LACK OF EFFECT OF LONG-TERM USE OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS BY HEMODIALYSIS PATIENTS ON THIRST AND FLUID WEIGHT GAIN

Abstract

Volume overload is a chronic, troublesome problem in many patients on hemodialysis. These patients suffer from hyperdipsia with inability to excrete water. Angiotensin-converting enzyme inhibitor (ACEI) has been shown to decrease thirst and interdialytic weight gain in 2–4 weeks of usage. We investigated the effect of long-term use of ACEI, as levels of angiotensin II tends to go back to normal level after 6 months of use. We compared hemodialysis patients on ACEI for more than 6 months to patients not on ACEI. Seven patients were taking ACEI compared to 51 controls in the other group. Almost one third of patients in each group had an interdialytic weight gain >5% of dry weight. No significant difference was found between the two groups with regard to interdialytic weight gain, thirst and mouth dryness scores, and interdialytic mean blood pressure change. There was no demonstrable effect of angiotensin receptor blocking drugs on weight gain or thirst. We conclude that long-term ACEI may not continue to suppress inappropriate thirst and fluid intake after 6 months in hemodialysis patients.

• Thirst
• Angiotensin-converting enzyme inhibitors
• Hemo-dialysis
• Chronic renal failure

INTRODUCTION

Volume overload is a major problem in one third of patients on hemodialysis not only because of their inability to eliminate excess water and sodium but also because many of them do not restrict their fluid intake, often complaining of inappropriate thirst.[[1]] The interval between dialyses in these patients is marked by excessive weight gain. Many stimuli of thirst have been identified, including increased plasma osmolality (detected by cerebral osmoreceptors),[[2]], [[3]] decreased blood volume (detected by cardiac stretch receptors),[[2]] increased circulating levels of angiotensin II (detected by angiotensin II receptors in the subfornical organ),[[4]], [[5]] increased gastric sodium load (apparently detected by putative sodium receptors in the abdominal viscera)[[2]] and antidiuretic hormone (ADH).[[2]], [[6]] Three earlier studies[[7]], [[8]], [[9]] showed some success in the short-term use (less than 6 months) of angiotensin-converting enzyme inhibitors (ACEI) to decrease interdialytic weight gain. However, although chronic administration of ACEI is effective in controlling blood pressure, it is known that plasma levels of angiotensin II often return to their initial range after a patient has taken these medications for about 6 months.[[10]] In this study we looked at the long-term effect of ACEI on thirst and volume overload.

METHODS

Records of all patients with end stage renal disease on chronic maintenance hemodialysis therapy at Nassau University Medical Center were reviewed. Patients previously on ACEI or who had been on hemodialysis therapy for <6 months were excluded. The patients in the study were observed for a one-month period. We looked at systolic and diastolic blood pressures after each dialysis session and before the following dialysis session (48 h period). Interdialytic (48 h) weight and blood pressure (BP) changes were recorded weekly and averaged over 4 weeks.

Thirst analysis was done using visual–analogue assessments of the patients’ sense of thirst and mouth dryness. The answers given by the patients were assigned a numerical scale. These ratings have previously been used successfully to evaluate thirst.[[11]] We defined fluid overload as 48 h interdialytic weight gain >5% of dry weight.[[9]]

Statistical analysis used Student's t-test or χ-square tests as indicated. Statistical significance was defined as p<0.05. Data are presented as mean ± standard error of the mean.

RESULTS

We initially looked at 61 hemodialysis patients. Seven patients were on dialysis and/or ACEI for less than 6 months and were excluded; two patients expired during the period of follow up. Three patients were taking angiotensin II receptor blockers (ARB). The most common causes for their end stage renal disease were hypertension and diabetes mellitus (83% of the total group). Seven patients had been taking ACEI for hypertension for 9–27 months (mean 17.1 ± 3); 51 hemodialysis patients were not taking ACEI.

Differences between the two groups (ACEI vs. non ACEI) in age, sex, interdialytic weight gain, mouth dryness score, thirst score, interdialytic BP change (systolic and diastolic) are shown in Table 1. None of these measurements was statistically different between the 2 groups. No correlation was found between mouth dryness or thirst and either interdialytic weight gain or change in BP among the controls. Dry mouth nearly correlated with weight gain in the 7 patients on ACEI (r = 0.65, 0.05<p<0.10), but thirst did not correlate either with weight gain or change in BP in these patients (r = 0.26).

Table 1. Comparison Between Chronic Hemodialysis Patients On and Not On ACEI

	Patients On ACEI	Patients Not On ACEI	p
Number	7	51
Sex (% Male)	71.4	62.7	NS
Mean age (years)	58.0±5.9	50.0±2.1	NS
Fluid overload (% of group)	28.5	39.2	NS
Mouth dryness score	4.0±1.2	5.3±0.6	NS
Thirst Score	5.1±1.0	5.6±0.6	NS
Weight gain/Dry weight (%)	4.0±0.6	4.5±0.2	NS
Systolic BP (mm Hg)	193±7.8	164±2.2	NS
Diastolic BP (mm Hg)	81±5.1	103±1.2	NS

We performed the same testing on patients who were taking ARB (3 patients) and compared them to the control group (hemodialysis patients not on ACEI: 51 patients) (Fig. 1). Both groups had similar dry mouth and thirst scores and interdialytic weight gain, and the ARB group had more volume overload. This result is consistent with the fact that ARB's do not cross the blood-brain barrier and cannot reach the receptors in the subfornical organ.

Figure 1. Comparison between patients taking angiotensin receptor blockers and the control group with regard to thirst and dry mouth scores, weight gain, and percentage of patients with volume overload.

DISCUSSION

The relationship between elevated levels of renin and AII and thirst was first described by Fitzsimons, who showed that ligation of the inferior vena cava of a rat increased the rat's drinking while ligation of the inferior vena cava in bilaterally nephrectomized rats had no effect on thirst.[[12]] Epstein et al. demonstrated that injection of angiotensin directly into the hypothalamus of the rat stimulated thirst.[[13]] Two subsequent reports describe patients on hemodialysis who had excessive volume overload with severe thirst and hyperreninemia, whose thirst was relieved pari passu with the decrease in renin levels following bilateral nephrectomy.[[14]], [[15]] Phillips et al. reported that intravenous infusion of a supraphysiologic quantity of AII could elicit thirst and cause a mild elevation in ADH.[[4]]

The use of angiotensin converting enzyme inhibitors (ACEI) to decrease inappropriate thirst and consequently control volume overload has been suggested for patients on chronic hemodialysis, many of whom have increased plasma renin activity and AII levels.[[16]] Although 3 recent studies (Table 2) showed some effectiveness of ACEI in achieving a minor decrease in volume overload (average < 0.4 kg), they did not look at whether the long-term use of ACEI continues to suppress thirst over a longer period of time, since plasma AII returns to baseline normal after few months.[[10]] The decrease in weight gain in those studies was associated by (and actually attributed to) a decrease in AII level and reversed after stopping ACEI and the return of AII level to normal.[[7]], [[8]], [[9]] In contrast, the 7 long-term ACEI users in our study had no statistically significant inhibition of thirst and mouth dryness compared to patients not taking ACEI.

Table 2. Summary of Previous Studies of the Short-Term Effectiveness of ACEI on Thirst and Weight Gain

Author	Year	Number of Patients	ACEI	Duration of Study (Weeks)	Reduction of Interdialytic Weight Gain
Yamamoto et al.	1986	4	Captopril	2–5	Not reported
Oldenburg et al.	1988	25	Enalapril	4	0.25 kg
Kuriyama et al.	1996	5	Cilazapril	1	0.4 kg

CONCLUSION

In a study of patients on chronic hemodialysis, we found that long-term use of ACEI may not continue to suppress inappropriate thirst and fluid intake as shown before on the short-term use. We conclude that ACEI does not have an important role in decreasing volume overload complications in hemodialysis patients. Reinforcement of restriction of fluid intake for dialysis patients with excessive weight gain remains the mainstay treatment for this problem.