**Direct renin inhibitor**

116 Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease

orally in 2 daily doses of 25 to 200 mg in 8 HDD-CKD patients. These patients showed HT despite intensive ultrafiltration and conventional antihypertensive therapy. For 4 patients with the highest PRA, their BP was normalized by captopril alone. For the 4 remaining patients, captopril therapy was complemented by salt subtraction, which consisted of replacement of 1-2 liters of ultrafiltrate by an equal volume of 5% dextrose until BP was controlled. After an average treatment period of 5 months, BP of all 8 patients was reduced from 179/105 ± 6/3 (mean ±SEM) to 134/76 ± 7/5 mmHg (p <0.001) without a significant change in body weight. These clinical studies demonstrated that ACE inhibitor has beneficial effects to control BP in HDD-CKD patients. In addition, some studies reported that ACE inhibitors showed cardiovascular protective effects in HDD-CKD patients as follows. London et al. reported that perindopril (2-4 mg after each HD session) significantly reduced left ventricular mass (317±18 to 247±21 g, p=0.036) after 12 months in 14 HDD-CKD patients whereas a calcium channel antagonist, nitredipine (20-40 mg/day), did not when perindopril and nitredipine showed similar reductions of BP. Matsumoto et al. reported that imidapril (2.5 mg/day) significantly reduced left ventricular mass index (132±10 to 109±6 g/m2, p<0.05) after 6 months; however, placebo did not produce a change in HDD-CKD patients. SBP and DBP were not significantly changed in either imidapril or placebo group. In that study, ACE was reduced (12±1 to 5±2 U/I, p<0.01) and PRA was increased (3.3±0.8 to 8.1±3.2 ng/ml/h, p<0.01) but plasma AT II and aldosterone (Ald) were not significantly changed (13±3 to 17±3 pg/ml and 365±125 to 312±132 pg/ml, respectively). These results suggested that the beneficial effect of imidapril against left ventricular mass was independent of BP lowering effect. Zannad et al. reported that no significant benefit was found with fosinopril (5-20 mg/day) for the prevention of cardiovascular events such as cardiovascular death, resuscitated death, nonfatal stroke, heart failure, myocardial infarction, or revascularization in HDD-CKD patients; however, there was a trend that fosinopril treatment may be associated with a lower risk of cardiovascular events after adjustment for risk factors. These lines of evidence suggested that ACE inhibitors are effective in controlling BP and preventing CVD in HDD-CKD patients. It is highly likely that the cardioprotective effects of ACE inhibitors are independent of their BP lowering effect in

Saracho et al. reported on a multicenter, open 6 month study designed to test the tolerability and efficacy of losartan as an antihypertensive in 406 hypertensive HDD-CKD patients who were previously untreated, treated but uncontrolled, or treated with poor tolerability. There were significant reductions in pre- and postdialysis SBP and DBP at 3 months (pre SBP/DBP: 155 ± 15/84± 9 mmHg, post SBP/DBP: 140 ± 19/78± 10 mmHg) and 6 months (pre SBP/DBP: 152 ± 16/83± 9 mmHg, post SBP/DBP: 139± 18/77± 9 mm Hg) compared with those at baseline (pre SBP/DBP: 163 ± 16/88± 10 mmHg, post SBP/DBP: 148± 18/82± 9 mmHg). Shibasaki et al. reported that losartan (50 mg/day) reduced left ventricular mass index (-24.7±3.2%) after 6 months more than a calcium channel antagonist, amlodipine (5 mg/day: -10.5±5.2%), or an ACE inhibitor, enalapril (5 mg/day: -11.2±4.1%), although all three groups had similar decreases in mean BP. Kanno et al. reported that losartan (100 mg/TIW) reduced left ventricular hypertrophy (145±5 to 122±3 g/m2, p<0.001) after 12 months in 24 diabetic patients on HD therapy whereas a placebo group showed no change. In this study, SBP and DBP were controlled below 140/90 mmHg with a calcium antagonist,

HDD-CKD patients.

**Angiotensin receptor blockers in HDD-CKD patients** 

An oral direct renin inhibitor, aliskiren, is effective against essential HT by reducing PRA, resulting in suppression of RAAS; however, little was known about the effects of aliskiren in HDD-CKD patients. Recently, we reported on antihypertensive and potential cardiovascular protective effects of aliskiren, in hypertensive HDD-CKD patients. Aliskiren (150 mg/day) significantly reduced SBP and DBP after 2 month in hypertensive HDD-CKD patients (Figure 3). RAAS was suppressed by aliskiren treatment (PRA: 3.6±4.0 to 1.0 ±1.5 ng/ml/hr, p=0.004; AT I: 1704.0±2580.9 to 233. 7±181.0 pg/ml, p=0.009; AT II: 70.2±121.5 to 12.4±11.5 pg/ml, p=0.022) (Figure 4). Surrogate markers for cardiovascular disease such as BNP, highsensitivity CRP (hs-CRP), and an oxidative stress marker, diacron-reactive oxygen metabolite (d-ROM), were inhibited by aliskiren (BNP: 362.5±262.1 to 300.0±232.0 pg/ml, p=0.043; hs-CRP: 6.2±8.1 to 3.5±3.7 mg/l, p=0.022; d-ROM: 367.0±89.8 to 328.3±70.9 U.CARR, p=0.022) (Figure 5). The levels of inhibition of these surrogate markers for CVD by aliskiren did not correlate with the decreased levels of BP. Two treatments were discontinued owing to an adverse event and symptomatic hypotension by aliskiren. The adverse event was eyebrow alopecia (1 patient). A possible connection of this event to aliskiren treatment could not be excluded. The symptomatic hypotension recovered to the basal level after aliskiren withdrawal. Increased serum potassium was not observed in any patients. Several studies reported that mean trough plasma aliskiren concentrations were increased by renal impairment; however, an increase in exposure did not correlate with the severity of renal impairment. Moreover, renal clearance of aliskiren was found to occur for only a small fraction (0.1-1.0%). These data suggest that adjustment of the aliskiren dose is

The Renin-Angiotensin-Aldosterone System in Dialysis Patients 119

Fig. 5. Change in brain natriuretic peptide (BNP), highly sensitive C-reactive protein (hs-CRP), and diacron-reactive oxygen metabolite (d-ROM) by aliskiren treatment in hemodialysis-dependent chronic kidney disease patients (Morishita *et al.*, 2011a).

A few studies reported on a RAAS blockade effect in peritoneal dialysis-dependent CKD (PDD-CKD) patients. Fang et al. reported that a group (n=165) treated with ACE inhibitors/ ARBs had a significantly longer survival than an untreated group (n= 141) (log rank 19.191, P < 0.001) in PDD-CKD patients. After adjusting for age, BP, and other demographic and clinical parameters, multivariable Cox proportional hazards modeling showed that the use of ACE inhibitors/ARBs was associated with 62% reduced risk of death (HR 0.382, 95% CI 0.232-0.631, P < 0.001) in PDD-CKD patients. Jing et al. reported that ultrafiltration of a group treated with ACE inhibitors/ARBs group (n=38) had not changed after 12 months whereas that of an untreated group (n=28) had decreased (P < 0.05). The expressions of fibronectin, Transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) in dialysate effluent were significantly increased in the untreated group, but not in the group treated with ACE inhibitors/ARBs. These results suggested that RAAS blockade has beneficial effects for mortality and peritoneal function in PDD-CKD patients. Suzuki et al. reported that ARB (valsartan) slowed the decline in residual renal function

**3.3 Caridioprotective effects of RAAS blockers independent of their BP lowering** 

mechanism of cardioprotective effects of RAAS blockade on DD-CKD patients.

Increasing evidence suggested that elevation of RAAS contributes directly to cardiac hypertrophy via its growth factor properties on smooth muscle cells and cardiac myocytes among DD-CKD patients, independent of BP effects. RAAS also plays a role in cardiac fibrosis by stimulating TGF-β1 gene expression and induction of fibroblast proliferation and collagen deposition. RAAS blockers may directly effects for cardiac hypertrophy and fibrosis via these pathways independent of their BP lowering effects in DD-CKD patients. In addition, several studies reported that RAAS blockers showed beneficial effects for pulse wave velocity which is recognized as a potent predictor of mortality in DD-CKD patients, independent of their BP lowering effects. Further studies will be needed to investigate the

**3.2 PDD-CKD patients** 

**effect in DD-CKD patients** 

independent of BP lowering effect in PDD-CKD patinets.

unlikely to be required in HDD-CKD patients. Further studies will be required to investigate the pharmacokinetics of aliskiren in HDD-CKD patients. In summary, these results suggest that aliskiren is effective in BP control and extend the possibility that aliskiren may have cardiovascular protective effects in hypertensive HDD-CKD patients.

Fig. 3. Change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline (Week 0) to Week 8 with aliskiren (150 mg/day) treatment in hemodialysisdependent chronic kidney disease patients (Morishita *et al.*, 2011a).

Fig. 4. Change in plasma renin activity (PRA), angiotensin I (ATI), angiotensin II (ATII), and aldosterone (Ald) by aliskiren treatment in hemodialysis-dependent chronic kidney disease patients (Morishita *et al.*, 2011a).

Fig. 5. Change in brain natriuretic peptide (BNP), highly sensitive C-reactive protein (hs-CRP), and diacron-reactive oxygen metabolite (d-ROM) by aliskiren treatment in hemodialysis-dependent chronic kidney disease patients (Morishita *et al.*, 2011a).

#### **3.2 PDD-CKD patients**

118 Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease

unlikely to be required in HDD-CKD patients. Further studies will be required to investigate the pharmacokinetics of aliskiren in HDD-CKD patients. In summary, these results suggest that aliskiren is effective in BP control and extend the possibility that aliskiren may have

Fig. 3. Change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline (Week 0) to Week 8 with aliskiren (150 mg/day) treatment in hemodialysis-

Fig. 4. Change in plasma renin activity (PRA), angiotensin I (ATI), angiotensin II (ATII), and aldosterone (Ald) by aliskiren treatment in hemodialysis-dependent chronic kidney disease

patients (Morishita *et al.*, 2011a).

dependent chronic kidney disease patients (Morishita *et al.*, 2011a).

cardiovascular protective effects in hypertensive HDD-CKD patients.

A few studies reported on a RAAS blockade effect in peritoneal dialysis-dependent CKD (PDD-CKD) patients. Fang et al. reported that a group (n=165) treated with ACE inhibitors/ ARBs had a significantly longer survival than an untreated group (n= 141) (log rank 19.191, P < 0.001) in PDD-CKD patients. After adjusting for age, BP, and other demographic and clinical parameters, multivariable Cox proportional hazards modeling showed that the use of ACE inhibitors/ARBs was associated with 62% reduced risk of death (HR 0.382, 95% CI 0.232-0.631, P < 0.001) in PDD-CKD patients. Jing et al. reported that ultrafiltration of a group treated with ACE inhibitors/ARBs group (n=38) had not changed after 12 months whereas that of an untreated group (n=28) had decreased (P < 0.05). The expressions of fibronectin, Transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) in dialysate effluent were significantly increased in the untreated group, but not in the group treated with ACE inhibitors/ARBs. These results suggested that RAAS blockade has beneficial effects for mortality and peritoneal function in PDD-CKD patients. Suzuki et al. reported that ARB (valsartan) slowed the decline in residual renal function independent of BP lowering effect in PDD-CKD patinets.

#### **3.3 Caridioprotective effects of RAAS blockers independent of their BP lowering effect in DD-CKD patients**

Increasing evidence suggested that elevation of RAAS contributes directly to cardiac hypertrophy via its growth factor properties on smooth muscle cells and cardiac myocytes among DD-CKD patients, independent of BP effects. RAAS also plays a role in cardiac fibrosis by stimulating TGF-β1 gene expression and induction of fibroblast proliferation and collagen deposition. RAAS blockers may directly effects for cardiac hypertrophy and fibrosis via these pathways independent of their BP lowering effects in DD-CKD patients. In addition, several studies reported that RAAS blockers showed beneficial effects for pulse wave velocity which is recognized as a potent predictor of mortality in DD-CKD patients, independent of their BP lowering effects. Further studies will be needed to investigate the mechanism of cardioprotective effects of RAAS blockade on DD-CKD patients.

The Renin-Angiotensin-Aldosterone System in Dialysis Patients 121

Cooper, A.C., Robinson, G., Vinson, G.P., Cheung, W.T., Broughton Pipkin, F., 1999. The

Crawford, D.C., Chobanian, A.V., Brecher, P., 1994. Angiotensin II induces fibronectin expression associated with cardiac fibrosis in the rat. Circ Res 74, 727-739. Diskin, C.J., Stokes, T.J., Dansby, L.M., Carter, T.B., Radcliff, L., 2004. The clinical

Dostal, D.E., Baker, K.M., 1999. The cardiac renin-angiotensin system: conceptual, or a

Fang, W., Oreopoulos, D.G., Bargman, J.M., 2008. Use of ACE inhibitors or angiotensin

Heerspink, H.J., Ninomiya, T., Zoungas, S., de Zeeuw, D., Grobbee, D.E., Jardine, M.J.,

Herzog, C.A., Ma, J.Z., Collins, A.J., 2002. Long-term survival of dialysis patients in the

Huang, W.H., Hsu, C.W., Chen, Y.C., Hung, C.C., Huang, J.Y., Lin, J.L., Yang, C.W., 2007.

Ichihara, A., Hayashi, M., Kaneshiro, Y., Suzuki, F., Nakagawa, T., Tada, Y., Koura, Y.,

Ichihara, A., Hayashi, M., Kaneshiro, Y., Takemitsu, T., Homma, K., Kanno, Y., Yoshizawa,

Ichihara, A., Kaneshiro, Y., Takemitsu, T., Sakoda, M., Suzuki, F., Nakagawa, T., Nishiyama,

Ito, S., Nakura, N., Le Breton, S., Keefe, D., 2010. Efficacy and safety of aliskiren in Japanese hypertensive patients with renal dysfunction. Hypertens Res 33, 62-66. Jing, S., Kezhou, Y., Hong, Z., Qun, W., Rong, W., 2010. Effect of renin-angiotensin system

Jurewicz, M., McDermott, D.H., Sechler, J.M., Tinckam, K., Takakura, A., Carpenter, C.B.,

on valve selection be modified? Circulation 105, 1336-1341. Hsueh, W.A., Baxter, J.D., 1991. Human prorenin. Hypertension 17, 469-477.

throughout pregnancy. Placenta 20, 467-474.

regulator of cardiac function? Circ Res 85, 643-650.

author reply 1332.

Transplant 23, 3704-3710.

Lancet 373, 1009-1015.

Fail 29, 843-848.

1128-1135.

45, 866-874.

Hypertension 47, 894-900.

Nephrology (Carlton) 15, 27-32.

localization and expression of the renin-angiotensin system in the human placenta

significance of aldosterone in ESRD: Part II. Nephrol Dial Transplant 19, 1331-1332;

receptor blockers and survival in patients on peritoneal dialysis. Nephrol Dial

Gallagher, M., Roberts, M.A., Cass, A., Neal, B., Perkovic, V., 2009. Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials.

United States with prosthetic heart valves: should ACC/AHA practice guidelines

Angiotensin II receptor antagonists supplementation is associated with arterial stiffness: insight from a retrospective study in 116 peritoneal dialysis patients. Ren

Nishiyama, A., Okada, H., Uddin, M.N., Nabi, A.H., Ishida, Y., Inagami, T., Saruta, T., 2004. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. J Clin Invest 114,

M., Furukawa, T., Takenaka, T., Saruta, T., 2005. Low doses of losartan and trandolapril improve arterial stiffness in hemodialysis patients. Am J Kidney Dis

A., Inagami, T., Hayashi, M., 2006. Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension.

inhibitors on prevention of peritoneal fibrosis in peritoneal dialysis patients.

Milford, E., Abdi, R., 2007. Human T and natural killer cells possess a functional
