Complement in Kidney Disease: Core Curriculum 2015
Complement in Kidney Disease: Core Curriculum 2015
Eculizumab has been approved by the FDA for the treatment of aHUS and has been tested in several other kidney diseases. It is a humanized murine monoclonal antibody to complement C5 that prevents the formation of C5a and C5b-9, but does not prevent the generation of C3a and C3b. Leaving the early complement system intact may reduce the risk of infection, but C3a and C3b also may contribute to the pathogenesis of some inflammatory diseases. Because eculizumab prevents formation of the membrane attack complex, the CH50 in treated patients should be close to 0. This functional readout aids in monitoring dosing of the drug. C5 blockade does not directly affect circulating C3 and C4 levels and does not block C3 deposition within glomeruli. The primary risk of complement inhibition is that of infection, and all patients who receive eculizumab should be either immunized for meningococcus or prophylactically treated for this infection with antibiotics.
Eculizumab is an expensive drug, limiting its use for diseases in which its benefit is uncertain or that have other effective treatments. Even in patients with aHUS, the optimal duration of treatment is unknown. Patients with complement mutations are at lifelong risk of recurrence, and it is not clear whether patients should be treated indefinitely or only during periods of active disease. Disease flares often are triggered by illness (particularly diarrheal illnesses), pregnancy, and certain drugs. In some cases, disease recurrence has been attributed to very minor stressors, such as vaccination. A dilemma then is that flares may be triggered by minor events and may rapidly lead to irreversible kidney injury, yet prevention of these flares could require life-long therapy.
Other complement inhibitory drugs are in development, some of which block specific activation pathways or activation fragments. One difficulty developing new drugs for the treatment of aHUS and C3 glomerulopathy is the large number of underlying genetic mutations and autoantibodies associated with these diseases. Depending on their mechanisms of action, many of the new drugs likely will not work for patients with particular underlying complement defects. For example, gain-of-function mutations in C3 that resist inactivation by endogenous complement regulatory proteins also might be resistant to inactivation by some anticomplement drugs. Although complete genetic and molecular testing of each patient may take weeks or months to complete, functional assays of complement inhibition may provide a rapid means of testing complement inhibition by a specific drug in an individual patient.
Therapeutic Complement Blockade
Complement Inhibitory Drugs
Eculizumab has been approved by the FDA for the treatment of aHUS and has been tested in several other kidney diseases. It is a humanized murine monoclonal antibody to complement C5 that prevents the formation of C5a and C5b-9, but does not prevent the generation of C3a and C3b. Leaving the early complement system intact may reduce the risk of infection, but C3a and C3b also may contribute to the pathogenesis of some inflammatory diseases. Because eculizumab prevents formation of the membrane attack complex, the CH50 in treated patients should be close to 0. This functional readout aids in monitoring dosing of the drug. C5 blockade does not directly affect circulating C3 and C4 levels and does not block C3 deposition within glomeruli. The primary risk of complement inhibition is that of infection, and all patients who receive eculizumab should be either immunized for meningococcus or prophylactically treated for this infection with antibiotics.
Eculizumab is an expensive drug, limiting its use for diseases in which its benefit is uncertain or that have other effective treatments. Even in patients with aHUS, the optimal duration of treatment is unknown. Patients with complement mutations are at lifelong risk of recurrence, and it is not clear whether patients should be treated indefinitely or only during periods of active disease. Disease flares often are triggered by illness (particularly diarrheal illnesses), pregnancy, and certain drugs. In some cases, disease recurrence has been attributed to very minor stressors, such as vaccination. A dilemma then is that flares may be triggered by minor events and may rapidly lead to irreversible kidney injury, yet prevention of these flares could require life-long therapy.
Other complement inhibitory drugs are in development, some of which block specific activation pathways or activation fragments. One difficulty developing new drugs for the treatment of aHUS and C3 glomerulopathy is the large number of underlying genetic mutations and autoantibodies associated with these diseases. Depending on their mechanisms of action, many of the new drugs likely will not work for patients with particular underlying complement defects. For example, gain-of-function mutations in C3 that resist inactivation by endogenous complement regulatory proteins also might be resistant to inactivation by some anticomplement drugs. Although complete genetic and molecular testing of each patient may take weeks or months to complete, functional assays of complement inhibition may provide a rapid means of testing complement inhibition by a specific drug in an individual patient.
Additional Readings
Ricklin D, Lambris JD. Progress and trends in complement therapeutics. Adv Exp Med Biol. 2013;735:1–22.
Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol. 2007;25(11):1256–1264.
Zhang Y, Nester CM, Holanda DG, et al. Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. J Am Soc Nephrol. 2013;24(11):1820–1829.
Zuber J, Quintrec ML, Krid S, et al. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant. 2012;12(12):3337–3354.
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