Complement deposition is detected in kidney biopsies of various types of kidney disease. The type of complement fragments and the location along with other deposited materials describe mechanistically the pattern of glomerular injury encountered and point toward a specific type of glomerular disease. Glomerular disorders, where complement mediated glomerular injury has been documented, include immune complex (IC) mediated kidney disease as seen in lupus nephritis and certain types of membranoproliferative glomerulonephritis (MPGN), where the classic complement pathway is being activated. Other disorders can result from activation of the alternative pathway as in C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) where dysregulation of the alternative pathway is prominent, or the mannose‐binding lectin pathway as in IgA nephropathy. Moreover, the complement system is involved directly and indirectly in several other glomerular disorders as in membranous nephropathy (MN) and ANCA associated vasculitis. Complement activation through any of the pathways leads to the proteolytic cleavage and activation of C3 to C3b. The full activation of any of the complement pathways generates C5b‐9 (the membrane attack complex), a multimeric structure that form pores in the membranes of target cells causing injury and lysis.1
The renin‐angiotensin‐aldosterone system (RAAS) plays an important role in the pathogenesis of chronic kidney disease. Aliskerin is the first orally active, nonpeptide direct renin inhibitor approved for clinical use.2 Interestingly, Aliskerin has been shown to attenuate tubulo‐interstitial fibrosis suggesting significant renal tissue distribution of the drug.3 In addition, Aliskiren is known to have long half‐life of 34‐41 hours compared to other agents which provides an additional benefit of less frequent dosing.4 In patients with diabetic nephropathy, this drug has been shown to have significant anti‐proteinuric effect that was sustained for 2 weeks after withdrawal of the drug which cannot be explained by the plasma half‐life or by the pharmacokinetics of this agent.5, 6
Recently, Bekassy et al7 demonstrated a novel property of renin to cleave C3 in vitro into its physiological cleavage products C3b and C3a in a manner identical to C3 convertase activating the alternate complement pathway. They then demonstrated that this cleavage reaction by renin was specifically blocked by the renin inhibitor Aliskerin. In order to further test their theory in clinical practice, the authors demonstrated a favorable effects of Aliskiren in three patients with dense deposit disease (DDD) on levels of C3 and glomerular C3 deposition.7
This brings to attention a possible mechanism by which Aliskiren and possibly other renin inhibitors can explain additional benefits in complement mediated renal disease apart from its established anti‐proteinuric and antifibrotic effects. Let's also keep in mind that the other members of the RAAS blockade family, the angiotensine converting enzyme inhibitors (ACEI's) and the angiotensin receptor antagonists (ARB's) are of particular importance to this observation. One might speculate that the consequence of hyperreninemia resulting from the use of ACEI and ARB use on C3 cleavage can be an unwanted effect of these very commonly prescribed medications on patients with complement mediated glomerular diseases potentially leading to increased complement activation that can be more injurious. Such potentially anticipated deleterious effects of ACEI's or ARB's on complement activation could have been masked previously by their significant antiproteinuric effects in patients with various types of kidney disease. There is clearly an urgent need for a well‐designed randomized controlled clinical trial addressing these very observations and looking specifically at hard renal outcome end‐points along with markers of complement activation with the use of different RAAS‐targeting medications in patients with different types of kidney disease.
CONFLICT OF INTEREST
None.
Pramod S, Mustafa BO, Khitan ZJ. Can Aliskiren "COMPLEMENT" our management of kidney disease? J Clin Hypertens. 2019;21:687–688. 10.1111/jch.13524
All authors had access to the data and a role in writing the manuscript.
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