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- Patients and Methods
The renin-angiotensin-aldosterone system is not necessarily suppressed in end-stage renal disease patients undergoing dialysis. Of all the inhibitors of this system, the clinical efficacy of the renin inhibitor, aliskiren, has not been well demonstrated in dialysis patients. We evaluated the antihypertensive effect of aliskiren, administered as a single daily dose of 150 mg for 24 weeks, in 23 chronic hemodialysis patients (age 65 ± 12 years, 15 men and eight women) with blood pressure ≥140/90 mm Hg, and assessed the factors relating to blood pressure reduction. At 4 weeks, the average systolic blood pressure before the dialysis session was insignificantly reduced from 163 ± 10 mm Hg to 160 ± 15 mm Hg, while it was significantly lowered at 12 (154 ± 13 mm Hg) and 24 weeks (155 ± 10 mm Hg), although the pulse rate was not significantly altered. Serum K increased at 24 weeks from 4.9 ± 0.6 mEq/L to 5.2 ± 0.8 mEq/L. Only 10 out of 23 patients showed systolic blood pressure reduction by ≥10 mm Hg. Naturally, plasma renin immunoreactivity increased, while plasma renin activity, along with angiotensin II and aldosterone levels decreased. Basal levels of the components of the renin-angiotensin-aldosterone system were not significantly different in patients showing systolic blood pressure reduction by ≥10 mm Hg (n = 10) vs. those with <10 mm Hg changes (n = 13). The reduction in systolic blood pressure in all 23 patients taken as a whole correlated with changes in plasma renin activity (r = −0.432, P < 0.05) and angiotensin II (r = 0.467, P < 0.05). In chronic hemodialysis patients, aliskiren modestly lowers blood pressure over the long term, although the antihypertensive effect seems dependent on the changes, but not on the basal levels of plasma renin activity and angiotensin II.
Patients with ESRD undergoing dialysis therapy have increased morbidity and mortality as compared with the general population. In particular, the high incidence of cardiovascular diseases and infection limits the life expectancy of dialysis patients [1, 2]. In order to effectively prevent cardiovascular diseases in ESRD patients, not only the traditional cardiovascular risk factors such as hypertension, diabetes and dyslipidemia, but also the non-traditional risk factors should be considered . Such non-traditional risk factors include neurohumoral factors such as activation of the sympathetic nerve system and renin-angiotensin-aldosterone system (RAAS). Recent studies have shown that angiotensin II and aldosterone exhibit deleterious effects on the development and progression of tissue injuries in cardiovascular organs [4-6]. In addition, it has been shown that the circulating RAAS is not necessarily suppressed in patients on chronic HD .
Patients with renal failure have a high prevalence of hypertension [8-10], which is a major traditional cardiovascular risk factor. Among the many different classes of antihypertensive drugs available, calcium channel blockers (CCB) are widely used because of their potent hypotensive effects. As compared with CCB, the hypotensive effects of RAAS inhibitors, such as ACE inhibitors and angiotensin II receptor blockers (ARB) are less consistent, although they alleviate the deleterious effects of angiotensin II and aldosterone on cardiovascular tissues and organs [11-14]. Direct renin inhibitors are a new class of RAAS inhibitors; hence, their effectiveness in ESRD patients has not yet been fully delineated, especially with chronic use. In this study, we administered aliskiren, a direct renin inhibitor, to HD patients and evaluated its long-term effects as an antihypertensive agent.
Patients and Methods
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- Patients and Methods
This multicenter clinical study was performed at four dialysis units in Dokkyo Medical University Hospital, Utsunomiya Chuo Hospital, Ohba Clinic and Hashimoto Clinic. The inclusion criteria of study subjects were: (i) undergoing stable maintenance HD as an outpatient for more than 3 months; (ii) hypertension, defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg before three consecutive dialysis sessions; and (iii) age 20 to 79 years. The exclusion criteria were: (i) treatment with ACE inhibitors or ARB within 2 weeks of start of the study, (ii) untreated cancer, (iii) cardiovascular diseases such as stroke and myocardial infarction within 6 months prior to the study, (iv) organ failure other than that of the kidney, such as heart and liver failure, (v) hyperpotassemia exceeding 5.5 mEq/L, and (vi) poorly controlled diabetes mellitus with glycosylated hemoglobin (HbA1c) greater than 9%. Patients taking antihypertensive drugs other than ACE inhibitors and ARB were eligible for the study if their blood pressure was 140/90 mm Hg or higher. After the one-week run-in period, each patient was given 150 mg aliskiren, a direct renin inhibitor, once daily in the morning for the study period of 24 weeks. The prescription of other antihypertensive drugs was not changed throughout the study period.
In all patients, blood pressure was measured before each dialysis session in the supine position after resting for more than 10 min, and the average value for the week was used for evaluation at each time point [15, 16]. Additionally, blood pressure was monitored every 30 min during each dialysis session and the average of the lowest levels in three sessions of the week was calculated. The difference between the blood pressure before starting the HD session and the lowest level during the session was defined as the maximum blood pressure change, and the average value of the three sessions of the week was calculated. Body weight gains between dialysis sessions were also averaged for each week. Blood samples were obtained at the beginning (0-weeks) and at 4-weeks, 12-weeks and 24-weeks after starting aliskiren treatment. Each peripheral blood sample was obtained before the start of the dialysis session and after more than 15 min of supine rest. In addition to routine hematological tests and blood chemistry, circulating components of the renin-angiotensin-aldosterone (RAA) system were evaluated. Plasma renin activity and plasma concentrations of aldosterone were determined by their respective radioimmunoassays. Plasma angiotensin II level was directly radioimmunoassayed using the Angiotensin II RIA kit (SRL, Tokyo, Japan).
The study protocol was in accordance with the recommendations of the World Medical Association for biomedical research involving human subjects (Tokyo version, 2004) and was approved by the local institutional review board. Informed consent was obtained from all subjects.
Values are expressed as means ± SD. The time-course of changes in the measured parameters was analyzed using anova for repeated measures followed by Tukey's method for post-hoc multiple comparisons. Inter-group values were compared by the t-test, Mann–Whitney U-test or χ2 test as appropriate. Correlations between variables were evaluated by linear regression analysis. A P-value less than 0.05 was considered to indicate statistical significance.
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- Patients and Methods
A total of 25 hypertensive HD patients were enrolled in this study. Table 1 shows the background characteristics of these patients. Diabetic nephropathy and chronic glomerulonephritis were the most frequent causes of renal failure, accounting for 60% and 28% of the cases, respectively. Average systolic, but not diastolic, blood pressure was in the hypertensive range before starting aliskiren therapy in the study subjects. Twenty patients (80%) were already receiving antihypertensive medication, calcium channel blockers (CCB) being the most frequently used class of drugs (17 patients, 68%), followed by diuretics in 12 patients (48%), β-blockers in four (16%) and α-blockers in two (8%). Nine patients were on monotherapy, while eight patients were receiving two antihypertensive drugs and three were receiving three or more drugs. Eight patients had complicating cardiovascular diseases, as listed in Table 1.
Table 1. Background characteristics of the chronic hemodialysis patients at the start of aliskiren therapy
|Age, year||63.9 ± 12.6|
|Cause of renal failure|| |
|Duration of hemodialysis, year||5.8 ± 4.9|
|Body mass index, kg/m2||21.9 ± 3.3|
|Systolic blood pressure, mm Hg||164.3 ± 11.4|
|Diastolic blood pressure, mm Hg||79.7 ± 8.9|
|Pulse rate, bpm||76.4 ± 6.1|
|Complication of cardiovascular disease|| |
|Coronary heart disease||2|
Of the 25 patients enrolled, two patients discontinued aliskiren therapy because of symptomatic hypotension at 8- and 15-weeks, respectively. In the first case, the patient's blood pressure decreased from 181/95 mm Hg to 163/88 mm Hg at 4-weeks. At 8-weeks, he suddenly collapsed while playing pinball, at which time his measured blood pressure was 101/65 mm Hg. In the second case, the blood pressure also decreased markedly from 179/93 mm Hg to 137/73 mm Hg at 4-weeks and to 129/73 mm Hg at 12-weeks. Thereafter, the blood pressure further decreased to 106/66 mm Hg at 16-weeks, with frequent complaints of dizziness. These two patients were not included in the analyses of measured variables. The remaining 23 patients completed the 24 weeks of therapy. Figure 1 depicts the changes in pre-dialysis blood pressure and pulse rate over the study period. Systolic blood pressure was not significantly reduced at 4-weeks, but was significantly lowered by 8.4 mm Hg and 8.2 mm Hg at 12-weeks and 24-weeks, respectively, while diastolic blood pressure did not change significantly during the study period. Neither the pulse rate nor the dry weight altered during the 24-week study period.
Figure 1. Time course of changes in blood pressure, heart rate and dry weight in hemodialysis patients during the study period. *P < 0.05, †P < 0.01 vs. 0 weeks.
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As shown in the left panel of Figure 2, the lowest blood pressure level during the dialysis session was significantly decreased at 24-weeks, although the changes were not statistically significant at 4-weeks and 12-weeks. The right panel of Figure 2 shows the maximum blood pressure changes during the dialysis session, demonstrating that the extent of diastolic blood pressure changes was significantly larger at 24 weeks than at 0 weeks. The maximum systolic blood pressure reduction was not significantly changed because the lowest systolic blood pressure decreased along with the decrease in systolic blood pressure before the dialysis session. On the other hand, the maximum diastolic blood pressure reduction increased along with the decrease in lowest diastolic blood pressure while the diastolic blood pressure before the dialysis session was not significantly changed. With regard to the parameters of body fluid volume changes, neither the cardiothoracic ratio on chest roentgenogram nor the average body weight increase between dialysis sessions varied significantly during the study period (Fig. 2, left panel). All the patients received erythropoietin administration for the treatment of renal anemia, which is known to raise blood pressure. Darbopoietin was used in 22 patients and epoetin-β was used in one patient. When the dose of epoetin-β was divided by 225 to estimate the comparable darbopoietin dose, the weekly darbopoietin doses were 24 ± 14 μg, 24 ± 15 μg, 23 ± 15 μg and 21 ± 12 μg at 0 weeks, 4 weeks, 12 weeks and 24 weeks, respectively, which were insignificant changes.
Figure 2. Time-course of changes in the lowest blood pressure recorded during the dialysis session, the interdialysis weight increase, cardiothoracic ratio on chest roentgenogram (left panel), and maximal blood pressure changes during the dialysis session (right panel) in hemodialysis patients during the study period. *P < 0.05, †P < 0.01 vs. 0 weeks. DBP, diastolic blood pressure; ΔDBP, change in diastolic blood pressure; SBP, systolic blood pressure; ΔSBP, change in systolic blood pressure.
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Table 2 lists the laboratory data of the patients during the study period. Blood cell counts did not change significantly during the 24 weeks of aliskiren therapy. There were no significant changes in any of the blood chemistry data such as serum proteins, liver enzymes or electrolytes, although serum potassium was significantly increased at 24-weeks.
Table 2. Time-course of changes in laboratory findings during the study period in chronic hemodialysis patients on aliskiren therapy
|Parameter||0 weeks||4 weeks||12 weeks||24 weeks|
|White blood cells, ×103/mm3||6.64 ± 1.82||6.24 ± 1.27||6.24 ± 1.49||6.05 ± 1.19|
|Red blood cells, ×106/mm3||3.29 ± 0.50||3.31 ± 0.34||3.50 ± 0.41||3.58 ± 0.42|
|Blood hemoglobin, g/dL||10.0 ± 1.4||10.0 ± 1.0||10.7 ± 0.9||11.1 ± 1.0|
|Hematocrit, %||30.8 ± 4.4||30.9 ± 2.9||33.0 ± 2.8||33.6 ± 3.5|
|Platelet count, ×103/mm3||213 ± 49||205 ± 52||193 ± 59||202 ± 57|
|Blood chemistry|| || || || |
|Total protein, g/dL||6.4 ± 0.4||6.3 ± 0.5||6.3 ± 0.4||6.5 ± 0.3|
|Albumin, g/dL||3.8 ± 0.4||3.7 ± 0.4||3.7 ± 0.3||3.9 ± 0.3|
|AST, U/L||14 ± 10||13 ± 6||13 ± 7||13 ± 6|
|ALT, U/L||12 ± 4||11 ± 5||10 ± 5||10 ± 6|
|Urea nitrogen, mg/dL||66.5 ± 16.6||63.2 ± 15.0||60.0 ± 13.3||64.5 ± 18.6|
|Creatinine, mg/dL||10.5 ± 2.3||10.7 ± 2.4||10.7 ± 2.7||10.4 ± 2.4|
|Uric acid, mg/dL||7.0 ± 1.3||6.9 ± 1.2||7.0 ± 1.3||6.7 ± 1.7|
|Na, mEq/L||137.6 ± 2.8||138.6 ± 3.4||139.9 ± 4.0||137.5 ± 3.4|
|K, mEq/L||4.9 ± 0.6||4.9 ± 0.6||4.8 ± 0.5||5.2 ± 0.8*|
|Ca, mg/dL||9.1 ± 0.8||8.9 ± 0.8||9.0 ± 1.0||9.4 ± 0.9|
|P, mg/dL||5.8 ± 2.1||5.8 ± 1.7||6.0 ± 1.8||6.1 ± 2.2|
Figure 3 shows the time-course of changes in circulating components of RAAS during the study period. As naturally expected, plasma renin activity was markedly suppressed and plasma renin concentration was greatly increased by aliskiren. Further, plasma angiotensin II and aldosterone concentrations were significantly decreased.
Figure 3. Changes in the circulating components of the renin-angiotensin-aldosterone system in hemodialysis patients during the study period. *P < 0.05, †P < 0.01, ¶P < 0.001 vs. 0 weeks.
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Table 3 compares the baseline characteristics of the 10 patients showing ≥10 mm Hg reduction in systolic blood pressure with aliskiren therapy at 24-weeks (responders) with those of the 13 patients whose systolic blood pressure reductions were <10 mm Hg (non-responders). Responders were more likely to be younger, female, and with higher systolic blood pressures and heart rates before starting aliskiren administration. Significant differences were not observed in plasma renin, angiotensin II or aldosterone levels between the responders and non-responders at 0 weeks. The systolic blood pressure reduction at 24-weeks was not significantly correlated with plasma renin activity, angiotensin II or aldosterone. In terms of changes in the circulating components of the RAAS after 24 weeks of therapy, the change in plasma renin activity was more prominent in the responders than the non-responders. As depicted in Figure 4, in all 23 patients taken as a whole, changes in plasma renin activity and angiotensin II levels significantly correlated with the reductions in systolic blood pressure at 24 weeks. However, there were no significant correlations between the changes in plasma aldosterone concentrations and blood pressure changes.
Figure 4. Correlations between changes in systolic blood pressure with changes in plasma renin activity (left panel), changes in plasma angiotensin II levels (middle panel) and changes in plasma aldosterone levels (right panel) in hemodialysis patients given aliskiren for 24 weeks.
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Table 3. Comparison of the groups divided on the basis of the antihypertensive response to aliskiren
|Parameter||ΔSBP ≥ 10 mm Hg (n = 10)||ΔSBP < 10 mm Hg (n = 13)||P-value|
|Age, year||63.6 ± 13.2||67.2 ± 10.5||n. s.|
|Diabetic nephropathy, %||80.0%||46.2%||n. s.|
|Duration of hemodialysis, year||5.5 ± 4.9||6.6 ± 5.3||n. s.|
|Body mass index, kg/m2||22.8 ± 3.6||20.6 ± 2.7||n. s.|
|Systolic blood pressure, mm Hg||171.4 ± 9.4||156.9 ± 5.8||0.001|
|Diastolic blood pressure, mm Hg||80.2 ± 11.5||77.1 ± 4.4||n. s.|
|Heart rate, bpm||78.7 ± 4.6||73.3 ± 3.9||0.007|
|PRC at 0 weeks, pg/mL||22.0 ± 22.3||20.2 ± 40.0||n. s.|
|PRA at 0 weeks, ng/mL/hr||3.0 ± 2.4||2.9 ± 4.7||n. s.|
|Plasma AngII at 0 weeks, pg/mL||9.5 ± 2.7||11.1 ± 10.8||n. s.|
|PAC at 0 weeks, pg/mL||118 ± 3.9||348 ± 533||n. s.|
|Change in PRC, %||+793 ± 550||+943 ± 1371||n. s.|
|Change in PRA, %||−74.0 ± 22.3||−45.4 ± 39.3||0.039|
|Change in plasma AngII, %||−28.4 ± 33.8||−9.6 ± 72.1||n. s.|
|Change in PAC, %||−13.2 ± 37.8||−17.1 ± 43.8||n. s.|
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- Patients and Methods
In the present study, aliskiren showed modest blood pressure lowering effect and this effect was gradual over several months in chronic HD patients. On the other hand, aliskiren inhibited plasma renin activity and lowered plasma angiotensin II and aldosterone levels at 4 weeks. In hypertensive patients without renal failure, aliskiren has been shown to lower blood pressure within a few weeks, although the hypotensive effect is known to increase even after 12–18 weeks, as observed in this study . Orally-administered aliskiren is very slowly metabolized, with a plasma half-life as long as 40 h. This pharmacokinetic property of aliskiren is the supposed cause of the slowness of exhibition of its maximum hypotensive effect. In addition, aliskiren has high tissue affinity and has been shown to bind to vascular and glomerular tissues . It is thought that cardiovascular tissues themselves have the ability to produce the components of RAAS, such as renin, angiotensinogen, ACE and aldosterone [4-6]. It is speculated that aliskiren suppresses not only the circulating RAAS, but also the cardiovascular tissue RAAS, which is supposed to contribute to long-term reduction in blood pressure.
Among the 25 patients enrolled in this study, two patients exhibited excessive blood pressure reduction necessitating discontinuation of aliskiren therapy. In these two patients, plasma renin activity was somewhat elevated (5.6 and 5.9 ng/mL per h), plasma aldosterone concentration was markedly elevated (3090 and 2173 pg/mL), and plasma angiotensin levels were not markedly increased (9 and 19 pg/mL). Since they developed marked hypotension after several weeks of aliskiren therapy, this may have had some relation to the RAAS activity.
Since the enzymatic activity of renin is the rate-limiting step of RAAS, the renin inhibitor aliskiren is theoretically thought to be effective in suppressing RAAS. Morishita et al.  reported a significant blood pressure reduction 4 and 8 weeks after starting aliskiren therapy in HD patients. In their study, most patients were taking ACE inhibitors or ARBs. In this study, we excluded patients taking ACE inhibitors and ARBs, in order to clearly elucidate the relationship of RAAS to the effects of aliskiren. We observed that aliskiren did not exhibit significant hypotensive effects in HD patients at 4 weeks, but significantly lowered systolic blood pressure at 12 weeks and 24 weeks. This discrepancy may be due to the small numbers of patients involved in both studies. In addition, our study may have underestimated the hypotensive effects of aliskiren in HD patients, because we excluded the two patients who showed excessive blood pressure reduction and discontinued aliskiren therapy. Even considering this, however, the hypotensive effect of aliskiren in HD patients seems inconsistent and not very prominent.
In the present study, the time-course of changes in circulating RAAS and their relationship to blood pressure reduction were assessed. Plasma angiotensin II and aldosterone levels were significantly lowered at 4 weeks, the suppression being sustained for as long as 24 weeks. With long-term treatment with ACE inhibitors and ARBs, plasma aldosterone levels have been shown to increase in a certain percentage of patients, which is recognized as aldosterone escape or breakthrough . With aliskiren, a renin inhibitor, such aldosterone escape seems unlikely to occur, at least until 6 months. This is in accordance with the earlier observation by Morishita et al. . Basal plasma renin activity was not significantly different between responders and non-responders, and there was not a significant correlation between the blood pressure reduction and the basal levels of plasma RAAS components such as renin, angiotensin II and aldosterone. However, the blood pressure reduction by aliskiren correlated with the changes in plasma renin activity and angiotensin II levels. Hence, it is believed that the antihypertensive effect of aliskiren is mainly due to suppression of renin activity and consequent angiotensin II generation in HD patients, as is naturally expected.
Although most HD patients are anuric or oliguric, hyperkalemia is a possible adverse effect of RAAS inhibitors because aldosterone also affects ion transport through the intestinal epithelium. In the present study, serum potassium remained unchanged at 4 weeks and 12 weeks, but was significantly increased at 24 weeks. Considering the long half-life of aliskiren in plasma, care should be taken to regularly monitor serum potassium levels in HD patients on prolonged aliskiren therapy. Additionally, the lowest blood pressure level during the dialysis session in this study was reduced by aliskiren, the reduction being statistically significant at 24 weeks. This may be parallel to the blood pressure reduction before the dialysis session. It is generally considered that sympathetic nerve activity plays a major role in the maintenance of blood pressure in the face of fluid removal during HD , with little being known about the participation of RAAS in this process [23-26]. Yet, attention should be paid to blood pressure monitoring during the HD session in patients chronically given RAAS inhibitors.