Direct Renin Inhibitor: Aliskiren in Chronic Kidney Disease

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression and its increased complications such as hypertension (HT) and cardiovascular diseases (CVD). Previous studies suggested that aliskiren a direct renin inhibitor, blocks RAAS and may be effective for the management of CKD and its complications. This review focuses on the effects of aliskiren on CKD.


Introduction
Aliskiren is an orally active nonpeptide direct renin inhibitor, which acts by binding to the active site of renin (1). Aliskiren directly inhibits plasma renin activity (PRA), which acts at the initial and rate-limiting step in the renin-angiotensin-aldosterone system (RAAS), unlike the blockade of RAAS by angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) which cause a reactive rise in PRA (2).
RAAS plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression (3). It has been reported that CKD is associated with increased risk of hypertension (HT) and cardiovascular diseases (CVD) (4)(5)(6). RAAS has been also shown to contribute to HT and CVD development in CKD (7,8). Many clinical trials have demonstrated that blockade of RAAS by ACEIs or ARBs could prevent the development and progression of CKD and its complications such as HT and CVD (9)(10)(11)(12)(13)(14). Recent evidences suggest that aliskiren would be effective for CKD management and its complications such as HT and CVD (15)(16)(17)(18)(19)(20)(21). This review focuses on clinical studies that have demonstrated the effects of aliskiren on CKD.

RAAS in CKD
RAAS plays pivotal roles in the pathogenesis of CKD (3). Among RAAS components, angiotensin II (ATII) mainly causes vasoconstriction in the efferent glomerular arteries rather than the afferent ones, which induces glomerular hypertrophy (22). ATII also causes vasoconstriction at glomerular capillaries, which affects the glomerular filtration rate (23). ATII also contributes to increase connective tissue production and extracellular matrix deposi- Abbreviations: ARBs; angiotensin receptor blockers, ACEIs; angiotensin I-converting enzyme inhibitors, BNP; brain natriuretic peptide, DBP; diastolic blood pressure, d-ROM; diacron-reactive oxygen metabolite, hs-CRP; high-sensitivity C-reactive protein, L-ABP; L-fatty acid binding protein, MSBP; mean systolic blood pressure, MSNA; muscle sympathetic nerve activity, SBP; systolic blood pressure, UACR; urinary albuminto-creatinine ratio tion (24). RAAS also plays pivotal roles in the pathogenesis of HT and the development of CVD in CKD (7,8). The role of RASS in patients with hypertensive CKD was confirmed by the normalization of blood pressure (BP) following administration of an angiotensin antagonist, saralasin (25). Normally, volume overload and elevation of BP result in suppression of RAAS production. Since this feedback is often incomplete in CKD, patients with CKD often show HT and high or normal RAAS activity (7). Among RASS, ATII mainly contributes to the development of CVD. ATII has cellular effects that promote proliferation and hypertrophy of vascular smooth muscle cells and cardiac fibroblasts (26,27). ATII also increases inflammatory mediators, which is an independent risk factor for CVD by directly increasing proinflammatory gene expression and activating oxidative stress, leading to progressive inflammation of the vascular endothelium (28-30).
Parving et al. reported that treatment with aliskiren (150 mg daily for 3 months, followed by an increase in the dosage to 300 mg daily for another 3 months) added to losartan (100 mg daily) reduced the mean urinary albumin-to-creatinine ratio (UACR) by 20%; however, placebo did not reduce this ratio in 599 patients with hypertensive diabetic nephropathy (eGFR: 68.5 ± 25.7 mL/ min/1.73m2 (aliskiren group), 66.8 ± 24.5 mL/min/1.73m2 (placebo group) (15). Furthermore, only small differences in BP (SBP: 2 mmHg lower (P = 0.07) and DBP: 1 mmHg lower (P = 0.08) in the aliskiren group) were seen between the aliskiren group and the placebo group by the end of the study period (15). Moriyama et al. reported that aliskiren reduced the UACR in 10 patients with CKD (eGFR 30-90 mL/min) (18). In that study, aliskiren (150 mg daily) reduced the UACR by about 40% after 16 weeks from baseline when it was added to olmesartan (10-40 mg daily); however, it did not change eGFR and BP throughout the study period (18). These results suggest that aliskiren may have renoprotective effects regardless of BP lowering effects.

Adverse Effects of Aliskiren on CKD
Hyperkalemia, which is a frequent concern in patients with HD regardless of medication use, is the primary danger from RAAS-blocking medications. The blockade of RAAS leads to a decrease in aldosterone levels. Since aldosterone has a central role in the excretion of potassium, RAAS blockers can cause potassium retention. Several clinical trials of aliskiren in patients with CKD tracked potassium levels (15,16,19,21). No significant trend for increased hyperkalemia by aliskiren in patients with CKD was observed in these trials (15,16,19,21). Although careful and periodical monitoring of plasma potassium level is required, these results suggested that the risk of hyperkalemia by aliskiren in patients with CKD is small. One study reported that 15% of patients with CKD had adverse events that were suspected of being related to aliskiren. The most frequently reported adverse events were mild to moderate nasopharyngitis, back pain, and dizziness (5% each) (19).
Several studies reported that mean trough plasma aliskiren concentrations increased with renal impairment (19,31); however, an increase in exposure did not correlate with the severity of renal impairment (31). Moreover, renal clearance of aliskiren represents only a small fraction (0.1-1.0%) (2). Although these data suggest that initial adjustment of the aliskiren dosage is unlikely to be required in patients with CKD, careful observation of BP change is required for aliskiren treatment in patients with CKD because several studies have reported symptomatic hypotension with aliskiren in patients with CKD.

Conclusion
From previous studies, it is suggested that aliskiren has beneficial effects for renoprotection, the control of BP, and the prevention of CVD in patients with CKD. However, the choice of aliskiren as well as its use in the treatment of patients with CKD has to be carefully determined considering the possible adverse effects and potential interactions with other drugs being used together. Further high-quality studies that are well designed and have an adequate sample size are still needed to confirm the effects of aliskiren in patients with CKD.