SUBJECTS AND METHODS
Twenty-four diabetic patients with ESRD who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from 3 dialysis units staffed by the faculty of Saitama Medical School (Saitama, Japan) between 1998 and 2001. Written informed consent was obtained from every patient. Once eligibility for study entry had been determined, patients were randomly assigned to 1 of the 2 treatment groups. All patients were followed up 1 year, or until death, whichever was first.
Subjects with any one the following diagnoses were excluded: peripheral vascular diseases, valvular diseases, malignancies, hepatitis or severe liver disease, recent evidences of myocardial infarction or cerebrovascular accidents, and type 1 diabetes. The subjects were on a diet with protein content of 1.0 g/kg/d, and with restriction of salt intake of less than 10 g/d.
Group 1 received an AT1 antagonist, losartan 100 mg per day. The patients of group 2 received placebo. In both groups, treatment was started 2 months after the initiation of dialysis therapy.
Blood Pressure Control
A systolic blood pressure (SBP) below 140 mm Hg, and diastolic blood pressure (DBP) below 90 mm Hg was the goal. If bp control was not satisfactory, a calcium antagonist, benidipine 4 mg, was prescribed, or patients who received other calcium antagonists were advised to be switched from other calcium antagonists to benidipine. Subsequently, the dose of benidipine was increased up to 12 mg daily, and the α1-blocker doxazosin, 2 to 4 mg, was added until the bp goal was achieved. In the case of symptomatic hypotension or excessive bp reduction the dose of antihypertensive agents was reduced except for losartan.
Blood Pressure Evaluation
Evaluation of bp measurement was essentially performed according to Cannella et al. 6 Blood pressure was monitored throughout the entire study by measuring supine bp with an automated arm-cuff device. Three separate measurements were taken each month as follows: once during a midweek interdialysis day, once just before hemodialysis, and once within 20 minutes after hemodialysis ended. Each measurement lasted 15 minutes. These 3 sets of measurements were averaged, and the resulting bp level was recorded. For day-to-day purposes, the bp was also measured before and after each dialysis session by a mercury sphygmomanometer.
All echocardiograms were taken on a midweek interdialysis day. Echocardiographic evaluations were performed within 1 week before the start of AT1 antagonist or placebo, and again at 4, 8, and 12 months after the start of the treatment. All echocardiographic measurements were performed according to the recommendations of the American Society of Echocardiography. 11 The measurements included the end-diastolic diameter of the left ventricular chamber, the interventricular septum thickness, and the thickness of the left ventricular posterior wall. The left ventricular mass (LVM) was calculated from the above measurements according to Devereux et al. 12 The cut-off level for defining LVH was >120 g/m2 of LVMi (index), which was defined in our previous study. 13
Blood glucose levels and hemoglobin A1c were monitored every month and the doses of insulin were adjusted to maintain fasting blood glucose levels below 160 mg/dl, and that of hemoglobin A1c below 7.0 g/dl.
Hemodialysis was done during a 4-hour period, 3 times/wk using high-flux synthetic membranes (polysulphone or polyacrylonitrile). Bicarbonate was used as the buffer. Water quality was regularly monitored to ensure tight bacteriological standards. Dry body weight was reassessed twice each month according to bedside clinical criteria. Radiographs of the chest were taken every month for evaluation of the cardiothoracic ratio.
Correction of Anemia
Recombinant erythropoietin (rHuEPO) was administered through the intravenous route at the end of the hemodialysis session, and the doses were adjusted monthly. Patients were given oral iron supplementation if they were diagnosed to be iron deficient. The goal for blood hemoglobin level for correction of anemia was approximately 10g/dl of hemoglobin.
Biochemical Data Evaluation
At the beginning of each 4-month period, the following parameters were measured: body weight, serum creatinine, blood urea nitrogen, total protein, serum albumin, serum electrolytes, and alkaline phosphatase. During each 4-month period, laboratory values were recorded. Six-month means were calculated for these valuables. Parathyroid hormone (PTH) levels (intact molecule assay), serum cholesterol, and triglycerides were measured once every 4 months.
Based on the PTH levels, patients who had higher levels than 200 pg/mL were treated with 1,25(OH)2D3 and CaCO3 supplements, while patients who had lower levels than 70 pg/mL were treated with CaCO3 to correct hyperphosphatemia. The doses were adjusted to produce a value of (calcium × phosphate) of approximately 70.
Lipid Metabolism Control
Lipid lowering drugs (mainly statin derivatives) were administered if serum cholesterol levels were above 240 mg/dL.
Results were expressed as mean ± SEM when appropriate. For statistical comparison of means, Student t test for unpaired samples, or when applicable, the Mann-Whitney U test was used. ANOVA was used to compare the serial changes in 2 group means. A P value of < 0.05 was considered to be significant.
Characteristics of Patients
The mean values of measurements performed for each patient group at the initiation of the study is shown in Table 1. The mean age was 64 ± 3 years. There were 17 females and 7 males. The mean initial values for body weight, hemoglobin, hematocrit, intact PTH, calcium, and phosphate of the 2 groups were very similar. Most patients were hypertensive at the time of initiation of dialysis therapy. They were receiving dihydropyridine calcium antagonists (91%), α1-blocker (45%), and centrally acting agents (12%). None of the patients was taking ACE inhibitors or AT1 antagonists before the start of the study.
Changes in Blood Pressure
The changes in both systolic and diastolic bp are shown in Figures 1A and 1B. The data were included from all patients who participated in this study. An initial steady decline was noted for the first 8 months followed by a steady state toward the end of the study. The initial decline was more pronounced in SBP, while DBP was not significantly changed in either group throughout the study.
Changes in Echocardiographic Variables
Echocardiographic records taken every 4 months in both groups are depicted in Figures 2 to 7. The echocardiographic dimensions of the left ventricles were almost the same in both groups at the start of the study. LVMi decreased significantly from 145 ± 5 to 138 ± 3 g/m2 (P < 0.05) in the losartan group, whereas in the placebo group it did not change from 147 ± 3 to 147 ± 3 g/m2, at 4 months. In the placebo group, LVMi did not decrease until 8 months; however, at 12 months, it decreased to 139 ± 5 g/m2, but this change was not statistically significant. In the losartan group, LVMi gradually decreased throughout the study, and at the end of the study it was 122 ± 3 g/m2 (P < 0.001) (Fig. 2). The thickness of the septal and posterior walls were significantly reduced in the losartan group compared with the start of study (P < 0.05), but not in the placebo group. The findings were similar with LVMi (Figs. 3 and 4). Left ventricular internal diameters, volumes, and their derived parameters (e.g., ejection fraction) remained almost constant throughout the study in both groups (Figs. 5, 6, and 7).
Sixty percent of patients were on insulin therapy at the initiation of the dialysis therapy; however, 1 year after the initiation of the dialysis therapy only 25% of patients were receiving insulin. Moreover, in these patients the doses of insulin were reduced compared with the start of the study.
Doses of rHuEPO
The doses of rHuEPO 1 year after the initiation of the study were not different between the two groups.
In the present study, since the target bp levels were intended to be similar in the placebo- and the active-drug-treatment groups, there were no significant differences in bp noted between the losartan group and the placebo group. In spite of equal control of bp, a greater regression of LVH was observed in the losartan group than the placebo group. We interpret these results to mean that losartan was cardioprotective in the diabetic patients on dialysis therapy. These findings are analogous to the previous reports by Cannella et al 14 demonstrating that the treatment with ACE inhibitor induced a regression of LVH in dialyzed uremic patients independently from hypotensive effects. Moreover, the benefits of losartan were observed also in spite of simultaneous therapy with calcium antagonists. The role of calcium antagonists in the protection of the kidneys and heart still remains controversial. 7,8 This is because calcium antagonists have been shown to augment the production of angiotensin II and the activation of the sympathetic nervous system, 15,16 especially in the patients with chronic renal insufficiency. In the present study, we did not directly compare the effects of losartan and calcium antagonist, because in both losartan and placebo groups, more than 90% of patients received calcium antagonists.
In the present study, we have demonstrated that the blockade of the renin-angiotensin system with an AT1 antagonist produced regression of LVH in diabetic patients receiving dialysis therapy under conditions of bp control. Both ACE inhibitors and AT1 antagonists are suggested to regress the LVH independently of bp levels in diabetic patients. 17 However, the benefit of ACE inhibitor therapy in diabetic patients undergoing maintenance hemodialysis therapy has been demonstrated. 18 This likely relates to the facts that in diabetic patients, continuous fluid-overload may cancel the beneficial action of ACE inhibitors, since the efficacy of ACE inhibitors is fully realized under conditions of volume depletion. Moreover, in diabetic patients with accelerated arteriosclerosis and disturbed sympathetic nerve activity, the inhibition of renin angiotensin constriction by ACE inhibitors, and AT1 antagonist, may dramatically aggravate hypotensive episodes during dialysis, and in this manner prevent optimal fluid removal. In this study, we administered losartan after every dialysis therapy to prevent the increased risk of severe hypotension during the session. Indeed, if the drug was given after dialysis treatment, there were less frequent hypotensive episodes during the dialysis session.
In the present study, bp control was achieved mainly by a calcium antagonist in combination with losartan. Two recent studies, namely, HOT (Hypertension Optimal Treatment) 19 and FACET (Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial), 20 have clearly demonstrated that the group treated with ACE inhibitors and a calcium antagonist in combination had far lower cardiovascular event rates. In the HOT trial, over 75% received an ACE inhibitor to achieve the lower bp goal, which showed a 51% reduction in major cardiovascular events. More recently, in large clinical trails such as RENAAL, 21 calcium antagonists were used in more than three fourths of diabetic patients with nephropathy treated with or without losartan. Kestenbaum et al 22 analyzed the data from USRDS DMMSII and were able to demonstrate that the use of a calcium antagonist is associated with lower total and cardiovascular-specific mortality. In their study, the use of a β-blocker, ACE inhibitor, or aspirin was not associated with a difference in cardiovascular-specific mortality, and the superiority of the use of a combination therapy was not mentioned. The relative lack of protection against cardiovascular events by calcium antagonists may relate to an increase in sympathetic neural activity. Studies in a group of patients with renal insufficiency have recently demonstrated that amlodipine increases sympathetic neural activity, whereas ACE inhibition decreases such activity. 23 Moreover, it is suggested that overactivation of the sympathetic nervous system might contribute to development of LVH in patients on dialysis therapy. In the present study, more than 60% of patients were treated with an α1-blocker, indicating that adverse action of calcium antagonist might be mitigated with concomitant administration of α1-blocker and losartan.
A particularly troubling methodological issue in studies assessing bp control in dialysis patients is the confounding effect of concurrent use of antihypertensive agents. The degree of bp control of a patient who requires multiple antihypertensives to achieve a normal bp, and another who has normal bp while on no drugs, is clearly not identical.
In diabetic patients, high SBP, and moderately elevated DBP have been found. This may be explained by intensive arteriosclerosis and aortosclerosis. In addition to the reduced elasticity of the aorta, marked fluid overload exacerbates the hypertension and cardiac workload. All these factors contributed to the augmentation of the LVH that is frequently found in diabetic patients with ESRD. 18,24
It is controversial whether the blockage of the renin-angiotensin system regresses LVH with or without bp control in hypertensive and diabetic patients, as well as patients receiving dialysis therapy. 25 Cannella et al 26 proposed that prolonged antihypertensive therapy with strict bp control (SBP below 140 mm Hg and DBP below 85 mm Hg) was able to considerably reduce the LVH in chronically hemodialyzed patients. On the contrary, the same group demonstrated that ACE inhibitors given at doses not affecting bp were able to reverse LVH. 14 However, in both studies, ACE inhibitors were included in the antihypertensive regimen. In the former study, a combination of β-blockers, calcium antagonists, and ACE inhibitors was employed. It is therefore likely that ACE inhibitors are needed to regress LVH in hemodialyzed patients. In the present study, we expanded this notion to the diabetic patients with LVH using an AT1 antagonist. Compared with the efficacy of ACE inhibitors on regression of LVH in diabetic patients with nephropathy who are under dialysis therapy, the beneficial effects of AT1 antagonists have been less frequently documented. In the ELHE (Evaluation of the Losartan in Hemodialysis) study, 27 it was demonstrated that losartan is a well-tolerated antihypertensive in hemodialysis patients, with a very low incidence of adverse reactions. In the latter study, the percentage of patients achieving good bp control is low, probably due to a single administration of losartan instead of multiple antihypertensive regimens in the patients undergoing dialysis.
However, the reduction of LVMi after the antihypertensive therapy may not only be due to a better control of bp, because some drugs (such as ACE inhibitors) can produce a decrease in angiotensin II levels, which has been shown to have a proliferative effect on cardiac fibroblasts and cardiomyocytes, independently of the antihypertensive and hemodynamic effects of this group of drugs. 28,29
Many factors have been suspected to be etiopathogenic factors for LVH in chronic uremia patients, including uremic toxin, high PTH levels, and aluminum overload. The patients in this study underwent adequate dialysis three times a week, and therefore it is unlikely that these factors contributed to development of LVH. Of note, partial correction of anemia by rHuEPO has been shown to be effective in reversing the LVH in dialysis patients. 26 However, in the present study, these factors seemed not to be important for regression of LVH, because there were no significant differences between those who responded to the treatment with enalapril or losartan and those who did not (data not shown).
Caution must be used in extrapolating the conclusion drawn from our present findings to the diabetic patients receiving dialysis therapy at large. First, under maintenance dialysis therapy, the excessive cardiac morbidity and mortality in diabetic patients seems to be mediated more by ischemic myocardial disease than by progression of cardiomyopathy. Therefore, it is much more important to emphasize the importance of adequate fluid removal, correction of anemia, and improvement in nutrition. Second, since it is thought that the therapeutic window for intervention to prevent progressive cardiac enlargement does not remain open much beyond 1 year, 30 our study would not apply to the diabetic patients who had already received dialysis therapy more than 1 year. Lastly, the drawback of this study is the number of patients. We have only examined 24 patients. It is absolutely necessary to examine many more patients to elucidate our hypothesis.
In conclusion, adequate management of patients on hemodialysis must include strict control of bp, preferably with ACE inhibitors, together with other early measures, to avoid the development of LVH by other causes. 31
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