The Rational Use of Complement Inhibitors in Kidney Diseases

Abstract

The development of complement inhibitors represented one of the major breakthroughs in clinical nephrology in the last decade. Complement inhibition has dramatically transformed the outcome of one of the most severe kidney diseases, the atypical hemolytic uremic syndrome (aHUS), a prototypic complement-mediated disorder. The availability of complement inhibitors has also opened new promising perspectives for the management of several other kidney diseases in which complement activation is involved to a variable extent. With the rapidly growing number of complement inhibitors tested in a rapidly increasing number of indications, a rational use of this innovative and expensive new therapeutic class has become crucial. The present review aims to summarize what we know, and what we still ignore, regarding complement activation and therapeutic inhibition in kidney diseases. It also provides some clues and elements of thoughts for a rational approach of complement modulation in kidney diseases. The development of complement inhibitors represented one of the major breakthroughs in clinical nephrology in the last decade. Complement inhibition has dramatically transformed the outcome of one of the most severe kidney diseases, the atypical hemolytic uremic syndrome (aHUS), a prototypic complement-mediated disorder. The availability of complement inhibitors has also opened new promising perspectives for the management of several other kidney diseases in which complement activation is involved to a variable extent. With the rapidly growing number of complement inhibitors tested in a rapidly increasing number of indications, a rational use of this innovative and expensive new therapeutic class has become crucial. The present review aims to summarize what we know, and what we still ignore, regarding complement activation and therapeutic inhibition in kidney diseases. It also provides some clues and elements of thoughts for a rational approach of complement modulation in kidney diseases. The introduction in clinical practice of complement inhibitors was one of the most significant therapeutic achievements during the last decade. The taming of the old and powerful complement system has opened new clinical perspectives that materialized with the dramatic impact of the first C5 blocker, eculizumab, on the prognosis of 2 severe diseases—aHUS1Legendre C.M. Licht C. Muus P. et al.Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.N Engl J Med. 2013; 368: 2169-2181https://doi.org/10.1056/NEJMoa1208981Crossref PubMed Scopus (914) Google Scholar,2Fakhouri F. Zuber J. Fremeaux-Bacchi V. Loirat C. Haemolytic uraemic syndrome [published correction appears in Lancet. 2017;390:648].Lancet. 2017; 390: 681-696https://doi.org/10.1016/S0140-6736(17)30062-4Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar and paroxysmal nocturnal hemoglobinuria (PNH).3Hillmen P. Young N.S. Schubert J. et al.The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.N Engl J Med. 2006; 355: 1233-1243https://doi.org/10.1056/NEJMoa061648Crossref PubMed Scopus (829) Google Scholar This breakthrough has fueled among clinicians and patients a renewed interest in complement and high expectations regarding the potential benefit of complement modulation in various kidney diseases, but also in the setting of kidney transplantation and of disorders affecting other organs. More than 10 years after the introduction of eculizumab, and with the growing number of complement inhibitors in development, it is time to reflect on the rational use of this innovative therapeutic class. C5 blockade using eculizumab opened a new era for the therapeutic inhibition of the complex complement cascade (Figure 1). It was a turning point in the management of 2 rare but severe complement-mediated diseases, aHUS and PNH. C5 blockade provided a targeted, efficacious treatment, with a reasonable safety profile, for patients affected with these disorders. In patients with PNH, eculizumab significantly reduced, if not halted, complement-induced hemolysis, alleviated or decreased the need for repeated transfusions, reduced thrombosis-related morbidity, but proved inefficacious for treating bone marrow failure associated to PNH.4Brodsky R.A. How I treat paroxysmal nocturnal hemoglobinuria.Blood. 2021; 137: 1304-1309https://doi.org/10.1182/blood.2019003812Crossref PubMed Scopus (17) Google Scholar,5Sicre de Fontbrune F. Peffault de Latour R. Ten years of clinical experience with eculizumab in patients with paroxysmal nocturnal hemoglobinuria.Semin Hematol. 2018; 55: 124-129https://doi.org/10.1053/j.seminhematol.2018.04.001Crossref PubMed Scopus (11) Google Scholar In aHUS, C5 blockade not only induced rapid and sustained hematological remission but also led to a significant improvement in kidney function of affected patients, and the risk of end-stage kidney disease decreased from ∼50% to 60% to ∼10% to 15%2Fakhouri F. Zuber J. Fremeaux-Bacchi V. Loirat C. Haemolytic uraemic syndrome [published correction appears in Lancet. 2017;390:648].Lancet. 2017; 390: 681-696https://doi.org/10.1016/S0140-6736(17)30062-4Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar,6Fakhouri F. Hourmant M. Campistol J.M. et al.Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial.Am J Kidney Dis. 2016; 68: 84-93https://doi.org/10.1053/j.ajkd.2015.12.034Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar with the use of eculizumab. The effect of C5 blockade on the natural history of PNH and aHUS was undoubtedly spectacular. However, this led to a misunderstanding and some level of confusion about what one may expect from complement blockade in other diseases. 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