The renin-angiotensin system (RAS) is a vital, modifiable target in treating renal and cardiovascular diseases. Therapy targeting the angiotensin-converting enzyme (ACE) or the angiotensin II type 1 (AT1) receptor is an important strategy not only for treating hypertension but also for reducing proteinuria and slowing the progression of mild-to-moderate chronic kidney disease. Other therapies targeting the RAS include mineralocorticoid receptor blockers and renin inhibitors. Several renin inhibitors have been synthesized, but aliskiren is the only US Food and Drug Administration-approved renin inhibitor used clinically to treat essential hypertension. However, a specific contraindication concerning its combination with an ACE inhibitor or AT1 blocker in patients who are diabetic limits its use due to risk of hyperkalemia, declining renal function, low blood pressure, and non-fatal stroke (1). In addition, the potential reno-protective effects of aliskiren have not been widely studied in clinical trials (2).
An hypothesis suggests that by suppressing the RAS, increased renin production may activate the alternative complement pathway, leading to the cleavage of C3 into C3b and the formation of a functional C3 convertase. This mechanism implies that aliskiren, due to its specific inhibition of renin, might be a more suitable treatment than ACE inhibitors or AT1 receptor blockers for patients with C3 glomerulopathy (C3G) or primary atypical hemolytic uremic syndrome (aHUS). In their 2018 article in Kidney International, Békássy and colleagues (3) reported that aliskiren use was associated with decreased systemic and renal complement activation, in addition to glomerular basement membrane thickness in three patients with dense depot disease over a follow-up period of 4 to 6 years. In 2019, Plasse et al. (4) reported a favorable evolution of aHUS, initially resistant to the combination of conventional-dose aliskiren and eculizumab, with aliskiren at a supratherapeutic dose. Thus, aliskiren may be preferable to other renin-angiotensin-aldosterone system inhibitors for the treatment of the rare complement-mediated kidney diseases caused by dysregulation of the alternate fluid-phase (C3G) and/or cell-surface (aHUS) complement pathways (5, 6). Based on these studies and the possibility of an interaction between renin and the complement system, a phase 2 clinical trial evaluating the efficacy of aliskiren in patients with C3G is currently underway (7).
A study by Zhang et al. (8), recently published in Kidney International, questions the use of aliskiren in complement-associated kidney diseases. The authors provide seven lines of evidence showing that renin does not cleave C3, suggesting that the use of aliskiren as a renin inhibitor to reduce C3 convertase formation in patients with C3G and aHUS is misguided (Figure 1).
Renin and renin blockade have no role in complement activity
Citation: Kidney News 16, 2
Given the current evidence and awaiting further clinical research, physicians may prefer ACE inhibitors and AT1 blockers over aliskiren due to a more established safety profile across various renal pathologies. This preference will likely persist until larger studies can definitively compare the efficacy and safety of aliskiren with these more traditional therapies.
Footnotes
References
- 1.↑
Parving HH, et al.; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012; 367:2204–2213. doi: 10.1056/NEJMoa1208799
- 2.↑
Nakano D, Nishiyama A. A novel role of renin inhibitor in the complement cascade. Kidney Int 2018; 94:650–652. doi: 10.1016/j.kint.2018.05.025
- 3.↑
Békássy ZD, et al. Aliskiren inhibits renin-mediated complement activation. Kidney Int 2018; 94:689–700. doi: 10.1016/j.kint.2018.04.004
- 4.↑
Plasse RA, et al. Aliskiren as an adjunct therapy for atypical hemolytic uremic syndrome. Clin Kidney J 2019; 13:39–41. doi: 10.1093/ckj/sfz146
- 5.
Heiderscheit AK, et al. C3 glomerulopathy: Understanding an ultra-rare complement-mediated renal disease. Am J Med Genet C Semin Med Genet 2022; 190:344–357. doi: 10.1002/ajmg.c.31986
- 6.
Leon J, et al. Complement-driven hemolytic uremic syndrome. Am J Hematol 2023; 98 (Suppl 4):S44–S56. doi: 10.1002/ajh.26854
- 7.↑
Evaluation of a renin inhibitor, aliskiren, compared to enalapril, in C3 glomerulopathy. ClinicalTrials.gov identifier: NCT04183101. Updated March 29, 2023. https://clinicaltrials.gov/study/NCT04183101
- 8.↑
Zhang Y, et al. Renin and renin blockade have no role in complement activity. Kidney Int (published online November 25, 2023). doi: 10.1016/j.kint.2023.11.005