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[The complement system-a "hot topic" not only for kidney diseases]
Kerstin Amann1, Christoph Daniel2, Maike Büttner-Herold2
1Abt. Nephropathologie, Pathologisches Institut, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054, Erlangen, Deutschland. kerstin.amann@uk-erlangen.de.
Insights
The complement system, particularly its alternative pathway, is increasingly linked to systemic and renal diseases like atypical hemolytic uremic syndrome (aHUS). Therapies targeting complement activation show promise in treating these conditions.
Area of Science:
- Immunology
- Nephrology
- Genetics
Background:
- The complement system, especially the alternative pathway, plays a crucial role in systemic and renal diseases.
- Atypical hemolytic uremic syndrome (aHUS) is a key example, characterized by thrombotic microangiopathy (TMA) due to complement overactivation.
- Genetic analyses have significantly advanced our understanding of aHUS pathogenesis.
Purpose of the Study:
- To review the growing interest and recent insights into complement system involvement in systemic and renal diseases.
- To highlight the therapeutic implications of understanding complement pathway dysregulation.
- To discuss the identification of new complement-mediated diseases.
Main Methods:
- Review of recent pathophysiological and therapeutic insights.
- Analysis of genetic findings in atypical hemolytic uremic syndrome (aHUS).
- Identification of systemic and renal diseases linked to complement pathway mutations or auto-antibodies.
Main Results:
- Excessive alternative complement pathway activation is central to aHUS and TMA.
- Inhibition of the terminal complement cascade (C5b9 inhibitor) successfully reduced local tissue damage in aHUS.
- New complement-mediated diseases have been identified, often triggered by infections or hormonal changes in predisposed individuals.
Conclusions:
- Understanding complement regulation allows for therapeutic modulation of complement pathways.
- The increasing availability of complement-inhibiting drugs fuels interest in treating complement-mediated diseases.
- Complement-mediated systemic and renal diseases are a rapidly evolving and significant area of medical research.
Abstract:
Increasing interest in the role of the complement system in systemic and renal disease is based on new pathophysiological and therapeutic insights of the recent past and particularly in genetic analyses in children with atypical hemolytic uremic syndrome (aHUS). aHUS is the prototypical systemic disease associated with excessive activation of the alternative complement pathway and manifests in the kidney, but also in other organs as thrombotic microangiopathy (TMA). Pathomechanisms discovered to induce the overactivation of the alternative complement pathway in aHUS led to the first successful therapeutic application of a C5b9 inhibitor. This suppression of the terminal complement cascade succeeded in inhibiting local tissue damage. Thereafter, thanks to advanced modern technologies, further systemic and renal diseases associated with mutations or auto-antibodies targeting the complement pathway were identified. Hereby, disease onset is frequently associated with an additional trigger, e.g. infection or hormonal alterations/imbalances, against the background of a pre-existing predisposition of the patient.Due to the growing understanding of the regulation, and thus the possibility of therapeutic modulation of the different complement pathways, and due to the increasing availability of a variety of drugs inhibiting the complement system, interest in complement-mediated systemic and renal disease has been steadily increasing, making it a "hot-topic" in medicine in recent years.
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