal of apoptotic/dead cells and immune complexes from circulation. A tight regulation of the complement system is essential to avoid unwanted complement-mediated damage to the host. This regulation is ensured by a set of proteins called complement regulatory proteins. Deficiencies or malfunction of these regulatory proteins may lead to pro-thrombotic hematological diseases, renal and ocular diseases, and autoimmune diseases, among others. This review focuses on the importance of two complement regulatory proteins of the alternative pathway, Factor H and properdin, and their role in human diseases with an emphasis on: (a) characterizing the main mechanism of action of Factor H and properdin in regulating the complement system and protecting the host from complement-mediated attack, (b) describing the dysregulation of the alternative pathway as a result of deficiencies, or mutations, in Factor H and properdin, (c) outlining the clinical findings, management and treatment of diseases associated with mutations and deficiencies in Factor H, and (d) defining the unwanted and inadequate functioning of properdin in disease, through a discussion of various experimental research findings utilizing in vitro, mouse and human models.
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Affiliation(s)
- Claudio Cortes
- Department of Foundational Medical Studies, Oakland University William Beaumont School of Medicine, Rochester, MI, United States.
| | - Caroline Desler
- Oakland University William Beaumont School of Medicine, Rochester, MI, United States
| | - Amanda Mazzoli
- Oakland University William Beaumont School of Medicine, Rochester, MI, United States
| | - Jin Y Chen
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Viviana P Ferreira
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States.
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35
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Abstract
Hyperactivation of the complement and coagulation systems is recognized as part of the clinical syndrome of COVID-19. Here we review systemic complement activation and local complement activation in response to the causative virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their currently known relationships to hyperinflammation and thrombosis. We also provide an update on early clinical findings and emerging clinical trial evidence that suggest potential therapeutic benefit of complement inhibition in severe COVID-19.
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Affiliation(s)
- Behdad Afzali
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
| | - Marina Noris
- Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", Ranica, Italy.
- "Centro Anna Maria Astori", Bergamo, Italy.
| | - Bart N Lambrecht
- Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
- Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
| | - Claudia Kemper
- Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
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36
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Milone G, Bellofiore C, Leotta S, Milone GA, Cupri A, Duminuco A, Garibaldi B, Palumbo G. Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology. J Clin Med 2022; 11:jcm11030623. [PMID: 35160072 PMCID: PMC8837122 DOI: 10.3390/jcm11030623] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/19/2022] [Accepted: 01/23/2022] [Indexed: 12/12/2022] Open
Abstract
Endothelial dysfunction (ED) is frequently encountered in transplant medicine. ED is an argument of high complexity, and its understanding requires a wide spectrum of knowledge based on many fields of basic sciences such as molecular biology, immunology, and pathology. After hematopoietic stem cell transplantation (HSCT), ED participates in the pathogenesis of various complications such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy (TA-TMA), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), and engraftment syndrome (ES). In the first part of the present manuscript, we briefly review some biological aspects of factors involved in ED: adhesion molecules, cytokines, Toll-like receptors, complement, angiopoietin-1, angiopoietin-2, thrombomodulin, high-mobility group B-1 protein, nitric oxide, glycocalyx, coagulation cascade. In the second part, we review the abnormalities of these factors found in the ED complications associated with HSCT. In the third part, a review of agents used in the treatment of ED after HSCT is presented.
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37
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Aiello S, Gastoldi S, Galbusera M, Ruggenenti P, Portalupi V, Rota S, Rubis N, Liguori L, Conti S, Tironi M, Gamba S, Santarsiero D, Benigni A, Remuzzi G, Noris M. C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19. Blood Adv 2022; 6:866-881. [PMID: 34852172 PMCID: PMC8945302 DOI: 10.1182/bloodadvances.2021005246] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/19/2021] [Indexed: 11/20/2022] Open
Abstract
Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.
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Affiliation(s)
- Sistiana Aiello
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Sara Gastoldi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Miriam Galbusera
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Piero Ruggenenti
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Valentina Portalupi
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Stefano Rota
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Nadia Rubis
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Lucia Liguori
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Sara Conti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Matteo Tironi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Sara Gamba
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Donata Santarsiero
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Marina Noris
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
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Palma LMP, Vaisbich-Guimarães MH, Sridharan M, Tran CL, Sethi S. Thrombotic microangiopathy in children. Pediatr Nephrol 2022; 37:1967-1980. [PMID: 35041041 PMCID: PMC8764494 DOI: 10.1007/s00467-021-05370-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 11/19/2022]
Abstract
The syndrome of thrombotic microangiopathy (TMA) is a clinical-pathological entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ involvement. It comprises a spectrum of underlying etiologies that may differ in children and adults. In children, apart from ruling out shigatoxin-associated hemolytic uremic syndrome (HUS) and other infection-associated TMA like Streptococcus pneumoniae-HUS, rare inherited causes including complement-associated HUS, cobalamin defects, and mutations in diacylglycerol kinase epsilon gene must be investigated. TMA should also be considered in the setting of solid organ or hematopoietic stem cell transplantation. In this review, acquired and inherited causes of TMA are described with a focus on particularities of the main causes of TMA in children. A pragmatic approach that may help the clinician tailor evaluation and management is provided. The described approach will allow for early initiation of treatment while waiting for the definitive diagnosis of the underlying TMA.
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Affiliation(s)
- Lilian Monteiro P. Palma
- grid.411087.b0000 0001 0723 2494Department of Pediatrics, Pediatric Nephrology, State University of Campinas (UNICAMP), Rua Tessalia Vieira de Camargo, 126, Cidade Universitaria, Campinas, SP 13,083–887 Brazil
| | | | - Meera Sridharan
- grid.66875.3a0000 0004 0459 167XHematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN USA
| | - Cheryl L. Tran
- grid.66875.3a0000 0004 0459 167XPediatric Nephrology, Department of Pediatrics, Mayo Clinic, Rochester, MN USA
| | - Sanjeev Sethi
- grid.66875.3a0000 0004 0459 167XDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN USA
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Filippone EJ, Newman ED, Li L, Gulati R, Farber JL. Thrombotic Microangiopathy, an Unusual Form of Monoclonal Gammopathy of Renal Significance: Report of 3 Cases and Literature Review. Front Immunol 2021; 12:780107. [PMID: 34858436 PMCID: PMC8631422 DOI: 10.3389/fimmu.2021.780107] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 10/22/2021] [Indexed: 12/25/2022] Open
Abstract
Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.
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Affiliation(s)
- Edward J Filippone
- Divsion of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Eric D Newman
- Divsion of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Li Li
- Department of Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Rakesh Gulati
- Divsion of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - John L Farber
- Department of Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
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40
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Treatment of Shiga-Toxin Hus with Severe Neurologic Features with Eculizumab. Case Rep Pediatr 2021; 2021:8053246. [PMID: 34812294 PMCID: PMC8605924 DOI: 10.1155/2021/8053246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 11/05/2021] [Indexed: 11/18/2022] Open
Abstract
Hemolytic Uremic Syndrome (HUS) is a constellation of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Shiga toxin-producing Escherichia coli- (STEC-) mediated HUS is a common cause of acute renal failure in children and can rarely result in severe neurological complications such as encephalopathy, seizures, cerebrovascular accidents, and coma. Current literature supports use of eculizumab, a monoclonal antibody that blocks complement activation, in atypical HUS (aHUS). However, those with neurologic complications from STEC-HUS have complement activation and deposition of aggregates in microvasculature and may be treated with eculizumab. In this case report, we describe a 3-year-old boy with diarrhea-positive STEC-HUS who developed severe neurologic involvement in addition to acute renal failure requiring renal replacement therapy. He was initiated on eculizumab therapy, with clinical improvement and organ recovery. This case highlights systemic complications of STEC-HUS in a pediatric patient. The current literature is limited but has suggested a role for complement mediation in cases with severe complications. We review the importance of early recognition of complications, use of eculizumab, and current data available.
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Haydock L, Garneau AP, Tremblay L, Yen HY, Gao H, Harrisson R, Isenring P. Genetic abnormalities in biopsy-proven, adult-onset hemolytic uremic syndrome and C3 glomerulopathy. J Mol Med (Berl) 2021; 100:269-284. [PMID: 34714369 PMCID: PMC8770394 DOI: 10.1007/s00109-021-02102-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 06/03/2021] [Accepted: 06/08/2021] [Indexed: 12/25/2022]
Abstract
Abstract Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) have been linked to mutations in many of the proteins that are involved in alternative complement pathway activation. Age and etiology confounded, the prevalence of such mutations has been reported to be over 30 to 50% in these diseases. However, the cohorts studied included many children or individuals with a familial history of complement-related disorders and genetic tests were usually limited to exome sequencing of known causative or risk-associated genes. In this study, a retrospective adult cohort of 35 patients with biopsy-proven thrombotic microangiopathy (the largest in Canada) and 10 patients with C3 glomerulopathy was tested through an extended exome panel to identify causative defects in associated or candidate genes including those of the alternative and terminal complement pathways. A variant of unknown significance was also analyzed for pathogenicity through in vitro studies. To our surprise, the prevalence of known causative or risk-associated variants in either of these cohorts was found to be less than ~ 15% overall. However, the panel used and analyses carried out allowed to identify novel variants of potential clinical significance and a number of candidate genes. The prevalence of known genetic defects in adult-onset aHUS and C3G is thus probably much lower than 30 to 50%. Our results also point towards the importance of investigating diseases of the alternative complement pathway through extended exome panels and in vitro analyses. Key messages
The alternative complement pathway plays a major role in the pathogenesis of hemolytic uremic syndrome and C3 glomerulopathy. Based on previous studies, both disorders have been commonly linked to variants in the various intermediates that sustain or regulate this pathway. The prevalence of such mutations in the adult-onset and sporadic forms of these diseases is probably much lower than expected based on larger series. The sporadic forms of complementopathies are likely to involve additional genes that are yet to be uncovered. Supplementary information The online version contains supplementary material available at 10.1007/s00109-021-02102-1.
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Affiliation(s)
- Ludwig Haydock
- Nephrology Research Group, L'Hôtel-Dieu de Québec Research Center, Department of Medicine, Faculty of Medicine, Laval University, Quebec, QC, G1R2J6, Canada
| | - Alexandre P Garneau
- Nephrology Research Group, L'Hôtel-Dieu de Québec Research Center, Department of Medicine, Faculty of Medicine, Laval University, Quebec, QC, G1R2J6, Canada.,Cardiometabolic Axis, School of Kinesiology and Physical Activity Sciences, Faculty of Medicine, University of Montréal, 900, rue Saint-Denis, Montreal, QC, H2X 0A9, Canada
| | - Laurence Tremblay
- Nephrology Research Group, L'Hôtel-Dieu de Québec Research Center, Department of Medicine, Faculty of Medicine, Laval University, Quebec, QC, G1R2J6, Canada
| | - Hai-Yun Yen
- Fulgent Genetics, Temple City, CA, 91780, USA
| | - Hanlin Gao
- Fulgent Genetics, Temple City, CA, 91780, USA
| | - Raphaël Harrisson
- Nephrology Research Group, L'Hôtel-Dieu de Québec Research Center, Department of Medicine, Faculty of Medicine, Laval University, Quebec, QC, G1R2J6, Canada
| | - Paul Isenring
- Nephrology Research Group, L'Hôtel-Dieu de Québec Research Center, Department of Medicine, Faculty of Medicine, Laval University, Quebec, QC, G1R2J6, Canada.
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The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin E. coli Mediated HUS. Microorganisms 2021; 9:microorganisms9102157. [PMID: 34683478 PMCID: PMC8537462 DOI: 10.3390/microorganisms9102157] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/03/2021] [Accepted: 10/12/2021] [Indexed: 02/02/2023] Open
Abstract
In 90% of the cases, childhood hemolytic uremic syndrome (HUS) is caused by an infection with the Shiga toxin (Stx) producing E. coli bacteria (STEC-HUS). Stx preferentially binds to its receptor, the glycosphingolipid, globotriaosylceramide (Gb3), present on the surface of human kidney cells and various organs. In this study, the glycosphingolipid pathway in endothelial cells was explored as therapeutic target for STEC-HUS. Primary human glomerular microvascular endothelial cells (HGMVECs) and human blood outgrowth endothelial cells (BOECs) in quiescent and activated state were pre-incubated with Eliglustat (Cerdelga®; glucosylceramide synthase inhibitor) or Agalsidase alpha (Replagal®; human cell derived alpha-galactosidase) in combination with various concentrations of Stx2a. Preincubation of endothelial cells with Agalsidase resulted in an increase of α-galactosidase activity in the cell, but had no effect on the binding of Stx to the cell surface when compared to control cells. However, the incubation of both types of endothelial cells incubated with or without the pro-inflammatory cytokine TNFα in combination with Eliglustat resulted in significant decrease of Stx binding to the cell surface, a decrease in protein synthesis by Stx2a, and diminished cellular Gb3 levels as compared to control cells. In conclusion, inhibition of the synthesis of Gb3 may be a potential future therapeutic target to protect against (further) endothelial damage caused by Stx.
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Complement Activation in Human Sepsis is Related to Sepsis-Induced Disseminated Intravascular Coagulation. Shock 2021; 54:198-204. [PMID: 31917735 DOI: 10.1097/shk.0000000000001504] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION In human sepsis, little is known about the relationships between complement activation and the clinical characteristics of sepsis, including disseminated intravascular coagulation (DIC), interventions, and prognosis. PATIENTS AND METHODS Adult patients with sepsis admitted from November 2016 to December 2018 were included. We used the plasma levels of soluble C5b-9 (SC5b-9) as a marker of complement activation. We compared the clinical characteristics and complement components between patients with and without DIC. We also compared the clinical characteristics and each DIC parameter across quartile groups for the SC5b-9 value. RESULTS Forty-nine sepsis patients were eligible. Thirty-four patients developed DIC, and eight patients died. The median (interquartile range) SC5b-9 value was 342 (261-501) ng/mL. Compared with patients without DIC, patients with DIC showed lower C3 levels (mean, 95.7 vs. 70.4 mg/dL, P < 0.01) and higher SC5b-9 levels (median, 287 vs. 400 ng/mL, P = 0.01). Patients were stratified by SC5b-9 quartile (ng/mL: low: < 260, moderate: 260-342, high: 343-501, highest: > 501). The mean Sequential Organ Failure Assessment score varied across these groups (P = 0.02). In the high and highest groups, many more patients received vasopressors and developed DIC. In the highest group, the coagulation parameters were severe, and thrombocytopenia was prolonged. In-hospital mortality tended to be high (33%) in the highest group. CONCLUSIONS The degree of complement activation is related to DIC, severity, intensive interventions, and mortality. Further studies are needed to confirm the usefulness of SC5b-9 for stratifying sepsis patients.
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Nording H, Baron L, Haberthür D, Emschermann F, Mezger M, Sauter M, Sauter R, Patzelt J, Knoepp K, Nording A, Meusel M, Meyer-Saraei R, Hlushchuk R, Sedding D, Borst O, Eitel I, Karsten CM, Feil R, Pichler B, Erdmann J, Verschoor A, Chavakis E, Chavakis T, von Hundelshausen P, Köhl J, Gawaz M, Langer HF. The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets. Nat Commun 2021; 12:3352. [PMID: 34099640 PMCID: PMC8185003 DOI: 10.1038/s41467-021-23499-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 03/28/2021] [Indexed: 02/05/2023] Open
Abstract
Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1-/- mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo.In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.
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Affiliation(s)
- Henry Nording
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany ,grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany
| | - Lasse Baron
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - David Haberthür
- grid.5734.50000 0001 0726 5157Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Frederic Emschermann
- grid.10392.390000 0001 2190 1447University Hospital, Department of Cardiovascular Medicine, Eberhard Karls University, Tübingen, Germany
| | - Matthias Mezger
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Manuela Sauter
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Reinhard Sauter
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Johannes Patzelt
- grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Kai Knoepp
- grid.9018.00000 0001 0679 2801Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Martin-Luther-University Halle (Saale), Halle (Saale), Germany
| | - Anne Nording
- grid.10392.390000 0001 2190 1447Institute of Medical Genetics and Applied Genomics, Eberhard Karls University, Tübingen, Germany
| | - Moritz Meusel
- grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Roza Meyer-Saraei
- grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Ruslan Hlushchuk
- grid.5734.50000 0001 0726 5157Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Daniel Sedding
- grid.9018.00000 0001 0679 2801Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Martin-Luther-University Halle (Saale), Halle (Saale), Germany
| | - Oliver Borst
- grid.10392.390000 0001 2190 1447University Hospital, Department of Cardiovascular Medicine, Eberhard Karls University, Tübingen, Germany
| | - Ingo Eitel
- grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Christian M. Karsten
- grid.4562.50000 0001 0057 2672Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Robert Feil
- grid.10392.390000 0001 2190 1447Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Bernd Pichler
- grid.10392.390000 0001 2190 1447Institute for Preclinical Imaging, Eberhard Karls University, Tübingen, Germany
| | - Jeanette Erdmann
- grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.4562.50000 0001 0057 2672Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
| | - Admar Verschoor
- grid.4562.50000 0001 0057 2672Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Emmanouil Chavakis
- grid.411088.40000 0004 0578 8220Department for Internal Medicine III/Cardiology, University Hospital of the Johann-Wolfgang Goethe University, Frankfurt am Main, Germany
| | - Triantafyllos Chavakis
- grid.4488.00000 0001 2111 7257Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
| | - Philipp von Hundelshausen
- grid.5252.00000 0004 1936 973XInstitute for Cardiovascular Prevention, Ludwig Maximilians University Munich, Munich, Germany
| | - Jörg Köhl
- grid.4562.50000 0001 0057 2672Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany ,grid.239573.90000 0000 9025 8099Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Meinrad Gawaz
- grid.10392.390000 0001 2190 1447University Hospital, Department of Cardiovascular Medicine, Eberhard Karls University, Tübingen, Germany
| | - Harald F. Langer
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany ,grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
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Chung CH, Tsai IJ, Tseng MH, Chou HH, Tain YL, Tsai JD, Chiou YY, Chiou YH, Lin CY. Clinical characteristics, triggering etiologies, and response of plasmapheresis in thrombotic microangiopathy in Taiwan. Medicine (Baltimore) 2021; 100:e25986. [PMID: 34011089 PMCID: PMC8137071 DOI: 10.1097/md.0000000000025986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/28/2021] [Indexed: 01/05/2023] Open
Abstract
Thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse in clinical presentations and etiologies. However, there are still a limited number of large cohort studies focusing on the underlying causes, outcomes, and response to plasmapheresis.A retrospective study was designed to understand trigger etiologies, organ dysfunctions, clinical outcomes, and efficacy of plasmapheresis in patients with TMA. The whole population of Taiwan was set up into 2 cohorts: 875 patients with TMA in the 2006 cohort (2006-2010) and 1352 patients with TMA in the 2011 cohort (2011-2015). One hundred ninety-five patients in the 2006 cohort and 272 patients in the 2011 cohort were under plasmapheresis treatment.The common underlying etiologies were pregnancy, followed by systemic lupus erythematosus, rheumatoid arthritis, transplantation and drugs, which were significantly higher than the control group. Stroke, seizure, arterial thrombosis, vascular stenosis, hypertension, myocardial infarction, and pancreatitis were the main clinical signs and extra-renal involvements. In the multivariate regression analysis, stroke, arterial thrombosis, peripheral arterial disease, and uremia were significantly higher compared with the control group. The mortality rate in TMA under plasmapheresis was significantly higher than all TMA cases (39.33% vs 15.39% in the 2006 cohort and 39.27% vs 15.06% in the 2011 cohort).This study indicated the spectrum of underlying causes, extra-renal characteristics, and the response to plasmapheresis of patients with TMA in Taiwan. Of note, the poor clinical outcomes of plasmapheresis in patients with TMA might highlight the masked underlying etiology or worse disease condition that should be noticed.
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Affiliation(s)
- Ching-Hu Chung
- Department of Medicine, Mackay Medical College, New Taipei City
| | - I-Jung Tsai
- Division of Nephrology, Department of Pediatrics, National Taiwan University Children Hospital, Taipei
| | - Min-Hua Tseng
- Division of Nephrology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Pediatrics, Xiamen Chang Gung Hospital, Ximen, China
| | - Hsin-Hsu Chou
- Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi
- Department of Bioinformatics and Medical Engineering, College of Information and Electrical Engineering, Asia University, Taichung
| | - You-Lin Tain
- Division of Pediatric Nephrology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung
| | - Jeng-Daw Tsai
- Division of Nephrology, Department of Pediatrics, MacKay Children's Hospital, Taipei
| | - Yuan-Yow Chiou
- Departments of Pediatrics, Institute of Clinical Medicine, National Cheng Kung University Medical College and Hospital, Tainan 704
| | - Yee-Hsuan Chiou
- Department of Pediatrics, Kaohsiung Veterans General Hospital
- Department of Medical Technology, Fooyin University, Kaohsiung 831
| | - Ching-Yuang Lin
- Clinical Immunological Center, Children's Hospital, China Medical University, Taichung, Taiwan
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Mucosal IFNγ production and potential role in protection in Escherichia coli O157:H7 vaccinated and challenged cattle. Sci Rep 2021; 11:9769. [PMID: 33963240 PMCID: PMC8105325 DOI: 10.1038/s41598-021-89113-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 04/15/2021] [Indexed: 11/16/2022] Open
Abstract
Shiga-toxin producing Escherichia coli O157:H7 (O157)-based vaccines can provide a potential intervention strategy to limit foodborne zoonotic transmission of O157. While the peripheral antibody response to O157 vaccination has been characterized, O157-specific cellular immunity at the rectoanal junction (RAJ), a preferred site for O157 colonization, remains poorly described. Vaccine induced mucosal O157-specific antibodies likely provide some protection, cellular immune responses at the RAJ may also play a role in protection. Distinct lymphoid follicles were increased in the RAJ of vaccinated/challenged animals. Additionally, increased numbers of interferon (IFN)γ-producing cells and γδ + T cells were detected in the follicular region of the RAJ of vaccinated/challenged animals. Likewise, adjuvanted-vaccine formulation is critical in immunogenicity of the O157 parenteral vaccine. Local T cell produced IFNγ may impact epithelial cells, subsequently limiting O157 adherence, which was demonstrated using in vitro attachment assays with bovine epithelial cells. Thus, distinct immune changes induced at the mucosa of vaccinated and challenged animals provide insight of mechanisms associated with limiting O157 fecal shedding. Enhancing mucosal immunity may be critical in the further development of efficacious vaccines for controlling O157 in ruminants and thus limiting O157 transmission to humans.
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Delvasto-Nuñez L, Jongerius I, Zeerleder S. It takes two to thrombosis: Hemolysis and complement. Blood Rev 2021; 50:100834. [PMID: 33985796 DOI: 10.1016/j.blre.2021.100834] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 01/12/2023]
Abstract
Thromboembolic events represent the most common complication of hemolytic anemias characterized by complement-mediated hemolysis such as paroxysmal nocturnal hemoglobinuria and autoimmune hemolytic anemia. Similarly, atypical hemolytic uremic syndrome is characterized by hemolysis and thrombotic abnormalities. The main player in the development of thrombosis in hemolytic diseases is suggested to be the complement system. However, the release of extracellular hemoglobin and heme by hemolysis itself can also drive procoagulant responses. Both, complement activation and hemolysis promote the activation of neutrophils resulting in the formation of neutrophil extracellular traps and induce inflammation and vascular damage which all together might (synergistically) lead to hypercoagulability. In this review we aim to summarize the current knowledge on the role of complement activation and hemolysis in the onset of thrombosis in hemolytic diseases. This review will discuss the interplay between different biological systems and neutrophil activation contributing to the pathogenesis of thrombosis. Finally, we will combine this fundamental knowledge and address the pathophysiology of hemolysis in prototypical complement-driven diseases.
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Affiliation(s)
- Laura Delvasto-Nuñez
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Ilse Jongerius
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Pediatric Immunology, Amsterdam UMC, University of Amsterdam, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam, the Netherlands
| | - Sacha Zeerleder
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, University of Bern, Switzerland.
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Travert B, Rafat C, Mariani P, Cointe A, Dossier A, Coppo P, Joseph A. Shiga Toxin-Associated Hemolytic Uremic Syndrome: Specificities of Adult Patients and Implications for Critical Care Management. Toxins (Basel) 2021; 13:306. [PMID: 33925836 PMCID: PMC8145702 DOI: 10.3390/toxins13050306] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 04/21/2021] [Accepted: 04/21/2021] [Indexed: 01/28/2023] Open
Abstract
Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is a form of thrombotic microangiopathy secondary to an infection by an enterohemorrhagic E. coli. Historically considered a pediatric disease, its presentation has been described as typical, with bloody diarrhea at the forefront. However, in adults, the clinical presentation is more diverse and makes the early diagnosis hazardous. In this review, we review the epidemiology, most important outbreaks, physiopathology, clinical presentation and prognosis of STEC-HUS, focusing on the differential features between pediatric and adult disease. We show that the clinical presentation of STEC-HUS in adults is far from typical and marked by the prevalence of neurological symptoms and a poorer prognosis. Of note, we highlight knowledge gaps and the need for studies dedicated to adult patients. The differences between pediatric and adult patients have implications for the treatment of this disease, which remains a public health threat and lack a specific treatment.
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Affiliation(s)
- Benoit Travert
- Service de Médecine Interne, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, 75018 Paris, France; (B.T.); (A.D.)
- Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, 75012 Paris, France; (C.R.); (P.C.)
| | - Cédric Rafat
- Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, 75012 Paris, France; (C.R.); (P.C.)
- Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020 Paris, France
| | - Patricia Mariani
- Service de Microbiologie, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, 75019 Paris, France; (P.M.); (A.C.)
| | - Aurélie Cointe
- Service de Microbiologie, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, 75019 Paris, France; (P.M.); (A.C.)
| | - Antoine Dossier
- Service de Médecine Interne, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, 75018 Paris, France; (B.T.); (A.D.)
- Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, 75012 Paris, France; (C.R.); (P.C.)
| | - Paul Coppo
- Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, 75012 Paris, France; (C.R.); (P.C.)
- Service d’Hématologie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France
| | - Adrien Joseph
- Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, 75012 Paris, France; (C.R.); (P.C.)
- Médecine Intensive Réanimation, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, 75010 Paris, France
- Centre de Recherche des Cordeliers, Équipe Labellisée par la Ligue Contre le Cancer, Inserm U1138, Université de Paris, Sorbonne Université, 75006 Paris, France
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Influenza-associated hemolytic uremic syndrome: The pathogenic role of the virus. Clin Nephrol Case Stud 2021; 9:45-48. [PMID: 33884256 PMCID: PMC8056317 DOI: 10.5414/cncs110219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 01/26/2021] [Indexed: 11/18/2022] Open
Abstract
A 3-year-old girl came to our attention for fever and upper respiratory tract infection associated with thrombocytopenia, non-immune hemolytic anemia, and acute kidney injury (AKI). Complete blood count and renal function slowly normalized, with no need for dialysis. She was always normotensive with valid diuresis; her neurological status also rapidly improved. Nasal swab turned out positive for influenza A H1N1; stool test was negative for Shiga toxin-producing Escherichia coli (STEC). The patient was treated with oseltamivir for 5 days with a favorable outcome. Association between hemolytic uremic syndrome (HUS) and H1N1 influenza is poorly reported in literature [1, 2, 3, 4]. The pathogenic role of the virus in causing HUS is still controversial and debated [1, 2, 3, 4]. In our patient, complement activity markers (serum C3 and C5b-9) alteration suggested a transient, virus-mediated complement activation.
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50
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Blasco M, Guillén E, Quintana LF, Garcia-Herrera A, Piñeiro G, Poch E, Carreras E, Campistol JM, Diaz-Ricart M, Palomo M. Thrombotic microangiopathies assessment: mind the complement. Clin Kidney J 2021; 14:1055-1066. [PMID: 33841853 PMCID: PMC8023218 DOI: 10.1093/ckj/sfaa195] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 08/31/2020] [Indexed: 12/11/2022] Open
Abstract
When faced with microangiopathic haemolytic anaemia, thrombocytopenia and organ dysfunction, clinicians should suspect thrombotic microangiopathy (TMA). The endothelial damage that leads to this histological lesion can be triggered by several conditions or diseases, hindering an early diagnosis and aetiological treatment. However, due to systemic involvement in TMA and its low incidence, an accurate early diagnosis is often troublesome. In the last few decades, major improvements have been made in the pathophysiological knowledge of TMAs such as thrombotic thrombocytopenic purpura [TTP, caused by ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13) deficiency] and atypical haemolytic uraemic syndrome (aHUS, associated with dysregulation of the alternative complement pathway), together with enhancements in patient management due to new diagnostic tools and treatments. However, diagnosis of aHUS requires the exclusion of all the other entities that can cause TMA, delaying the introduction of terminal complement blockers, which have shown high efficacy in haemolysis control and especially in avoiding organ damage if used early. Importantly, there is increasing evidence that other forms of TMA could present overactivation of the complement system, worsening their clinical progression. This review addresses the diagnostic and therapeutic approach when there is clinical suspicion of TMA, emphasizing complement evaluation as a potential tool for the inclusive diagnosis of aHUS, as well as for the improvement of current knowledge of its pathophysiological involvement in other TMAs. The development of both new complement activation biomarkers and inhibitory treatments will probably improve the management of TMA patients in the near future, reducing response times and improving patient outcomes.
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Affiliation(s)
- Miquel Blasco
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), University of Barcelona, Barcelona, Spain
- Institute of Biomedical Research August Pi i Sunyer (IDIPABS), Malalties Nefro-Urològiques i Trasplantament Renal, Barcelona, Spain
| | - Elena Guillén
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), University of Barcelona, Barcelona, Spain
| | - Luis F Quintana
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), University of Barcelona, Barcelona, Spain
- Institute of Biomedical Research August Pi i Sunyer (IDIPABS), Malalties Nefro-Urològiques i Trasplantament Renal, Barcelona, Spain
| | | | - Gastón Piñeiro
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), University of Barcelona, Barcelona, Spain
- Institute of Biomedical Research August Pi i Sunyer (IDIPABS), Malalties Nefro-Urològiques i Trasplantament Renal, Barcelona, Spain
| | - Esteban Poch
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), University of Barcelona, Barcelona, Spain
- Institute of Biomedical Research August Pi i Sunyer (IDIPABS), Malalties Nefro-Urològiques i Trasplantament Renal, Barcelona, Spain
| | - Enric Carreras
- Josep Carreras Leukaemia Research Institute, Hospital Clinic/University of Barcelona Campus, Barcelona, Spain
- Barcelona Endothelium Team, Barcelona, Spain
| | - Josep M Campistol
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), University of Barcelona, Barcelona, Spain
- Institute of Biomedical Research August Pi i Sunyer (IDIPABS), Malalties Nefro-Urològiques i Trasplantament Renal, Barcelona, Spain
| | - Maribel Diaz-Ricart
- Barcelona Endothelium Team, Barcelona, Spain
- Department of Pathology, Hematopathology Unit, Hospital Clínic of Barcelona, Biomedical Diagnosis Centre (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Marta Palomo
- Josep Carreras Leukaemia Research Institute, Hospital Clinic/University of Barcelona Campus, Barcelona, Spain
- Barcelona Endothelium Team, Barcelona, Spain
- Department of Pathology, Hematopathology Unit, Hospital Clínic of Barcelona, Biomedical Diagnosis Centre (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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