Treatment of carvedilol for refractory hypertension in patients with renal diseases: A multicentre, prospective clinical trial

Biomedicine & Aging Pathology 1 (2011) 203–209

Original article

Treatment of carvedilol for refractory hypertension in patients with renal diseases: A multicentre, prospective clinical trial Hong Fan a,b,1 , Ming Zhang a,b,1 , Jing Chen a,∗,b , Chuanming Hao a,b , Yong Gu a,b , Shanyan Lin a,b , Carvedilol Multicenter Clinical Study Group2 a b

Division of Nephrology, Huashan Hospital, Fudan University, 12, Wulumuqi Road, Shanghai 200040, China Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China

a r t i c l e

i n f o

Article history: Received 4 September 2010 Accepted 19 June 2011 Keywords: Carvedilol Renal disease Refractory hypertension

a b s t r a c t Hypertension is one of the main risk factors for cardiovascular diseases. In this study we aimed to evaluate efficiency and safety of carvedilol treatment in refractory hypertensive patients with renal diseases, including chronic kidney disease (CKD), polycystic kidney disease (PKD), dialysis and post-transplantation population. A multicentre, prospective, open label, self-compared trial was conducted in the east area of China in 2005. Two hundred and seventeen patients were enrolled in this study. Mean arterial blood pressure (systolic/diastolic) at 4 weeks significantly reduced in comparison with that before the use of carvedilol (142.6 ± 14.4/84.2 ± 10.1 mmHg vs 166.2 ± 18.1/90.4 ± 11.0 mmHg, P < 0.05), and then it continued to drop to 136.9 ± 12.4 mmHg/80.1 ± 10.6 mmHg at the completion of trial (week 8). Total efficiency (subjects with a BP less or equal to 130/80 mmHg or having a fall of greater or equal to 10 mmHg in DBP or greater or equal to 30 mmHg in systolic blood pressure) was 57.1% at 4 weeks and 79.7% at 8 weeks, and dominant efficiency (subjects with a BP of less or equal to 130/80 mmHg and those showing a fall of greater or equal to 10 mmHg in diastolic blood pressure) was 11.5% and 26.7%, respectively. Mean heart rate declined from 79.3 ± 10.2/min to 75.9 ± 7.6/min at 4 weeks and 75.0 ± 8.5/min at 8 weeks (P < 0.05). Plasma norepinephrine level decreased from 38.7 pg/mL before this trial to 17.6 pg/mL (P < 0.05). The total number of patients experiencing at least one adverse event was 13. None resulted in withdrawal of the patient from study. This study suggests that carvedilol is an efficient and safe drug in treatment of refractory hypertensive patients with renal diseases. © 2011 Elsevier Masson SAS. All rights reserved.

1. Introduction It is well known that hypertension is one of the main risk factors for cardiovascular diseases (CVD) [1–3]. Various large-scale clinical studies have shown that treatment of hypertension with medication can prevent onset of CVD and reduce mortality and morbidity [4,5], and treating hypertension has been associated with

∗ Corresponding author. Tel.: +86 21 52889387; fax: +86 21 62268509. E-mail address: jingchen [email protected] (J. Chen). 1 Hong Fan and Ming Zhang contributed equally to this work. 2 Huashan Hospital affiliated to Fudan University, Ruijin Hospital affiliated to Jiaotong University, Changzheng Hospital affiliated to the Second Military Medical University, Changhai Hospital affiliated to the Second Military Medical University, Renji Hospital affiliated to Jiaotong University, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou Hospital of Traditional Chinese Medicine, Ningbo Lihuili Hospital, the Second Affiliated Hospital of Soochow University, the First Affiliated Hospital of Wenzhou Medical College, Zhongda Hospital affiliated to Southeast University, Jiangsu Province Hospital. 2210-5220/$ – see front matter © 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biomag.2011.06.009

an approximately 40% reduction in the risk of stroke and an approximately 15% reduction in the risk of myocardial infarction [6]. The pathogenesis of hypertension in patients with renal diseases has been classically considered to be due to the combined result of volume overload/sodium retention and inappropriate activation of the renin–angiotensin–aldosterone system (RAAS). There is an emerging, strong body of evidence to indicate that the sympathetic nervous system in general also plays an important role in the development of hypertension [7,8]. Human studies examining muscle sympathetic nerve activity (MSNA) have unequivocally shown elevated sympathetic nerve activity in patients with renal failure [9,10]. This appears to be driven by the impaired kidneys, because patients who had bilateral renal nephrectomy had both correction of blood pressure and MSNA [11–13]. In addition to showing increased MSNA, renal failure patients also demonstrate increased plasma catecholamines, whether measured as plasma levels or total body noradrenaline spillover. In experimental animal models of renal failure, renal denervation has also been shown to attenuate or even reverse increased blood pressure. This includes established models of renovascular hypertension [14], autosomal

204

H. Fan et al. / Biomedicine & Aging Pathology 1 (2011) 203–209

dominant polycystic kidney disease [15] and a model of neurogenic hypertension caused by renal phenol injection [16]. The ␤-blockers have a mild antihypertensive effect; they are widely used in the treatment of essential hypertension [17–19]. However, they are rarely used alone in patients with renal hypertension because they decrease the cardiac output, thus reducing the renal perfusion pressure and potentially leading to worsening of renal function [20]. Carvedilol is a new ␤-blocker possessing a vasodilating action and has been reported to increase the renal blood flow [21]. This drug is metabolized in the liver and is excreted mainly in the faeces [22]. Hence, its nephrotoxicity is likely to be low, even in patients with impaired renal function, and it is unlikely to accumulate. In 2006, Weber et al. carried out a multicentre study, this randomized controlled trial suggest that carvedilol has a clinically meaningful defined dose-dependent antihypertensive effect [23]. Carvedilol is thus a potentially useful agent for patients with renal hypertension. In the management of hypertension, it is critically important to lower blood pressure to levels of less than 140/90 mmHg in the general population, and even lower in the chronic kidney disease (CKD) group. Unfortunately, data from NHANES – demonstrated that only 27% of individuals actually achieved a blood pressure of less than 140/90 mmHg [24]. Five separate trials (UKPDS, HOT, MDRD, ABCD, and AASK) showed that renal disease progression was reduced by an additional 30–50% and the cardiovascular disease risk was reduced by an additional 40–70% over the higher blood pressure control groups [25–29]. Hypertension occurs commonly and early in renal disease and is paralleled by increases in sympathetic nerve system (SNS) activity [7,10]. Especially in patients with polycystic kidney disease (PKD) or dialysis, increased BP is always hard to control and increased MSNA have been demonstrated [12,30], but few trials have conducted in this group, so in the present multicentre trial at 12 sites in East China, we gave carvedilol to refractory hypertensive patients with kidney diseases and investigated its efficacy, safety, and optimal dose. 2. Subjects and methods 2.1. Subjects The subjects were 217 refractory hypertensive patients with chronic kidney diseases who fulfilled the conditions in Table 1. They were selected from patients attending 12 participating institutions. Informed consent was obtained from each subject after a full explanation of the study. These patients were divided into four groups according to their therapy style: (1) maintenance dialysis (MD) group (including hemodialysis and peritoneal dialysis), measured Kt/V greater or equal to 1.2 or URR greater or equal to 65% for hemodialysis patients or weekly Kt/V greater or equal to 1.8 for peritoneal dialysis patients; (2) kidney transplantation (KT) group, all patients must receive cyclosporin A or tacrolimus therapy, and the renal function is stable in the last 8 weeks without any rejection phenomenon; (3) CKD group (including various kinds of primary and secondary kidney diseases), having not entered dialysis yet and not receiving any hormone or immunosuppressive drugs in the last 8 weeks; (4) PKD group, patients with an established diagnosis of PKD and had not entered dialysis yet.

Table 1 Criteria for entry and exclusion. Inclusion criteria 1. Patients with an established diagnosis of refractory hypertensive, patients received a combined antihypertensive drug therapy (at least 3 types of drugs, diuretic agent, calcium-channel blocker [CCB], RAS blocker or others for at least 1 month), the diastolic blood pressure (DBP) was still ≥ 95 mmHg and/or systolic blood pressure (SBP) was ≥ 145 mmHg. This decision was based on the investigator’s clinical judgment of the patient’s current hypertensive status and history 2. Aged, < 70 years in general 3. Both genders were enrolled Exclusion criteria 1. Patients with abnormal liver function 2. Patients experiencing sudden episodes of hypotension 3. Unstable heart failure, advanced bradycardia, conduction abnormalities (including sick sinus syndrome and advanced atrial ventricular block), cardiac shock or recent myocardial infarction (within 3 months of study) 4. Patients with chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) 5. Patients suspected of having pheochromocytoma 6. Pregnant or possibly pregnant women and women who were breast-feeding 7. Hypersensitivity to carvedilol 8. Other patients judged to be unsuitable for this study by the attending physicians

patients prior to receiving their consent to participate. All patients were free to withdraw from the study at any time. Antiadrenergic drugs (metoprolol) were withdrawn from subjects who received them before the trial, and subjects showing obvious withdrawal symptoms in the 7-day washout qualification period were not selected. The treatment period was 8 weeks, and the drug was taken once daily after breakfast. The initial dose of carvedilol was 12.5 mg daily, which was increased to 25 mg after 2 days and to 50 mg after a further 4 weeks if the effect was insufficient (if the blood pressure remained greater or equal to 150/90 mmHg or the mean pressure decreased less than 13 mmHg) and the patient could tolerate the higher dose. Other antihypertensive drugs were given without changing the route and dose throughout the trial period. If excessive hypotension, serious side effects, or worsening of renal function developed, the dose was reduced or administration was stopped by the judgment of the attending physician. Throughout the study, patients were required to maintain at least 75% compliance in taking study medication over the period preceding each visit. Use of other drugs considered likely to affect the blood pressure was prohibited. 2.3. Blood pressure, heart rate The blood pressure and heart rate were measured with the patient seated at least once every week about 3 h after administration of carvedilol. Blood pressure and heart rate were then measured three times at approximately 3-min intervals on the same arm by the same physician using a standard pressure cuff. At the completion of treatment periods, the presence or absence of orthostatic hypotension was determined by measurement of the blood pressure with the patient in the supine and standing positions (within three rain of standing up).

2.2. Study design 2.4. Laboratory and other studies This was a multicentre, prospective, open label, self-compared clinical trial (stage 4). Film-coated tablets containing 25 mg carvedilol were used. Approval of the local hospital (Huashan Hospital, Fudan University) ethics committee was obtained prior to the start of the study. The nature of the trial was fully explained to all

Study eligibility was determined at the initial screening visit on the basis of medical history, a complete physical examination, chest X-ray (taken within the preceding 12 months), 12-lead electrocardiogram (ECG), and routine laboratory studies. The following items

H. Fan et al. / Biomedicine & Aging Pathology 1 (2011) 203–209

were examined at the completion of treatment periods: hematological tests [red blood cell (RBC) count; hemoglobin, hematocrit; white blood cell (WBC) count; hemogram; platelet count], biochemical tests [total protein, SGOT, SGPT, alkaline phosphatase (ALP), lactic dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine, uric acid, electrolytes], and urinalysis (protein, glucose, sediment). An ECG was also performed. Plasma norepinephrine level was detected at the baseline and final visits. Before blood draw patients should rest for at least 10 min, slacken muscle, breath naturally, and then hold in a quiescent condition. Venous blood was collected in standard sterile polystyrene vacuum tubes, with 5 mM EDTA. After centrifugation (600 × g for 10 min), the plasma was stored at −70 ◦ C until use. Norepinephrine content was determined with high performance liquid chromatography (HPLC), using Hypersil, CDS C18 (150*2.1 mmm, 3 ␮m) chromatographic column, 0.1% acetate buffer (pH 2.5)-7% methanol-0.3 mmol/L EDTA-0.5% octane sulfonic sodium for moving phase, voltage 0.7 V and flow rate 0.2 mL/min.

205

Fig. 1. The combination form of the baseline antihypertensive drugs. Among all the baseline antihypertensive drugs, CCB was dominant, accounting for over 90%; next was RAS blocking agent, including ACEI and ARB, then there were ␤-blockers, ␣-blockers, diuretic agent. All patients received a combined antihypertensive drug therapy, and the dominant combination was CCB + ACEI/ARB + ␤-blockers/diuretic.

2.5. Side effects, complications, incidental illnesses If side effects, complications, or incidental illnesses developed, the symptom(s), date of onset, degree of severity, treatment, clinical course, duration, and relationship with the test drug were investigated. 2.6. Curative effect rating standard Dominant efficiency: subjects with a BP of less or equal to 130/80 mmHg and those showing a fall of greater or equal to 10 mmHg in diastolic blood pressure (DBP). Efficiency: subjects with BP still over 130/80 mmHg but having a fall of greater or equal to 10 mmHg in DBP or greater or equal to 30 mmHg in systolic blood pressure (SBP). Inefficiency: not reach above standards yet. 2.7. Statistical analysis The study was an open label, self-compared trial. The blood pressure, heart rate, and clinical findings were compared before and after administration of carvedilol by the paired t-test, and the level of significance was set at P < 0.05. The data were expressed as the mean ± SEM. Safety and generality data were recorded with descriptive statistics. Statistical analysis was performed using the SPSS software (version 10.0; SPSS Inc., Chicago, IL). 3. Results 3.1. Population A total of 217 patients from 12 participating institutions entered the treatment phase; all of them completed the study. Among them, 79 (36.4%) patients fit into CKD group, 97 (44.7%) patients entered MD group, PKD group had 23 (10.6%) patients and KT group had 18 (8.3%) patients. There were 145 men and 72 women aged 50.2 ± 12.6 years on average. The mean nephropathy course was 6.6 (0.2–40.0) years, and the mean duration of hypertension was 8.5 (0.4–40.0) years. All patients received a combined antihypertensive drug therapy [at least three types of drugs, including diuretic agent, calciumchannel blocker (CCB), RAS blocker and others] for at least 1 month, the DBP is still greater or equal to 95 mmHg and/or SBP is greater or equal to 145 mmHg. Among all the baseline antihypertensive drugs, CCB was dominant, accounting for over 90%; next was RAS blocking agent, including angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB), each accounting

for about 50%; then there were ␤-blockers, ␣-blockers, diuretic agent, each accounting for nearly 30%. The dominant combination was CCB + ACEI/ARB + ␤-blockers/diuretic (Fig. 1). Blood pressures of patients at baseline in each group mainly belonged to WHO stage – (Fig. 2). The initial dose of carvedilol was 12.5 mg daily, which was increased to 25 mg after 2 days and to 50 mg after a further 4 weeks if the effect was insufficient. At the completion of treatment periods, a large proportion of the patients (77%) remained the dose of 25 mg daily, 7% of patients required dose doubling; another 9% remained 12.5 mg, 1% decreased to 6.25 mg and the rest 6% decreased to 3.125 mg daily.

3.2. Blood pressure Changes in blood pressure are shown in Figs. 3 and 4. The mean blood pressure (SBP/DBP) at baseline was 166.2 ± 18.1/90.4 ± 11.0 mmHg. It began to decline from around 2 weeks after the start of administration, dropping to 142.6 ± 14.4/84.2 ± 10.1 mmHg in 4 weeks. Then it continued to drop to 136.9 ± 12.4 mmHg/80.1 ± 10.6 mmHg at the completion of trial (week 8). A fall of 30/10.3 mmHg was observed relative to the baseline value. Patients in each group showed analogical tendency. At the completion of treatment periods, the blood pressure was measured in the sitting position and the change due to the alteration of posture was calculated. The normal changes in SBP and DBP due to posture were not affected.

percentage

73.42%

80%

73.20%

65.22%

61.11%

60% 40% 22.78% 20%

21.74% 13.04%

3.80%

23.71% 3.09%

27.78% 11.11%

0% CKD group

PKD group

MD group

KT group

stageI (SBP 140~159mmHg and/or DBP 90~99mmHg) stage II (SBP 160~179mmHg and/or DBP 100~109mmHg) stage III (SBP≥180mmHg and/or DBP≥110mmHg) Fig. 2. WHO stage of patients in each group at baseline. Blood pressures of patients at baseline in each group mainly belonged to WHO stage III. These patients whose baseline BP belonged to WHO stage III occupied about 60–75%.

206

H. Fan et al. / Biomedicine & Aging Pathology 1 (2011) 203–209

mmHg 0

week 4

week 8

*

percentage 60%

53.0%

50%

-5 -6.2

-10

45.6%

42.9%

40%

*

-10.3

-15

*

26.7%

30%

**

*

20.3%

20%

-20

11.5%

-25 -30

10%

-23.8 SBP

*

0%

DBP

-30.0

-35

week 4

**

week8

Dominant efficiency

Fig. 3. The mean blood pressure (systolic/diastolic) dropped at week 4 and week 8, compared with baseline. *P < 0.01, compared with baseline. **P < 0.01, compared with baseline and P < 0.05, compared with week 4. The mean blood pressure (SBP/DBP) at baseline was 166.2 ± 18.1/90.4 ± 11.0 mmHg. After 4 weeks of drug administration, it dropped to 142.6 ± 14.4/84.2 ± 10.1 mmHg. At the completion of trial (week 8), a fall of 30/10.3 mmHg was observed relative to the baseline value.

Efficiency

Inefficiency

Fig. 5. Changes in efficacy after 4 weeks and 8 weeks of carvedilol therapy. *P < 0.05 compared with week 4. Dominant efficiency is defined as those subjects with a BP of less or equal to 130/80 mmHg and those showing a fall of greater or equal to 10 mmHg in DBP. The efficiency is defined as subjects with BP still over 130/80 mmHg but having a fall of greater or equal to 10 mmHg in DBP or greater or equal to 30 mmHg in SBP. After 4 weeks of carvedilol therapy, total and dominant efficiency were 57.1%, 11.5%, and 79.7%, 26.7% at 8 weeks, respectively.

3.3. Efficacy After 4 weeks of carvedilol therapy, total and dominant efficiency were 57.1%, 11.5%, and 79.7%, 26.7% at 8 weeks, respectively (Fig. 5). This suggests that adding carvedilol in refractory hypertensive patients with kidney diseases can help to achieve the BP goal.

300

NE (pg/ml)

275 250 225 200 175

3.4. Plasma norepinephrine level

150

There were a total of 71 patients carrying out plasma norepinephrine detection at the baseline and final visit. With carvedilol therapy, the mean level decreased significantly from 38.7 to 17.6 pg/mL (P < 0.01) (Fig. 6).

125 100 75 50 25

3.5. Safety

0

3.5.1. Heart rate The mean heart rate at baseline was 79.3 ± 10.2 beats/min, after 4 weeks and 8 weeks of carvedilol therapy; it reduced to 75.9 ± 7.6 and 75.0 ± 7.6 beats/min, respectively. Though there was significant change in HR compared with baseline, the mean heart rate was still in normal range and no patient had notable complaint related to the HR drop. 3.5.2. Laboratory findings When compared before and after administration, no clinically significant changes were seen in the red blood cell (RBC) count, the hemoglobin level, the lymphocyte count, as well as SGOT, SGPT, CPK and LDH. The effects of carvedilol on renal function were evaluated in the KT group, PKD group and CKD group, no worsening of serum

Fig. 6. Change of plasma norepinephrine level after carvedilol therapy. After 8 weeks of carvedilol therapy, the mean plasma norepinephrine level decreased significantly from 38.7 to 17.6 pg/mL (P < 0.01).

creatinine was seen, even when the degree of the decrease in blood pressure was considerable (Table 2). 3.5.3. Side effects Table 3 shows the summary of all adverse events, regardless of their relationship to the study medications. The total number of patients experiencing at least one adverse event was 13. In most cases, the adverse events were of mild or moderate severity and short-lived. None resulted in withdrawal of the patient from study. A few events were judged to be probably related to the study

DBP mmHg 95 SBP mmHg 180

93 91

170

89 87 85

160 150

83 81

140

79 77

130

75

120 baseline

CKD group

PKD group

week 4 MD group

week 8 KT group

baseline CKD group

week 4 PKD group

week 8 MD group

KT group

Fig. 4. Changes of blood pressure in each group. Patients in each group showed analogical tendency. The blood pressure (DBP/SBP) dropped after carvedilol treatment.

H. Fan et al. / Biomedicine & Aging Pathology 1 (2011) 203–209 Table 2 The effects of carvedilol on renal function. Scr (␮mol/L)

CKD group

PKD group

KT group

Baseline Week 4 Week 8

273.8 ± 170.5 274.4 ± 190.3 275.5 ± 192.7

197.8 ± 195 211.8 ± 202.4 214.0 ± 201.6

126.5 ± 62.1 168.5 ± 152.6 157.5 ± 137.7

Self-compared t-test (vs baseline) does not show significant difference in all three groups (P > 0.05).

medication: three cases of orthostatic hypotension, one of bradycardia and two of nausea. 4. Discussion and conclusion It is clear from more than four decades of data that a higher blood pressure is associated with a higher cardiovascular mortality risk, regardless of whether a person is taking antihypertensive therapy. In most renal diseases, particularly those primarily affecting the glomeruli, raised BP contributes in a major way to the progressive and irreversible decline in function that often occurs [31]. All efforts thus far to alter the incidence of renal disease have been less than successful. This is due, in part, to a failure to adequately lower BP level. An importance of the kidney in the long-term control of arterial pressure is perhaps to be expected given the well-known ‘Guytonian theory’ which states that, in order for hypertension to develop, there must be some alteration in the renal fluid balance relationship [32,33]. Thus there are still many individuals with kidney diseases who fail to achieve this blood pressure goal, especially in PKD, dialysis and kidney transplantation [34,35]. So, in our study, we chose these types of hypertensive patients as our research object. In the present study, refractory hypertensive patients with kidney diseases was defined as those who received a combined antihypertensive drug therapy (at least three types of drugs) for at least 1 month, DBP is still greater or equal to 95 mmHg and/or SBP is greater or equal to 145 mmHg. The baseline BP (SBP/DBP) was 166.2 ± 18.1/90.4 ± 11.0 mmHg that is to say in CKD patients their blood pressure was always difficult to control. After 4 weeks of carvedilol therapy, the mean blood pressure (systolic/diastolic) dropped to 142.6 ± 14.4/84.2 ± 10.1 mmHg and then it continued to drop to 136.9 ± 12.4 mmHg/80.1 ± 10.6 mmHg at the completion of trial. Total and dominant efficiency at 4 weeks were 57.1%, 11.5%, and 79.7%, 26.7% at 8 weeks. These results suggested that adding carvedilol in refractory hypertensive patients with kidney diseases was helpful to achieve the BP goal. In another randomized controlled trial (RCT) study, it is also concluded antihypertensive treatment with carvedilol in patients with metabolic syndrome effectively reduces blood pressure [36]. But there are few studies focused on these special populations, so it is the first time to demonstrate the effect of carvedilol on controlling refractory hypertension in patients with kidney diseases. There is an emerging, strong body of evidence to indicate that the sympathetic nervous system plays an important role in the development of hypertension. The renal nerve links the kidney and Table 3 Number of patients experiencing adverse events. Number of adverse events (n) Orthostatic hypotension Nausea Bradycardia Gastralgia Headache/vertigo Angina Thrombocytopenia

3 2 1 2 6 1 1

Total number of patients experiencing at least one adverse event was 13, and the number of all adverse events was 16.

207

the SNS, with the kidney receiving a dense innervation of both sympathetic and sensory fibres [37]. The SNS has a number of effects on the kidney, including effects on renal vascular resistance, stimulation of renin release from the juxtaglomerular apparatus and direct stimulation of transtubular sodium reabsorption [38]. Conversely, the kidney is a source of activating afferent signals, which, via the afferent renal nerves, communicate with central autonomic pathways. These central integrative centres, in turn, influence sympathetic output to a variety of vascular beds and modulate the release of neurohypophyseal hormones [39]. Therefore; the kidney is not only a target of sympathetic activity, but also a source of signals that have the potential to directly modulate sympathetic drive and blood pressure. Not simply, increased SNS activity has significant implications with regard to increased risk of cardiovascular disease and is an obvious target in the treatment of kidney disease. In this study we chose four types of patients, including dialysis, kidney transplantation, CKD and PKD. In humans with PKD, a condition characterized by the accumulation of fluid-filled cysts in the kidneys, increased MSNA have been demonstrated [30]. In dialysis patients, volume overload/sodium retention may be the dominant factor. Patients after kidney transplantation have to receive ciclosporin A or tacrolimus therapy, which can result in the inappropriate activation of the RASS, so these patients are facility to refractory hypertension [40,41]. NE is the adrenergic receptor agonist, compared with adnephrin and isoproterenol; it has the strongest action to ␣-receptor. In our study, the mean NE level decreased significantly from 38.7 to 17.6 pg/mL (P < 0.01). This suggests analogous antihypertensive response can be obtained with carvedilol in various kidney diseases complicating refractory hypertension and its hypotensive effect may be related to changed sympathetic activity. Carvedilol is a new multiple-action cardiovascular agent designed to produce the two complementary pharmacologic actions of mixed venous and arterial vasodilation and noncardioselective ␤-adrenergic blockade. It is also free from any intrinsic sympathomimetic activity [42]. Its ␤-blocking action is related to its vasodilating effect [43], and it is also said to have a direct, smooth-muscle-relaxant effect [42]. Its oral administration to patients with essential hypertension is reported to decrease renovascular resistance without affecting the glomerular filtration rate or the filtration fraction [44]. Since carvedilol maintains the renal circulation and does not accumulate, even in hypertensive patients with kidney disease it appears to be a potentially valuable drug for the control of blood pressure. In the present study, carvedilol was given to patients with kidney diseases, no clinically significant changes were seen in the laboratory examination. In the KT group, PKD group and CKD group, no worsening of serum creatinine was seen. A total of 13 patients experienced at least one adverse event. In most cases, the adverse events were of mild or moderate severity and short-lived. None resulted in withdrawal of the patients from study. A few events were judged to be probably related to the study medication, including orthostatic hypotension, bradycardia and nausea. After 4 weeks and 8 weeks of carvedilol therapy, the mean heart rate was reduced to 75.9 ± 7.6 and 75.0 ± 7.6 beats/min, respectively, compared with a baseline of 79.3 ± 10.2 beats/min. Though there was significant change in HR, the mean heart rate was still in normal range and no patient had notable complaints related to the HR drop. In particular, in chronic hemodialyzed patients that usually show a peculiar neurohumoral status [11,45,46], these benefits are justified by the adequate management of systemic hypertension, arrhythmias, and “silent” angina [47]. Moreover, among other beta-blocking agents, in such patients carvedilol is endowed with favorable kinetic characteristics, in view of its prevalent hepatic metabolism that does not require dose adjustment in case of impaired renal function [48].

208

H. Fan et al. / Biomedicine & Aging Pathology 1 (2011) 203–209

In patients with CKD, including those receiving long-term dialysis and those who have received kidney transplants, heart failure (HF) is more common than and at least as lethal as ischemic coronary heart disease (CHD). Results of recent studies have indicated that carvedilol therapy attenuates the echocardiographic signs of pathologic remodeling, insofar as LV cavity diameters were reduced and ejection fraction increased after one year of carvedilol therapy [49–51]. Of course, some retrospective analysis consider that use of ␤-blocker was independently associated with a reduced risk of incident HF and cardiovascular-related and all-cause death in long-term dialysis patients who did not have a known diagnosis of HF at the time of dialysis initiation [52]. Because our study only lasted for 8 weeks, there has not been enough time to observe these cardiovascular complications. The main limitation of this study is the lack of a double-blind, randomized, controlled design. However, it should be underlined that our population represents a very select group of hypertensive patients. It must be stressed that part of these patients had received antiadrenergic drugs (metoprolol) previously, so we presume the favorable effect is relevant to carvedilol. 5. Perspectives The data of the current investigation demonstrate that carvedilol is an efficient and safe antihypertensive drug in treatment of patients with kidney diseases. Such beneficial effects were obtained via inhibiting SNS activity and decreasing plasma norepinephrine level. Recent hypertension guidelines emphasize that drugs with an additive or synergistic hypotensive effect should be added to the treatment regimen if the target BP level is not achieved [53–55]. Therefore, except for those patients with sick sinus syndrome and advanced atrial ventricular block, carvedilol should be considered first-line therapy for hypertensive with kidney disease. Further double-blinded, placebo-controlled trials may be necessary to confirm such beneficial effects. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments This trial was co-accomplished by Huashan Hospital affiliated to Fudan University, Ruijin Hospital affiliated to Jiaotong University, Changzheng Hospital affiliated to the Second Military Medical University, Changhai Hospital affiliated to the Second Military Medical University, Renji Hospital affiliated to Jiaotong University, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou Hospital of Traditional Chinese Medicine, Ningbo Lihuili Hospital, the Second Affiliated Hospital of Soochow University, the First Affiliated Hospital of Wenzhou Medical College, Zhongda Hospital affiliated to Southeast University, Jiangsu Province Hospital. Thanks to all these participated people. References [1] Kannel WB, Castelli WP, McNamara PM, McKee PA, Feinleib M. Role of blood pressure in the development of congestive heart failure. The Framingham Study. N Engl J Med 1972;287:781–7. [2] MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765–74. [3] Flack JM, Neaton J, Grimm Jr R, Shih J, Cutler J, Ensrud K, et al. Blood pressure and mortality among men with prior myocardial infarction. Multiple Risk Factor Intervention Trial Research Group. Circulation 1995;92:2437–45.

[4] Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985;291:97–104. [5] Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998;351:1755–62. [6] Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, et al. Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827–38. [7] Klein IH, Ligtenberg G, Neumann J, Oey PL, Koomans HA, Blankestijn PJ. Sympathetic nerve activity is inappropriately increased in chronic renal disease. J Am Soc Nephrol 2003;14:3239–44. [8] Campese VM. A new model of neurogenic hypertension caused by renal injury: pathophysiology and therapeutic implications. Clin Exp Nephrol 2003;7:167–71. [9] Johansson M, Elam M, Rundqvist B, Eisenhofer G, Herlitz H, Lambert G, et al. Increased sympathetic nerve activity in renovascular hypertension. Circulation 1999;99:2537–42. [10] Neumann J, Ligtenberg G, Klein II, Koomans HA, Blankestijn PJ. Sympathetic hyperactivity in chronic kidney disease: pathogenesis, clinical relevance, and treatment. Kidney Int 2004;65:1568–76. [11] Converse Jr RL, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 1992;327:1912–8. [12] Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, Kisters K, et al. Sympathetic nerve activity in end-stage renal disease. Circulation 2002;106:1974–9. [13] Augustyniak RA, Tuncel M, Zhang W, Toto RD, Victor RG. Sympathetic overactivity as a cause of hypertension in chronic renal failure. J Hypertens 2002;20: 3–9. [14] Kalaitzis C, Touloupidis S, Bantis E, Patris E, Triantafyllidis A. Effects of renal denervation of the contralateral kidney on blood pressure and sodium and eicosanoid excretion in the chronic phase of two-kidney, one-clip renovascular hypertension in rats. Scand J Urol Nephrol 2005;39:15–20. [15] Gattone VH, 2nd, Siqueira Jr TM, Powell CR, Trambaugh CM, Lingeman JE, et al. Contribution of renal innervation to hypertension in rat autosomal dominant polycystic kidney disease. Exp Biol Med (Maywood) 2008;233:952–7. [16] Ye S, Gamburd M, Mozayeni P, Koss M, Campese VM. A limited renal injury may cause a permanent form of neurogenic hypertension. Am J Hypertens 1998;11:723–8. [17] Prichard BNC, Owens CWI. Clinical pharmacology of beta-adrenoceptor blocking drugs. In: Kostis JB, de Felice EA, editors. Beta blockers in the treatment of cardiovascular disease. New York: Raven Press; 1984. p. 1–56. [18] Depelchin P, Sobolski J, Jottrand M, Flament C. Secondary prevention after myocardial infarction: effects of beta blocking agents and calcium antagonists. Cardiovasc Drugs Ther 1988;2:139–48. [19] O’Brien ET, MacKinnon J. Propranolol and polythiazide in treatment of hypertension. Br Heart J 1972;34:1042–4. [20] de Leeuw PW, Birkenhäger WH. Renal effects of beta blockade in essential hypertension. Eur Heart J 1983;4:13–7. [21] Hombach V, Kochs M, Höher M, Eggeling T, Haerer W, Wieshammer S, et al. Hemodynamic profile of carvedilol. Eur J Clin Pharmacol 1990;38:S101–3. [22] Neugebauer G, Akpan W, von Möllendorff E, Neubert P, Reiff K. Pharmacokinetics and disposition of carvedilol in humans. J Cardiovasc Pharmacot 1987;10:S85–8. [23] Weber MA, Bakris GL, Tarka EA, Iyengar M, Fleck R, Sica DA. Efficacy of a once-daily formulation of carvedilol for the treatment of hypertension. J Clin Hypertens 2006;8:840–9. [24] Ostchega Y, Dillon CF, Hughes JP, Carroll M, Yoon S. Trends in hypertension prevalence, awareness, treatment, and control in older US adults: data from the National Health and Nutrition Examination Survey 1988 to 2004. J Am Geriatr Soc 2007;55:1056–65. [25] Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR, et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63: 225–32. [26] Basile JN. Optimizing antihypertensive treatment in clinical practice. Am J Hypertens 2003;16:13S–7S. [27] Modification of Diet in Renal Disease Study. Effects of diet and antihypertensive therapy on creatinine clearance and serum creatinine concentration in the Modification of Diet in Renal Disease Study. J Am Soc Nephrol 1996;7:556–66. [28] Schrier RW, Savage S. Appropriate blood pressure control in type II diabetes (ABCD Trial): implications for complications. Am J Kidney Dis 1992;20: 653–7. [29] Wright Jr JT, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;288:2421–31. [30] Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J Am Soc Nephrol 2001;12:2427–33. [31] Barri YM. Hypertension and kidney disease: a deadly connection. Curr Hypertens Rep 2008;10:39–45. [32] Sahay M, Narayen G, Anuradha. Sodium transporters in kidney role in health and disease. J Assoc Physicians India 2007;55:135–9.

H. Fan et al. / Biomedicine & Aging Pathology 1 (2011) 203–209 [33] Campese VM, Park J. The kidney and hypertension: over 70 years of research. J Nephrol 2006;19:691–8. [34] Sica D, Carl D. Pathologic basis and treatment considerations in chronic kidney disease-related hypertension. Semin Nephrol 2005;25:246–51. [35] Weir MR. The role of combination antihypertensive therapy in the prevention and treatment of chronic kidney disease. Am J Hypertens 2005;18:100S–5S. [36] Uzunlulu M, Oguz A, Yorulmaz E. The effect of carvedilol on metabolic parameters in patients with metabolic syndrome. Int Heart J 2006;47:421–30. [37] Barajas L, Liu L, Powers K. Anatomy of the renal innervation: Intrarenal aspects and ganglia of origin. Can J Physiol Pharmacol 1992;70:735–49. [38] Ritz E, Amann K, Fliser D. The sympathetic nervous system and the kidney: its importance in renal diseases. Blood Press 1998;3:14–9. [39] Ciriello J, de Oliveira CV. Renal afferents and hypertension. Curr Hypertens Rep 2002;4:136–42. [40] Joles JA, Koomans HA. Causes and consequences of increased sympathetic activity in renal disease. Hypertension 2004;43:699–706. [41] Kotanko P. Cause and consequences of sympathetic hyperactivity in chronic kidney disease. Blood Purif 2006;24:95–9. [42] Sponer G, Bartsch W, Strein K, Müller-Beckmann B, Böhm E. Pharmacological profile of carvedilol as a f-blocking agent with vasodilating and hypotensive properties. J Cardiovasc Pharmacol 1987;9:317–27. [43] Cubeddu LX, Fuenmayor N, Varin F, Villagra VG, Colindres RE, Powell JR. Mechanism of the vasodilatory effect of carvedilol in normal volunteers: a comparison with labetalol. J Cardiovasc Pharmacol 1987;110:S81–4. [44] Dupont AG, Van der Niepen P, Taeymans Y, Ingels M, Piepsz A, Bossuyt AM, et al. Effect of carvedilol on ambulatory blood pressure, renal hemodynamics and cardiac function in essential hypertension. J Cardiovasc Pharmacol 1987;10:S130–6. [45] Remuzzi G. Sympathetic overactivity in hypertensive patients with chronic renal disease. N Engl J Med 1999;340:1360–1. [46] Zoccali C, Mallamaci F, Parlongo S, Cutrupi S, Benedetto FA, Tripepi G, et al. Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation 2002;105:1354–9.

209

[47] Cice G, Tagliamonte E, Ferrara L, Di Benedetto A, Iacono A. Complex ventricular arrhythmias and carvedilol: efficacy in uremic hemodialyzed patients. Cardiologia 1998;43:597–604. [48] Gehr TW, Tenero DM, Boyle DA, Qian Y, Sica DA, Shusterman NH. The pharmacokinetics of carvedilol and its metabolites after single and multiple dose oral administration in patients with hypertension and renal insufficiency. Eur J Clin Pharmacol 1999;55:269–77. [49] Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001;357:1385–90. [50] Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002;106:2194–9. [51] Remme WJ. The carvedilol and ACE-Inhibitor remodeling mild heart failure evaluationNtrial (CARMEN) rationale and design. Cardiovasc Drugs Ther 2001;15:69–77. [52] Abbott KC, Trespalacios FC, Agodoa LY, Taylor AJ, Bakris GL. ␤-Blocker use in long-term dialysis patients: association with hospitalized heart failure and mortality. Arch Intern Med 2004;164:2465–71. [53] Japanese Society of Hypertension Guidelines Subcommittee for the Management of Hypertension. Guidelines for the management of hypertension for general practitioners. Hypertens Res 2001;24:613–34. [54] Lenfant C, Chobanian AV, Jones DW, Roccella EJ. Joint National Committee on the prevention, detection, evaluation, and treatment of high blood pressure. Seventh report of the Joint National Committee on the prevention, detection, evaluation, and treatment of high blood pressure (JNC 7): resetting the hypertension sails. Hypertension 2003;41:1178–9. [55] European Society of Hypertension-European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–53.